Conditions: HIV Infections
Keywords: second line antiretroviral therapy dolutegravir
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 192
Healthy volunteers: no

Brief summary:
The strategy to support virological suppression on second-line antiretroviral treatment (ART) includes the provision of ART that has a low pill burden, good tolerability, low toxicity, is easily monitored, has a high barrier to resistance, and that is low cost. The fixed-dose combination of tenofovir-lamivudine-dolutegravir offers significant advantage as a potential second-line regimen compared to the World Health Organization standard of care second-line regimen of zidovudine-lamivudine-dolutegravir, in terms of cost, tolerability and monitoring requirements.

The ARTIST study is a phase 2, randomised, double-blind, placebo-controlled trial aiming to determine the proportion of patients achieving virological suppression when recycling the tenofovir-emtricitabine/lamivudine backbone with dolutegravir (tenofovir-lamivudine-dolutegravir fixed-dose combination) as a second-line with and without a lead-in supplementary dose of dolutegravir, in patients failing a tenofovir-emtricitabine/lamivudine-efavirenz first-line regimen.

There is evidence to suggest that even in the presence of resistance mutations to tenofovir and lamivudine (K65R or M184V/I), using this backbone with dolutegravir will provide an effective second-line regimen in patients who have failed a first-line regimen of tenofovir-emtricitabine/lamivudine-efavirenz. The strategy of giving a lead-in supplementary dose of dolutegravir is in view of the inducing effect of efavirenz on dolutegravir metabolism and transport that persists for 2 weeks after efavirenz is stopped; the inducing effect decreases with time after efavirenz is stopped.

Given that these patients will have elevated viral loads, a high baseline risk of nucleoside reverse transcriptase inhibitor (NRTI) resistance and efavirenz resistance, and the inducing effect of efavirenz on dolutegravir metabolism and transport that persists for 2 weeks, this study will comprise two stages. The first stage will evaluate virological suppression in 62 participants initiated on the fixed-dose combination of tenofovir-lamivudine-dolutegravir with a lead-in supplementary dose of dolutegravir for the first 14 days. The study will progress to the second stage if this strategy proves effective, and 130 participants will then be randomised to receive the fixed-dose combination of tenofovir-lamivudine-dolutegravir with and without this lead-in dose.

The primary endpoint is virological suppression (viral load \<50 copies/mL) at 24 weeks.

A pharmacokinetic sub-study will be conducted on 12 participants in stage 1 and 24 participants in stage 2, to assess the trough concentrations of dolutegravir and off-treatment concentrations of efavirenz at day 3, 7, 14, and 28. This is to evaluate the need for the lead-in supplementary dose of dolutegravir.

Detailed description:

Arms:
arm 1: Tenofovir-lamivudine-dolutegravir fixed-dose combination tablet daily with an additional dolutegravir 50 mg dose taken 12 hours later for the first 14 days. arm 2: Tenofovir-lamivudine-dolutegravir fixed-dose combination tablet daily with a matching placebo taken 12 hours later for the first 14 days.

Interventions: intervention 1: Dolutegravir 50 mg intervention 2: Placebo
Intervention descriptions: intervention 1: Tenofovir-lamivudine-dolutegravir fixed-dose combination tablet with a lead-in supplementary dose of 50 mg dolutegravir taken 12 hours later for the first 14 days, with continuation of tenofovir-lamivudine-dolutegravir for the duration of the study (48 weeks). intervention 2: Tenofovir-lamivudine-dolutegravir fixed-dose combination tablet with a matching placebo taken 12 hours later for the first 14 days, with continuation of tenofovir-lamivudine-dolutegravir for the duration of the study (48 weeks).

Protocol document:
Prot_005.pdf: 
ARTIST Trial Protocol Version 4.0. (dated 17 June 2020) 
 
1 
 
 
 
 
 
 
 
  17 June 2020 
AntiRetroviral Therapy In Second-line: investigating 
Tenofovir-lamivudine-dolutegravir (ARTIST): a 
randomised controlled trial 
ARTIST Trial Protocol Version 4.0. 
CORE STUDY TEAM 
Graeme Meintjes (principal investigator) 
Institute of Infectious Disease and Molecular Medicine and Department of Medicine, University 
of Cape Town 
graemein@mweb.co.za 
Claire Keene (co-investigator (co-principal investigator for Stage 1)) 
Médecins Sans Frontières (MSF), Khayelitsha, Cape Town 
msfocb-khayelitsha-hivmam@brussels.msf.org 
Gary Maartens (co-investigator) 
 
Division of Clinical Pharmacology, Department of Medicine, University of Cape Town 
 
gary.maartens@uct.ac.za 
Tali Cassidy (co-investigator) 
Médecins Sans Frontières (MSF), Khayelitsha, Cape Town 
 
MSFOCB-Khayelitsha-Epid@brussels.msf.org 
Paola Lopez (co-investigator) 
Médecins Sans Frontières (MSF), Khayelitsha, Cape Town 
 
MSFOCB-Khayelitsha-Coord@brussels.msf.org  
Rulan Griesel (co-investigator) 
 
Division of Clinical Pharmacology, Department of Medicine, University of Cape Town 
 
grsrul001@myuct.ac.za 


ARTIST Trial Protocol Version 4.0. (dated 17 June 2020) 
 
2 
Ying Zhao (lead investigator for Stage 2) 
Institute of Infectious Disease and Molecular Medicine and Department of Medicine, University 
of Cape Town 
 
yingzhao1126@gmail.com 
Eric Goemaere (co-investigator) 
Médecins Sans Frontières (MSF), Khayelitsha, Cape Town 
Eric.GOEMAERE@joburg.msf.org 
Andrew Hill (study statistician) 
Department of Pharmacology and Therapeutics, University of Liverpool, UK 
 
ahill.IC@clintonhealthaccess.org; microhaart@aol.com  
 
PI contact details: 
Prof Graeme Meintjes 
Centre for Infectious Diseases Research in Africa 
Institute of Infectious Disease and Molecular Medicine 
Faculty of Health Sciences 
University of Cape Town 
+27 21 4066075 
Graeme.meintjes@uct.ac.za 
 
SPONSOR 
University of Cape Town 
 
FUNDERS 
Médecins Sans Frontières 
Wellcome Trust 


ARTIST Trial Protocol Version 4.0. (dated 17 June 2020) 
 
3 
Summary 
As the HIV epidemic matures and more patients are initiated on antiretroviral treatment, focus is on 
ensuring that those on antiretroviral therapy (ART) are virologically suppressed. The ideal second-line 
ART regimen should have a low pill burden, good tolerability, low toxicity, is easily monitored, has a 
high barrier to resistance and that is low cost. A fixed-dose combination of tenofovir, lamivudine and 
dolutegravir (TLD) fulfils these criteria. 
Indirect evidence suggests that recycling the tenofovir + lamivudine or emtricitabine (TDF/XTC) 
backbone from first through to second line could protect the regimen from the development of resistance 
mutations to dolutegravir. Stage 1 of the ARTIST trial has a single arm in which 65 participants who are 
failing a first-line regimen of tenofovir, emtricitabine or lamivudine and efavirenz or nevirapine (TXE or 
TXN) are initiated on the fixed dose combination of TLD supplemented with a dose of 50 mg 
dolutegravir taken 12 hours later for the first 14 days. The fixed dose combination of TLD is continued 
thereafter for the duration of the study (48 weeks). This strategy of giving a lead-in supplemental dose of 
dolutegravir is to compensate for the inducing effect of efavirenz on dolutegravir metabolism and 
transport that persists for 2 weeks after efavirenz is stopped. Patients with undetectable HIV viral load 
(VL) can be safely switched from efavirenz to dolutegravir without the need for dolutegravir dose 
adjustment as plasma concentrations of efavirenz remain therapeutic for the 3-6 days it takes for 
dolutegravir concentrations to become therapeutic. However, most patients failing efavirenz-based ART 
have resistance to both efavirenz and nucleoside reverse transcriptase inhibitors (NRTIs), therefore, sub-
therapeutic dolutegravir concentrations could select for resistance mutations to integrase strand transfer 
inhibitors (InSTIs). 
The original study design for Stage 2 of the ARTIST trial was a randomised, open-label, active-controlled 
trial aiming to determine the virological suppression of patients failing the standard of care first-line 
regimen of TXE or TXN switching to a dolutegravir based second-line randomised to one of two NRTI 
backbones: recycled TDF/XTC or zidovudine and lamivudine (which is recommended by the WHO as the 
preferred second-line ART combination in the absence of genotype resistance tests at switch). 
Enrolment for Stage 1 started on August 08, 2019. As of June 17, 2020, 61 participants were enrolled. At 
week 24, 33 (87%) of 38 participants achieved virological suppression (defined as plasma HIV VL <50 
copies/mL). Four of the 5 participants with HIV VL ³50 copies/mL at 24 weeks had low level viraemia 
with HIV VL <100 copies/mL. Results at week 12 were consistent with those at week 24, at which point 
virological suppression was achieved in 41 (82%) of 50 participants. Adverse events graded 3 or 4 
occurred in 4 participants, none of which was considered treatment related or led to discontinuation of 
TLD. Based on these positive preliminary findings, we decided to change the study design for Stage 2 to a 
Phase II, randomised, double-blind, placebo-controlled trial of TLD fixed dose combination daily with a 
lead-in supplemental 50 mg dose of dolutegravir versus matching placebo taken 12 hours later for the first 
14 days in patients failing a first-line regimen of TXE. The primary endpoint remains the proportion of 
participants achieving plasma HIV VL <50 copies/mL at 24 weeks. 
Another argument for dropping the zidovudine, lamivudine and dolutegravir (ALD) comparison is that 
there are two ongoing studies investigating recycling of the TDF/XTC backbone with dolutegravir in 
second-line. Both the Dolutegravir and Darunavir Evaluation in Adults Failing Therapy (D²EFT) study 


ARTIST Trial Protocol Version 4.0. (dated 17 June 2020) 
 
4 
and the Nucleosides and Darunavir/Dolutegravir In Africa (NADIA) study are non-inferiority trials 
powered for formal comparisons and will have results available in 2021. Neither study is using the lead-in 
supplemental dose strategy. Our proposed new Stage 2 would address this key unanswered question of 
whether a lead-in dolutegravir dose is required to minimize the risk of developing InSTI resistance and 
treatment failure in patients switching from an efavirenz-based regimen to TLD with raised VL in a Phase 
II design that could provide important data to supplement the findings of D²EFT and NADIA in 
informing policy or a Phase III trial. 
1. Background and rationale 
As the HIV epidemic matures, focus is turning to the last 90 in the 90-90-90 strategy: aiming for 90% of 
those on treatment to be virally suppressed by 2020 (1). Antiretroviral (ARV) drug resistance necessitates 
a change in regimen and is a major obstacle to achieving this target. Resistance results not only in poor 
outcomes for individuals, but also compromises public health treatment strategies, interferes with efforts 
to reduce transmission and financially burdens healthcare systems (2). 
By 2020, 25.6 million people could be receiving ARVs in Sub-Saharan Africa, and up to 3 million 
(15.6%) will be on second-line treatment (under conditions of perfect retention, immediate switching and 
universal viral load (VL) monitoring, as is done in the South African context) (3). This proportion is 
expected to increase further by 2030 (3). The reasons for this potential growth in demand for second-line 
treatment are diverse, but include the fact that the cohort on ARVs is maturing; about half the patients on 
ARVs worldwide started treatment before 2010 (3) and as patients remain on treatment long-term, their 
cumulative incidence of disengagement increases (4). This population of patients with poor engagement 
has a large requirement for second-line treatment, as 30% who then restart first-line treatment have been 
shown to have resistance mutations (5). Challenges with antiretroviral therapy (ART) adherence while on 
treatment also contribute to first-line ART failure and requirement for second-line. 
1.1. 
Dolutegravir as second-line 
Currently in the Western Cape, the standard of care for first-line treatment is the fixed dose combination 
of tenofovir, emtricitabine and efavirenz (TDF/FTC/EFV – TXE regimen, where X can stand for 
emtricitabine (FTC) or lamivudine (3TC) interchangeably) unless there are contraindications, and the first 
choice second-line is zidovudine, lamivudine and lopinavir/ritonavir (AZT/3TC/LPV/r) (6). This 
guidance is in-line with World Health Organization (WHO) recommendations (7).  
Those requiring second-line treatment often have health facility and regimen-related barriers to engaging 
with treatment, but second-line options are less ‘adherence-friendly’ than the first-line ARVs that have 
already failed. Second-line options are currently 2.5 to 3 times more expensive than WHO recommended 
first-line treatment (3,8), require additional monitoring (haemoglobin for AZT toxicity and cholesterol 
and triglycerides for LPV/r) (6), require a more burdensome twice daily dosing (9) and are poorly 
tolerated (6,9). The gastro-intestinal side effects of the protease inhibitors (PIs) make adherence difficult, 
increasing the risk of the development of virologic failure and contributing to the reluctance of patients 


ARTIST Trial Protocol Version 4.0. (dated 17 June 2020) 
 
5 
and clinicians to switch to second-line. 
The WHO recommends regimens that have low toxicity, low cost, high genetic barriers to resistance, high 
potency, and usefulness across different populations (10). Dolutegravir (DTG), an integrase strand 
transfer inhibitor (INSTI), fulfils many of these criteria: it has good tolerability and has been shown to 
have a lower risk of discontinuation in a regimen with two nucleoside reverse transcriptase inhibitors 
(NRTIs), has a low pill burden with once daily dosing (11,12), as well as a lower potential for drug-drug 
interactions than the current standards of care (EFV and LPV/r) (12). At $75 per person per year, a new 
generic fixed dose formulation of DTG with TDF and 3TC is cheaper than both current first and second-
line options (13). A major transition to newer drugs, including DTG, could represent savings up to US$3 
billion globally by 2025 (14) and allow more people to be on ART within available resource limits (15).  
Multiple studies have shown DTG to be a more efficacious option for first-line compared with EFV 
(SPRING-1 and SINGLE), raltegravir (SPRING-2) and darunavir (DRV)/ritonavir (r) (FLAMINGO) 
(11). As a second-line regimen it has proved superior to raltegravir with an optimised backbone in 
patients with resistance to at least two ARV classes, irrespective of the backbone drugs (SAILING) and 
has been shown to be effective with twice daily dosing at achieving viral suppression even in the presence 
of resistance to other InSTIs (VIKING, VIKING-3 and VIKING-4). 
In the DAWNING study, DTG with two NRTIs (at least one fully active) was superior in safety and 
efficacy to the current standard of care (LPV/r with two NRTIs) as second-line treatment, achieving 82% 
viral suppression (VL<50 copies/mL) compared to 69% of the LPV/r patients (16). This provides 
compelling evidence to consider DTG as the preferential second-line option. The WHO now supports the 
use of DTG as second-line for its superiority in viral suppression, quicker CD4 recovery, tolerability and 
safety profile, and suggests that both adults and children failing a non-nucleoside reverse transcriptase 
inhibitor (NNRTI) or PI based first line regimen should be given DTG as the preferred second-line option 
(12). The South African public sector introduced a second-line regimen of ALD for patients failing TXE 
in January 2020 (46).  
1.2. 
 Choice of NRTI backbone 
1.2.1 DTG Resistance 
DTG selects for the R263K mutation and sequential mutations along the same pathway that reduce the 
efficacy of DTG. However the R263K mutation may reduce viral replicative capacity and reduce the 
magnitude of viral rebound (11,17). DTG has a very high barrier to resistance, but resistance has been 
described using DTG monotherapy as maintenance in the DOMONO study (three patients) (18) and the 
MONCAY study (two patients) (19). In both studies, this resistance was delayed and tended to occur 6-12 
months after switch (18,19).  
DTG resistance has also been described in patients on DTG as second-line. The DAWNING and 
SAILING studies each found two patients who developed InSTI (including R263K) mutations (17,20). 
There have also been reports of the development of InSTI resistance in treatment-naïve patients initiating 
TDF/3TC/DTG (TLD regimen) (21,22), with the R263K mutation as a pathway to the development of 


ARTIST Trial Protocol Version 4.0. (dated 17 June 2020) 
 
6 
resistance (22). This potential for the development of resistance means that the backbone must be 
carefully considered in order to ensure the durability of a DTG-based second-line regimen. 
1.2.2 Optimised backbone 
The DAWNING study showed superiority of DTG with an optimised backbone over a PI second-line and 
the results can be applied when there is at least one fully active NRTI (16). Thus the WHO recommends 
the use of an optimised backbone to improve the durability of DTG regimens (2,10,12). However, 
optimisation requires genotypic resistance testing, and in the DAWNING study genotyping was used to 
ensure the selection of at least one fully active NRTI (16). This testing is not widely available in low and 
middle income countries (LMICs) (23), and where it is, its use is restricted by cost to second-line failures 
only. Without genotypic testing to determine the optimum regimen, the WHO recommends AZT (ALD 
regimen) as the first choice backbone for second-line if failing a regimen containing TDF or abacavir 
(ABC) (12).  
1.2.3 Recycling TDF and XTC (3TC or FTC) in a second-line backbone 
However, there are two arguments for recycling TDF and 3TC or FTC as the backbone for a DTG-based 
second-line (TLD regimen) instead of using an optimised backbone. Firstly AZT is less well tolerated, 
requires twice daily dosing, needs more intensive monitoring and is less efficacious than TDF if there is 
no resistance to either drug (6,9).  
Secondly, it is well established that NRTI resistance impairs viral fitness in both in vitro and clinical 
studies, particularly the M184I/V mutations (3TC and FTC). In the EARNEST trial, the NRTI/LPV/r 
combination outperformed the LPV/r/raltegravir and LPV/r monotherapy arms (86%, 81% and 78% 
suppression respectively) in patients who were no longer responding to a first-line combination 
containing two NRTIs, even though 95% of the enrolled patients had at least one NRTI mutation and 59% 
had no active NRTIs (24). Similar results were found in the SELECT and the SECOND LINE trials 
(25,26), showing that compromised NRTIs could be recycled with a boosted PI.  
Oliveira et al showed that under DTG drug pressure in vitro, only the wild type virus was able to acquire 
R263K resistance mutations and that K65R (TDF) and M184I/V mutations protected against the 
development of DTG resistance (an additional advantage over raltegravir and elvitegravir, which were not 
afforded this protection) (2). In this study the effect of the combination of K65R and M184I/V mutations 
was not assessed, but as these mutations do not compensate each other it is suspected that this 
combination will have the same protective effect together as separately (2).  
While patients have developed DTG resistance mutations on DTG monotherapy (18), clinical studies 
suggest that resistance does not develop if DTG is paired with even an inactive backbone. DTG with 3TC 
as dual therapy was found to be non-inferior to triple ART and no resistance was found (GEMINI 1 and 2 
trials), showing that even if TDF is not active, the regimen is efficacious (20). Post-hoc analysis of the 
SAILING study found that in patients with resistance to at least two classes, those receiving DTG with 
two NRTIs did not develop DTG resistance, even when both NRTIs were inactive (27).  
Multiple small studies have also supported this finding: the DOLULAM switch trial found that none of 


ARTIST Trial Protocol Version 4.0. (dated 17 June 2020) 
 
7 
the 27 patients switched to DTG/3TC dual therapy developed virological failure by 96 weeks, despite 
37% having the M184V mutation (28). A French study that switched 239 virally suppressed patients to a 
DTG-based regimen, found that regardless of the genotypic susceptibility score, only one patient (who 
had a history of raltegravir use) developed virological failure (29,30). This suggests that the crippling 
effect of the NRTIs translates to protection from the development of second-line resistance in vivo and 
that a second-line TLD regimen could be effective. 
There are two ongoing studies investigating the recycling of the TDF/XTC backbone. The DTG and 
Darunavir Evaluation in Adults Failing Therapy (D²EFT) is an ongoing non-inferiority trial to compare 
TDF/XTC/DTG, DTG/DRV/r and the WHO standard of care NRTI/PI (DRV/r) combination in HIV-1 
patients failing first-line ARVs in predominantly LMICs. The backbone in the standard of care arm will 
be based on clinical judgement and may be guided by resistance testing if available, whereas the 
backbone in the experimental NRTI-DTG arm is pre-specified as TDF/XTC (31). This study is expected 
to be completed in December 2021 (31). The NADIA study is a Phase III trial to investigate DTG and 
DRV/r with TDF/XTC compared to an AZT backbone as a second-line option for 420 patients failing 
EFV-based first-line treatment. While D²EFT and NADIA are conducted, our study aims to investigate 
the recycling of the TDF/XTC backbone with DTG (TLD) and provide evidence in the interim to address 
this important public health question. 
1.3 Dosing 
EFV induces enzymes (UGT1A1 and CYP3A4) and transporters (P-glycoprotein and breast cancer 
resistance protein) involved with DTG absorption and metabolism, which reduce plasma DTG 
concentrations at the end of the dosing interval up to 75% (33, 34). In a study assessing a DTG/EFV 
combination, DTG required twice daily dosing when co-administered with EFV (33). However, 
simulations of switching from EFV to DTG based regimens done by Generaux et al. estimated that EFV 
concentrations remains above the minimum effective concentration (MEC) up to 3 days after 
discontinuation, and DTG trough concentrations reach MEC 3 days after switch. In CYP2B6 slow 
metaboliser genotypes, this is extended for DTG to 6 days post switch, however the EFV concentrations 
take 8 days to drop below the MEC (34).  
Generaux et al. thus predict that no DTG dose adjustment is required when switching from an EFV-based 
regimen in virologically suppressed patients. A pharmacokinetic sub-study of the STRIIVING study 
confirmed this in patients, finding that DTG concentrations were maintained above the IC90 
(concentration required for 90% inhibition) at all times after switch from an EFV-based regimen, and that 
there was no point post-switch at which both EFV and DTG concentrations were below their respective 
IC90 concentrations (35).  
However, our study population will be switched with a raised VL and a high likelihood of EFV and NRTI 
resistance mutations; in this setting exposure to sub-therapeutic concentrations of DTG could drive the 
development of InSTI resistance mutations. Thus in Stage 1, patients are initiated on a supplemented 
regimen of TLD with 50 mg DTG taken 12 hours later for the first 14 days, after which they receive TLD 
once daily for the duration of the study (48 weeks). 


ARTIST Trial Protocol Version 4.0. (dated 17 June 2020) 
 
8 
1.4 Rationale for protocol amendment 
Between August 08, 2019 and June 17, 2020, 61 participants were enrolled in Stage 1. The primary 
efficacy outcome was defined as the proportion of participants achieving plasma HIV VL <50 copies/mL 
at 24 weeks. Our interim findings suggest excellent virological suppression with TLD in second-line with 
a lead-in dose of DTG 50 mg twice daily for the first 14 days, showing 33 (87%) of 38 participants 
achieving HIV VL <50 copies/mL at 24 weeks. 37 (97%) participants achieved HIV VL <100 copies/mL 
at 24 weeks. Secondary outcomes were the proportions of participants achieving virological suppression 
at 12 and 48 weeks. Results at week 12 were consistent with those at week 24, at which point virological 
suppression was achieved in 41 (82%) of 50 participants. The higher dose of DTG at 50 mg twice daily 
for the first 14 days was well tolerated. No drug-related grade 3 or 4 adverse events occurred. Virological 
failure (defined as 2 consecutive VL >1000 copies/mL after 12 weeks) on TLD as second-line was not 
observed, despite high levels of baseline NRTI drug resistance, with 65% of participants having no fully 
active NRTI. Review of Stage 1 preliminary findings led us to modify the study design for Stage 2 to a 
Phase II, randomised, double-blind, placebo-controlled trial of TLD fixed dose combination daily with a 
lead-in supplemental 50 mg dose of DTG versus matching placebo taken 12 hours later for the first 14 
days in patients failing a first-line TXE regimen. 
This strategy of giving a lead-in supplemental dose of DTG is in view of the inducing effect of EFV on 
DTG metabolism and transport that persists for 2 weeks after EFV is stopped. It is safe to switch patients 
with undetectable VL from EFV to DTG without the need for dose adjustment. Additionally, 
pharmacokinetic studies show that as plasma concentrations of EFV fall, there are gradual rises in DTG 
plasma concentrations so that at no time point are both drugs at sub-therapeutic concentrations. However, 
DTG plasma concentrations are slightly below normal concentrations for the first 2 weeks of dosing and 
this might be an issue for those that already harbour NRTI and EFV drug resistance, which is common in 
patients failing first-line regimens. Previous TLD efficacy without a lead-in supplemental dose of DTG 
has also only been proven in virologically suppressed patients switching from TXE to TLD. In patients 
with virological failure on a first line TXE regimen switching to TLD, we will investigate whether DTG 
dose adjustment to achieve effective plasma concentrations during the period that induction wanes is 
required to avoid InSTI resistance and thus virological failure. 
We decided to drop the ALD arm as there are two ongoing studies investigating the recycling of the 
TDF/XTC backbone with DTG in second line. Both D²EFT and NADIA will address the question of 
whether patients with virological failure on TDF-based first line regimen must switch to AZT, or can 
remain on TDF. However, neither of the ongoing large trials investigating TLD as second-line is using the 
lead-in supplemental dose strategy. Our proposed new Stage 2 would thus address a knowledge gap that 
these two trials are not addressing.  
The additional dose of DTG may be challenging to implement in high burden settings. The need for DTG 
as single tablets increases cost, pill burden and the risk of stock outs. However, DTG single tablets need 
to be made available for second-line treatment as part of the ALD combination. If the TLD combination 
with lead-in supplemental dose strategy is proven to be effective, it would reduce the pressure on DTG 
demand by requiring only a 2 week supply of DTG rather than an ongoing supply as would be required 
for ALD as second-line. 


ARTIST Trial Protocol Version 4.0. (dated 17 June 2020) 
 
9 
DTG 50 mg twice daily was well tolerated in an InSTI experienced population in the VIKING study, with 
similar safety profile to that observed for DTG 50 mg once daily. No association was found between DTG 
exposure and relevant safety parameters (48). Nevertheless, a variety of safety measures will be put in 
place to ensure that no harm will come to the participants. 
One major risk to participants is the development of ARV resistant mutations. We will monitor for 
virological failure at frequent intervals. Virological suppression will be monitored by a drug safety 
monitoring board (DSMB) who will convene at two monthly intervals. Resistance testing will be 
performed on those participants who develop virological failure and an alternative ART regimen will be 
available should DTG resistance develops. During follow up visits, any adverse events reported by 
participants or observed by the investigators will be recorded in the source documents. Adverse events 
will be graded for severity according to the Division of AIDS table, and any serious adverse events (SAE) 
will be reported to the principal investigator immediately. SAEs and all unexpected adverse events 
suspected to be related to the study drugs will be reported to UCT’s HREC according to the current 
guidelines. 
1.4 Importance 
There are already 500 000 people using DTG worldwide, with South Africa lagging behind Botswana, 
Kenya and Brazil who have already started using DTG as the first-choice first-line (12). Many of these 
countries are switching patients on a TXE blindly to TLD  in a setting where VL monitoring is not readily 
available (<50% of patients in LMICs have access to regular VL testing (23)). As of July 2018, there is no 
clinical data to support switching patients from TXE directly to TLD without a known, suppressed VL 
(23). Evidence on viral suppression and the development of DTG resistance mutations in the presence or 
absence of resistance to the backbone drugs would be invaluable in informing this strategy further and in 
interpreting patient outcomes. The ongoing studies, such as D²EFT and NADIA will have results 
available from 2021, thus interim answers to the question of a TDF/XTC backbone with DTG in second-
line are urgently needed. 
Furthermore, patients who struggle with adherence and engagement are a vulnerable group of patients 
who need better second-line options as part of a strategy to support their care. DTG has already proven an 
attractive second-line option, and a regimen with a recycled TDF/XTC backbone addresses many of the 
problems with the current second-line options, affording a unique opportunity to test a second-line 
regimen that could potentially be better than our current first-line option. 
Finally, our hypothesis is that a lead-in supplemental dose of DTG may reduce the risk for the 
development of resistant viral strains and thus treatment failure. The alternative hypothesis is that the 
lead-in dose is not required and virological suppression and protection from emergence of resistance will 
be comparable in both arms. To our knowledge, this is the first study to evaluate the strategy of a lead-in 
supplemental DTG dose in patients with virological failure switching from an EFV-based to DTG-based 
regimen. If the proportion of patients achieving virological suppression is acceptable in both arms, this 
study together with other studies being conducted on TLD in second-line could pave the way for a Phase 
III trial to address this question or could directly influence clinical policy. 


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2. Problem statement 
In order to increase retention on second-line regimens as well as increase the availability of treatment to a 
growing population in need of second-line options, more efficacious, cheaper regimens with better 
tolerability and a lower pill burden are required. DTG fulfils the WHO recommended criteria and 
overcomes most of the issues associated with current second-line options.  
The question of which backbone to use is still open and results of the D²EFT and NADIA studies will not 
be available until 2021 at least. We hypothesise that when DTG is used with TDF and 3TC, even if both 
are compromised by resistance mutations, the residual activity and crippling will result in an effective 
second-line regimen that has good tolerability, a low pill burden, low monitoring requirements and low 
costs. 
As TDF/XTC in second-line is not an established second-line NRTI backbone, we will do frequent VL 
testing as well as genotypes (at baseline and in the event of failure) to clarify the impact that the 
combination has on outcomes in the presence or absence of K65R and M184I/V mutations. An 
assessment of impact on viral suppression and retention in care of a TLD regimen in second-line patients 
who have failed a first-line TXE regimen, can only be undertaken as research with close monitoring. 
Our interim findings from Stage 1 showed excellent virological suppression with TLD in second-line with 
a lead-in dose of DTG 50 mg twice daily for the first 14 days. In the new Stage 2, we will evaluate 
virological suppression with and without this lead-in dose. 
3. Research aims and objectives 
3.1.  Research aims 
The aim of this study is to determine the proportion of patients achieving virological suppression when  
recycling the TDF/XTC backbone with DTG (TLD combination) as a second-line with and without a 
lead-in supplemental dose of DTG, in patients failing a TXE first-line regimen. 
3.2.  Research objectives 
Primary objectives 
1. Stage 1: to describe the proportion of patients achieving HIV VL <50 copies/mL at 24 weeks on 
TLD (with a lead-in supplemental DTG dose for 14 days) as a second-line regimen in patients 
who have failed a TXE first-line regimen  
a. Overall 
b. Stratified by the presence or absence of resistance to both TDF and 3TC on initiation of 
the second-line regimen 
2. Stage 2: to describe the proportion of patients achieving HIV VL <50 copies/mL at 24 weeks on 
TLD with and without a lead-in supplemental DTG dose for 14 days, as a second-line regimen in 


ARTIST Trial Protocol Version 4.0. (dated 17 June 2020) 
 
11 
patients who have failed a TXE first-line regimen 
a. Overall 
b. Stratified by the presence or absence of resistance to both TDF and 3TC on initiation of 
the second-line regimen 
Secondary objectives 
1. To describe the proportion of patients achieving HIV VL <50 copies/mL at other time points (12 
and 48 weeks) and by per protocol analysis, on TLD as a second-line regimen in patients who 
have failed a TXE first-line regimen in Stage 1 and 2 
a. Overall 
b. Stratified by the presence or absence of resistance to both TDF and 3TC on initiation of 
the second-line regimen 
2. To determine the proportion of patients who develop DTG resistance mutations and new NRTI 
mutations on second-line TLD 
a. To determine whether the development of DTG resistance mutations is associated with 
the presence or absence of resistance to both TDF and 3TC on initiation of the second-
line regimen 
3. To describe the resistance profile of patients failing a TXE first-line regimen in this setting  
4. To evaluate the trough concentrations of DTG when switching from an EFV based first-line 
regimen, and to assess the pharmacokinetic requirement for a lead-in supplemental dose of DTG 
5. To describe markers of adherence between those failing TLD at 24 and 48 weeks and to compare 
to a group of matched controls 
6. To describe other clinical characteristics, adverse events and all-cause mortality among the study 
cohort 
4. Methodology 
5.1. 
 Study design 
This study will be a Phase II, randomised, double-blind, placebo-controlled trial of TLD fixed dose 
combination daily with a lead-in supplemental 50 mg dose of DTG versus matching placebo taken 12 
hours later for the first 14 days in patients failing a first-line TXE regimen. Given that these patients will 
all have elevated VL, the high baseline risk of NRTI and EFV resistance these patients are at and the 
inducing effect of EFV on DTG metabolism that persists for 2 weeks after EFV is stopped, we propose 
two stages: 
• 
Stage 1: patients initiated on TLD with a lead-in supplemental dose of 50 mg DTG taken 12 
hours later for 14 days (to make the dose 50 mg twice daily), with continuation of TLD for the 
duration of the study (48 weeks) 
• 
Stage 2: will describe VL suppression in two parallel arms, but will not be powered for a formal 


ARTIST Trial Protocol Version 4.0. (dated 17 June 2020) 
 
12 
non-inferiority comparison between the two: 
o Arm 1: patients initiated on DTG at 50 mg once a day as part of a fixed dose combination of 
TLD, with a lead-in supplemental 50 mg dose of DTG taken 12 hours later for 14 days, with 
continuation of TLD for the duration of the study (48 weeks) 
o Arm 2: patients initiated on DTG at 50 mg once a day as part of a fixed dose combination of 
TLD, with a matching placebo taken 12 hours later for 14 days, with continuation of TLD for 
the duration of the study (48 weeks) 
A pharmacokinetic sub-study will be conducted on 12 participants in Stage 1 and in 24 participants in 
Stage 2 (the first 36 participants in both stages who consent and is logistically feasible for enrolment into 
the pharmacokinetic sub-study), to assess the trough concentrations of DTG and off-treatment 
concentrations of EFV at day 3, 7, 14, and 28. Eligibility criteria are not different from eligibility for the 
parent study, with the only additional inclusion criterion being willingness to participate. 
Progression from Stage 1 to Stage 2 will be based on the lower bound of the 95% confidence interval (CI) 
for the primary endpoint (VL suppression at 24 weeks) in a subset of the first 23 participants being 
≥65.0%. This proportion will be determined in participants who have an HIV VL done at 24 weeks, have 
had a pharmacy refill collected at the prior visit and who are still on TLD (i.e. per protocol analysis to 
decide on progression to Stage 2). 
If the lower bound of the 95% CI for the primary endpoint of the first 23 participants is <65.0%, 
enrolment for Stage 2 will not commence but the follow up of participants in Stage 1 will continue to 24 
weeks. If it is ≥65.0%, the enrolment of participants for Stage 2 will commence alongside the follow-up 
of Stage 1 participants. 
Whether Stage 2 enrolment has commenced or not, the results will be re-evaluated after the full cohort of 
65 participants reaches 24 weeks. 
1. If the lower bound of the 95% CI is ≥65.0%, enrolment for Stage 2 can proceed if it has not 
already after the interim analysis of 23 participants. 
2. If the lower bound remains below 65.0% or is now <65.0% after enrolment for Stage 2 has 
already started, we will refer to the DSMB for a decision on whether to not progress to Stage 2 or 
continue Stage 2 enrolment and on the further follow up of Stage 1 patients, with the option of 
discontinuing the trial and transferring patients back into clinic care (as outlined in the safety 
section of the protocol). 
This study is not powered for formal statistical comparison between the two arms in Stage 2 yet informal 
comparison of virologic suppression (point estimates and 95% CI) achieved in the two arms will be 
possible. There are precedents for conducting Phase II non-comparative trials with active controls arms to 
evaluate virologic suppression endpoints with InSTI-based ART regimens. The INSPIRING study was 
also a non-comparative, active-control, randomised, open-label study with two arms randomising patients 
on tuberculosis treatment to DTG or EFV-based treatment. It was designed to describe the primary 


ARTIST Trial Protocol Version 4.0. (dated 17 June 2020) 
 
13 
outcomes at 48 weeks with 95% CI without making claims on the statistical significance of comparisons 
(36). The REFLATE (Raltegravir for the treatment of patients co-infected with HIV and tuberculosis) 
study randomised patients on tuberculosis treatment to three non-comparative ART arms and describes 
the virological suppression at 24 weeks in each arm without statistically comparing them (37). In the 
same way, our study will describe the outcomes in each arm without making statistical claims of 
significance in a comparison between the two arms. 
 
5.2. 
 Study area and setting 
The study will be conducted through the ART clinic, Welcome Service and Risk of Treatment Failure 
(ROTF) programmes at Michael Mapongwana Community Health Centre (CHC) and Ubuntu 
Antiretroviral Clinic at Site B CHC in Khayelitsha.  
Khayelitsha is a large, peri-urban informal settlement outside of Cape Town, South Africa. It is home to 
approximately 500 000 people, most of whom speak isiXhosa as their first language. It has a large 
population of people living with HIV (43 281 patients on antiretrovirals in 2018).  
The Welcome Service is a Médecins Sans Frontières (MSF) intervention for patients who have 
disengaged with care or who are intermittently engaging with services. It links these patients to the clinic 
and provides a package of medical and psychosocial support over nine visits, with the aim of improving 
retention in care and preventing treatment failure. It is suspected that many of these patients already 
harbour resistant mutations and will require switch to second-line treatment. It is provided at Michael 
Mapongwana CHC and Ubuntu Antiretroviral Clinic at Site B CHC currently. 
The ROTF programme is a four-visit series of nurse-led enhanced adherence settings for patients 
identified with a high VL. It was implemented by MSF and is now run by the clinic staff and supported 
by other NGOs. We also suspect that this population already harbour resistant mutations as many patients 
do not suppress even after the enhanced adherence support and require switch to second-line. This service 
is provided at Michael Mapongwana CHC and Ubuntu Clinic. 
Patients will be enrolled at both sites through the ART clinics, ROTF and the Welcome Service.  
5.3. 
 Study population and sampling 
5.3.1 Eligibility 
5.3.1.1 Inclusion criteria 
HIV positive patients over 18 years old, who have failed their first-line ART regimen of TXE, are able to 
attend the study clinic for one year of scheduled visits and who have given written, informed consent will 
be enrolled in this study. In female patients of child-bearing potential, those willing to use effective and 


ARTIST Trial Protocol Version 4.0. (dated 17 June 2020) 
 
14 
reliable contraception for the duration of the study will be eligible (see ‘Management of women of child 
bearing age in both phases’) 
Failure of a first-line regimen is defined as: 
• A VL of >1000 copies/mL (within the previous two months) and an immediately prior VL >1000 
copies/mL, taken 2-24 months prior (based on data captured by National Health Laboratory 
Service(NHLS)) 
5.3.1.2 Exclusion criteria 
• 
If the patient has two VLs 2-3 months apart: >2 log drop in VLs between the most recent VL 
(within the previous two months) and the immediately prior VL (taken 2-3 months prior)  
• 
CD4 count <100 cells/µl 
• 
Renal impairment (estimated Cr Cl <50 ml/min using the MDRD formula) 
• 
ALT >100 U/L or total bilirubin >twice the upper limit of normal 
• 
Pregnant or desire to become pregnant during the study period (48 weeks) 
• 
Breastfeeding 
• 
Being treated for active tuberculosis or concern that patient has undiagnosed active tuberculosis 
(based on symptom screening) as rifampicin reduces the concentrations of DTG and thus requires 
dose adjustments (10) 
• 
Any current diagnosis of malignancy 
• 
Allergy or intolerance to one of the drugs in regimen 
• 
Active, severe psychiatric disease judged likely to impact adherence 
• 
Current substance abuse judged to be likely to impact adherence  
• 
On treatment for AIDS-defining condition (not including secondary prophylaxis maintenance 
therapy) 
• 
Any other clinical condition that in the opinion of an investigator puts the patient at increased risk 
if participating in the study 
 
5.3.3. Management of women of child bearing age in both phases 
Women of child-bearing age will not be excluded from this study, but their reproductive health needs will 
be actively managed as pregnancy and the intention to become pregnant within the 48 weeks of the study 
are exclusion criteria. This is because of an identified signal indicating a potential increase in risk of 
neural tube defects in infants born to women taking DTG at conception (38). Since August 2014, the 
Botswana Harvard AIDS Institute Partnership has monitored birth outcomes at eight government 
hospitals in Botswana to evaluate the prevalence of neural-tube defects associated with ART exposure at 
the time of conception, alongside Botswana’s implementation of DTG as the first-option first-line ART 
across the country from 2016. As of May 2018, four infants born to women taking DTG at the time of 
conception had been found to have a neural-tube defect, equating to a 0.94% prevalence compared to 
0.12% in the infants born to mothers taking a non-DTG ART at conception (38). Ongoing birth-outcome 
surveillance in Botswana showed decreasing prevalence of neural tube defects associated with DTG 
exposure at conception, however it is still slightly higher than with exposure to non-DTG ART at 
conception (3 per 1000 deliveries vs. 1 per 1000 deliveries) (47). 


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15 
The WHO recommends a woman-centred approach to the management of this risk, empowering women 
to make informed decisions about their health. There are no reported or expected drug-drug interactions 
between DTG and hormonal contraception, thus the WHO recommends providing women of childbearing 
potential with reliable contraception alongside DTG (12).  
Women of child-bearing potential consenting to take part in this study will be required to commit to the 
use of effective and reliable contraception, including IUCDs, injectable, implantable or oral hormonal 
contraception, for the duration of the study. The study will facilitate their access to these through 
government services and study doctors will be required to frequently check that this is maintained. We 
will also implement additional counselling about the potential risks associated with the use of 
dolutegravir and conception so that fully informed consent to participate is obtained.  
 
Pregnancy tests will be done at baseline and regularly throughout the study. If a woman is found to be 
pregnant on the DTG arm during the study or expresses the wish to become pregnant, she will be 
switched to a standard PI-based second-line. If a woman becomes pregnant during the study period, she 
will be followed up throughout the pregnancy. We will refer the mother and infant pair to a paediatric 
colleague at Red Cross Childrens Hospital for a formal assessment for foetal anomalies in the first 4 
weeks of the post-partum period. Outcomes will be reported to the ethics committees and DSMB. Any 
pregnancy complication that results in a non-viable pregnancy outcome (eg. miscarriage) will be 
investigated in partnership with gynaecology and obstetric colleagues and reported to the ethics 
committees and DSMB. 
5.3.4. Sample size 
Assuming VL suppression (HIV VL <50 copies/mL at week 24) of 82% (as achieved by the DTG arm at 
24 weeks in the DAWNING trial (16)) is achieved at the modified intention to treat (mITT) analysis at 24 
weeks, a sample size of 57 will produce a 95% CI of 72 - 92%. To account for participants discontinuing 
the regimen or dropping out (e.g. stopping contraception), 65 patients will be enrolled into Stage 1 and 
into each arm of Stage 2 (total of 195 participants).  
Sample size for the Pharmacokinetic study  
We used SAS Programmer 9.4 (SAS Institute, Cary, NC, USA) to calculate the sample size. In Stage 1 it 
is unclear what the geometric mean ratio (GMR) of TDG trough concentrations between an EFV-induced 
and non-induced state will be for 50 mg DTG 12 hourly, but it is likely that GMR will exceed 1. A GMR 
of 1.22 was reported in a study of 12 participants that assessed the interaction between rifampicin and 
DTG – 14 days on rifampicin with 50 mg DTG 12 hourly versus 7 days on only 50 mg DTG daily (40). 
Given that EFV is a weaker inducer than rifampicin it is not unreasonable to assume that the GMR will be 
higher than 1.22 making 12 enrolled participants in Stage 1 adequate.   
Based on a pharmacokinetic study of patients switching from EFV to DTG, we expect the GMR of DTG 
trough concentrations on day 7 versus day 28 to be 0.66 for participants receiving 50 mg DTG daily (39). 
With an expected coefficient of variance of 55%, power of 80%, and 10% level of significance a sample 
of 10 participants would be sufficient to determine a difference of this magnitude in the GMR for 
participants not receiving a lead-in supplemental DTG dose. Based on an assumed withdrawal rate of 
20% we will need to enrol 12 participants. In order to compensate for the blinding in Stage 2 the sample 
size will be doubled to 24 participants. Therefore a total of at least 36 participants will be enrolled in the 


ARTIST Trial Protocol Version 4.0. (dated 17 June 2020) 
 
16 
pharmacokinetic sub-study. 
Sample size for the analysis to progress from stage 1 to stage 2 
Assuming a VL suppression (HIV VL <50 copies/ml at week 24) rate of 82% is achieved at the mITT 
analysis at 24 weeks, a sample size of 23 will produce a 95% CI of 66 - 98%. Thus the decision to 
progress from Stage 1 to Stage 2 will be taken after 23 participants have completed 24 week assessment 
and who have an HIV VL done at 24 week who have had a pharmacy refill collected at the prior visit and 
who are still on TLD. 
5.4 Study procedure 
5.4.1. Recruitment & pre-screening 
Patients will be recruited from the clinics, the Welcome Services and ROTF at both study sites. The 
clinician at their routine visit will identify eligible patients from their routine VL, explain the purpose of 
the study and make clear that the patient’s routine care is in no way contingent on participation in the 
study. If the patient agrees, they will be referred to the study for screening and enrolment. 
MSF has played a key role in the Ubuntu Site B and Michael Mapongwana ART clinics since 2002. MSF 
initially established these clinics in partnership with the provincial government and after handing over the 
running of these clinics to the province, has continued to play a strategic role in supporting key initiatives 
aimed at enhancing quality of care and outcomes of patients on ART with a focus on patients with 
specific challenges. Presently, MSF is supporting initiatives aimed at enhancing retention in care and 
reducing delays in switches to second line ART in clinics in Khayelitsha. As part of this MSF has 
permission to access electronic data systems which flag patients who have had repeated high HIV VLs 
and are eligible for switch to second line. We propose that MSF staff will work with provincial staff at the 
clinic to flag such patients and ask them to attend the clinic for a discussion regarding switching to second 
line with clinic staff. As part of this discussion the option of enrolling in the ARTIST trial will be 
discussed. If they are interested they will be referred to the study staff. If patients do not wish to enrol in 
the ARTIST trial but are eligible for second line switch this will be done within the ART clinic according 
to state protocols and separate from the trial.  
 
5.4.2.  Informed consent  
After referral from the Welcome Service/ROTF clinician, the patient will be contacted by the study staff. 
They will be taken through the process of informed consent and will have the study explained in detail by 
the counsellor, with the study nurse and doctor available to answer any questions. If they agree, informed 
consent will be taken. 
5.4.3. Screening & enrolment 
Screening 
The patients will be seen by the study nurse and doctor who will perform an assessment for eligibility, 
perform all blood tests and manage the collected specimens. 


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17 
The bloods taken on the screening visit will be sent for a CD4 count, creatinine, total bilirubin and ALT. 
A urine dipstick pregnancy test will be performed if the patient is female, unless the patient is post-
menopausal. 
Clinical status (history and examination), mental health status (history), substance abuse, tuberculosis 
status (symptom screening and history) and the patient’s desire to fall pregnant will also be assessed. 
Enrolment  
Enrolment (week 0 visit) will take place within 8 weeks of the screening visit. If a patient returns after 
this time they will require re-screening.  
On enrolment, the first 65 participants will receive TLD with supplemental DTG 50 mg for the first 14 
days. The subsequent 130 participants will be randomised 1:1 to either TLD daily with a lead-in 
supplemental 50 mg dose of DTG or matching placebo taken 12 hours later for 14 days and started on 
treatment at the week 0 visit. Baseline VLs (and urine pregnancy tests in female participants) will be 
performed on week 0. Participants will be examined and contraception use and desire to fall pregnant 
checked.  
Neuropsychiatric testing, neurocognitive testing and sleep assessments will be performed by a trained 
doctor or nurse at baseline (enrolment visit). The following neuropsychiatric and neurocognitive tests will 
be performed:  
• 
Brief Symptoms Inventory – 18, Anxiety Subscale (BSA) 
• 
Centre for Epidemiologic Studies Depression Scale (CESD) 
• 
Simioni Neurocognitive Symptom Questions 
• 
Cognitive Assessment Tool – Rapid Version 2.0 (CAT-rapid V2) 
Blood for genotypic resistance testing will be taken and stored for testing at the end of the study. In Stage 
1 and Stage 2, dried blood spots (DBS) will be taken for storage to test concentrations of tenofovir-
diphosphate (TDF-DP) after analysis of VL suppression, in order to assess adherence. Samples will be 
securely stored under appropriate conditions at the CIDRI-Africa lab until analysed.  
An extra blood sample will be taken at enrolment for DNA and stored for genetic testing at the end of the 
study, to determine CYP2B6 metaboliser genotype. The following single nucleotide polymorphisms 
(SNP) will allow categorisation of participants into slow, intermediate, and extensive metabolisers: 
CYP2B6 516G→T (rs3745274), 983T→C (rs28399499), 15582C→T (rs4803419), and CYP2A6 48A→C 
(rs28399433) (42). We will also store DNA for future genetic studies that are related to HIV and its 
treatment, such as evaluation for genetic polymorphisms associated with DTG metabolism. We would 
require HREC approval of any such future study. A separate informed consent for genetic testing will be 
performed at screening visits. For participants already enrolled in Stage 1, informed consent for genetic 
testing will be performed at the next study visits and consenting participants will have samples for storage 
collected at the same visits. We intend to approach all participants in Stage 1 and Stage 2 to participate in 
the genetic sub-study (n=195). 
Randomisation  
The participants enrolled in Stage 1 will not be randomised. Randomisation will occur in Stage 2 to either 


ARTIST Trial Protocol Version 4.0. (dated 17 June 2020) 
 
18 
TLD daily with a lead-in supplemental 50 mg dose of DTG or matching placebo. The purpose of the 
Stage 1 is to provide initial data regarding the safety of the strategy with the lead-in DTG dose. The 
purpose of Stage 2 is to evaluate the strategy with and without the lead-in supplemental dose of DTG and 
allow informal comparison between the two arms, and thereby provide preliminary Phase II data as to the 
requirement for a lead-in dose. After the initial 65 participants are enrolled in Stage 1, subsequent 
participants in Stage 2 will be randomized in a 1:1 ratio to receive either TLD daily with a lead-in 
supplemental 50 mg dose of DTG or matching placebo. A randomisation sequence will be prepared by an 
independent pharmacist before Stage 2 commences using block randomisation utilizing a block size of 6. 
The independent pharmacist will prepare opaque sealed envelopes labelled 1 to 130 containing the 
allocation assignment for the sequentially enrolled participants. The independent pharmacist will share 
the randomisation sequence with the study pharmacist and study statistician. The trial will be double-
blind. Only the independent and study pharmacists and study statistician will have access to the 
randomisation code. 
5.4.4. Follow-up Visits 
Patients will be followed up at weeks 2, 4, 8, 12, 16, 20, 24, 36, 48 and 52 weeks after enrolment. 
A doctor or nurse will perform the clinical consultation, ARV prescription and subsequent follow-up 
assessment. Sleep assessment will be done at every visit. Neuropsychiatric and neurocognitive testing will 
be done at weeks 0, 2, 4, 12, 24, and 48. The study nurse will perform all blood tests and manage the 
collected specimens, as well as provide standardised enhanced adherence counselling along with the 
counsellor for all patients in the study. This will be based on the enhanced adherence counselling that was 
developed for patients in the Welcome Service. Contraception use and pregnancy wishes will be checked 
at each visit (for female participants), as well as the physical status of the patient. Self-reported adherence 
will also be determined by the study nurse. 
 
Participants will be given a window period of 16 days to attend after the scheduled appointment, and may 
also attend up to 16 days before the scheduled visit. A text message will be sent to participants the day 
before the appointment to remind them. If participants miss an appointment a text message will be sent 
the next day to follow up, and if they do not return or make contact by day 3 after the scheduled 
appointment date, they will be called. Consent for text messaging and calls will be specifically obtained. 
If participants miss three consecutive visits they will be considered lost to follow up (LTFU) by the study 
definition and traced by routine clinic procedures (counsellor phone calls and community care worker 
home visits) in order to assess their clinical status and adverse events and to encourage their return to 
care. This is both to ensure complete data collection and ensure continuity of care for the patient. If they 
return to care, the patient will continue to be seen by the study staff for the remainder of their 48 weeks 
after enrolment to ensure full follow up. If the LTFU was triggered by an adverse event or other outcome 
which may have implications for the research, as judged by the PI, this will be reported to the DSMB and 
ethics committees. This information will be gathered either by phone or at home visit or when they return 
to care.  
5.4.5. Monitoring  
HIV VL will be performed at baseline and at weeks 4, 8, 12, 16, 20, 24, 36, and 48. If any of the VL after 


ARTIST Trial Protocol Version 4.0. (dated 17 June 2020) 
 
19 
week 12 are >50 copies/mL, or if there is <1 log decline in HIV VL from baseline value at any visit from 
week 4 onward, or if VL was suppressed at any time during treatment and subsequently rebound to >50 
copies/mL, enhanced adherence support will be given and the VL repeated 2 weeks after enhanced 
adherence counselling. If there is no decline and the repeat VL is >500 copies/mL, genotypic resistance 
testing will be performed on a new as well as the baseline stored sample, and the case reviewed by the 
trial steering committee to decide on further management. If the repeat VL is 50-500 copies/mL, 
enhanced adherence counselling and routine VL monitoring will be continued. We define the endpoint of 
virological failure as having 2 consecutive VL >1000 copies/mL after week 12.   
Participants will have a repeat CD4 count at weeks 24 and 48, and a repeat creatinine at weeks 4, 16 and 
48. If the eGFR declines to <50 mL/min then TDF will be discontinued and replaced with AZT as per 
national guidelines. TDF may be reintroduced if there is an alternative explanation for the decline in renal 
function once the eGFR has increased to >60 mL/min. 
Urine pregnancy tests will be performed in female participants at every visit, unless postmenopausal. In 
Stage one and Stage two, DBS will be taken and stored for TDF-DP concentrations at weeks 0, 12, 24, 36 
and 48 in order to assess adherence in those who do not virologically suppress. These will be analysed in 
a case control sub-study (cases will be participants who do not achieve virologic suppression at weeks 24 
and 48). In Stage 2, DTG trough concentrations will be taken at weeks 2, 12 and 24 weeks. 
Blood samples will be taken by the study nurse and sent to the NHLS laboratory as study specimens. 
5.4.5.1 Pharmacokinetic component 
Twelve participants from Stage 1 and 24 from Stage 2 will be invited to participate in the 
pharmacokinetic sub-study. DTG trough concentrations (prior to a DTG dose) will be taken on days 3, 7, 
14, and 28. Residual EFV plasma concentrations will be taken at enrolment and at the same time points as 
the DTG trough concentrations on day 3, 7, 14, and 28.  
We will perform genetic testing on all participants to determine CYP2B6 metaboliser genotype as it has 
been shown that the induction effect of EFV is greater in slow metabolizers (41), which would result in 
lower DTG trough concentrations when switching from EFV. The following SNPs will allow 
categorisation of participants into slow, intermediate, and extensive metabolisers: CYP2B6 516G→T 
(rs3745274), 983T→C (rs28399499), 15582C→T (rs4803419), and CYP2A6 48A→C (rs28399433) (42). 
Pharmacokinetic blood samples will be taken by the study nurse. The participant will not need to see the 
clinician for a consultation, but has the opportunity to ask questions or bring up issues, upon which the 
nurse taking the blood will assess whether the patient requires an ad hoc consultation that day. 
The drug assays will be done at the Division of Clinical Pharmacology laboratory, University of Cape 
Town (UCT), which has developed validated assays for DTG and EFV in plasma and TFV-DP on DBS 
using liquid chromatography-tandem mass spectrometry. Whole blood will be used for DNA extraction 
by Qiasymphony® according to manufacturer’s instructions. Targeted genotyping will be done with 


ARTIST Trial Protocol Version 4.0. (dated 17 June 2020) 
 
20 
Taqman® assays for selected SNPs that determine CYP2B6 metaboliser status. 
5.4.6. Post-trial access to the study drug 
At the end of 48 weeks, participants will exit the study and resume per guideline follow up in the 
government ART clinic. On their week 48 visit an appointment will be made for the following month in 
the ART clinic for the participant to transition back to provincial care. The decision on further treatment 
will made according to the findings of the study, the availability of the study drug in the public sector at 
that point and the discretion of the treating clinician. Available options include ALD, the WHO 
recommended second line (10,12) and AZT/3TC/LPV/r (6). If the participant has virologically failed at 
the end of the study, darunavir, rilpivirine or raltegravir could also be incorporated into the regimen 
depending on genotypic resistance results. The participants’ results and progress will be communicated in 
writing to their chosen clinic. 


ARTIST Trial Protocol Version 4.0. (dated 17 June 2020) 
 
21 
Figure 1. Study Procedure 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Participants will exit the study follow up and resume 
per guideline follow up at 48 weeks, transitioning 
back to provincial care with the decision on further 
treatment made according to the findings of the 
study, the availability of the study drug in the public 
sector and the discretion of the treating clinician. 
Not eligible for study 
Enroll in study: blood for genotypic resistance 
testing, DNA (separate consent), VL, DBS for TFV-DP 
Repeat VL at weeks 4, 8, 12, 16, 20, 24, 36 and 48  
Repeat CD4 at weeks 24 and 48 
Repeat urine pregnancy test at weeks 2, 4, 8, 12, 16, 
20, 24, 36 and 48 
Repeat creatinine at weeks 4, 16 and 48  
DBS TDF-DP at weeks 0, 12, 24, 36 and 48 
DTG trough concentrations at weeks 2, 12, and 24 
Inclusion 
Over 18 years old 
Failed first-line regimen of TXE 
In females: effective contraception acceptable 
Continue adherence 
and engagement 
support  
Continue on regimen 
Screening: Assess patient history, CD4 count, creatinine, ALT, total bilirubin, medical history, 
clinical examination, TB status, a pregnancy test and desire to fall pregnant in women, VL 
Continue treatment as per 
guidelines  
First 65 patients: 
• Initiate on TLD with lead-in 50 mg DTG dose 
Subsequent 130 patients randomized to initiate on: 
• TLD with lead-in 50 mg DTG dose for 14 days 
Or 
• TLD with matching placebo for 14 days 
12 patients consented for pharmacokinetic component of 
the study in Stage 1, and 24 patients in Stage 2 
Gatekeeper analysis for 
progression of the study 
The lower bounds of the 
95% CI for the VL 
suppression at 24 weeks 
in a subset of 23 
participants being 
≥65.0%. 
VL >1000 copies/mL (within the previous two months)  
and  
VL >1000 copies/mL taken 2-24 months prior  
VL <1000 copies/mL 
Or  
If VL>1000 copies/mL 
and 
>2 log drop in VL (2-3 
months apart) 
ART clinic patients screened at  VL results visit 
Exclusion 
CD4 count <100 cells/µl 
Renal impairment (estimated Cr 
Cl <50 ml/min using the MDRD 
formula) 
ALT >100 U/L or total bilirubin 
>2 ULN 
Pregnant or desire to become 
pregnant during the study 
period (48 weeks) 
Breastfeeding 
Being treated for active 
tuberculosis (TB) or concern 
that patient has undiagnosed 
active TB (based on symptom 
screening)  
Any current diagnosis of 
malignancy 
Allergy or intolerance to one of 
the drugs in regimen 
Active psychiatric disease or 
substance abuse  
On treatment for AIDS-defining 
condition (not including 
secondary prophylaxis 
maintenance therapy) 
Any other clinical condition that 
in the opinion of an investigator 
puts the patient at increased 
risk if participating in the study 
 


ARTIST Trial Protocol Version 4.0. (dated 17 June 2020) 
 
22 
Table 1. Schedule of events 
Visit 
Screening 
Week 
0 
2 
4 
8 
12 
16 
20 
24 
36 
48 
52 
Informed 
consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusions & 
exclusions 
X 
X 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Confirm use of 
acceptable 
contraception 
X  
X  
X 
X 
X 
X 
X 
X 
X 
X 
X  
X  
Physical exam if 
symptoms 
X 
X  
X 
X 
X 
X 
X 
X 
X 
X 
X  
X  
Adverse event 
screening 
 
X 
(Baseline) 
X 
X 
X 
X 
X 
X 
X 
X  
X  
X  
Sleep assessment 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Neuropsychiatric 
and 
neurocognitive 
testing 
 
X 
X 
X 
 
X 
 
 
X 
 
X 
 
Pregnancy test 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X  
X  
X  
Creatinine  
X 
 
 
X 
 
 
X  
 
 
 
X  
 
ALT 
X 
 
 
 
 
 
 
 
 
 
 
 
Total bilirubin 
X 
 
 
 
 
 
 
 
 
 
 
 
HIV VL 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X  
 
CD4 count 
X 
 
 
 
 
 
 
 
X  
 
X  
 
Genotype 
 
X  
 
 
 
 
 
 
 
 
 
 
Stored blood for 
DNA 
 
X 
 
 
 
 
 
 
 
 
 
 
DTG trough and 
EFV 
concentrations 
(PK sub-study) 
 
Day 0, 3, 
7 
X 
X 
 
 
 
 
 
 
 
 
DTG trough 
concentrations 
 
 
X 
 
  
X  
  
  
X 
 
  
 
TDF-DP 
DBS 
 
X  
 
 
 
X  
 
 
X 
X 
X  
 
 


ARTIST Trial Protocol Version 4.0. (dated 17 June 2020) 
 
23 
6. Data management and analysis 
6.1 Data collection 
6.1.1 Data to be collected 
Demographics  
• Age 
• Gender 
• Address 
 
Baseline clinical information 
• Medical history 
o VL history 
o CD4 history 
o ART history: ART regimens and start dates, periods of interruptions >3 months and other 
pertinent aspects of the ART history 
o Encounter history 
o Appointment/engagement history 
o Tuberculosis history 
o Obstetric history 
o Mental health history 
o Substance use screening 
o Other comorbidities 
• Clinical examination findings 
 
Follow up visit information 
• Symptoms and clinical examination findings 
• Barriers to adherence as recorded in the counselling notes 
• Time and date of last treatment dose 
• Neuropsychiatric and neurocognitive testing at weeks 0, 2, 4, 12, 24, and 48 using the following battery 
o Brief Symptoms Inventory – 18, Anxiety Subscale (BSA) 
o Centre for Epidemiologic Studies Depression Scale (CESD) 
o Simioni Neurocognitive Symptom Questions 
o Cognitive Assessment Tool – Rapid Version 2.0 (CAT-rapid V2) 
• Sleep assessment at weeks 0, 2, 4, 8, 12, 16, 20, 24, 36 and 48 
 
Laboratory values 
• VL at baseline and weeks 4, 8, 12, 16, 20, 24, 36 and 48  


ARTIST Trial Protocol Version 4.0. (dated 17 June 2020) 
 
24 
• CD4 at baseline and weeks 24 and 48  
• Residual EFV concentrations in 12 participants in Stage 1, and 24 participants in Stage 2 
• DTG trough concentrations in 12 participants in Stage 1, and 24 participants in Stage 2 
• EFV metaboliser genotype 
• Stored blood for DNA 
• Genotypic resistance results 
o Baseline 
o Repeat results in those with VL >500 copies/mL after enhanced adherence support 
• Creatinine at baseline and weeks 4, 16 and 48 
• Urine pregnancy test results at baseline and weeks 0, 2, 4, 8, 12, 16, 20, 24, 36, 48 and 52 
• ALT and total bilirubin at baseline  
• DBS for TDF-DP concentrations at weeks 0, 12, 24, 36 and 48 (case-control) 
• DTG trough concentrations at weeks 2, 12 and 24 in stage 2 
• Other blood results ordered as needed 
 
Clinical Outcomes  
• Adverse events 
o Grade 3 or 4 
o Serious 
o Requiring discontinuation of any of the ARVs in the regimen 
o Neuropsychiatric adverse events 
• Mortality (all-cause) with causality assessment 
• Appointments and attendance 
6.1.2 Method of collection 
All data will be recorded by the clinicians, nurses and counsellors on the case report forms (CRFs). Data 
will be captured from the CRFs on a weekly basis and uploaded into a study database (RedCap) by dual 
capturing. 
Background information will be collected from provincial Single Patient Viewer. 
6.2 Storage 
Patient data will be stored on a password-encrypted hard drive, kept off the clinic premises at UCT.  
6.3 Analysis  
Analysis will be performed in Stata Version 14 (43). Descriptive statistics will be presented with 95% CI. 
The detailed analysis plan will be described in a Statistical Analysis Plan which will be written before the 
first participant is enrolled. 
Unless otherwise specified, we will use the modified intention to treat analysis (mITT) according to the 
FDA snapshot analysis algorithm for analysing virological failure. The FDA snapshot algorithm regards 


ARTIST Trial Protocol Version 4.0. (dated 17 June 2020) 
 
25 
those with measured HIV VL ≥50 copies/mL, those with missing HIV VL within the visit window, 
intolerance or adverse event due to any drug in the regimen requiring switch, and those with drug 
substitution not permitted by the protocol as failures (44). LTFU will be considered failure. Stopping or 
switching due to DTG or NRTI intolerance or adverse events will be regarded as failure. Switching for 
reasons of stopping contraception or wish to become pregnant, or becoming pregnant, transfer out for 
non-clinical reasons and death from non-HIV and non-drug causes (as assessed by the study doctor) will 
not be regarded as failure. 
6.3.1 Primary outcome:  
VL suppression of HIV VL <50 copies/mL at 24 weeks is the primary end point. The proportion (with 
95% CI) of participants achieving HIV VL <50 copies/mL at 24 weeks will be assessed, in Stage 1 and in 
each arm in Stage 2.  
a. Overall 
b. Stratified by the presence or absence of resistance to both TDF and 3TC on initiation of 
the second-line regimen 
 
6.3.2 Secondary outcomes:  
1. Resistance 
a. Resistance profile at enrolment (NRTI and EFV resistance) 
b. DTG and NRTI resistance in those who experience virologic failure  
2. Pharmacokinetics 
a. The median (and IQR) residual EFV concentrations in the first 28 days will be described. 
b. The GMR (with 90% confidence intervals) of DTG trough concentrations for both 
supplemented and non-supplemented participants will be analysed as day 3 versus day 
28, day 7 versus day 28, and day 14 versus day 28. 
c. The proportion of participants with DTG trough concentrations above the PA-IC90 at all 
pharmacokinetic time points will be described.  
d. All metrics will be stratified by CYP2B6 metaboliser genotype. 
e. Adherence to treatment (as indicated by self-reporting, DBS TDF-DP concentrations at 
weeks 0, 12, 24 and 48 in stage one and stage two) in those who experience virological 
failure and matched controls from among those who are suppressed at 24 and 48 weeks 
3. Other clinical outcomes  
a. Number of adverse events: 
i. Grade 3 or 4 
ii. Serious 
iii. Requiring discontinuation of any of the ARVs in the regimen 
iv. Mortality (all-cause) 
b. CD4 counts: median (IQR) at 24 and 48 weeks, and change from week 0 
c. Virological suppression  
i. Modified intention to treat at 12 and 48 weeks 
ii. Per protocol at 12, 24 and 48 weeks 
1. In addition, a sensitivity analysis will be performed where those patients 
who met the definition of failure at 24 and 48 weeks but who had no 


ARTIST Trial Protocol Version 4.0. (dated 17 June 2020) 
 
26 
TDF-DP concentrations at 24 and 48 weeks, indicating poor adherence, 
will be removed from analysis 
2. Virological failure is defined as having 2 consecutive VL >1000 
copies/mL after 12 weeks 
iii. Overall and stratified by baseline resistance with both K65R and M184I/V 
mutations 
 
6. Ethical considerations 
7.1 Confidentiality  
All participants interactions will maintain strict confidentiality and names will be removed from the 
datasets for analysis. Participant identifiers (including study numbers linked to patient name) will be 
stored in one participant log file that will be locked in a cabinet. All other study documents will use the 
study number only. 
7.2 Autonomy 
Informed consent will be obtained from every participant for screening and for the study in advance of 
enrolment into the study. Participants will be assessed by the counsellor or study nurse taking consent for 
their capacity to consent. All participants providing consent will be >18 years old, with no clinical reason 
to suspect that they are not of sufficient capacity to consent. 
Additional consent will also be taken for pharmacogenomics analyses. Consenting participants will have 
an additional blood sample taken and stored for future genetic studies that are related to HIV and its 
treatment. A separate informed consent for genetic testing will be obtained from every participant at 
screening in both stages. For participants that have already enrolled in Stage 1, informed consent for 
genetic testing will be obtained at the next study visit. Consenting participants will have stored blood 
sample taken at the same study visit. Unwillingness to participate in genetic testing will not exclude 
participants from the main study. 
Consent will be explained verbally and in a written form. isiXhosa speaking patients will have the option 
of a translated consent form in isiXhosa, with explanation by an isiXhosa-speaking healthcare worker. 
The explanation will include information to inform the participant of: 
1. The nature of the research study 
2. The voluntary nature of their participation 
3. The aims of the study 
4. The duration of the participant’s involvement 
5. The expected benefits to the participant and to others 
6. The expected nature of the drugs being tested 
7. The procedures involved in participation, including text messaging and calls to remind the patient 
of their appointment 
8. The alternative standard of care medical therapy 


ARTIST Trial Protocol Version 4.0. (dated 17 June 2020) 
 
27 
9. The risks, inconvenience, discomfort and distress that may reasonably be anticipated by 
participating in the study 
10. The potential for unforeseen risks 
11. Their ability to refuse to participate and withdraw their consent at any time without reason, and 
that this will not affect their care 
12. That the participant may be withdrawn from the study if the investigating physician considers this 
is necessary in the best interests of the participant 
13. That personal information may be scrutinised during audit by competent authorities and properly 
authorised people, but all personal information will be treated as strictly confidential and will not 
be made publicly available 
14. That information generated by the study may be published but that no details will be divulged 
from which the participant could be identified 
15. That their samples will be stored and kept secure and confidential, but that they may be used for 
further testing for future studies outside the scope of this study 
16. That study information will be retained for a period after the end of the trial 
17. The compensation arrangements that are available 
18. Contact details for emergencies 
7.3 Beneficence 
Depending on the results of this study together with other studies being conducted, the evidence could be 
used to advocate for the use of fixed-dose TLD formulations as second-line, which could benefit future 
patients by providing them with an efficacious regimen that is more tolerable, has low monitoring 
requirements and has a low pill burden.  
7.4 Non-maleficence  
The potential for the development of DTG resistance is considered low (2, 9, 24, 27–29, 31) but we will 
monitor for virologic failure at frequent intervals (0, 4, 8, 12, 16, 20, 24, 36, and 48 weeks). Virologic 
suppression will be monitored by the DSMB who will convene at two monthly intervals during the study 
to review data with a pre-defined stopping rule based on failure to achieve a threshold of virologic 
suppression. Resistance testing will be performed on those participants who has a HIV VL >500 
copies/mL after enhanced adherence support and an alternative ART regimen will be available (through 
public sector access that would include a boosted PI) should DTG resistance develop. 
In order to address the potential risk for neural tube defects if taking DTG peri-conception, women of 
child-bearing potential will be offered reliable and consistent contraception as recommended by the WHO 
(12) and only those for whom this is an acceptable option will be eligible for the study. 
Fair monetary compensation will be provided to participants for attending study visits, in line with the 
National Health Research Ethics Council (NHREC) guidance in order to compensate them for their time 
and inconvenience and to reimburse them for their expenses (45). 
7.5 Justice 
This study has potential applicability to other populations 


ARTIST Trial Protocol Version 4.0. (dated 17 June 2020) 
 
28 
1. In the coming years DTG will become widely available in lower resource settings and 70 low and 
middle income countries have already included or are planning to include DTG in national 
guidelines (12). The knowledge gap on the safety of transitioning patients from EFV to DTG if 
they are not known to be virologically suppressed forms a barrier to expanding DTG access in 
countries where VL monitoring is not routinely available. VL testing is currently only available 
on a national level in South Africa, Namibia and Botswana, covering less than 50% of patients in 
LMICs (23). There is a need for clinical data to support switching patients from TXE to TLD 
with a detectable or unknown VL (23). If the TLD regimen proves robust in the face of NRTI 
resistance mutations, there is potential for mass transfer from TXE to TLD without the 
requirement for a VL to guide the decision. Maintaining the same backbone and removing the 
need to perform a VL would simplify implementation and reduce the cost of transition. TLD in a 
generic fixed dose combination will also already be procured for first-line ART programmes so 
would be readily available at a low cost. This study could contribute evidence to inform this 
strategy and facilitate this programmatic transition.  
2. Children have even fewer second-line options than adults, especially if they were initiated on a 
PI-based regimen. The use of DTG is supported by the FDA for children over six years of age 
and >30 kg and the WHO recommends its use for all HIV positive individuals older than 6 years 
and >15 kg (12). Thus there is the potential for expansion of TLD to younger populations in 
whom TDF is already recommended (>15 years and ≥40 kg (6)). 
3. Evidence on the use of DTG in second-line regimens can help to advocate for access to DTG as a 
valuable second-line option that is efficacious, tolerable and has a low pill burden. 
8. Safety 
1. Intense monitoring of HIV VL (0, 4, 8, 12, 16, 20, 24, 36, and 48 weeks) allows for a change in 
regimen if virologic suppression is not achieved or maintained. 
a. If a participant has a VL >500 copies/mL despite enhanced adherence support, a second 
genotype will be performed and the resistance results of the genotype on initiation and on 
failure will be discussed by the trial steering committee and used to inform the design of 
a new regimen that could include standard of care PIs, darunavir, rilpivirine and/or 
raltegravir. 
b. We anticipate that such events, if they do occur, will be infrequent (around 5% of 
participants in DTG monotherapy studies, and likely less with two NRTIs added). 
Furthermore, we anticipate that because no patients will be PI-experienced, a PI-based 
alternative suppressive regimen will be available in all cases where DTG resistance 
develops. We will communicate a detailed written ART plan after study completion to 
the clinic who is taking over care of such a patient and Prof Meintjes will be available to 
advise on on-going care of such patients after the trial – he has provided patient advice to 
clinicians in Khayelitsha since 2003. We anticipate that it is very unlikely such mutants 
would result in onward transmission. The availability of suppressive alternative regimens 
make this unlikely and the signature DTG mutation (R263K) severely compromises the 


ARTIST Trial Protocol Version 4.0. (dated 17 June 2020) 
 
29 
virus in terms of replicative capacity meaning that viruses carrying the mutation 
disappear rapidly from the circulating population of viruses when DTG drug pressure is 
removed. 
2. If a participant experiences any new symptom or is concerned, they will be encouraged to make 
telephonic contact with the clinic regarding any new symptoms by sending a “Please Call Me 
Message” which is free of charge. We will phone them. If they have symptoms of an SAE or 
unexpected event they will then be asked to attend the clinic and be reimbursed. 
3. An independent DSMB will be established consisting of four independent, experienced HIV 
clinical researchers (quorum will be two HIV clinical researchers). The study statistician will 
prepare the report for the DSMB but will not be a voting member of the DSMB. Two-monthly 
teleconferences will take place after the first participant enrolled reaches 12 weeks in the study, to 
monitor VL data. 
a. Stopping rule: if <65% of participants fail to achieve HIV VL <50 copies/mL by week 16 
(after a minimum of 10 participants have reached 16 weeks, excluding those who have 
been transferred out or died from non-HIV related causes). This rule may be modified by 
the DSMB prior to the trial starting when the Charter is agreed. 
b. Adverse events or factors with implications for the research or that trigger a participant to 
become LTFU will be reported to the DSMB. 
4. If a participant falls pregnant or expresses the wish to fall pregnant during the trial she will be 
immediately switched to a PI-based regimen. 
5. All ARVs will be sourced from the Western Cape Department of Health. Until the ARVs are 
available in state, they will be purchased from quality assured sources and will be WHO pre-
qualified and registered for use in South Africa by SAHPRA (South African Health Products 
Regulatory Authority – SA regulator).   
9. Human resources 
A nurse study coordinator, two medical officers, two nurses, three counsellors, a pharmacist, a data 
capturer and a driver will be employed for the specific purpose of implementing this trial and the 
RADIANT TB trial (MSF ERB approval reference 18109, received 15 February 2019).  All research staff 
will undergo Good Clinical Practice (GCP) training. Study staff will undergo appropriate training (GCP, 
BLS, ACLS where appropriate and on SOPs) before commencing patient enrolment and receive adequate 
supervision from the PIs. Staff training will include a 2 day start-up meeting covering all SOPs for both 
this trial and the other trial (RADIANT TB) which will be supported by the same staff.  The external 
study monitor and PIs will be present at both days of this start-up meeting.   
10. Timeline 
 
2018 
2019 
2020 
2021 
Quarter: 
4 
1 
2 
3 
4 
1 
2 
3 
4 
1 
2 
3 
4 
Protocol &ethics 
submission 
X 
X  
 
 
 
 
 
 
 
 
 
 
 
Preparation of 
CRFs 
X  
X 
 
 
 
 
 
 
 
 
 
 
 
Staff recruitment 
 
X 
X 
 
 
 
 
 
 
 
 
 
 


ARTIST Trial Protocol Version 4.0. (dated 17 June 2020) 
 
30 
Enrolment 
 
 
X 
X 
X 
X  
 
X  
X  
X 
 
 
 
 
Follow up 
 
 
X 
X 
X 
X 
 
X 
X 
X 
X  
 X  
X  
X 
Analysis 
 
 
 
 
 
Progress 
to stage 2 
Interim 
analysis  
 
 
 
 
Complete 
analysis 
 
Write up 
 
 
 
 
 
 
 
 
X (stage 1) 
 
 
  
X 
Dissemination 
 
 
 
 
 
 
 
 
 
 
 
 
X  
References 
1.  
UNAIDS. 90-90-90: An ambitious treatment target to help end the AIDS epidemic [Internet]. 2018 
[cited 2018 Sep 2]. Available from: http://www.unaids.org/en/resources/909090 
2.  
Oliveira M, Ibanescu RI, Pham HT, Brenner B, Mesplede T, Wainberg MA. The M184I / V and 
K65R nucleoside resistance mutations in HIV-1 prevent the emergence of resistance mutations 
against dolutegravir. AIDS. 2016;30(June):2267–73.  
3.  
Estill J, Ford N, Salazar-Vizcaya L, Haas A, Blaser N, Habiyambere V, et al. Estimating the need 
of second-line antiretroviral therapy in adults in sub-Saharan Africa up to 2030: a mathematical 
model. Lancet HIV. 2016;3(3):e132–9.  
4.  
Kaplan SR, Oosthuizen C, Stinson K, Little F, Euvrard J, Schomaker M, et al. Contemporary 
disengagement from antiretroviral therapy in Khayelitsha, South Africa: A cohort study. PLoS 
Med. 2017;14(11):1–24.  
5.  
World Health Organization. Global Action Plan on HIV Drug Resistance 2017-2021: 2018 
Progress Report. 2018.  
6.  
Western Cape Government. The Western Cape Consolidated Guidelines for HIV Treatment: 
Prevention of Mother- to- Child Transmission of HIV (PMTCT), Children, Adolescents and 
Adults. 2018 (Amended Version). Vol. 2018. 2018.  
7.  
World Health Organization. Consolidated guidelines on the use of antiretroviral drugs for treating 
and preventing HIV infection: recommendations for a public health approach. World Heal Organ. 
2016;155 p.  
8.  
Haas A, Keiser O, Balestre E, Brown S, Bissagnene E, Chimbetete C, et al. Monitoring and 
Switching of First-line Antiretroviral Therapy in sub-Saharan Africa: Collaborative Analysis of 
Adult Treatment Cohorts. Lancet HIV. 2015;2(7):1–21.  
9.  
Gallant JE, DeJesus E, Arribas JR, Pozniak AL, Gazzard B, Campo RE, et al. Tenofovir DF, 
Emtricitabine, and Efavirenz vs. Zidovudine, Lamivudine, and Efavirenz for HIV. N Engl J Med 
[Internet]. 2006;354(3):251–60. Available from: 
http://www.nejm.org/doi/abs/10.1056/NEJMoa051871 


ARTIST Trial Protocol Version 4.0. (dated 17 June 2020) 
 
31 
10.  
World Health Organization. Technical Update: Transition to new antiretroviral drugs in HIV 
programmes: clinical and programmatic considerations. 2017.  
11.  
Kandel CE, Walmsley SL. Dolutegravir – a review of the pharmacology , efficacy , and safety in 
the treatment of HIV. Drug Des Dev Ther. 2015;9:3547–55.  
12.  
World Health Organization. Policy Brief Update on Antiretroviral Regimens for Treating and 
Preventing HIV Infection and Update on early Infant Diagnosis of HIV: July 2018. 2018.  
13.  
USAID, PEPFAR. The Dolutegravir Opportunity: Managing supply chain risk for the introduction 
of a new antiretroviral (ARV) medicine. USAID Glob Heal Supply Chain Progr Procureent 
Supply Manag. 2017;(September):2017–8.  
14.  
Prabhu VR, Wong C, Jenkins S, Nizami S, Catlin K, Domanico P. New ARVs Could Represent 
Over USD 3 Billion in Cost Savings Through 2025. In: Conference on retroviruses and 
Opportunistic Infections. 2016.  
15.  
Dutta A, Barker C, Kallarakal A. The HIV Treatment Gap : Estimates of the Financial Resources 
Needed versus Available for Scale-Up of Antiretroviral Therapy in 97 Countries from 2015 to 
2020. PLoS Med. 2015;5:1–43.  
16.  
Aboud M, Brites C, Lu H, Supparatpinyo K, Hercilla L, Sievers J, et al. DTG Versus LPV/r in 
Second Line (DAWNING): Outcomes by WHO-Recommended NRTI Backbone. Conf 
Retroviruses Opportunistic Infect. 2018;2018.  
17.  
Charpentier C, Descamps D. Resistance to HIV integrase inhibitors: About R263K and E157Q 
mutations. Viruses. 2018;10(1):1–8.  
18.  
Wijting I, Rokx C, Boucher C, Kampen J van, Pas S, Vries-Sluijs T de, et al. Dolutegravir as 
maintenance monotherapy for HIV (DOMONO): a phase 2, randomised non-inferiority trial. 
Lancet HIV. 2017;4:e547-54.  
19.  
Hocqueloux L, Allavena C, Prazuck T, Bernard L, Sunder S, Esnault J-L, et al. Dolutegravir 
monotherapy versus dolutegravir/abacavir/lamivudine for HIV-1-infected virologically suppressed 
patients: Results from the randomized non-inferiority MONCAY trial. In: AIDS2018. 2018.  
20.  
Cahn P, Sierra-Madero J, Arrivas J, Antinori A, Ortiz R, Clarke A, et al. Non-inferior efficacy of 
dolutegravir (DTG) plus lamivudine (3TC) versus DTG plus tenofovir/emtricitabine (TDF/FTC) 
fixed-dose combination in antiretroviral treatment-naïve adults with HIV-1 infection - 48-week 
results from the GEMINI studies. In: AIDS2018. 2018.  
21.  
Fulcher JA, Du Y, Zhang T, Sun R, Landovitz RJ. Emergence of Integrase Resistance Mutations 
During Initial Therapy Containing Dolutegravir. Clin Infect Dis. 2018;67(5):791–4.  
22.  
Lopez MJP, Chueca N, Hernández-Febles M, Fernandez-Caballero JA, Garcia F, Zarzalejos JM. 
Virological failure through the R263K pathway to a first line Doluegravir containing regimen. In: 
AIDS2018. 2018.  


ARTIST Trial Protocol Version 4.0. (dated 17 June 2020) 
 
32 
23.  
Vitoria M, Hill A, Ford N, Doherty M, Clayden P, Venter F, et al. The transition to dolutegravir 
and other new antiretrovirals in low-income and middle-income countries:  what are the issues? 
AIDS [Internet]. 2018;32(12). Available from: 
https://journals.lww.com/aidsonline/Fulltext/2018/07310/The_transition_to_dolutegravir_and_oth
er_new.1.aspx 
24.  
Hakim JG, Thompson J, Kityo C, Hoppe A, Kambugu A, Oosterhout JJ Van, et al. Lopinavir plus 
nucleoside reverse-transcriptase inhibitors , lopinavir plus raltegravir , or lopinavir monotherapy 
for second-line treatment of HIV ( EARNEST ): 144-week follow-up results from a randomised 
controlled trial. Lancet Infect Dis. 2018;18:47–57.  
25.  
Rosa AM La, Harrison LJ, Taiwo B, Wallis CL, Zheng L, Kim P, et al. Raltegravir in second-line 
antiretroviral therapy in resource-limited settings (SELECT): a randomised, phase 3, non-
inferiority study. Lancet HIV. 2016;3(6):PE247-E258.  
26.  
SECOND-LINE Study Group, Boyd M, Kumarasamy N, Moore C, Nwizu C, Losso M, et al. 
Ritonavir-boosted lopinavir plus nucleoside or nucleotide reverse transcriptase inhibitors versus 
ritonavir-boosted lopinavir plus raltegravir for treatment of HIV-1 infection in adults with 
virological failure of a standard first-line ART regimen (SECOND. Lancet. 2013;381(9883):2091–
9.  
27.  
Demarest J, Underwood M, St-Clair M, Dorey D, Almond S, Cuffe R, et al. DTG-containing 
regimens are active in INI-naïve patients with a history of NRTI resistance. In: 20th International 
AIDS Conference. 2014.  
28.  
Reynes J, Meftah N, Tuaillon E, Charpentier C, Montes B. Dual regimen with dolutegravir and 
lamivudine maintains virologic suppression even in heavily treatment experienced HIV-infected 
patients: 96 weeks results from maintenance DOLULAM study. In: International AIDS Society 
Conference. 2017.  
29.  
Charpentier C, Peytavin G, Le M, Joly V, Cabras O, Perrier M, et al. High virological suppression 
rates regardless to the genotypic susceptibility score after switching to a dolutegravir-based 
regimen: W48 results in a prospective cohort. In: International AIDS Society Conference. 2017.  
30.  
Charpentier C, Peytavin G, Lê MP, Joly V, Cabras O, Perrier M, et al. High virological 
suppression regardless of the genotypic susceptibility score after switching to a dolutegravir-based 
regimen: week 48 results in an observational cohort. J Antimicrob Chemother [Internet]. 2018 Jun 
1;73(6):1665–71. Available from: http://dx.doi.org/10.1093/jac/dky062 
31.  
Kirby Institute. Protocol for Dolutegravir and Darunavir Evaluation in Adults Failing Therapy 
(D2EFT) [Internet]. ClinicalTrials.gov. 2017 [cited 2018 Sep 2]. Available from: 
https://clinicaltrials.gov/ct2/show/NCT03017872 
32.  
Clayden P. Fit for purpose: Antiretroviral treatment optimisation [Internet]. 2018 [cited 2018 Nov 
15]. Available from: http://i-base.info/htb/34533 
33.  
Song I, Borland J, Chen S, Guta P, Lou Y, Wilfret D, et al. Effects of enzyme inducers efavirenz 
and tipranavir/ritonavir on the pharmacokinetics of the HIV integrase inhibitor dolutegravir. Eur J 


ARTIST Trial Protocol Version 4.0. (dated 17 June 2020) 
 
33 
Clin Pharmacol. 2014;70(10):1173–9.  
34.  
Generaux G, Song I, Bowers G, Piscitelli S. A Mechanistic SimCYP Simulation Evaluating 
Dolutegravir and Efavirenz Pharmacokinetics Following a Switch From Once-daily Efavirenz to 
Once-daily Dolutegravir. In: 15th International Workshop on Clinical Pharmacology of HIV and 
Hepatitis Therapy. 2014.  
35.  
DeWet J, DeJesus E, Sloan L, Koteff J, Brennan C, Adkison K, et al. Pharmacokinetics of 
Dolutegravir After Switching to Abacavir/Dolutegravir/ Lamivudine From an Efavirenz-Based 
Regimen: A PK Sub-Study From STRIIVING. In: 17th International Workshop on Clinical 
Pharmacology of HIV and Hepatitis Therapy. 2016.  
36.  
ViiV Healthcare. Open-label Study of Dolutegravir (DTG) or Efavirenz (EFV) for Human 
Immunodeficiency Virus (HIV) - Tuberculosis (TB) Co-infection [Internet]. ClinicalTrials.gov. 
2018. Available from: https://clinicaltrials.gov/ct2/show/NCT02178592 
37.  
Grinsztejn B, De Castro N, Arnold V, Veloso VG, Morgado M, Pilotto JH, et al. Raltegravir for 
the treatment of patients co-infected with HIV and tuberculosis (ANRS 12 180 Reflate TB): a 
multicentre, phase 2, non-comparative, open-label, randomised trial. Lancet Infect Dis. 2014 
Jun;14(6):459–67.  
38.  
Zash R, Makhema J, Shapiro RL. Neural-Tube Defects with Dolutegravir Treatment from the 
Time of Conception. N Engl J Med [Internet]. 2018;NEJMc1807653. Available from: 
http://www.nejm.org/doi/10.1056/NEJMc1807653 
39.  
Wet J de, DeJesus E, Sloan L, Koteff J, Brennan C, Adkison K, et al. Pharmacokinetics of 
Dolutegravir After Switching to Abacavir/Dolutegravir/ Lamivudine From an Efavirenz-Based 
Regimen: A PK Sub-Study From STRIIVING. In: 17th International Workshop on Clinical 
Pharmacology of HIV and Hepatitis Therapy. Washington DC; 2016.  
40.  
Dooley KE, Sayre P, Borland J, Purdy E, Chen S, Song I, et al. Safety, tolerability, and 
pharmacokinetics of the HIV integrase inhibitor dolutegravir given twice daily with rifampin or 
once daily with rifabutin: results of a phase 1 study among healthy subjects. J Acquir Immune 
Defic Syndr. 2013;62(1):21–7.  
41.  
Ngaimisi E, Minzi O, Mugusi S, Reidel KD, Suba A, Eueda N. Pharmacokinetic and 
pharmacogenomic modelling of the CYP3A activity marker 4b-hydroxycholesterol during 
efavirenz treatment and efavirenz/rifampicin co-treatment. J Antimicrob Chemother. 
2014;69:3311–9.  
42.  
Sinxadi PZ, Leger PD, McIlleron HM, Smith PJ, Dave JA, Levitt NS. Pharmacogenetics of plasma 
efavirenz exposure in HIV-infected adults and children in South Africa. Br J Clin Pharmacol. 
2015;80(1):146–56.  
43.  
StataCorp. Stata Statistical Software: Release 12. College Station, TX: StataCorp LP.; 2011.  
44.  
U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug 
Evaluation and research (CDER). Human Immunodeficiency Virus-1 Infection : Developing 


ARTIST Trial Protocol Version 4.0. (dated 17 June 2020) 
 
34 
Antiretroviral Drugs for Treatment Guidance for Industry Human Immunodeficiency Virus-1 
Infection : Developing Antiretroviral Drugs for Treatment Guidance for Industry. 2015.  
45.  
NHREC. Payment of Trial Participants in South Africa: Ethical Considerations for Research 
Ethics Committees. 2012. 
 46. 
National Department of Health, South Africa. "ART clinical guidelines for the management of 
HIV in adults, pregnancy, adolescents, children, infants and neonates." (2019). 
47. 
Zash, Rebecca, et al. "Neural-tube defects and antiretroviral treatment regimens in 
Botswana." New England Journal of Medicine 381.9 (2019): 827-840. 
 
48. 
Castagna, Antonella, et al. "Dolutegravir in antiretroviral-experienced patients with raltegravir-
and/or elvitegravir-resistant HIV-1: 24-week results of the phase III VIKING-3 study." The Journal of 
infectious diseases 210.3 (2014): 354-362. 
 
 
 

SAP_007.pdf: 
Antiretroviral therapy in second-line: investigating tenofovir-
lamivudine-dolutegravir (ARTIST): a randomised controlled trial 
 
NCT03991013 
 
Statistical Analysis Plan for ARTIST Stage 2 
Version 1.0; 09 May 2022 
 
 
Signed  
 
Professor Graeme Meintjes 
Role: Principal Investigator 
Date: 09 May 2022 
 
 
 
 
 
 
 
 


ARTIST STUDY SUMMARY 
 
As the HIV epidemic matures and more patients are initiated on antiretroviral therapy (ART), 
focus is on ensuring that those on ART are virologically suppressed. Strategies to support 
virologic suppression on second-line regimens include the provision of ART that has a low pill 
burden, good tolerability, a high genetic barrier to resistance, low potential for drug-drug 
interaction, reduced need for laboratory safety monitoring, and low cost. A fixed-dose 
combination of tenofovir-lamivudine-dolutegravir (TLD) fulfils these criteria. 
 
Evidence from the NADIA study 1 and the first stage of the ARTIST study 2 suggested that 
recycling the tenofovir plus lamivudine or emtricitabine (TDF/XTC) backbone from first-line 
through to second-line could protect the regimen from development of resistance mutations to 
dolutegravir. This study (ARTIST stage 2) is a phase 2, randomised, double-blind, placebo-
controlled, non-comparative trial to determine the proportions of participants achieving 
virologic suppression when recycling the TDF/XTC backbone with dolutegravir (TLD fixed-dose 
combination) as a second-line regimen with and without a 14-day lead-in supplementary 50 mg 
dose of dolutegravir, in those failing a tenofovir-emtricitabine-efavirenz (TEE) first-line regimen. 
The rationale for the strategy of giving a lead-in supplementary dose of dolutegravir is to 
compensate for the induction effect of efavirenz on dolutegravir metabolism and transport that 
persists after efavirenz is stopped. 
 
In ARTIST stage 1, 62 participants were initiated on TLD fixed-dose combination daily with a 
lead-in supplementary 50 mg dose of dolutegravir taken 12 hours later (to make the dose 50 
mg twice daily) for the first 14 days, with continuation of TLD for the duration of the study (48 
weeks). Our study findings demonstrated excellent virologic suppression with TLD as a second-
line regimen, showing 85% (95% confidence interval [CI], 73 – 93%) achieving plasma viral load 
<50 copies/mL at 24 weeks, despite substantial baseline nucleoside reverse transcriptase 
inhibitor (NRTI) resistance 2.  
 


In ARTIST stage 2, 130 participants have been randomised to initiate on TLD fixed-dose 
combination daily with a lead-in supplementary 50 mg dose of dolutegravir or placebo taken 12 
hours later for the first 14 days, with continuation of TLD for the duration of the study (48 
weeks). This study is not powered for formal statistical comparison, but the point estimates 
(and 95% CIs) of the two study arms will be informally compared. The protocol for stage 2 
followed the SPIRIT guidelines and has been published 3. 
 
MAIN STUDY PRIMARY AND SECONDARY OUTCOMES 
Primary outcome measure 
• Plasma viral load <50 copies/mL at 24 weeks 
 
Secondary outcome measures 
• Plasma viral load <50 copies/mL at 12 and 48 weeks 
• Plasma viral load <400 copies/mL at 12, 24, and 48 weeks 
• Plasma viral load <50 copies/mL, <400 copies/mL, and <1000 copies/mL at 4 weeks 
• Resistance mutations to dolutegravir by 24 and 48 weeks 
• Acquired resistance mutations to NRTIs by 24 and 48 weeks 
• CD4 cell count change from baseline at 24 and 28 weeks 
• Death by 24 and 48 weeks 
• Grade 3 or 4 adverse events by 24 and 48 weeks 
• Adverse events leading to treatment discontinuation by 24 and 48 weeks 
• Serious adverse events by 24 and 48 weeks 
 
Other outcome measures 
• Creatinine change from baseline at 4, 16, and 48 weeks 
• Body weight change from baseline at 24 and 48 weeks 
• Body mass index change from baseline at 24 and 48 weeks 
• Change in sleep assessment from baseline at 2, 4, 8, 12, 16, 20, 24, 36, and 48 weeks 
• Change in neuropsychiatric assessment from baseline at 2, 4, 12, 24, and 48 weeks 


• Change in neurocognitive assessment from baseline at 2, 4, 12, 24, and 48 weeks 
• Adherence to ART as measured by tenofovir-diphosphate concentrations at 12, 24, and 
48 weeks 
 
This document describes the statistical analysis plan for ARTIST stage 2. 
 
1. Study information 
The number of patients screened and enrolled (or excluded) will be summarised by reasons for 
exclusion. For participants enrolled in the study, the number of participants discontinued study 
or lost to follow-up (LTFU) will be tabulated by reasons and last study visits. This information 
will be summarised in a CONSORT flow diagram, according to the 2010 CONSORT Statement 4. 
 
2. Baseline characteristics 
Baseline characteristics will be described in each study arm (tabulated as below). Categorical 
characteristics will be described using numbers and percentages. Continuous characteristics will 
be described using medians and interquartile ranges (IQRs).  We will describe means (standard 
deviations) for continuous variables that are normally distributed. 


 
 
3. Analysis of the primary endpoint  
The primary endpoint is the proportion of participants achieving virologic suppression (defined 
as plasma viral load [VL] <50 copies/mL) at 24 weeks. We will describe the proportion (and 95% 
CI) of participants achieving a VL <50 copies/mL at 24 weeks in each study arm. The visit 
window for the primary endpoint is +/- 6-weeks. No formal between-group comparison will be 
made for the primary endpoint as we do not have sufficient power. 
 
We will use the modified intention to treat (ITT) analysis according to the Food and Drug 
Administration (FDA) Snapshot algorithm for analysing virologic failure 5. All participants who 
receive ≥1 dose of the study medication will be part of the analysed cohort. The FDA Snapshot 
algorithm regards those with measured VL ≥50 copies/mL, discontinued study/study drug due 


to lack or loss of efficacy, missing VL within the visit window, intolerance or adverse event 
because of any drug in the regimen requiring switch, and drug substitution not permitted by 
the protocol as failures 5. LTFU will be regarded as failure. Stopping or switching because of 
dolutegravir or NRTI intolerance or adverse events will be regarded as failure. Switching for 
reasons of stopping contraception, wish to become pregnant, becoming pregnant, transfer out 
for nonclinical reasons, and death from non-HIV and nondrug causes (as assessed by the study 
investigator) will not be regarded as failure and will be excluded from the population. 
 
4. Analysis of secondary efficacy endpoints and time to event analysis 
A modified ITT analysis at 12 and 48 weeks will be performed to describe the proportions (and 
95% CIs) of participants achieving a VL <50 copies/mL (using the FDA Snapshot algorithm as 
described above) in each study arm. A secondary analysis will describe the proportions (and 
95% CIs) of participants achieving a VL <400 copies/mL at 12, 24, and 48 weeks using the 
modified ITT analysis and the FDA Snapshot algorithm in each study arm. We will describe the 
median VL (and IQR) and the proportions (and 95% CIs) of participants achieving a VL <50 
copies/mL, a VL <400 copies/mL, and a VL <1000 copies/mL, at 4 weeks using the modified ITT 
analysis and the FDA Snapshot algorithm in each study arm. 
 
The proportions of participants with a VL <50 copies/mL at each VL testing timepoint 
(measured at weeks 4, 8, 12, 16, 20, 24, 36, and 48) will be presented with 95% CIs in each 
study arm. The visit window is +/- 16-days around each visit except week 24 which has a 
window of +/- 6-weeks. A graph that plots proportions (with 95% CIs) of participants with VL 
<50 copies/mL at each VL testing timepoint in each study arm will be presented. We will 
tabulate VL outcomes at each study visit (virologic suppression [defined as a VL <50 copies/mL 
or a VL <400 copies/mL] and virologic non-suppression) using percentages and 95% CIs. If the 
proportion suppressed is 0 or 100%, a one-sided 97.5% CI will be estimated. The median time to 
virologic suppression (and IQR) will be described and a Kaplan Meier survival analysis will be 
performed to describe this outcome.  
 


We will describe CD4 cell count measured at weeks 24 and 48 using medians and IQRs, and 
describe change in CD4 cell count from baseline. 
 
Between-group differences for secondary endpoints will be analysed with Chi-squared tests (or 
Fisher’s exact tests if the number in any cell is ≤5) for binary data and with Wilcoxon rank sum 
tests for continuous data. 
 
5. Analysis of participants who do not virologically suppress 
5.1. 
Description of participants by outcome (suppressed versus unsuppressed) 
We will describe the following characteristics comparing participants who are virologically 
suppressed (achieving a VL <50 copies/mL and a VL <400 copies/mL) and those not suppressed 
(VL ≥50 copies/mL and VL ≥400 copies/mL) at 24 and 48 weeks. 
• Age (median and IQR) 
• Sex (proportion female) 
• NRTI resistance at baseline (proportion) using the Stanford algorithm for prediction of 
drug-susceptibility, with a score of ≥15 indicating at least low-level resistance 6: 
o 2 fully active NRTIs (both with a Stanford score <15 indicating susceptibility or only 
potential of low-level resistance) 
o 1 fully active NRTI (one with a Stanford score <15 and one with a Stanford score ≥15) 
o No fully active NRTIs (both with a Stanford score ≥15 indicating at least low-level 
resistance to both NRTIs) 
• Baseline VL (median and IQR) 
• Baseline CD4 count (median and IQR) 
• Previous ART duration (median and IQR) 
• Prior exposure to AZT or D4T (proportion) 
• Tenofovir-diphosphate (TFV-DP) concentrations at 24 and 48 weeks (proportion in each 
concentration category) described in details in section 5.3 below 
 


5.2. 
Description of treatment-emergent dolutegravir and NRTI resistance 
VL measurement is obtained at baseline, 4, 8, 12, 16, 20, 24, 36, and 48 weeks. If any VL after 
week 12 is ≥50 copies/mL, or if there is less than one log decline in VL from baseline, or if VL is 
suppressed at any timepoint and subsequently rebounds to ≥50 copies/mL, intensive 
adherence counselling is performed, and VL measurement is repeated after two weeks. If there 
is no decline and the repeat VL is ≥500 copies per mL, a genotypic resistance testing is 
performed on a new sample at this timepoint and on the baseline sample.  
 
The number and proportion of participants who develop dolutegravir resistance mutations and 
emergent NRTI mutations by 24 and 48 weeks in each study arm will be described.  The 
individual mutations and Stanford scores 6 will also be described. We will describe the number 
and proportion of participants who had virologic failure (defined as having two consecutive VLs 
>1000 copies/mL after 12 weeks) by 24 and 48 weeks in each study arm. 
 
5.3. 
Analysis of adherence 
TFV-DP concentrations on dried blood spots are conducted as an objective measure of 
adherence. Proportions in each concentration category will be described at 24 and 48 weeks for 
participants who are not virologically suppressed (VL ≥50 copies/mL and VL ≥400 copies/mL) 
and compared with those who achieved virologic suppression (VL <50 copies/mL and VL <400 
copies/mL) in each study arm. 
 
TFV-DP concentrations will be categorised using the threshold defined by Anderson et al 7. 
• <350 fmol/punch (men: <1.2 doses per week and women: <0.6 doses per week) 
• 350 – 700 fmol/punch (men: 1.2 – 3.2 doses per week and women: 0.6 – 2.0 doses per 
week)  
• 700 – 1250 fmol/punch (men: 3.2 – 6 doses per week and women: 2.0 – 5.3 doses per 
week) 
• >1250 fmol/punch (men: >6 doses per week and women: >5.3 doses per week) 
 


TFV-DP concentrations (median and IQR) and the proportion of participants in each category 
using the threshold defined by Anderson et al 7 will be described at baseline, 12, 24, and 48 
weeks for all participants (regardless of virologic success or failure).  
 
6. Analysis of secondary safety and tolerability endpoints 
Secondary safety and tolerability analyses will be performed, using the all-patients-treated 
approach (excluding participants who were randomised but never started on the study 
medication). We will describe the numbers and proportions of participants in each study arm 
who develop serious adverse events, laboratory and/or clinical Grade 3-4 adverse events 
(graded according to the Division of AIDS [DAIDS] criteria 8), and discontinuation of any drug in 
the TLD regimen by 24 and 48 weeks.  
 
We will describe creatinine at weeks 4, 16, and 48 using medians and IQRs at each time point. 
We will describe weight (and BMI) at weeks 24 and 48 using medians and IQRs, and describe 
change in weight (and BMI) from baseline. 
 
We will describe the numbers and proportions of participants in each study arm who develop 
insomnia (measured with the insomnia severity index 9 at baseline, 2, 4, 8, 12, 16, 20, 24, 36, 
and 48 weeks), and describe change in insomnia severity index scores from baseline. We will 
describe the numbers and proportions of participants in each study arm who develop anxiety 
and depressive symptoms (measured with the brief symptoms inventory anxiety subscale 10 and 
the centre for epidemiology studies depression scale 11 at baseline, 2, 4, 12, 24, and 48 weeks), 
and describe change in scores from baseline. We will describe the time to development of such 
events and the severity where available. We will describe the median and IQRs of 
neurocognitive assessment scores in each study arm (measured with the Simioni symptom 
questionnaire 12 and the cognitive assessment tool rapid version 13 at baseline, 2, 4, 12, 24, and 
48 weeks), and describe change in scores from baseline.  
 


We will describe the number and proportion of women of child-bearing potential who become 
pregnant within the study period (48 weeks), and describe the outcomes of the mother and of 
the newborn child.  
 
We will describe the number and proportion of deaths (all-cause) within the study period (48 
weeks) and report specific causes of death. 
 
7. Subgroup analyses related to the primary endpoint, secondary efficacy endpoints, and 
time to event analysis 
We will describe the proportions (and 95% CIs) of participants who achieve a VL <50 copies/mL 
at 24 and 48 weeks and the time to virological suppression (Kaplan Meier survival curves), 
overall and in each study arm, stratified by NRTI resistance present at baseline 6: 
• 2 fully active NRTIs (both with a Stanford score <15) 
• 1 fully active NRTI (one with a Stanford score <15 and one with a Stanford score ≥15) 
• No fully active NRTIs (both with a Stanford score ≥15) 
 
A secondary analysis will describe the proportions (and 95% CIs) of participants who achieve a 
VL <400 copies/mL at 24 and 48 weeks and the time to suppression (Kaplan Meier survival 
curves), overall and in each study arm, stratified by NRTI resistance at baseline. 
 
8.  Sensitivity analyses 
A sensitivity analysis at weeks 12, 24, and 48 will describe the proportions (and 95% CIs) of 
participants who achieve a VL <50 copies/mL and those who achieve a VL <400 copies/mL in 
each study arm. This sensitivity analysis will include only those still in the study and receiving 
the study drug. The following participants will be excluded from this sensitivity analysis: 
• Participants who have evidence of poor adherence (low TFV-DP concentration <350 
fmol/punch) 
• Participants who are LTFU or missing a VL within the visit window 


• Participants who stop or were changed from the study drug for reasons other than 
failure of the regimen (i.e., for lack or loss of efficacy, intolerance, or adverse event 
because of any drug in the regimen requiring switch) 
• Participants excluded from the modified ITT analysis for reasons described in section 3 
above 
 
9.  Protocol deviations 
A list of all protocol deviations (major and minor) will be compiled. These will be defined 
according to the relevant trial Standard Operating Procedures, and in accordance with the 
guidance of the Human Research Ethics Committee at the University of Cape Town. These will 
be presented as supplementary material in the trial publication. 
 
10.  Publication  
This statistical analysis plan will be published online (updated on clinicaltrials.gov) before 
locking the database for analysis. 
 
 
References 
1. 
Paton NI, Musaazi J, Kityo C, et al. Dolutegravir or darunavir in combination with zidovudine or 
tenofovir to treat HIV. New Engl J Med. 2021;385(4):330-341.  
2. 
Keene CM, Griesel R, Zhao Y, et al. Virologic efficacy of tenofovir, lamivudine and dolutegravir as 
second-line antiretroviral therapy in adults failing a tenofovir-based first-line regimen: a prospective 
cohort study. AIDS (London, England). 2021;35(9):1423.  
3. 
Zhao Y, Keene C, Griesel R, et al. AntiRetroviral Therapy In Second-line: investigating Tenofovir-
lamivudine-dolutegravir (ARTIST): protocol for a randomised controlled trial. Wellcome Open Research. 
2021;6(33):33.  
4. 
Schulz KF, Altman DG, Moher D. CONSORT 2010 statement: updated guidelines for reporting 
parallel group randomised trials. Trials. 2010;11(1):1-8.  
5. 
Human immunodeficiency virus-1 infection: developing antiretroviral drugs for treatment. 
Rockville, MD: Food and Drug Administration, Center for Drug Evaluation and Research. [November 
2015]. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/human-
immunodeficiency-virus-1-infection-developing-antiretroviral-drugs-treatment. 
6. 
Liu TF, Shafer RW. Web resources for HIV type 1 genotypic-resistance test interpretation. Clin 
Infect Dis. 2006;42(11):1608-1618.  


7. 
Anderson PL, Liu AY, Castillo-Mancilla JR, et al. Intracellular tenofovir-diphosphate and 
emtricitabine-triphosphate in dried blood spots following directly observed therapy. Antimicrob Agents 
Chemother. 2018;62(1):e01710-17.  
8. 
U.S. Department of Health and Human Services, National Institutes of Health, National Institute 
of Allergy and Infectious Diseases, Division of AIDS. Division of AIDS (DAIDS) Table for Grading the 
Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1. [July 2017]. 
https://rsc.niaid.nih.gov/sites/default/files/daidsgradingcorrectedv21.pdf 
9. 
Morin CM, Belleville G, Bélanger L, Ivers H. The Insomnia Severity Index: psychometric indicators 
to detect insomnia cases and evaluate treatment response. Sleep. 2011;34(5):601-608.  
10. 
Derogatis LR, Unger R. Symptom checklist-90-revised. The Corsini encyclopedia of psychology. 
2010:1-2.  
11. 
Radloff LS. The CES-D scale: A self-report depression scale for research in the general 
population. Applied psychological measurement. 1977;1(3):385-401.  
12. 
Simioni S, Cavassini M, Annoni J-M, et al. Cognitive dysfunction in HIV patients despite long-
standing suppression of viremia. Aids. 2010;24(9):1243-1250.  
13. 
Joska J, Witten J, Thomas K, et al. A comparison of five brief screening tools for HIV-associated 
neurocognitive disorders in the USA and South Africa. AIDS and Behavior. 2016;20(8):1621-1631.  
 

ICF_006.pdf: 
            
 
PARTICIPANT INFORMATION AND INFORMED CONSENT 
 
STUDY TITLE: AntiRetroviral Therapy In Second-line: investigating Tenofovir-lamivudine-dolutegravir 
(ARTIST) Stage 2: a randomised controlled trial 
Participant 
ID                  
A 
R 
T 
 
 
 
 Participant Initials 
 
 
 
 
 
 
 
Patient informed consent and information leaflet v.4.0. 17 June 2020                      Investigator’s Name: Prof Graeme Meintjes            
 
 
 
Page 1 of 14 
Introduction 
You are invited to take part in this study. You should understand the research before you agree to join 
the study. This form will explain the reason for the research, what you will need to do, and any risks or 
benefits. Please read this information carefully. 
 
Taking part in this study is your choice. You are free to leave the study at any time. If you decide not to 
take part, or to leave the study, your rights will not be affected in any way. You will be treated in the 
same manner as before at this clinic and other health care facilities now and in the future.  
 
About the study 
Patients who are infected with HIV (the “Human Immunodeficiency Virus”) can be treated and kept 
healthy by taking medicine called antiretroviral treatment (ARV) every day, which is usually a 
combination of three different types of ARVs. Each one of these ARVs treats HIV in a slightly different 
manner to avoid the virus becoming resistant to one of the drugs on its own. Resistance to one or more 
ARVs may cause the medicine to become ineffective. Different ARVs can be combined into single 
tablets to decrease the amount of pills a patient must take. In South Africa the first choice (or first-line) 
of ARVs has been a single daily pill fixed dose combination (FDC) of tenofovir disoproxil fumarate, 
emtricitabine, and efavirenz; the combination of all three can be abbreviated as “TXE”. Some patients 
have taken a combination of tenofovir disproxil fumarate, emtricitabine or lamivudine, and nevirapine 
as first line; the combination can be abbreviated as “TXN”. HIV can easily become resistant to TXE or 
TXN if someone takes their ARVs irregularly, and their treatment must then be changed to second-line 
ARVs. This has until recently included a combination tablet of zidovudine and lamivudine (which is 
almost exactly the same as emtricitabine) taken twice daily, as well as lopinavir/ritonavir (known as 
Aluvia). Lopinavir/ritonavir is taken as two tablets twice daily, and often causes unpleasant side-effects 
like diarrhoea. 
 
A new ARV called dolutegravir has much less chance of causing side-effects than lopinavir/ritonavir, 
and acts faster to suppress (decrease to almost zero) the level of HIV (viral load) in the blood. Therefore, 
many patients who need to switch to second line ARVs are now getting a single dolutegravir pill 
(instead of lopinavir/ritonavir) once daily, along with the twice daily tablet containing zidovudine and 


Participant ID    A 
R 
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Participant Initials 
 
 
 
 
Patient informed consent and information leaflet v.4.0. 17 June 2020                      Investigator’s Name: Prof Graeme Meintjes 
 
 
  
 
 
 
Page 2 of 14 
lamivudine (the combination of the three is abbreviated “ALD”). Zidovudine is given as part of second-
line treatment because HIV often becomes resistant to tenofovir when a person takes their first line 
treatment irregularly. Zidovudine may also commonly cause side-effects like nausea and low blood cell 
counts. 
 
Recent studies have shown, however, that if a person gets dolutegravir as part of their second-line 
treatment, it might be possible to avoid having to take zidovudine by continuing with tenofovir, even if 
HIV has become resistant to it. The advantages are fewer side-effects, and the fact that there is a fixed 
dose combination tablet available containing tenofovir, lamivudine and dolutegravir (abbreviated 
“TLD”), which only has to be taken once daily. 
 
When patients on first-line with efavirenz are switched to TLD, efavirenz stays in the blood for a few 
weeks. Efavirenz interacts with dolutegravir, resulting in less dolutegravir in the blood when 
dolutegravir is started. This could cause the HIV virus to become resistant to dolutegravir and lead to an 
increased HIV viral load – we do not know if this will happen. The problem of low dolutegravir level in 
the blood when a patient switched to TLD after efavirenz can be overcome by adding an extra 50 mg to 
the regular dose of dolutegravir for the first 14 days.  
 
Why is this study being done? 
In this study we are wanting to assess whether using TLD as second-line after a patient has failed an 
efavirenz-containing first-line regimen results in most patients having a good outcomes in terms of their 
viral load response over a 48 weeks period. We also want to compare the outcomes between people who 
take TLD alone from the start to those patients who take TLD with an extra 50 mg of dolutegravir taken 
12 hours later for the first 14 days. We will look to see how well HIV viral load is decreased, if the HIV 
virus develops new resistance to the ARVs, and how safe the double dose is. This study will help us get 
an indication whether it is necessary to add the extra 50 mg dolutegravir for the first 2 weeks or not. It 
may also inform policymakers in developing guidelines in South Africa and other parts of the world. 
 
Why are you being asked to take part?  
You have been invited to take part in this study because you have a HIV viral load (VL) >1000 
copies/mL, and a previous VL >1000 copies/mL in the past two years, which means that the HIV in 
your blood is not responding to first line ARVs and may have become resistant to them. You need to 
start on second line ARVs, and this study will provide you with the chance to use new medications that 
was not available previously, for the duration of the study period. 
 
What happens in this research study? 
Patients who agree to participate in our study will be randomly selected to receive either the TLD fixed 
dose combination daily or TLD with an extra 50 mg dolutegravir 12 hours later daily for the first 14 
days. The term “randomly” means that the decision is made similarly to flipping a coin. This is how a 
randomised controlled trial is done and it is the best scientific way to find out whether a treatment is 
beneficial or not. Patients and the investigators will not know who is getting the extra dose of 
dolutegravir, as all patients will get an extra tablet to take 12 hours after the TLD. Half patients will be 
getting “placebo” (looks the same as the 50 mg dolutegravir tablet but does not contain any 


Participant ID    A 
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Participant Initials 
 
 
 
 
Patient informed consent and information leaflet v.4.0. 17 June 2020                      Investigator’s Name: Prof Graeme Meintjes 
 
 
  
 
 
 
Page 3 of 14 
dolutegravir) and the other half will receive 50 mg dolutegravir. Thereafter all patients will continue 
with a single tablet of TLD daily for 48 weeks. 130 people will be part of this study in total. 
 
How long will the study last?  
You will remain enrolled in the study for 48 weeks, after which you will be transferred back to your 
normal ARV clinic. The type of ARVs that you must continue with will either be the standard second 
line treatment given to most patients in the country, or another specialised regimen (medication 
combination), depending on the results of your blood tests during the study. 
 
What will happen if you decide to take part in the study?  
If you want to take part in the study, the study doctor/nurse will discuss the reason for the study with 
you, what will happen during the study, and your risks, rights and study obligations.  
 
If you agree to take part, you will need to sign the consent form at the end of this document. Once you 
have signed the consent form, the study team will check whether it is safe for you to be on the study 
(screening). If eligible you will be enrolled and assigned one of the treatment options mentioned above. 
After that there will be frequent follow-up visits at week 2, 4, then every 4 weeks until week 24, and 
again at week 36 and 48. At every follow-up visit we will do a brief exam of your body and assess if 
there are any side-effects from the treatment you are on. There is a small risk of sleeping poorly and 
changes in mood with dolutegravir. Therefore we will do sleep assessment at every visit, and 
questionnaires to look for side effects affecting your thoughts and mood from the treatment at the 
enrolment visit (week 0) and at week 2, 4, 12, 24 and 48. Blood tests will be performed at weeks 2, 4, 8, 
12, 16, 20, 24, 36 and 48. See box 1: study schedule for more detail. 
 
Screening: The study doctor will review your medical records, ask you about your medical history and 
current health, ask you about substances you are using, and examine your body. Your contact details 
will also be taken in case we need to call you or text you, or do a home visit at a later date. 
Your blood (up to 20 ml or 4 teaspoons) will be tested:  
• To check how well your liver and kidneys are working  
• To test if you are pregnant if the urine test result is not clear (if you are capable of becoming 
pregnant) 
• To measure your CD4 count 
• To measure your HIV viral load 
 
Suitability:  
In order to take part in the study you need to:  
• Be 18 years or older 
• Clinically stable 
• Have a current HIV VL >1000 copies/mL and a HIV VL >1000 copies/mL in the past 2 years (at 
least 2 months before the current VL) 
• Have a CD4 count >100 cells/µl 
• If you are a woman and there is any possibility of you becoming pregnant during the study you 
must be willing to be on effective family planning (contraception, i.e. “the Pill” or “injection” or 
implant or intrauterine contraceptive device (IUCD)). 


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You will not be able to take part:  
• If you are pregnant or breastfeeding, or would like to become pregnant in the next 1 year 
• If your blood tests are not normal 
• If you are allergic or intolerant to any of the study medicines  
• If you are on any other medicine that may influence the drug level of dolutegravir 
• If you have any mental illness that could affect you taking medication 
• If you are using recreational drugs (i.e. Tik, dagga, Mandrax, Unga, cocaine, heroin, etc.) or 
drinking large amounts of alcohol that could affect you taking medication 
• If you are suspected of having, or being treated for active tuberculosis (TB) 
• If you are being treated for any serious AIDS related disease  
• If you have active cancer  
• If you are unable to attend study visits 
• If the study doctor thinks that it is best for you not to be on the study 
 
Enrolment: If the screening finds that you are able to take part in the study, we will contact you (by 
telephone call, sms, whatsapp or home visits) to confirm your participation. We will make an 
appointment for the first study visit (which should be on the same day that you are switched to your 
second-line ARV treatment). You will be reminded of things you need to do and the things that you 
cannot do whilst taking part in the study.  
 
We will also access your routine clinical data, such as laboratory results, medication prescriptions, 
appointments and clinic encounters and previous diagnoses on electronic databases. 
 
If you miss an appointment we will call you or send you a text message the next day and if you do not 
return to the clinic we will call you on the phone. We may also call or send you a text message to 
remind you about appointments. 
 
The order and timing of the study visits is shown in box 1:  
BOX 1: STUDY SCHEDULE 
Time 
Visit type 
Description 
Appointment 
before 
enrolment 
Screening 
Your contact details and address will be noted. The study team will ask 
you about your health, other medicines you are taking, and do a physical 
examination. They will also ask you about your medical history and any 
previous diagnoses, and will ask you about substances you might be 
using, including alcohol and other drugs. The study team will also take 
blood and do a urine test for pregnancy (if you are a woman of child-
bearing age). We will check to see if you meet all the conditions to be 
part of the study and have none of the conditions that would mean that 
you cannot take part in the study. You will be given a study appointment 
calendar outlining the dates and times of your scheduled study visits.  
Please bring all your regular medicines with you to the next study 
visit. 
If any of your blood results are out of the normal range, we could 


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ask you to come back to repeat them before the enrolment visit. 
Day 0 
Enrolment 
and start 
of 
treatment 
We will check to see if you meet all the conditions to be part of the study 
and have none of the conditions that would mean that you cannot take 
part in the study. The study doctor will do a brief physical exam and 
urine will be taken to test for pregnancy (if you are a woman of child-
bearing age). We will also do sleep assessment and questionnaires. 
 
You will receive the fixed dose combination of TLD and either the extra 
50 mg of dolutegravir or the placebo tablet (with no active medicine) to 
take 12 hours later daily for the first 14 days. Thereafter you will take the 
fixed dose combination of TLD once daily. 
 
We will also take a blood sample (6 ml or 1 teaspoon) to do HIV 
genotyping (testing the genes of the virus for any changes, also called 
mutations). This test will only be done at the end of the study to test 
whether the virus was resistant to any of the ARVs before you started 
ARVs in the study. If your viral load is high during the study, we will 
take another sample of blood to test the genotype again. This will help 
doctors to plan for future treatment (see below under “What are the risks 
of taking part?”). Another blood sample (5 ml or 1 teaspoon) will be 
taken to check that you are taking your medicines every day*. 
 
Your contact details and address will be checked. 
Week 2 
Follow-up 
visit 
This will be a follow-up visit where the study doctor will do a brief 
physical exam and take a history about any side-effects of the treatment 
you are taking. We will do sleep assessment and questionnaires to look 
for side effects from the treatment. A blood sample (5 ml or 1 teaspoon) 
will be taken for the level of dolutegravir in your blood and urine will be 
taken to test for pregnancy (if you are a woman of child-bearing age).  
 
Your contact details and address will be checked. 
Week 4 
Follow-up 
visit 
This will be a follow-up visit where the study doctor will do a brief 
physical exam and take a history about any side-effects of the treatment 
you are taking. We will do sleep assessment and questionnaires to look 
for side effects from the treatment. Blood (10 ml or 2 teaspoons) will be 
taken for kidney function  and HIV viral load and urine will be taken to 
test for pregnancy (if you are a woman of child-bearing age). 
 
Your contact details and address will be checked. 
Week 8 
Follow-up 
visit 
This will be a follow-up visit where the study doctor will do a brief 
physical exam and take a history about any side-effects of the treatment 
you are taking. A sleep assessment will be done. Blood (5 ml or 1 
teaspoons) will be taken for HIV viral load, and urine will be taken to 
test for pregnancy (if you are a woman of child-bearing age). 
 


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Your contact details and address will be checked. 
Week 12 
Follow-up 
visit 
This will be a follow-up visit where the study doctor will do a brief 
physical exam and take a history about any side-effects of the treatment 
you are taking. We will do sleep assessment and questionnaires to look 
for side effects from the treatment. Blood (15 ml or 3 teaspoons) will be 
taken for HIV viral load, the level of dolutegravir in your blood, and to 
check that you are taking your medicines every day*, and urine will be 
taken to test for pregnancy (if you are a woman of child-bearing age). 
 
Your contact details and address will be checked. 
Week 16 
Follow-up 
visit 
This will be a follow-up visit where the study doctor will do a brief 
physical exam and take a history about any side-effects of the treatment 
you are taking. A sleep assessment will be done. Blood (10ml or 2 
teaspoons) will be taken for kidney function and HIV viral load and 
urine will be taken to test for pregnancy (if you are a woman of child-
bearing age). 
 
Your contact details and address will be checked. 
Week 20 
Follow-up 
visit 
This will be a follow-up visit where the study doctor will do a brief 
physical exam and take a history about any side-effects of the treatment 
you are taking. A sleep assessment will be done. Blood (5 ml or 1 
teaspoons) will be taken for HIV viral load and urine will be taken to test 
for pregnancy (if you are a woman of child-bearing age). 
 
Your contact details and address will be checked. 
Week 24 
Follow-up 
visit 
This will be a follow-up visit where the study doctor will do a brief 
physical exam and take a history about any side-effects of the treatment 
you are taking. We will do sleep assessment and questionnaires to look 
for side effects from the treatment. Blood (20 ml or 4 teaspoons) will be 
taken for HIV viral load, CD4 count, the level of dolutegravir in your 
blood, and to check that you are taking your medicines every day*, and 
urine will be taken to test for pregnancy (if you are a woman of child-
bearing age). 
 
Your contact details and address will be checked. 
Week 36 
Follow-up 
visit 
This will be a follow-up visit where the study doctor will do a brief 
physical exam and take a history about any side-effects of the treatment 
you are taking. A sleep assessment will be done. Blood (10 ml or 2 
teaspoons) will be taken for HIV viral load and to check that you are 
taking your medicines every day*, and urine will be taken to test for 
pregnancy (if you are a woman of child-bearing age). 
 
Your contact details and address will be checked. 
Week 48 
Follow-up 
visit 
The study team will ask you about your health and do a physical 
examination. We will do sleep assessment and questionnaires to look for 


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side effects from the treatment. The study team will also take blood (20 
ml or 4 tablespoons) to check your kidney function, your HIV viral load, 
CD4 count, and to check that you are taking your medicines every day*, 
and urine will be taken to test for pregnancy (if you are a woman of 
child-bearing age). 
 
Your contact details and address will be checked. 
 
*The level of study medication in your blood will be measured by means of dried blood spots. A few 
drops of blood are put onto a special filter paper that can be used to test for levels of medicines in the 
blood.  
If your urine pregnancy test is unclear or positive, we will take additional blood for a blood pregnancy 
test (5 ml or 1 teaspoon). 
A follow up visit at week 52 will allow us to check everything is in order before we give you a letter and 
transfer you back into clinic care. 
 
What are the risks of taking part? 
The study medicines: Most people treated with these medicines do not experience bad side-effects. 
However, the study medicines can cause bad side-effects that you should know about. If you think you 
might be suffering from a bad side-effect of the medicines at any time during the study, you need to 
report this to the study doctor (or any other study team member) immediately. 
 
Dolutegravir may cause diarrhoea, nausea, abdominal pain and/or vomiting, as well as dizziness and 
headaches. It may also cause difficulty with sleep and unusual dreams and can make you feel anxious, 
unable to concentrate or feel unhappy or depressed. Rarely it can cause severe liver damage and/or skin 
reactions. In most patients dolutegravir do not cause side effects. 
 
Tenofovir may cause problems with kidney function in a small amount of people. People with kidney 
problems should not take this ARV. If your first blood results show that your kidney function is normal 
it should be safe for you to continue with this treatment. We will monitor your kidney function after 
month 1, 4, and 12, and we will not give it to you if it looks like it is causing any problems with your 
kidneys and will change it to an alternative ARV. If any problem does occur, this usually improves 
when the medication is stopped. 
 
Lamivudine may cause low red blood counts in a very small number of patients. We will monitor for 
this based on symptoms and during physical examinations. If this occurs you may be switched to a 
different ARV. 
  
Resistance. When HIV is not responding to first line treatment anymore, there is a high likelihood of it 
being resistant to treatment as a result of various changes in the virus (mutations). It is difficult to say if 
resistance to tenofovir might make it more likely to get resistance to dolutegravir if it is given with 
tenofovir. Being on TLD as second line ART might increase the risk of you developing ARV resistance 
or it might not – that is one of the questions we are planning to answer in this study. There is a small 
chance that you may develop resistance to the ARV treatment you are given in this study whatever 
treatment you receive (the ARV medicines will not work as well as they should, because your HIV has 


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found a way to escape their action). We will test your HIV viral load frequently, and if it is not 
adequately decreased when it should be, we will perform a special test on the HIV in your stored blood 
(from before you started the ARV treatment) and the HIV in a current blood sample. This will be to see 
if the HIV has become resistant to the ARVs you are using and which new ARVs we can prescribe to 
you that will work effectively.  
 
Risks of taking blood samples. You may have discomfort and mild pain with blood taking (insertion of 
a needle into your vein). You might have mild bruising. However, as the study staff are experienced, 
these effects should be minimal. The total amount of blood taken during the study will not exceed a 100 
ml of blood. This is less than ½ a cup and far less than the amount of blood drawn at a single blood 
donation. 
 
Safety monitoring. To monitor the safety of the study treatments we will ask you at each study visit 
about your health and about any problems that could be caused by the medicines. We will also take 
regular blood to test your kidney function, and monitor your HIV viral load. If you are worried about a 
change in your condition, you should contact the study team.  
 
Risk to pregnancy and unborn child. We do not want you to be pregnant before you enter the study or 
become pregnant during your time enrolled in this study. A recent study has shown that a small 
percentage of children born to women who became pregnant while using dolutegravir, were found to 
have neural tube defects. Neural tube defects are birth defects of the brain, spine, or spinal cord. They 
happen in the first trimester of pregnancy, often before a woman even knows that she is pregnant. This 
safety signal is not yet confirmed, but we are still concerned about it and want you to be aware of it.  
 
Some of the benefits of taking dolutegravir are that it has fewer side effects and you only have to take it 
once a day. The risk of these neural tube defects when taking dolutegravir is low: less than 1% of 
pregnancies. The risk on dolutegravir that was found was 0.3% of pregnancies, compared to 0.1% 
without dolutegravir. It is your decision to balance these risks against the potential benefits of taking 
dolutegravir as your treatment. 
 
However, for this reason, if you are a woman who is capable of becoming pregnant and would like to 
take part in this study, we do emphasise that you must be using an effective method of contraception to 
avoid becoming pregnant for the duration of the study. We will talk with you about contraception 
options and help you choose the best method for you at each visit. Your birth control method must be 
one that is considered effective: a hormonal injection, oral contraceptive, implant or an intrauterine 
contraceptive device. This can be provided by your usual clinic. We will check at each visit that you are 
consistently using an effective birth control method and in this way the chance of you becoming 
pregnant during the study is reduced. 
 
It is important that you inform the study doctor or study team whenever you change your pregnancy 
intentions. If you have decided to fall pregnant or become pregnant during the study, the study 
medication including dolutegravir will be stopped and you will be changed to alternative ARV 
medication. We will monitor your progress and follow up on the outcome of your pregnancy.  
 
What are the possible benefits of taking part? 


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Aside from receiving a treatment regimen (combination of treatments) that is only one pill a day and 
might prove to have fewer side-effects than the standard treatments, you will not benefit directly from 
taking part in the study. The results of the study may benefit future patients with HIV who need to be 
switched to second line ARVs, and may be able to take a single pill containing TLD instead of a multi-
pill regimen of ALD or other medication. We will inform your clinic doctor of the results of the tests 
performed at the screening and last study visits. This information will help your doctor to adjust your 
management appropriately when you resume your normal appointments at your ARV clinic. 
 
How will the information and samples collected in the study be handled and stored? 
Information will be recorded by the study staff on case report forms, which will be captured and 
uploaded into a study database. The data will be stored on a password protected hard drive, kept at the 
University of Cape Town. These records will be kept for ten years after the end of the trial. 
 
Blood samples will be taken and sent to the National Health Laboratory Service for the tests explained 
above. A small amount of blood will be stored for tests of dolutegravir levels at a later date in the study. 
Blood samples will be kept for ten years after the end of the trial. 
 
If in future, you decide that you do not wish for your samples to be stored anymore, you can contact the 
researchers or the UCT ethics committees and inform them of your decision. Your samples will then be 
destroyed and no further tests will be done on them. 
 
Use of the information for other studies 
Other researchers may apply to University of Cape Town Human Research Ethics Committee for 
permission to use the information we gather or the samples we store for other studies. Further tests on 
these samples and further analysis of the information will only be performed if the ethics committee 
agrees and grants this permission. The information and samples will not be linked to your name so any 
further research will not have access to your identity.  
 
When you sign the consent below, your permission to store your samples and use them for future testing 
will be asked as a separate question for you to agree to. You are free to decline the request to store your 
samples for future testing and still participate in this study. 
 
Will your privacy be protected?  
All patient interactions will maintain strict confidentiality. To protect your identity, all information and 
all samples collected will be labelled with a study code. This code (and not your name) will be used for 
all study data and samples. Your medical records and the information collected for the study will be 
looked at by authorised persons from the study team. Your records may be reviewed by the research 
ethics committee overseeing the study, the South African Health Products Regulatory Authority, the 
funders who have authority to check that the study is being carried out correctly, or by an independent 
committee of doctors who will be making sure that the study is safe. All persons will treat any 
information about you as a research participant confidentially, and nothing that could reveal your 
identity will be disclosed outside the research site.  
 
What if ‘Something Goes Wrong’? 


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This research study is covered by an insurance policy taken out by the University of Cape Town if you 
suffer a bodily injury because you are taking part in the study. The insurer will pay for all reasonable 
medical costs required to treat your bodily injury, according to the SA Good Clinical Practice 
Guidelines 2006, which are based on the Association of the British Pharmaceutical Industry Guidelines.  
 
The insurer will pay without you having to prove that the research was responsible for your bodily 
injury. You may ask the study doctor for a copy of these guidelines. The insurer will not pay for harm if, 
during the study, you:  
• Use medicines or other substances that are not allowed  
• Do not follow the study doctor’s instructions  
• Do not tell the study doctor that you have a bad side effect from the study medicine  
• Do not take reasonable care of yourself and your study medicine.  
 
If you are harmed and the insurer pays for the necessary medical costs, usually you will be asked to 
accept that insurance payment as full settlement of the claim for medical costs. However, accepting this 
offer of insurance cover does not mean you give up your right to make a separate claim for other losses 
based on negligence, in a South African court.  
 
You must notify the study doctor immediately of any side effects and/or injuries during the study, 
whether they are research-related or not. 
 
Will you be compensated for your travel costs, time and inconvenience?  
You will be compensated for your time, inconvenience and transport expenses for each scheduled visit 
(R300 per visit). Unscheduled visits will not be compensated unless the study team requests you to 
return for an appointment. 
 
Who is managing this study? 
This study is sponsored by the University of Cape Town, who are responsible for maintaining the 
quality of the trial and ensuring that the trial is conducted in compliance with the protocol, good clinical 
practice and regulatory requirements. The trial is funded by a grant from the Wellcome Trust and by 
Médecins Sans Frontières (MSF). There are no potential conflicts of interest for any of the researchers 
or organisations sponsoring, funding, supporting or involved with the study in any way 
 
What will happen with the results of the research?  
The results of the study will be published so that they are available to the medical profession throughout 
the world. No patients will be identified individually. 
 
Withdrawal from the study 
You have the right to stop taking part in the study at any time. If there are any new findings during the 
study that may affect whether you want to continue to take part, you will be told about them as soon as 
possible. The investigator may decide to stop your participation without your permission because he/she 
may decide that staying in the study will be bad for you. If one of the study medicines causes you harm, 
you will be withdrawn from the study and your treatment changed to an alternative. If you withdraw 
early, the study team will encourage you to continue to be followed up by the study team, but it is your 


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right to decide. You will be referred back to your local primary health clinic to continue your treatment 
if you choose not to be followed up by the study team.  
 
 
What if you have complaints about the study? 
The ethical oversight of this study is performed by the University of Cape Town Faculty of Health 
Sciences Human Research Ethics Committee. If you want any information regarding your rights as a 
research participant, or have complaints regarding this research, you may contact: your doctor or the 
Ethics committee, by contacting: 
Prof. Marc Blockman, the Chairperson of the Research Ethics Committee at the University of Cape 
Town  
The Human Research Ethics Committee  
Floor E53, Room 46 
Old Main Building 
Groote Schuur Hospital 
Observatory, 7925 
 
After you have consulted your doctor or the Ethics Committee, and if they have not provided you with 
answers to your satisfaction, you should write to the South African Health Products Regulatory 
Authority (SAHPRA) at: 
The Chief Executive Officer 
South African Health Products Regulatory Authority (SAHPRA) 
Department of Health 
Private Bag X828 
Pretoria 
0001 
 
Contacting the study team 
If you experience any worrying effects on the study treatment, please contact the study team as soon as 
possible. If you or your health care provider have important questions or concerns, please contact the 
study team.  
 
You can contact the study nurse or doctor  (073 815 9538) You can also send a please call me and we 
will call you back. 
 
If you have general questions about the study you can also contact the Principal Investigator: Prof 
Graeme Meintjes (telephone: 021 406 6075).  
 
Statements of agreement and signatures 
 
 
 
 
 
 
 
 
1. 
I have read the information pages about the study, or they have been read to me. I understand 
the advantages and disadvantages, as well as the benefits and risks, of taking part in the study. 
The details of the study have been explained to me and my questions have been addressed. I will 
receive a copy of this signed consent form. 


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2. 
I understand that participation in the study will involve: 
• Tests including physical examination and questionnaires, and collection of blood samples 
• Taking doses of the ARV medicines, fixed dose combination TLD with an extra dose of 
dolutegravir or placebo for the first 14 days 
• There might be or might not be an increased risk of developing ARV resistance if TLD is 
taken as second line ARV treatment. This might be different depending on whether I receive 
the extra dolutegravir or the placebo – this is the main question the research is asking.   
• Attending the study visits and taking of blood samples for safety tests and measurements of 
the blood ARV levels 
• If I am a woman capable of becoming pregnant that I will be on effective contraception 
throughout the study, and if I wish to become pregnant I will inform the study doctor before 
doing so.  
• The study team and the clinic staff may contact me by telephone, text messages, WhatsApp 
or home visits. 
 
 
3. 
I understand that I can withdraw permission to take part and leave the study at any time, without 
having to give a reason, and without affecting my normal care and treatment. 
 
 
4. 
I understand that the information will be reviewed by authorised individuals and that the 
individuals are obliged to treat the information as confidential. 
 
 
5. 
I agree to take part in the study. 
 
PLEASE INITIAL/MARK THE BOX IF YOU 
AGREE 
 
6.  
I agree to have blood samples stored. These will be used to test to see what ARVs 
the virus is resistant to and to test levels of ARVs in my blood.  This could help 
doctors to plan for future treatment if the current ARVs are no longer working. 
 
 
 
 
7.  
I agree to have blood samples stored after the study has been completed. Other 
tests related to HIV may be performed on these samples in the future if the UCT 
Human Research Ethics Committee agrees to this. 
 
 
 
 
 
 
 
 
 


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Participant’s signature 
Given (first & middle) names – please print 
 
 
 
Surname (last/family) name – please print 
 
 
Date: D D M O N 2 0 Y Y 
 
Witness signature (if applicable) 
Name – please print 
Date 
 
 
 
D D M O N 2 0 Y Y 
 
Responsible study team member’s 
signature 
Name – please print 
Date 
 
 
 
D D M O N 2 0 Y Y 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1st Review _________________________   ________/__________/20 
 
 
 
initials  
 
 
date 
 
2nd Review _________________________   ________/__________/20 
 
 
 
initials  
 
 
date 
 
Spot Check _________________________   ________/__________/20 
 
 
 
initials  
 
 
date