Over the last 30 years, there have been significant improvements in the efficacy and safety of antiretroviral therapy (ART). The current HIV treatment paradigm is to use three active antiretroviral agents. However, given the potency of new ART and the life-long duration that people living with HIV/AIDS (PLWHA) will require ART, there is a continued interest in 2-drug ART regimens. These interests include reducing costs and long term drug exposure with the associated cumulative renal, bone, and cardiovascular toxicities. In 2016, Achhra et al. conducted a systematic review and meta-analysis of 21 trials from 2008 to 2015 of the efficacy and safety of 2-drug ART as compared to standard 3-drug for ARTnaive patients or maintenance therapy.1 Analysis of the studies showed that 2-drug ART failed to achieve or maintain virologic suppression HIV-1 RNA <50 copies/mL (cpm) at a higher rate than standard 3-drug ART. When studies with maraviroc were removed, the relative risk of not achieving or maintaining VL <50 cpm on 2-drug ART as compared to 3-drug ART decreased but remained higher than 3-drug ART. This review serves to update the findings of Achhra et al. with the results of recent 2-drug ART trials.

The combination of dolutegravir plus lamivudine has generated attention as a potentially successful 2-drug combination given the potency of dolutegravir, minimal drug-drug interactions, and the safety profile of lamivudine. The AIDS Clinical Trials Group A5353 study was a Phase 2, multisite, open label, single arm study of dolutegravir 50 mg oral once daily plus lamivudine 300 mg oral once daily in ART naive adults with HIV-1 RNA <500,000 cpm.2 Participants who had any major resistance mutations, including integrase mutations, hepatitis B coinfection, or anticipated need for hepatitis C virus (HCV) treatment were ineligible to participate. The primary outcome was HIV-1 RNA <50 cpm at week 24. One hundred twenty-two participants were enrolled and 120 were included in the primary analysis. Participants were mainly male (87%) with a median age of 30 years and were racially diverse (40% black and 27% Latinx). At screening, 31% of participants had an HIV-1 RNA >100,000 cpm. At week 24, 90% of participants achieved virologic suppression. There was no statistically significant difference in virologic suppression when stratified by baseline HIV-1 RNA ≤100,000 vs HIV-1 RNA >100,000 cpm. Three participants had virologic failure (1 participant with screening HIV-1 RNA >100,000 cpm) and 1 participant developed the M184V mutation. Analysis of archived blood samples demonstrated that all three participants had undetectable dolutegravir levels at least once during the study period. Dolutegravir plus lamivudine was well tolerated with few Grade 3 or higher adverse events (AEs). Given these promising results, there are two large Phase 3 clinical trials underway, GEMINI 1 and 2 (NCT02831673 and NCT02831764).

The ANRS 167 LAMIDOL study was a Phase 1 open label, single arm, multicenter study that assessed the efficacy of dolutegravir 50 mg oral once daily plus lamivudine 300 mg oral once daily to maintain HIV-1 RNA <50 cpm.3 Participants were 18 years or older and had been virologically suppressed for 2 years. Participants had no history of virologic failure or major drug resistance mutations. One hundred ten participants were enrolled and first switched to dolutegravir with lamivudine plus a third agent. After 8 weeks, 104 participants maintained virologic suppression and proceeded to the second phase of the study, simplification to dolutegravir plus lamivudine. Participants were mainly male (86%) with a median age of 45 years. At week 40 of the second phase 2, 97% of participants had maintained virologic suppression.

Related: The Future of 2-Drug Regimens for People With HIV

The Antiretroviral Strategy to Promote Improvement and Reduce Exposure (ASPIRE) study investigated the efficacy of dolutegravir plus lamivudine to maintain virologic suppression as compared to standard 3-drug ART.4 The study was an open-label, randomized, multicenter trial of participants who were 18 years or older, had been on standard 3-drug ART for at least 48 weeks, and had no history of virologic failure or any major resistance mutations. Like other studies, pregnancy, breastfeeding, hepatitis B coinfection, and need for HCV treatment during the study period were exclusionary. Ninety participants were enrolled and 89 participants were included in the analysis. Participants were 88% male, 60% white, and the median age was 47 years old. At week 24, 93.2% of participants on dolutegravir plus lamivudine as compared to 91.1% of participants on standard 3-drug ART had HIV-1 RNA <50 cpm. The rate of virologic suppression was maintained throughout week 48 in both arms. Treatment failure at week 24 was 6.8% in the 2-drug arm and 6.7% in the 3-drug arm. Treatment with dolutegravir plus lamivudine was non-inferior to standard 3 drug therapy. Only one participant in the 2-drug arm had virologic failure and there were no major resistance mutations found. Both studies had few Grade 3 or higher AEs. Dolutegravir plus lamivudine appears to be efficacious for maintenance of HIV virologic suppression and the TANGO trial will be a large Phase 3 randomized trial to confirm this 2-drug strategy.

The ANDES trial is a Phase 4 open-label randomized, active-controlled trial of the virologic efficacy of generic fixed combination darunavir-ritonavir 800mg-100mg oral daily plus lamuvidine 300mg oral daily as compared to darunavir -- ritonavir plus tenofovir-lamuvidine 300mg-300mg orally once daily in ART naive participants. The week 48 primary endpoint data was recently presented at CROI 2018.5 One hundred forty-five participants were randomized and 93% participants in the 2-drug and 94% of participants in the 3-drug arm achieved HIV-1 RNA <50 cpm. Two-drug therapy was non-inferior to standard 3-drug therapy. Therapy was well tolerated in both arms but there was a statistically significant increase in total cholesterol in the dual therapy arm as well as a non-statistically significant trend toward increases in LDL-cholesterol and triglycerides. The lipid effects were likely due to the loss of the beneficial effects of tenofovir on lipids.

SWORD-1 and SWORD-2 are two identically designed, Phase 3, open-label, randomized, multicenter, parallel group, active-controlled, non-inferiority studies of 2-drug therapy with dolutegravir 50 mg orally once daily plus rilpivirine 25 mg orally once daily compared to standard three drug ART for the maintenance of virologic suppression.6 Participants were eligible if they were 18 years or older, not pregnant, had an HIV-1 RNA <50 cpm for 6 months prior to screening, and did not have a history of any VL blips ≥200 cpm during the 6-12 months prior to screening. Participants were excluded if they needed HCV treatment, had hepatitis B coinfection, had any drug resistance mutations, or a history of virologic failure requiring ART switch to second line therapy. The primary outcome was maintenance of HIV-1 RNA <50 cpm at week 48. The two studies enrolled a total of 1028 participants and 1024 participants were included in the primary endpoint analysis. Study participants were mainly white (80%) and male (78%) with a median age of 43 years. In the pooled analysis, 95% of participants in the 2-drug arm and 95% of participants in the standard three drug ART arm maintained virologic suppression.

The study was fully powered and confirmed that dolutegravir plus rilpivirine was non-inferior to three drug ART. There were 3 participants who experienced virologic failure in the dolutegravir plus rilpivirine group and resistance testing was successfully performed on 1 participant. That participant had a K101K/E mutation which did not affect the susceptibility to rilpivirine. Regarding secondary outcome measures, CD4 T-lymphocyte count increases were similar between the 2 groups and there were similar rates of AEs with few events leading to study withdrawal. Of note, neuropsychiatric AEs (insomnia, depression, and anxiety) were reported more frequently in the dolutegravir plus rilpivirine arm as compared to the 3-drug arm, 12% vs 6%, respectively; however, only 1% of neuropsychiatric AEs lead to withdrawal from the study in the 2-drug arm vs <1% in the 3-drug arm. The results of this trial led to the FDA approval of the single tablet formulation of dolutegravir plus rilpivirine (Juluca) for maintenance therapy in PLWHA who are virologically suppressed.

Many 2-drug studies exclude individuals with resistance mutations; however, ART resistance and need for second and third line regimens is an important treatment consideration for PLWHA. A retrospective analysis by Häggblom et al., reported that 14.2% of PLWHA in Sweden failed first-line ART with drug resistance mutations requiring a switch to second line ART.7 A paradox often exists for these individuals because their subsequent regimens become more complex and thus adherence and polypharmacy become further barriers to ART adherence. At CROI 2018, Pierone et al. presented the virologic outcomes between 2-drug and 3-drug regimens in the OPERA observational cohort.8 In the OPERA cohort, patients who received 2-drug regimens were older, had more comorbid conditions, and 41.7% had experienced 5 or more ART regimens as compared to patients on 3-drug regimens. Fifty-five percent of the 2-drug regimens were protease inhibitors plus integrase strand transfer inhibitors (INSTI) based regimens with ritonavir-boosted darunavir plus dolutegravir being the most common regimen. In patients who were viremic at the time of ART switch, 61% and 67% achieved HIV-1 RNA <50 cpm on 2-drug and 3-drug regimens, respectively. In patients who were suppressed at the time of ART switch, virologic suppression was maintained; 10% of patients on 2-drug regimens and 11% of patients on 3-drug regimens experienced virologic failure. Data on drug resistance was not provided but drug resistance was inferred to be present as the patients were heavily treatment experienced.

The Italian TIVicay plus PrezISTA Observation cohort (Tivista) followed patients from several Italian centers who were ART experienced and switched to ritonavir-boosted darunavir with dolutegravir.9 Ninety-one percent of the cohort had resistance to at least 1 class of ART, including 15% with reduced susceptibility to darunavir and 9% with reduced susceptibility to INSTIs. Depending on the patient's resistance mutations, their regimens were a combination of once or twice daily ritonavir-boosted darunavir plus once or twice daily dolutegravir. At the beginning of the study, 60% of participants had an HIV-1 RNA <50 cpm. At week 48, 91% of participants had virologic suppression. Six percent of participants had HIV-1 RNA ≥50 cpm, of which 3 had persistent viremia but slow virologic decline. Currently, the DUALIS study (NCT02486133), a Phase 3, randomized switch study is ongoing to confirm this 2-drug strategy.

The Long-Acting Antiretroviral Treatment Enabling (LATTE-1) trial was a Phase 2b, dose-ranging, parallel group, randomized trial to assess the efficacy of cabotegravir (a novel INSTI) with a standard ART backbone to achieve virologic suppression and to assess the efficacy of cabotegravir plus rilpivirine to maintain virologic suppression.10 Two hundred forty-four treatment-naive participants were enrolled and randomized to receive either cabotegravir 10 mg, 30 mg, or 60 mg versus efavirenz 600 mg orally once daily combined with a standard 2 drug nucleos(t)ide reverse transcriptase inhibitor (NRTI) backbone. At week 24, participants in the cabotegravir arms who achieved HIV-1 RNA <50 cpm had their NRTI backbone replaced with rilpivirine 25 mg once daily and were maintained on their cabotegravir dose. Participants were 96% male, 62% white, with a median age of 33 years. At week 48, 82% of participants in the cabotegravir plus rilpivirine arm and 71% of participants in the efavirenz arm had maintained an HIV-1 RNA <50 cpm. Through week 96, the cabotegravir arms continued to have slightly higher rates of virologic suppression compared to the efavirenz arm with lower rates of discontinuation due to AEs, 13% in the efavirenz arm vs 3% in the cabotegravir arms, and lower rates of virologic non-response, 16% in the efavirenz arm vs 10% in the cabotegravir arm. Three participants in the cabotegravir 10 mg arm experienced (or were suspected to have) virologic failure. Resistance genotyping demonstrated the development of significant non-nucleoside reverse transcriptase inhibitor (NNRTI) mutations (K101K/E and E138E/A/K/Q) and INSTI mutations (Q148R).

Currently, oral ART must be taken daily to maintain appropriate therapeutic drug levels in the blood. Adherence to daily ART remains a challenge. Ortego et al. estimated that only 62% of PLWHA had >90% adherence.11 Long acting injectable ART may offer a solution to some barriers to ART adherence. In the LATTE-2 trial, long-acting injectable cabotegravir (LA CAB) plus rilpivirine (LA RPV) were evaluated for the maintenance of virologic suppression.12 The study was a Phase 2b, randomized, parallel group, open label study. Participants were eligible if they were 18 years or older, ART naive, and had no major drug resistance mutations. Participants first underwent a 20-week oral lead-in phase: 16 weeks of oral cabotegravir 30 mg plus abacavir-lamivudine 600-300 mg followed by an additional 4 weeks with oral rilpivirine 25 mg added to the regimen. If participants achieved an HIV-1 RNA <50 cpm, they were randomly assigned to LA CAB 400 mg plus LA RPV 600 mg every 4 weeks (4W), LA CAB 600 mg plus LA RPV 900 mg every 8 weeks (8W), or to continue oral 3 drug therapy with cabotegravir plus abacavir-lamivudine. Three hundred nine participants were enrolled. They were 91% male with an average age of 36.6 years. Two hundred eighty-six participants completed the oral lead-in phase, achieved an HIV-1 RNA <50 cpm, and entered the long-acting injectable phase of the study.

At week 32, virologic suppression was 94%, 95%, and 91% in the 4W, 8W, and oral arms, respectively. Long-acting treatment was non-inferior to oral therapy and the efficacy of long-acting treatment was maintained through week 96. Nearly all participants experienced AEs with the most common being mild injection site reactions. There were few Grade 3 or higher AEs. Despite the injection site reactions, participants reported high levels of treatment satisfaction. Three participants had virologic failure, 2 in the 8W arm and 1 in the oral arm. There were no drug resistance mutations detected for the participant in the oral arm. The two participants on the 8W arm were found to have NNRTI (K103N, E138G, and K238T) and INSTI (R269R/G and Q148R) mutations. The second participant's mutations resulted in phenotypic resistance to all NNRTIs, except etravirine and all INSTIs (including cabotegravir), except dolutegravir.

The life expectancy of someone diagnosed with HIV is estimated to be as high as 78 years, which could potentially translate to 50 years of ART exposure.13 Newer 2-drug ART approaches are well tolerated and achieve and maintain virologic suppression at rates comparable to 3-drug regimens. Several national guidelines offer 2-drug regimens as alternates in certain clinical circumstances but this recommendation preceded the data from the studies in this review. Treatment guidelines are rapidly evolving and given the increasing potency of newer ART and decreased costs of 2-drugs as compared to 3-drugs, a shift in the HIV treatment paradigm to 2-drug regimens is on the horizon. These 2-drug regimens may not only be for individuals who have contraindications to NRTIs (those who require "nuke" sparing regimens") but also as first line, switch strategies, and salvage treatment. However, research gaps remain regarding the efficacy of 2-drug ART in PLWHA with HBV coinfection, women, and during pregnancy and breastfeeding. Two-drug ART is a viable treatment strategy and novel drug delivery strategies, such as long-acting injectable ART, will further strengthen the therapeutic armamentarium.


  1. Achhra AC, Mwasakifwa G, Amin J, Boyd MA. Efficacy and safety of contemporary dual-drug antiretroviral regimens as first-line treatment or as a simplification strategy: a systematic review and meta-analysis. Lancet HIV 2016;3:e351-e60.
  2. Taiwo BO, Zheng L, Stefanescu A, et al. ACTG A5353: A pilot study of dolutegravir plus lamivudine for initial treatment of HIV-1-infected participants with HIV-1 RNA < 500,000 copies/mL. Clin Infect Dis 2017.
  3. Joly V, Burdet C, Landman R, et al. Promising results of dolutegravir + lamivudine for maintenance in ANRS 167 LAMIDOL trial. Conference on Retroviruses and Opportunistic Infections. Boston, Massachesetts2017.
  4. Taiwo BO, Marconi VC, Berzins B, et al. Dolutegravir plus lamivudine maintain HIV-1 suppression through week 48 in a pilot randomized trial. Clin Infect Dis 2017.
  5. Figueroa MI, Sued OG, Gun AM, Belloso WH, Cecchini DM, Lopardo G. DRV/R FDC plus 3TC for HIV-1 treatment naive patients: Week 48 results of the ANDES study. Conference on Retroviruses and Opportunistic Infections; 2018; Boston, Massachusetts.
  6. Llibre JM, Hung CC, Brinson C, et al. Efficacy, safety, and tolerability of dolutegravir-rilpivirine for the maintenance of virological suppression in adults with HIV-1: phase 3, randomised, non-inferiority SWORD-1 and SWORD-2 studies. Lancet 2018.
  7. Haggblom A, Santacatterina M, Neogi U, et al. Effect of therapy switch on time to second-line antiretroviral treatment failure in HIV-infected patients. PLoS ONE 2017;12:e0180140.
  8. Pierone G, Henegar C, Fusco J, et al. Virologic Response to 2-Drug ART Regimens Among Treatment-Experienced HIV+ Patients. Conference on Retroviruses and Opportunistic Infections. Boston, Massachusetts 2018.
  9. Capetti AF, Cossu MV, Orofino G, et al. A dual regimen of ritonavir/darunavir plus dolutegravir for rescue or simplification of rescue therapy: 48 weeks' observational data. BMC Infect Dis 2017;17:658.
  10. Margolis DA, Brinson CC, Smith GH, et al. Cabotegravir plus rilpivirine, once a day, after induction with cabotegravir plus nucleoside reverse transcriptase inhibitors in antiretroviral-naive adults with HIV-1 infection (LATTE): a randomised, phase 2b, doseranging trial. Lancet Infect Dis 2015.
  11. Ortego C, Huedo-Medina TB, Llorca J, et al. Adherence to highly active antiretroviral therapy (HAART): a meta-analysis. AIDS Behav 2011;15:1381-96.
  12. Margolis DA, Gonzalez-Garcia J, Stellbrink HJ, et al. Long-acting intramuscular cabotegravir and rilpivirine in adults with HIV-1 infection (LATTE-2): 96-week results of a randomised, open-label, phase 2b, non-inferiority trial. Lancet 2017;390:1499-510.
  13. Antiretroviral Therapy Cohort C. Survival of HIV-positive patients starting antiretroviral therapy between 1996 and 2013: a collaborative analysis of cohort studies. Lancet HIV 2017;4:e349-e56.

Amesika N. Nyaku, M.D., M.S., is an Assistant Professor at Rutgers New Jersey Medical, Department of Medicine, Division of Infectious Diseases. She is also an investigator of the ACTG New Jersey Medical School Clinical Research Center CRS.

[Note from TheBodyPRO: This article was originally published by AAHIVM in April 2018. We have cross-posted it with their permission.]