Short Communication:Outcomes of Dual Versus Triple Antiretroviral Drug Regimens Among Virally Suppressed Adults in the DC Cohort

Abstract

This study explored virological outcomes of two-drug (2DRs) and three-drug (3DRs) antiretroviral regimens in adults with HIV in the DC Cohort. We analyzed 310 treatment-experienced adults with sustained HIV RNA ≤50 copies/mL at baseline, 53 of whom switched to 2DRs and 257 continued 3DRs. Adults on 2DRs and 3DRs had similar demographics (median age 53.3 years, 76.8% cisgender male, 76.1% Black). Adults on 2DRs had more participants with ≥2 comorbidities (62.3% vs. 42.8%, p = .019), had a longer time since HIV diagnosis (median years 20.4 vs. 13.2, p = .017), and received the regimen of interest for a shorter duration (median years 1.3 vs. 3.3, p < .001) compared with adults on 3DRs. Adults receiving 2DRs had a higher, although nonsignificant, risk for virological failure (two consecutive HIV RNA ≥50 copies/mL) at 24 months follow-up than adults on 3DRs (6.7% vs. 1.7%, respectively; p = .10). Future analysis of the effectiveness of 2DRs is needed.

Antiretroviral therapy (ART) regimen simplification is highly desirable for people with HIV (PWH) due to fewer drugs and pills with improved side effect profiles to improve quality of life and enhance medication adherence. Two-drug regimens (2DRs) have been increasingly recommended in place of three-drug regimens (3DRs) for the management of HIV,^1,2 with clinical trials reporting high safety and efficacy of 2DRs in treatment-naive and treatment-experienced adult PWH.^3,4 Outside of clinical trials, studies that have evaluated the virological outcomes of 2DRs compared with 3DRs in clinical settings have demonstrated mixed results among treatment-experienced adults, with either no difference in time to virological failure between 2DRs and 3DRs⁵ or a higher probability of virological failure on 2DRs than on 3DRs.^5,6

The DC Cohort study is a longitudinal clinical cohort of PWH who receive their HIV care at 15 clinics in Washington, DC, in the United States.⁷ The study protocol was approved by the George Washington University Institutional Review Board (IRB No. 071029) and/or the IRBs of participating sites. This analysis included a prospective cohort of treatment-experienced virally suppressed (i.e., two consecutive HIV RNA ≤50 copies/mL) adults in the DC Cohort who initiated a 2DR or continued a 3DR between January 1, 2017, and June 30, 2019.

We defined 2DRs as the following integrase strand transfer inhibitors (INSTI)-based regimens: dolutegravir (DTG) plus lamivudine (3TC), DTG plus boosted darunavir with cobicistat (DRV/c) or with ritonavir (DRV/r), DTG plus rilpivirine (RPV), raltegravir (RAL) plus DRV/r, and RAL plus etravirine (ETR). 3DRs were selected for inclusion if they included any of the 2DRs plus an additional active antiretroviral drug (Supplementary Table S1). Data were collected for 24 months after initiating or continuing the regimen of interest. Sustained viral suppression was documented within 30 days of initiating a 2DR or continuing a 3DR. Participants were on the selected regimens for at least 60 days. The primary outcome was time to virological failure, defined as two consecutive HIV RNAs ≥50 copies/mL.

The following baseline data (unless otherwise specified) were included in this analysis: age, gender, race/ethnicity, body mass index (BMI), insurance type, location of clinical care (community vs. hospital-based clinic), HIV transmission mode, history of AIDS, time since diagnosis at beginning of specified study regimen, duration on ART regimen, CD4 count, HIV RNA at each visit, number of comorbidities (including liver disease, hypertension, cardiovascular disease, hyperlipidemia, diabetes, chronic kidney disease, chronic hepatitis C infection, chronic hepatitis B infection, chronic obstructive pulmonary disorder, autoimmune disorder, neuropathy, and osteoporosis), and presence of a mental health diagnosis.

We compared participants' characteristics between 2DRs and 3DRs with chi-square tests for categorical variables and Wilcoxon rank sum tests for continuous variables. Time to virological failure was estimated using Kaplan–Meier method and log rank test was used to compare 2DRs and 3DRs. p < .05 was considered to indicate statistical significance. Analyses were performed using SAS 9.4 (SAS Institute, Cary, NC) and R 4.0.3 (R Core Team, Vienna, Austria).

We included 310 adults (53 initiated 2DRs, 257 continued 3DRs) in this analysis. Overall, the participants had similar demographics (median age [IQR] 53.3 [42.5–61.3] years; 76.8% cisgender male; 76.1% non-Hispanic Black; 47.1% with HIV risk factor of men who have sex with men; 66.8% public insurance; and 55.2% received care at community locations) and clinical characteristics (median BMI [IQR] 25.8 [23.1–29.6] kg/m²; 55.2% with mental health diagnosis, 95.2% CD4 count ≥200 cells/mm³, and 57.4% with history of AIDS) (Supplementary Table S2).

Participants received the following 2DRs: DTG plus RPV (n = 31, 58.5%), DTG plus DRV/c (n = 13, 24.5%), DTG plus DRV/r (n = 5, 9.4%), RAL plus ETR (n = 3, 5.7%), and RAL plus DRV/r (n = 1, 1.9%). Participants received 18 different 3DRs, with DTG plus 3TC plus abacavir (ABC), accounting for the most common regimen (n = 228, 88.7%; 226 received this as a single tablet regimen), followed by DTG plus DRV/c plus RPV (n = 6, 2.3%) and DTG plus RPV plus 3TC (n = 4, 1.6%).

Adults on 2DRs had more participants with ≥2 comorbidities (62.3% vs. 42.8%, p = .019), had a longer time since HIV diagnosis (median years [IQR] 20.4 [9.4–25.8] vs. 13.2 [8.8–20.9], p = .017) than adults on 3DRs, and received the regimen of interest for a shorter duration (median years 1.3 [0.9–3.2] vs. 3.3 [2.5–4.1], p < .001) than adults on 3DRs (Supplementary Table S1). Participants on 2DRs had a higher cumulative incidence of virological failure than those on 3DRs (6.7% vs. 1.7%, respectively; p = .1, Fig. 1) during 24 months of follow-up.

FIG. 1.

Time to virological failure for participants with sustained viral suppression at the time of study entry, stratified by 2DRs and 3DRs. Top: Cumulative incidence of virological failure over time. Solid line: Participants on 2DRs. Dotted line: Participants on 3DRs. Bottom: Number of participants at risk for virological failure over time. 2DRs, two-drug regimens; 3DRs, three-drug regimens.

Our findings demonstrate that PWH with sustained virological suppression have a higher but nonsignificant risk of virological failure after initiating 2DRs compared with those continuing 3DRs. Owing to the small sample size, we did not adjust for potential confounders. Baseline characteristics between 2DRs and 3DRs were similar except for the time since HIV diagnosis, which was longer in those on 2DRs (median 20.4 years) than in those on 3DRs (median 13.2 years), suggesting that clinicians may be more comfortable with switching to 2DRs in PWH who have been in care for longer periods of time and have a longer history of sustained medication adherence.

Longer durations of HIV may be associated with high rates of comorbidities, polypharmacy, and drug-related toxicities, leading to a switch to 2DRs. Within our cohort, we identified opportunities to simplify regimens among the 29 participants on 3DRs who were not on fixed-dose drug combinations (FDCs), to potentially reduce their pill burden or switch to drugs with better safety profiles. The duration of 2DRs (median 1.3 years) was shorter than that of 3DRs (median 3.3 years), due to 2DRs being initiated in participants during the study period and the temporal trend of ART prescription in the DC Cohort, as opposed to before the study period.

Notably, 45.3% of adults on 2DR in this study received the FDC of DTG plus RPV, which was approved by the U.S. Food and Drug Administration 10 months into our study period, on November 21, 2017.⁸ None of the participants on 2DRs received DTG plus 3TC, which is recommended for use in treatment-naive patients.¹ The majority of 2DRs and 3DRs included DTG that has a high resistance threshold, and only a small proportion included RAL that is associated with a lower barrier to resistance.⁹ In fact, the 2DRs included an INSTI with a boosted protease inhibitor (DRV/r or DRV/c) or a non-nucleoside reverse transcriptase inhibitor (RPV or ETR), all of which are known to have high barriers to resistance.¹⁰

This study had several limitations including a small sample size that was also associated with the inability to adequately control for potential confounders. In addition, the reasons for regimen switch, virological failure, and regimen discontinuation were not collected.

Our analysis contributes to the data on effectiveness of 2DRs compared with 3DRs in routine clinical settings. In this observational cohort of predominantly advanced age cisgender male adults with virologically suppressed HIV who initiated 2DRs or continued 3DRs, adults on 2DRs had a higher risk of virological failure at 24 months than adults on 3DRs. This was statistically nonsignificant, likely due to the small sample size. Future studies of 2DRs with longer follow-up periods are needed to evaluate their role in sustaining long-term virological suppression among PWH, and to evaluate the role of 2DRs in the management of pediatric and adolescent HIV infection.

Authors' Contributions

W.L.A.K. developed the original draft of this article. All authors (W.L.A.K., J.X., M.T., L.P.H., A.K.M., A.D.C., and N.Y.R.) have read, reviewed, edited, and approved the final article. All authors contributed to the conceptualization and methodology of this study. J.X. and L.P.H. analyzed the data for this study. N.Y.R. supervised the study.

Author Disclosure Statement

No competing financial interests exist.

Funding Information

This study was supported by the National Institute of Allergy and Infectious Diseases (NIAID), 5UM1AI069503-14 and 1R24AI152598-01 (DC Cohort).

This publication was facilitated (in part) by the infrastructure and services provided by the DC Center for AIDS Research, a National Institute of Health (NIH) funded program (P30AI117970), which is supported by the following NIH Co-Funding and Participating Institutes and Centers: NIAID; National Cancer Institute; Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Heart, Lung and Blood Institute; National Institute on Drug Abuse; National Institute of Mental Health; National Institute on Aging; Fogarty International Center; National Institute of General Medical Sciences; National Institute of Diabetes and Digestive and Kidney Diseases and Office of AIDS Research.

Supplementary Material

Supplementary Table S1

Supplementary Table S2