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Two-drug regimens for HIV

Declaration of sponsorship ViiV Healthcare
Last updated:3rd Mar 2025
Published:3rd Mar 2025

For many years, the success of modern antiretroviral therapy (ART) has been based on the three-drug regimen (3DR) of two nucleoside reverse transcriptase inhibitors (NRTIs) and a third drug from another antiretroviral class, such as a non-nucleoside reverse transcriptase inhibitor (NNRTI), integrase strand transfer inhibitor (INSTI) or boosted protease inhibitor (PI)1,2.

In this section

The recommendation for a 3DR approach emerged in the 1990s, as the characteristics and limitations of the first-generation antiretrovirals (e.g., low genetic barrier to resistance) required a combination of three drugs to achieve control of viral replication, demonstrated by complete virological control achieved with zidovudine, lamivudine and indinavir2,3. Many studies, including mathematical models, have shown that if the virus is subject to three-drug pressure (not from first-generation agents), it has a low likelihood of developing resistance4.

People with HIV on ART with high CD4 counts can now benefit from a normal or near-normal life expectancy. It is therefore important to establish treatment that is effective, well tolerated without major toxicity, ideally avoiding the potential for drug–drug interactions while limiting pill burden2.

Because of concerns with 3DRs about long-term toxicities, side effects (e.g., renal and bone toxicity, cardiovascular events), and cross-resistance, two-drug regimens (2DRs) have been investigated in several clinical trials, with promising results and several are now approved for use in people with HIV5.

The availability of newer, more potent agents with higher barriers to resistance (e.g., PIs and INSTIs) led to a number of studies of 2DRs, initially in virologically suppressed patients. The European AIDS Clinical Society (EACS) defines ‘virologically suppressed’ as an HIV viral load (HIV-RNA) of <50 copies/mL for at least 6 months6. US guidelines define this as a confirmed HIV-RNA below the lower limits of detection of available assays7.

The first 2DR studies in virologically suppressed individuals were constructed using boosted PIs in combination with lamivudine8.

DUAL

DUAL-GESIDA 8014-RIS-EST45 was a phase 4 randomised, open-label, parallel group non-inferiority trial9. At recruitment, participants were required to have a plasma HIV-RNA of <50 copies/mL for a minimum of six consecutive months, and were on a stable treatment regimen of darunavir/ritonavir and two NRTIs – tenofovir disoproxil fumarate/emtricitabine or abacavir/lamivudine – for at least 4 weeks9. Eligible individuals were randomly assigned 1:1 to continue with a 3DR or switch to a 2DR of lamivudine plus darunavir/ritonavir. The primary endpoint was the proportion of participants with suppressed viral load <50 copies/mL after 48 weeks.

Of 257 randomised participants, 249 received at least one dose of study medication. At week 48, 89% (112/126) of participants in the 2DR arm and 92.7% (114/123) of participants in the 3DR arm had HIV-RNA viral loads of <50 copies/mL, meeting the criteria for non-inferiority of the 2DR strategy9.

SALT

SALT was a randomised, open label, non-inferiority trial in adults with HIV-1 infection and HIV RNA <50 copies/mL for at least 6 months, who had not switched ART in the previous 4 months10. Participants were randomly assigned to a 2DR of atazanavir/ritonavir plus lamivudine or 3DR with atazanavir/ritonavir plus two NRTIs at the discretion of the study investigators. The primary endpoint was HIV RNA <50 copies/mL at week 48 in the per-protocol population10.

A total of 286 patients were randomised, 143 to each group. At week 48, 84% (112/133) of the patients in the 2DR arm met the virological response endpoint compared with 78% (105/135) in the 3DR arm, demonstrating non-inferiority at the prespecified level. Adverse events were similar between groups, and treatment discontinuations were less frequent in the 2DR arm10.

Two-drug regimens in the SALT study were shown to be non-inferior to 3DRs, with an acceptable safety profile10

At 96 weeks, results confirmed non-inferiority of the 2DR of atazanavir/ritonavir plus lamivudine11, with a favourable safety profile and no negative impact on neurocognitive performance12.

ATLAS-M

ATLAS-M was a 96-week open-label, randomised non-inferiority trial comparing a switch to atazanavir/ritonavir plus lamivudine with continuation of the 3DR of atazanavir/ritonavir plus two NRTIs in virologically suppressed individuals13. Adults with HIV-1 who had been on an antiretroviral regimen including atazanavir/ritonavir plus two NRTIs for at least 6 months with HIV-RNA <50 copies/mL and CD4 cell count >200 cells/mm3 for at least 6 months were randomised to either the 2DR arm or continued on their existing 3DR. A total of 266 participants were randomised, 133 in each study arm. The primary study outcome was HIV-RNA maintained at <50 copies/mL at week 4813.

After 48 weeks, 89.5% (119/133) of people in the 2DR arm and 79.7% (106/133) in the 3DR arm met the primary study outcome, demonstrating non-inferiority and superior efficacy of the atazanavir/ritonavir plus lamivudine arm. Two patients in the 2DR arm and six patients in the 3DR arm experienced virological failure without resistance selection, and there were a similar number of adverse events in both groups13.

At 96 weeks, the treatment switch to atazanavir/ritonavir plus lamivudine remained superior to continuation of the 3DR. In addition, there was a sustained benefit in terms of improvement in renal function and bone mineral density14.

An optimal 2DR should be convenient and effective, with minimal side effects and a high genetic barrier to resistance2

SWORD

Dolutegravir is a second-generation INSTI that is efficacious in regimens containing an NRTI or NNRTI as a companion drug2.

SWORD-1 and SWORD-2 studies are identically designed open-label, phase 3 studies investigating an early versus late switch (after 52 weeks) from three- or four-drug regimens to the 2DR of dolutegravir plus rilpivirine15.

Eligible patients were required to have at least a 6-month history of HIV-1 RNA <50 copies/mL, no previous treatment failure and/or no documented major resistance. Participants were randomly assigned to begin dolutegravir plus rilpivirine once daily (early switch group) or to continue their existing treatment for 52 weeks and then switch to dolutegravir plus rilpivirine if virologically suppressed at week 4815.

Primary analysis at week 48 demonstrated that switching to the 2DR was non-inferior in maintaining HIV-1 RNA <50 copies/mL (95% of participants achieved this in each group: 486 of 513 in the dolutegravir plus rilpivirine arm vs 485 of 511 in the arm continuing with existing treatment)15. Eleven (1%) participants across both groups met the confirmed virological withdrawal criterion (subsequent measures of HIV-1 RNA ≥50 copies/mL then ≥200 copies/mL) through week 14816 (Figure 1).

Viral suppression (<50 copies/mL) at weeks 48, 100 and 148 in the SWORD-1 and SWORD-2 trialsFigure 1. Viral suppression (<50 copies/mL) at weeks 48, 100 and 148 in the SWORD-1 and SWORD-2 trials15-17. CI, confidence interval; DTG, dolutegravir; RPV, rilpivirine.

By week 148, no integrase resistance was identified. After 148 weeks of treatment with dolutegravir plus rilpivirine, only 11/990 (1%) patients met the confirmed criteria for confirmed virological withdrawal. Of these, three cases occurred after week 100 and six patients harboured at least one rilpivirine-associated resistance mutation, while no treatment-emergent dolutegravir resistance was detected16.

There were significant improvements in bone and renal biomarkers in patients who had received tenofovir disoproxil fumarate prior to switching to the 2DR16.

The SWORD studies support the safety profile of the 2DR of dolutegravir plus rilpivirine, and the low frequency of virological failure supports the use of the 2DR dolutegravir plus rilpivirine as an NRTI- and PI-sparing alternative to 3DRs in virologically suppressed people living with HIV15-17.

Dolutegravir is efficacious in regimens containing an NRTI or NNRTI as a companion drug2

TANGO

TANGO, a non-inferiority, phase 3 study, evaluated the efficacy and safety of a switch to a 2DR of dolutegravir plus lamivudine from a three- or four-drug tenofovir alafenamide fumarate (TAF)-based regimen18,19.

Prior to the TANGO study, smaller studies – the pilot trial ASPIRE20 and the single-arm trial LAMIDOL21 – had demonstrated that viral suppression could be maintained following a switch to dolutegravir plus lamivudine in individuals initially treated with a first-line regimen of three or more drugs.

Exclusion criteria for the TANGO study included a history of NRTI or INSTI resistance-associated mutations, plasma HIV RNA ≥50 copies/mL within 6 months of screening, ≥2 measurements of ≥50 copies/mL or any measurement of >200 copies/mL within 6 and 12 months of screening, or a prior regimen switch due to virological failure or hepatitis B (HBV) infection18,19.

Primary analysis at week 48 showed that dolutegravir plus lamivudine was non-inferior to the TAF-based regimen in maintaining virological suppression. No confirmed virological withdrawals were observed up to week 48 among participants with baseline M184V/I (n=7; 1%) detected by pro-viral DNA genotyping on baseline samples18.

Switching from TAF-based regimens to the 2DR dolutegravir plus lamivudine is effective in supressing HIV18,19

At week 96, there were no confirmed virological withdrawals (defined as HIV-1 RNA ≥50 copies/mL followed by a second consecutive HIV-1 RNA assessment ≥200 copies/mL) in the dolutegravir plus lamivudine arm, and there was no resistance in either treatment group19.

Subgroup analyses of different CD4 categories showed that efficacy was consistent with overall week 96 results19. The safety profiles were similar for the two treatment regimens19.

At week 114, dolutegravir plus lamivudine remained non-inferior to continuing the TAF-based regimen22. In addition, a post-hoc analysis showed that archived, pre-existing resistance-associated mutations did not impact virologic outcomes22.

Early studies of two-drug regimens (2DRs) in treatment-naive patients used a combination of boosted protease inhibitors (PIs) and lamivudine, with positive results8.

GARDEL

GARDEL was a 48-week phase 3 randomised controlled, open-label, non-inferiority trial in 373 antiretroviral therapy (ART)-naive adults with HIV-1-RNA of at least 1,000 copies/mL. Participants were assigned to a 2DR of lopanivir/ritonavir plus lamivudine versus a 3DR of lopanivir/ritonavir plus two nucleoside reverse transcriptase inhibitors (NRTIs)23.

At week 48, 88.3% in the 2DR arm and 83.7% in the 3DR arm had a viral response. Patients with baseline viral load of at least 100,000 copies/mL showed similar results (87.2% and 77.9%, respectively)23.

Treatment discontinuations were more common in the 3DR arm (4.9%) than in the 2DR arm (0.4%)23.

ANDES

ANDES is a randomised, open-label, phase 4 study comparing the 2DR of fixed-dose darunavir/ritonavir plus lamivudine to a 3DR of darunavir/ritonavir plus lamivudine/tenofovir disoproxil fumarate or tenofovir disoproxil fumarate/emtricitabine in treatment-naive patients24.

Of 182 patients screened, 145 were randomised to the 2DR (n=75) or the 3DR (n=70) arm. At baseline, approximately 24% had a viral load >100,000 copies/mL24.

At week 48, 93% of patients on the 2DR and 94% on the 3DR achieved a viral load <50 copies/mL. Patients with baseline viral load >100,000 copies/mL showed a 92% response in the 3DR arm and 91% in the 2DR arm24. One patient in the 3DR arm presented with virological failure at week 4825.

The median increase in the CD4/CD8 ratio was similar in both arms: 0.261 with the 3DR and 0.273 with the 2DR24.

The findings provide further evidence about the efficacy of drug-sparing regimens in treatment-naive patients.

GEMINI-1 and GEMINI-2

GEMINI-1 and GEMINI-2 are large double-blind, non-inferiority, randomised, identically designed phase 3 studies in treatment-naive people with HIV, comparing a 2DR of dolutegravir plus lamivudine with the 3DR of dolutegravir plus tenofovir disoproxil fumarate/emtricitabine in participants with HIV RNA 1,000–500,000 copies/mL26,27.

The studies reported results at weeks 48, 96 and 14426-28. The primary endpoint was the proportion of participants achieving an HIV-1 RNA value <50 copies/mL.

Primary analysis at 48 weeks demonstrated that the 2DR was non-inferior to the 3DR in treatment-naive adults (719 and 722 patients, respectively)23. Dolutegravir plus lamivudine demonstrated non-inferiority at 48, 96 and 144 weeks, and had a high barrier to resistance26-28 (Figure 2).

GEMINI-1 and GEMINI-2: DTG + 3TC non-inferior to DTG + TDF/FTC at 144 weeksFigure 2. GEMINI-1 and GEMINI-2: DTG + 3TC non-inferior to DTG + TDF/FTC at 144 weeks28. 3TC, lamivudine; c, copies; CI, confidence interval; DTG, dolutegravir; FTC, emtricitabine; TDF, tenofovir disoproxil fumarate.

Twelve participants on the 2DR and nine on the 3DR met confirmed virological withdrawal criteria by week 144; none of whom had treatment-emergent integrase strand transfer inhibitor (INSTI) or NRTI resistance mutations28. One participant in the dolutegravir plus lamivudine arm, who did not meet the criteria for confirmed virological withdrawal, developed resistance following week 13228. Non-adherence to therapy was recorded28.

Bone and renal biomarkers favoured dolutegravir plus lamivudine26. Where there were changes in lipid parameters, the 3DR was generally favoured, although there were improvements in total cholesterol to high-density lipoprotein ratio (TC:HDL) in both treatment arms26.

Overall, when comparing the 2DR and 3DR, there was a decreased occurrence of drug-related adverse events in the 2DR arm, with this difference attaining statistical significance at 96 and 144 weeks of follow-up27,28. Safety results were broadly consistent across analysis timepoints23,27,28.

Adverse events in the GEMINI-1 and GEMINI-2 trials are summarised in Figure 3.

Summary of adverse events in the pooled safety populations for GEMINI-1 and GEMINI-2 at week 144Figure 3. Summary of adverse events in the pooled safety populations for GEMINI-1 and GEMINI-2 at week 144 (Adapted28). 3TC, lamivudine; AE, adverse event; DTG, dolutegravir; FTC, emtricitabine; TDF, tenofovir disoproxil fumarate.

The GEMINI findings demonstrate the durability of the high barrier to resistance of dolutegravir-based 2DRs and support long-term virological efficacy of dolutegravir plus lamivudine26-28.

STAT

The phase 3b, open-label, single-arm pilot study, STAT, evaluated the feasibility, efficacy and safety of dolutegravir plus lamivudine as a first-line treatment for people newly diagnosed with HIV29. This study investigated whether early initiation of therapy could safely achieve virological suppression when initiated within 14 days of diagnosis, before laboratory screening results for hepatitis B (HBV) co-infection status, resistance mutation and renal function became available29.

At week 24, among participants who had an HIV-1 RNA assessment (n=111), 92% had achieved HIV-1 RNA <50 copies/mL, and 98% had achieved HIV-1 RNA <200 copies/mL, irrespective of whether there had been an adjustment in dolutegravir plus lamivudine treatment because of HBV co-infection, genotypic resistance or creatinine clearance <30 mL/min/1.732)29.

Eight participants required treatment modification: five because of HBV co-infection, one because of rash, one because of baseline resistance to lamivudine, and one because of participant or proxy decision. Data were available for five of these cases and showed that rapid initiation of the dolutegravir plus lamivudine combination did not compromise outcome. All five achieved HIV-1 RNA <50 copies/mL at week 2429.

There were also few serious drug-related adverse events, supporting the premise that therapeutic adjustments can be made safely in the course of routine clinical care and with efficient follow-up after the 2DR of dolutegravir plus lamivudine has been initiated29.

Virological outcomes in the STAT trial are illustrated in Figure 4.

Virological outcomes for DTG + 3TC at week 24 in the STAT trialFigure 4. Virological outcomes for DTG + 3TC at week 24 in the STAT trial29. 3TC, lamivudine; DTG, dolutegravir; FDA, U.S. Food and Drug Administration; ITT-E missing, intention-to-treat efficacy missing = failure analysis.

Dolutegravir plus lamivudine is the only recommended 2DR for ART-naive adults with HIV7,30,31. European guidelines state that eligible patients must be HBsAg-negative, with a viral load of <500,000 copies/mL30. In the DHHS guidelines, patients are excluded from using this therapy if treatment is to begin prior to the results of HIV genotype resistance testing for reverse transcriptase, or if treatment is to begin before HBV testing is available7.

Mutation emergence

Depending on the drug used to treat HIV, different numbers of mutations are required to decrease susceptibility of the virus to the treatment.

HIV has a high mutation rate, enabling new viral variants to be rapidly produced8

Both the number of mutations required for resistance and the frequency or ease at which they develop contribute to the genetic barrier to resistance8. The genetic barrier to resistance is the threshold of mutations required for the virus to become resistant to treatment, with subsequent loss of virological control above which clinically relevant resistance develops32.

Clinical impact of resistance

As resistance has the potential to limit treatment options, it is an important consideration in the current and future understanding and development of antiretroviral therapy (ART).

In addition to the potency and durability of the ART selected and the probability of adherence, it is important to be aware of the resistance patterns that may exist when faced with virological failure, and how this will affect availability and effectiveness of future treatment28

The resistance profile can be markedly different between drug classes and generations33. While there is essentially no cross-resistance between drugs of different classes, there can be high levels of cross-resistance within drug classes8. Resistance emergence can be influenced by the structure of the drug, the ratio of drug exposure to viral susceptibility (inhibitory quotient), pharmacokinetics and the therapeutic index34,35.

Second-generation integrase strand transfer inhibitors (INSTIs), such as dolutegravir and bictegravir, have been shown to have a similar barrier to resistance as boosted protease inhibitors (PIs), but with better tolerability profiles and without the risk of drug–drug interactions associated with PIs33.

The high barrier to resistance of dolutegravir is attributable to a number of factors. With the first-generation INSTIs raltegravir and elvitegravir, an initial mutation in the virus under pharmacological pressure would often be followed by another mutation, which potentially removed any subsequent benefit of the drug, allowing the virus to replicate freely36.

Secondary mutations resulting from the use of dolutegravir do not appear to hugely affect the levels of resistance against the therapy. They do, however, mean that HIV viral fitness is suppressed37. It has been hypothesised that this could be due to dolutegravir being able to bind particularly effectively to the integrase enzyme37. Dolutegravir extends further into the target-binding site than first-generation INSTIs and is more able to adjust its position at the site in response to amino acid substitutions that occur as a result of viral mutation38. Additionally, dolutegravir has a longer half-life of dissociation from its active target site, the integrase–DNA complex38,39.

Prolonged residence time at the target binding site is thought to extend the duration of efficacy of dolutegravir, contributing to a higher barrier to resistance39

Choosing ART

The choice of antiretroviral therapy (ART) depends on clinical and logistical factors, including toxicities, resistance status and availability of therapies, but also patient-related factors. These can include whether a woman wishes to conceive or is pregnant, the presence of opportunistic infections, co-infection with tuberculosis or limitations due to comorbidities (renal and liver toxicity), swallowing difficulties and drug–drug interactions7,30. A single treatment regimen may also be advocated for ease of compliance or because of patient preference. A tailored approach is required, selecting the right treatment for each patient and taking into account the range of factors influencing choice of ART.

A number of two-drug regimens (2DRs) are recommended in guidelines as switch options in people with existing virological suppression, absence of resistance to current treatment, and no hepatitis B virus (HBV) infection7,30.

European guidelines specify that the use of the above strategies has not been associated with additional virological rebounds when compared with three-drug regimens30. There have been a few cases of resistance developing on dolutegravir plus rilpivirine29.

The indications, key principles and guideline recommendations for 2DRs in virologically suppressed patients are summarised in Figure 5.

Key pillars of switch strategies for people who are virologically supressedFigure 5. Key pillars of switch strategies for people who are virologically supressed30 3TC, lamivudine; ARV, antiretroviral; b, booster; CAB, cabotegravir; DRV, darunavir; DTG, dolutegravir; HBV, hepatitis B virus; RPV, rilpivirine. *In clinical trials, these two-drug regimens were not associated with more virological rebounds when compared with three-drug regimens. †In a few cases, resistance developed to DTG + RPV and CAB + RPV. ‡These two-drug regimens are indicated only in people who are not eligible for other treatment combinations.

A dual injection containing the second-generation integrase strand transfer inhibitor, cabotegravir, and rilpivirine has received FDA and EMA authorisation for use as a suitable option in virologically suppressed patients, presenting an important new milestone in HIV treatment strategies40,41. This follows its evaluation in two phase 3 randomised non-inferiority trials42,43. The data show that dosing every 8 weeks was non-inferior to dosing every 4 weeks, supporting its therapeutic potential for administration on a 2-monthly basis42,43. A twice-yearly subcutaneous injection for multi-drug resistance, lenacapavir, has also been approved for use in adults with HIV44.

Adherence to ART

Studies have suggested that adherence varies between 27% and 80% across different subgroups of individuals with HIV45. Optimum adherence is crucial to ensure adequate suppression of the virus, avoid the development of drug resistance, gain maximum immune system recovery and achieve as great as possible a reduction in transmission of the virus45. Systematic reviews and the Pharmacy Quality Alliance agree that ≥90% should be considered as optimal for ART regimens46,47. A 2021 cross-sectional analysis also concludes that, while 90% adherence maximises sensitivity and specificity of ART, >80% adherence gives similar viral suppression46. Adherence to ART rendering viral loads undetectable prevents sexual transmission of the virus to others48.

Lack of adherence can be due to a combination of reasons, including stigma associated with the disease, forgetfulness, suboptimal mental health, lack of resources and/or limitations in supply, inadequate education and support or a lack of appreciation of the importance of adherence. In addition, the associated pill-burden, side effects and drug interactions of multiple drugs co-administered with ART are important predictors of non-adherence45.

Perhaps the greatest drawback of treatment regimens for HIV is their complexity. The introduction of once-daily fixed dose regimens has been key in simplifying ART and is a relatively easy way to improve adherence. Side effects can impact adherence to ART, lead to discontinuation and influence the decision to use a 2DR45.

Weight change with ART

People with HIV often gain weight when first starting ART49. Switching from efavirenz-based regimens to integrase strand transfer inhibitor (INSTI)-based ART was noted to increase weight gain at 18 months49. The ADVANCE trial, studying dolutegravir, emtricitabine and tenofovir alafenamide or tenofovir disoproxil fumarate versus efavirenz plus emtricitabine plus tenofovir alafenamide in sub-Saharan African, mostly female, people living with HIV, noted weight gain across treatment arms of 2.3–7.1 kg at 96 weeks50. In the TANGO trial, weight gain was listed as an adverse event for 3 (0.8%) patients on dolutegravir plus lamivudine versus 6 (1.6%) remaining on a tenofovir alafenamide-based regimen18.

This is an area that warrants further investigation, as weight gain can increase the risk of cardiometabolic diseases.

References

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