Two-drug regimens for HIV

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/mL^26,27.

The studies reported results at weeks 48, 96 and 144^26-28. 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 resistance^26-28 (Figure 2).

Figure 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-up^27,28. Safety results were broadly consistent across analysis timepoints^23,27,28.

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

Figure 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 lamivudine^26-28.

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.

Figure 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 HIV^7,30,31. 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 index^34,35.

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 complex^38,39.

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 interactions^7,30. 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) infection^7,30.

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.

Figure 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 strategies^40,41. This follows its evaluation in two phase 3 randomised non-inferiority trials^42,43. 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 basis^42,43. 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 regimens^46,47. 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.