A Retrospective Study to Evaluate the Safety and Efficacy of a Nucleoside-Sparing Regimen of Darunavir, Ritonavir, and Dolutegravir
Conditions: HIV-1-infection
Sponsor: Southern Illinois Healthcare Foundation

 
A Retrospective Study To 
Evaluate The Safety And 
Efficacy Of A Neucleoside-
Sparing Regimen Of 
Darunavir, Ritonavir AND 
Dolutegravir 
NCT03198884 
 
 
8/2/2019 
 
 
 
 

1 
 
A Retrospective Study To Evaluate The Safety and Efficacy Of A Neucleoside-Sparing Regimen Of 
Darunavir, Ritonavir And Dolutegravir 
John Verna, PA-C, AAHIVS │ SIHF Healthcare, Sauget, IL 
Stephen Austin, MS │ Washington University in St. Louis, St. Louis, MO 
Background 
Aging with HIV infection is a relatively new phenomenon and investigators are only beginning to 
understand its implications for clinical care and for our understanding of aging more generally.  Several 
sequelae of aging with HIV have been identified, including increased cardiovascular risk, bone loss, and 
renal dysfunction. Various antiretrovirals have been implicated in contributing to or exacerbating these 
conditions, most specifically the nucleoside reverse transcriptase inhibitors (NRTI) class. Despite the 
approval of various new pharmaceutical compounds over the last few years, the NRTI class remains 
limited in safe therapeutic options.  The most commonly used NRTI, tenofovir, has been implicated in 
numerous studies causing and/or contributing to renal disorders in persons with HIV [1,2,3].  In addition, 
data from the D:A:D study has shown in increased risk of cardiovascular disease (CVD) among patients 
receiving treatment for HIV and that certain medications appear to be associated with that risk, 
including the NRTI abacavir [4].  HIV therapy is life-long and providers have opted to use nucleoside-
sparing regimens to minimize these toxic effects.  The purpose of this study is to determine the real-
world efficacy and safety of a nucleoside-sparing regimen of darunavir 800 mg, ritonavir 100 mg, and 
dolutegravir 50 mg by mouth once daily.  While not well studied, this two-drug regimen was chosen for 
its lack of drug-drug interactions [5], predictable pharmacokinetic profile [6] and exceptional tolerability 
[7,8,9]. 
 
Methods 
We conducted a retrospective chart review of approximately 400 HIV+ patients receiving treatment at 
SIHF Healthcare, an urban diverse FQHC to identify those who were receiving a NRTI-sparing regimen of 
DRV and DTG.  Subjects were included if they were ≥ 18 years of age, receiving DRV/r QD + DTG QD for ≥ 
24 weeks, and had laboratory data through 48 weeks of follow up. Subjects were excluded if they 
received a regimen of darunavir/ritonavir in combination with dolutegravir for <24 weeks duration, if 
they received darunavir/ritonavir + DTG + NRTI’s, missed more than five doses over two weeks prior to 
study visit or if there was missing laboratory data for ≥2  or more study time points. The primary 
endpoints evaluated were the percent of patients with an RNA  <50 copies/mL at 48 weeks after 
initiation of the once daily two-drug regimen, as well as, the change in serum creatinine from baseline to 
48 weeks.  Main secondary endpoints included changes from baseline in CD4+ cell counts, incidence and 
severity of adverse events and, analysis of RNA and serum creatinine at time points 24, 36 and 48 
weeks.  

2 
 
The percent of patients with an RNA <50 copies/mL at each time point was analyzed using McNemar’s 
test following the guidelines of the Snapshot algorithm. Missing RNA data was considered a treatment 
failure. Change in mean serum creatinine from baseline was analyzed using Wilcoxon signed rank test. 
Change in mean CD4+ cell counts from baseline was analyzed using a paired t-test. All analyses used a p-
value of less than or equal to 0.05 as significant. Statistical analyses were performed using R software, 
version 3.4.3.  
 
Results 
The Mean age of the cohort was 51 yrs and had an average of 12.5 years of HIV seropositivity.  Table 1.    
The cohort had a mean baseline CD4+ of 485 with an RNA of 20K copies.  Table 2.  Of note, 55% of study 
subjects had a viral load of > 50 copies at baseline.   95% of study subjects at week 48 met the primary 
endpoint of < 50 copies/mL (P-value 0.002), 95%CI [2.24, NA].  Figure 1.  The lone failure was due to 
missing data.  Also, there were no significant differences in serum creatinine from baseline to 48 weeks 
(p = 0.5753).   Figure 2. However, at week 24, one study subject did not have data (serum creatinine) in 
window.  There were no significant changes in CD4+ cell count from baseline at time points 24, 36 or 48 
weeks. Figure 3. 
 
Table 1 
Descriptive Stats - Demographics
N
%
Gender
Female
8
40%
Male
12
60%
Race
Black
15
75%
White
5
25%
Age in years
Mean (SE)
51.05 (0.96)
Median
53.00
Range
37.00 – 61.00
std
8.20
HIV in years
Mean (SE)
12.54 (0.98)
Median
9.50
Range
0.25 – 32.00
std
8.79
Weight in Pounds
Mean (SE)
160.30 (4.04)
Median
157.00
Range
106.00 – 244.0
std
33.77
 
 
 
 

3 
 
Table 2 
 
Descriptive Stats – CD4 and Viral Load
Viral Load
Baseline
Week 24
Week 36 
Week 48
N
20
19
14
19
Missing=Failure
0
1
6
1
Mean (SE)
20458 (12389.4)
10232 (9559.583)
33.57 (12.82)
22.63 (1.50)
Median
95.0
20
20.00
20.00
Range
20.0 – 207720.0
20 -1820101
20.00 – 200
20.00 – 40.00
SD
55407.07
41669.26
47.98
6.53
CD4 Count
Baseline
Week 24
Week 36 
Week 48
N
20
20
14
20
Missing=Failure
0
0
6
0
Mean (SE)
485.1 (67.0)
453.9 (67.22)
428.1 (67.95)
455.7 (64.98)
Median
458.5
379.5
376.0
428.5
Range
24.0 – 1011.0
93.0 – 1145.0
112.0 – 877.0
70.0 – 1142.0
SD
299.41
300.64
254.24
290.56
 
 
 
Figure 1 
 

4 
 
Figure 2 
 
 
Figure 3 
 

5 
 
Adverse Events 
As per the study protocol, an adverse event (AE) is any untoward medical occurrence in a patient 
administered a medicinal product. 
Of note, there was no treatment-emergent resistance detected or virological failures in any of the 
subjects.  Common side effects reported by patients were insomnia (30%), diarrhea (20%) and headache 
(15%).  There were no adverse events that led to discontinuation of the study regimen.  Table 3. 
Table 3 [10] 
Patient ID 
Adverse 
Event 
Severity 
Relationship to Study 
Product 
Action Taken 
Suspected study 
drug: DRV/r or DTG 
#2 
Diarrhea 
Grade 1 
Possible 
None 
DRV/r 
#4 
Insomnia 
Grade 1 
Possible 
None 
DTG 
#6 
Insomnia 
Grade 1 
Possible 
None 
DTG 
#7 
Headache, 
Diarrhea 
Grade 1 
Possible 
None 
Both 
#8 
Headache, 
Diarrhea 
Grade 1 
Possible 
None 
Both 
#9 
Insomnia 
Grade 1 
Possible 
None 
DTG 
#10 
Insomnia 
Grade 1 
Possible 
None 
DTG 
#14 
Insomnia 
Grade 1 
Possible 
None 
DTG 
#15 
Insomnia 
Grade 1 
Possible 
None 
DTG 
#20 
Headache, 
Diarrhea 
Grade 1 
Possible 
None 
Both 
 
 
Adverse Drug Reaction 
As per study protocol, an adverse drug reaction (ADR) is defined as a response to a medicinal product 
that is noxious and unintended. 
Of note, no adverse drug reactions   were reported during this study. 
Serious Adverse Event 
As per study protocol, this is defined as any untoward medical occurrence that at any dose:  results in 
death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, 
results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, is a 
suspected transmission of any infectious agent via a medicinal product or is otherwise medically 
important. 
Of note, no serious adverse events were reported during this study.   

6 
 
Finally, no female subject (40% or 8/20 subjects) became pregnant during the 48 weeks of the study. 
 
Discussion 
The results show that after 48 week of darunavir 800 mg, ritonavir 100 mg and dolutegravir 50mg by 
mouth once daily, patients were able to maintain virologic suppression and there were no 
discontinuations due to adverse events.  
Clinically, this regimen may be beneficial for patients who experience side effects with other 
antiretroviral therapy or for those who struggle with adherence issues as this is a once daily regimen.  
However, there are several limitations to this research.  Due to the small sample size and data selection 
from a single center, it is difficult to extrapolate the results to the general HIV population.  Additionally, 
using snapshot analysis to evaluate efficacy can be flawed as it may not reflect the true response 
characteristics over the whole treatment phase. 
Toxicities associated with antiretroviral compounds are drug-class specific.  A commonly used NtRTI was 
tenofovir disoproxil fumarate (TDF).  This compound is known to affect renal function and bone mineral 
density (BMD).  In 2016, the Food And Drug Administration (FDA) approved a TDF pro-drug, tenofovir 
alafenamide [11].  Switching to this compound was associated with statistically significant efficacy and 
safety advantages over TDF [12].   
 The NEAT study (NEAT001/ANRS143) found that the regimen of raltegravir in combination with 
darunavir/ritonavir was about equal to a triple drug regimen of tenofovir/emtricitabine in combination 
with darunavir/ritonavir in terms of efficacy and safety in treatment naïve patients [13].  However, 
subjects with CD4 counts below 200 cells/µL and viral loads above 100,000 copies/mL did not do as well    
A second study was SWORD-1/SWORD-2 which evaluated the N(t)RTI  sparing, dual-drug regimen of 
once-daily dolutegravir plus rilpivirine vs. current antiretroviral regimen (CAR).  The authors found that 
at week 48, the regimen of dolutegravir plus rilpivirine was non-inferior to CAR and showed a safety 
profile consistent with its components, supporting the use of this two-drug regimen to maintain HIV 
suppression [14]. 
 
Conclusion 
In this study the combination of darunavir/ritonavir in combination with dolutegravir yielded high rates 
of virologic suppression.  While some patients experienced adverse events known to be associated with 
darunavir or dolutegravir, all adverse events were low grade and did not require discontinuation of 
treatment or alteration in dose 
 
 

7 
 
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