By Rodrigo Burgos, PharmD, and Eric Wenzler, PharmD, BCPS, AAHIVP
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Three-drug regimens have become the gold standard for the treatment of HIV-1, primarily due to the trials and tribulations of early clinical studies evaluating single- and dual-drug regimens. Although early clinical trials of zidovudine (ACTG 002, ACTG 016, ACTG 019) showed decreased mortality, morbidity, and improved CD4+ T-cell count compared with placebo, these benefits were short-lived.1-3 Additional monotherapy studies with zidovudine, didanosine, zalcitabine, stavudine, and other agents also demonstrated detrimental outcomes.4-9 Subsequently, studies assessing combination therapy of dual nucleoside reverse transcriptase inhibitors (NRTIs) quickly demonstrated more sustained benefits compared with monotherapy.4,8-12

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Despite these improved outcomes over monotherapy, it was not until the introduction of protease inhibitors (PIs) in the mid-1990s, used with NRTIs and known as highly active antiretroviral therapy (HAART), that 3-drug regimens began to establish themselves as the optimal treatment for HIV-1.13-20 Two landmark trials solidifying the benefits of HAART compared with no treatment, monotherapy, and dual therapy include works by Palella et al (1998) in the United States and Mocroft et al (1998) in Europe.14,15

In the United States, Palella et al analyzed data on 1,255 patients from 8 cities in the HIV Outpatient Study.14 Data collected from 1994 to 1997 evaluated the adjusted risk for morbidity (from the opportunistic infections, Pneumocystis carinii pneumonia, Mycobacterium avium, and cytomegalovirus retinitis) and mortality stratified by the type of antiretroviral therapy. In this cohort, the greatest benefit in both morbidity and mortality was observed among patients taking PI-based combination therapy, and decreasing benefits were observed among patients taking combination therapy with nucleoside analogs, followed by monotherapy and no therapy. Similar results were reported by Mocroft et al when they analyzed data on 4,270 patients in the EuroSIDA cohort across Europe between 1994 and 1998.15 The death rate in this European cohort decreased with the increasing number of antiretrovirals used, with the lowest mortality observed in patients taking triple combination therapy consisting of nucleoside analogs with PIs. The addition of a fourth active antiretroviral to HAART demonstrated no significant differences in efficacy or safety outcomes compared with 3-drug combinations, which help solidify 3 drugs as the optimal number of active agents in the standard of HIV-1 treatment.21-23

Although 3-drug regimens quickly became the standard of care thereafter, the introduction of novel antiretroviral agents that promised better potency, lower toxicity, a higher genetic barrier to resistance, and improved pharmacokinetic and drug–drug interaction profiles compared with older agents warranted reevaluation of the optimal combination regimen. Reverting to a 2-drug strategy would require demonstrating similar virologic efficacy to 3-drug regimens, but also satisfying considerations regarding tolerability, toxicity, convenience (pill burden and dosing frequency), drug interactions, durability, resistance potential, cost, and access barriers to which classic 3-drug regimens are subjected.24 If proven effective, a 2-drug regimen could potentially avoid exposure to multiple antiretrovirals and their long-term toxicities (eg, cardiovascular risk, metabolic, renal or bone toxicities), preserve future treatment options, avoid some drug–drug interactions, repurpose older agents when newer ones lack evidence in special populations (eg, tenofovir alafenamide in pregnancy or tuberculosis), and reduce cost.

Given this theoretical benefit, modern 2-drug regimens have been evaluated repeatedly against 3-drug regimens over the last decade. Tables 1 and 2 summarize selected studies comparing 2- versus 3-drug regimens in treatment-naive and -experienced HIV populations, respectively. Although not an exhaustive list of studies to date, these data assessed together allow for some important clinical generalizations. First, the majority of 2-drug regimens include a PI, likely because this class has been considered highly potent with the highest genetic barrier to resistance. Second, combinations of a PI with either a non-NRTI, maraviroc, or early integrase strand transfer inhibitors (INSTIs) were unable to demonstrate noninferiority against 3-drug regimens for treatment-naive patients, particularly in cases of high viral loads or low CD4+ T-cell counts. However, clinical trials and a meta-analysis in which PIs are combined with lamivudine demonstrated the noninferiority of 2-drug regimens to 3-drug treatment in both treatment-naive and -experienced populations.19,29,31,37,38,40,43

Table 1. Selected Studies of 2- versus 3-Drug Regimens for HIV-1 in Treatment-Naive Patients
Studyimg-button
      N
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2DR
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3DR
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Primary End Point
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Results
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Secondary Outcomes
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Reference      
ACTG 5142753LPV/r + EFVEFV + 2 NRTIs
LVP/r + 2 NRTIs		Time to virologic failure
Regimen failure		Longer for EFV + 2 NRTIs vs LPV/r + 2 NRTIs (P=0.006) No difference LPV/r + EFV vs EFV + 2 NRTIs (P=0.49) or LPV/r + 2 NRTIs (P=0.13)New grade 3 or 4 laboratory abnormalities more common in the LPV/r + EFV arm Resistance mutations more frequent in the LPV/r + EFV armRiddler et al25
SPARTAN94ATV + RTGATV/r + TDF/FTCVirologic efficacy at week 24 as HIV-1 RNA <50 copies/mL74.6% in ATV + RTG 63.3% in ATV/r + TDF/FTCHigher systemic exposure to ATV in the ATV + RTG arm compared with historic ATV/r + TDF/FTC Grade 4 hyperbilirubinemia higher in ATV + RTG arm 4 virologic failures in ATV + RTGKozal et al26
PROGRESS206LPV/r + RTGLPV/r + TDF/FTCVirologic efficacy at week 96 as HIV-1 RNA <40 copies/mL (FDA-TLOVR)66.3% in LPV/r + RTG 68.6% in LPV/r + TDF/FTCIncrease in peripheral fat greater in LPV/r + RTG Greater eGFR reduction from baseline in LPV/r + TDF/FTC (P=0.035) Greater BMD reduction in the LPV/r + TDF/FTC armReynes et al27
NEAT 001/ANRS 143805DRV/r + RTGDRV/r + TDF/FTCVirologic or clinical failure at week 9619.2% in DRV/r + RTG 15.3% in DRV/r + TDF/FTCNot noninferior in patients with CD4+ T-cell counts <200 or HIV RNA >100,000 copies/mL 6 virologic failures in the DRV/r + DTG arm No differences in discontinuations from AEsRaffi et al28
GARDEL373LPV/r + 3TCLPV/r + 2 NRTIsVirologic efficacy at week 48 as HIV-1 RNA <50 copies/mL (FDA Snapshot)88.3% in LPV/r + 3TC 83.7% in LPV/r + 2 NRTIsMore discontinuations in LPV/r + 2 NRTIs Resistance mutations in 2 patients on LPV/r + 3TCCahn et al29
MODERN797DRV/r + MVCDRV/r + TDF/FTCVirologic efficacy at week 48 as HIV-1 RNA <50 copies/mL77.3% in DRV/r + MVC 86.8% in DRV/r + TDF/FTCEarly termination due to inferiority of DRV/r + MVC No differences in discontinuations from AEsStellbrink et al30
ANDES149DRV/r + 3TCDRV/r + TDF/3TCVirologic efficacy at week 48 as HIV-1 RNA <50 copies/mL (FDA Snapshot)93% in DRV/r + 3TC 94% in DRV/r + TDF/3TCHigher incidence of gastrointestinal AEs in the DRV/r + TDF/3TC arm Higher lipid elevations in the DRV/r + 3TC armFigueroa et al31
GEMINI-1 and -21,433DTG/3TCDTG + TDF/FTCVirologic efficacy at week 48 as HIV-1 RNA <50 copies/mL (FDA Snapshot)90% in DTG/3TC 93% in DTG + TDF/FTCAt week 96, similar results to week 48: 86% in DTG/3TC vs 89% in DTG + TDF/FTC; no resistance mutations observedCahn et al32,33
FLAIR566CAB + RPVDTG + ABC/3TCVirologic efficacy at week 48 as HIV-1 RNA >50 copies/mL (FDA Snapshot)2.1% in CAB + RPV 2.5% in DTG + ABC/3TCSimilar tolerability and virologic failureOrkin et al34
2DR, 2-drug regimen; 3DR, 3-drug regimen; 3TC, lamivudine; ABC, abacavir; AEs, adverse events; ATV, atazanavir; BMD, bone mineral density; CAB, cabotegravir; DRV, darunavir; DTG, dolutegravir; EFV, efavirenz; eGFR, estimated glomerular filtration rate; FTC, emtricitabine; LPV, lopinavir; MVC, maraviroc; NRTI, nucleoside/nucleotide reverse transcriptase inhibitor; r, ritonavir; RPV, rilpivirine; RTG, raltegravir; TDF, tenofovir disoproxil fumarate; TLOVR, time to loss of virologic response
Table 2. Selected Studies of 2- versus 3-Drug Therapy for HIV-1 Treatment-Experienced Patients
Studyimg-button
      N
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2DR
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3DR
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Primary End Point
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Results
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Secondary Outcomes
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Reference      
SECOND-LINE541LPV/r + RTGLPV/r + 2 or 3 NRTIsVirologic efficacy at week 48 as HIV-1 RNA <200 copies/mL83% in LPV/r + RTG 81% in LPV/r + 2 or 3 NRTIsIncreased lipids in the LPV/r + RTG arm SECOND-LINE Study Group35
EARNEST1,227PI/r + RTGLPV/r + 2 or 3 NRTIs PI/rHIV disease control composite at week 9664% in PI/r + RTG 60% in LPV/r + 2-3 NRTIs 55% in PI/rHIV RNA-1 <400 copies/mL 86% in both PI/r + RTG and LPV/r + 2-3 NRTI arms, 61% in the PI/r armPaton et al36
SALT286ATV/r + 3TCATV/r + 2 NRTIsVirologic efficacy at week 48 as HIV-1 RNA <50 copies/mL84% in ATV/r + 3TC 78% in ATV/r + 2 NRTIsSimilar rates of AEs between both armsPerez-Molina et al37
OLE250LPV/r + 3TCLPV/r + 2 NRTIsTreatment response composite at week 4887.8% in LPV/r + 3TC 86.6% in LPV/r + 2 NRTIsSimilar rates of AEs between both armsArribas et al38
HARNESS109ATV/r + RTGATV/r + TDF/FTCVirologic efficacy at week 24 as HIV-1 RNA <40 copies/mL80.6% in ATV/r + RTG 96.6% in ATV/r + TDF/FTCHigher discontinuation rates due to AEs in the ATV/r + RTG arm Higher grade 3 or 4 hyperbilirubinemia in the ATV/r + RTG arm Higher lipids compared with baseline in the ATV/r + RTG armvan Luzen et al39
ATLAS-M266ATV/r + 3TCATV/r + 2 NRTIsVirologic efficacy at week 48 as HIV-1 RNA <50 copies/mL89.5% in ATV/r + 3TC 79.7% in the ATV/r + 2 NRTIsHigher virologic failure in the ATV/r + 2 NRTI armDi Giambenedetto et al40
SWORD-1 and -21,024DTG/RPVCurrent treatmentVirologic efficacy at week 48 as HIV-1 RNA <50 copies/mL95% both armsHigher proportion of patients with discontinuations due to AEs in the DTG/RPV armLibre et al41
ATLAS616CAB + RPVCurrent treatmentVirologic efficacy at week 48 as HIV-1 RNA >50 copies/mL (FDA Snapshot)1.6% in CAB + RPV 1.0% in current treatmentSimilar tolerability and virologic failureSwindells et al42

Since these initial studies, the promise of an effective 2-drug regimen has increased with the introduction of the second-generation INSTIs, dolutegravir and cabotegravir, given their increased potency and improved genetic barrier to resistance compared with a first-generation INSTI such as raltegravir. The theoretical benefits of these second-generation INSTIs also have come to clinical fruition as both agents, in combination with lamivudine or rilpivirine, have demonstrated noninferiority compared with conventional 3-drug regimens with respect to virologic efficacy, tolerability, and safety.32-34,41,42 As a result, major guidelines in the Unites States and Europe have adopted a 2-drug regimen (dolutegravir plus lamivudine) for the first time as an option for the initial treatment of HIV, with the exception of those with HIV-1 RNA greater than 500,000 copies/mL, hepatitis B coinfection or serostatus unknown, or low CD4+ T-cell count.24,44 These recommendations are based primarily on the phase 3 GEMINI-1 and GEMINI-2 studies, which demonstrated noninferiority of this 2-drug regimen compared with dolutegravir plus tenofovir disoproxil fumarate with emtricitabine through week 96.33 Although these longer term data demonstrate a low risk for development of resistance and the durability of this dual regimen, there are concerns in the community that the results observed in this controlled clinical trial setting may not translate to real-world clinical practice where patients have lower rates of adherence and less frequent monitoring; and some early data may validate this concern.45,46

In addition to peripheral virologic failure, 2-drug regimens carry the potential for ongoing HIV replication in viral sanctuaries or reservoirs where these drugs do not penetrate.19 Outcomes related to potential differences in viral replication in lymphoid tissue or the central nervous system among patients taking 2-drug compared with 3-drug regimens are unknown at this time. Other areas of concern include the lack of evidence for 2-drug regimens in special populations where only 3-drug regimens have been studied or proven superior, including during pregnancy, prevention of vertical transmission, horizontal transmission from people whose virus is undetectable, and coinfection with tuberculosis.19

Finally, immune activation also may be different in people on 2- or 3-drug therapy. For example, a low CD4+/CD8+ T-cell ratio, a known predictor of non–AIDS-related complications, has been correlated with mono- or dual therapy in contrast with patients receiving 3-drug therapy. As such, it remains unclear whether 2-drug regimens are equivalent to 3-drug regimens in all aspects of HIV therapy (Table 3).

Table 3. Potential Advantages and Disadvantages of 2- versus 3-Drug Therapy for HIV-1
Potential AdvantagesPotential
Disadvantages
  • Similar efficacy to 3 antiretrovirals vs 2 in the clinical trial setting
  • Less exposure to multiple antiretrovirals, lower long-term toxicity
  • Preserve future treatment options
  • Delay development of resistance
  • Avoid drug–drug interactions
  • Reduce cost
  • Efficacy may not translate to real-world clinical setting
  • Even newer agents have potential for long-term toxicity
  • Virologic escape in viral sanctuaries or reservoirs and inadequate tissue penetration
  • Unknown role in special populations and prevention of virus transmission
  • Unknown role in special populations and prevention of virus transmission
  • Unknown effect on immune activation

Two-drug regimens for HIV-1 have come a long way over the past 3 decades, with many failures, especially associated with older antiretroviral agents. Newer agents with improved potency, higher genetic barrier to resistance, and lower toxicities have led to the availability of 2-drug combinations that are noninferior to more traditional 3-drug regimens, with respect to virologic efficacy in certain uncomplicated patient populations. Given that the complexities of HIV treatment go beyond controlling HIV RNA in the blood, more data are needed to determine the optimal number of agents to utilize in combination based on patient- and disease-specific factors.

References

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About the authors:

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Rodrigo Burgos, PharmD, is a clinical assistant professor in the Department of Pharmacy Practice, College of Pharmacy, University of Illinois at Chicago, in Chicago, Illinois.
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Eric Wenzler, PharmD, BCPS, AAHIVP, is an assistant professor in the Department of Pharmacy Practice, College of Pharmacy, University of Illinois at Chicago, in Chicago, Illinois.

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Two-Drug Treatment Regimens for HIV: Are We There Yet?

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