AntiRetroviral Therapy In Second-line: Investigating Tenofovir-lamivudine-dolutegravir (ARTIST): a Randomised Controlled Trial
Phase: PHASE2
Conditions: HIV Infections
Sponsor: University of Cape Town

ARTIST Trial Protocol Version 4.0. (dated 17 June 2020) 
 
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  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) 
 
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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) 
 
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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) 
 
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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 

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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 

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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 

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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). 

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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. 

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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 

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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). 

ARTIST Trial Protocol Version 4.0. (dated 17 June 2020) 
 
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. 

ARTIST Trial Protocol Version 4.0. (dated 17 June 2020) 
 
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  
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