Dual Antiretroviral Regimens for HIV—Here to Stay

Initial attempts starting around 2000 combined boosted protease inhibitors(PIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs) but still showed higher levels of toxicity and/or lower efficacy than triple-drug regimens and led to studies simplifying to a regimen containing a boosted PI and an NRTI [3]. Such switch studies included the open-label GARDEL study, which enrolled 416 patients naive to therapy comparing boosted lopinavir (LPV/r) and lamivudine (3TC) to LPV/r and 2NRTIs [4], and the ATLAS-M study [5], comparing boosted atazanavir (ATV/r) and 3TC in 266 virologically suppressed patients to ATV/r and 2NRTIs; both studies showed non-inferiority by intent to treat analysis. The open-label DUAL study evaluated switching to darunavir boosted with ritonavir (DRV/r) with lamivudine (3TC) in 249 patients virologically suppressed versus continuing a regimen of DRV/r and 2NRTIs. This study demonstrated non-inferiority at 48 weeks between the 2D and 3D regimens (88.9% vs. 92.7%) [6]. Despite these earlier studies, many concerns remained about the durability of the regimens, the inability to utilize them in certain populations such as pregnant women or those with tuberculosis, the concern about adequate suppression of viral reservoirs, the paucity of studies in naïve patients, and some conflicting data that did not show non-inferiority [3].

2.1.3. Dolutegravir and Lamivudine 2DR

To explore further treatment options that provide long-term safety, tolerability, and ease of use, the combination of DTG and 3TC was studied, initially in small exploratory trials, and later in large double-blind, randomized trials in both virologically suppressed and HIV treatment-naïve patients, and data out to 144 weeks have been recently presented showing sustained non-inferiority. The combined GEMINI 1 and 2 trials enrolled patients who were HIV naïve to therapy and randomly assigned 719 patients to DTG and 3TC vs. 722 patients to DTG and emtricitabine/tenofovir-disoproxil-fumarate (FTC/TDF). At 48 weeks, 91% in the dual therapy arm vs. 93% in the triple-therapy arm achieved, by intent-to-treat analysis, the primary endpoint of virologic suppression to <50 copies/ml [11]. Week 144 results showed that the dual arm continued to meet non-inferiority, with 82% suppressed vs. 84% in the triple-therapy arm [12]. Switch trials have been conducted using DTG/3TC as well. TANGO enrolled virologically suppressed patients who were randomly assigned to switch to DTG/3TC (369 patients) vs. continuing their tenofovir alafenamide (TAF)-based three-drug regimen (372 patients). At the 44th week primary endpoint time of analysis, 93.2% of patients in the dual arm vs. 93% patients in the triple arm achieved a viral load of <50 copies/ml [13]. Again, non-inferiority was maintained through week 144 (86% in the dual arm vs. 84% in the TAF containing triple arm [14]. Another trial, SALSA, enrolled treatment experienced and virologically suppressed patients on various three- and four-drug regimens who were then randomized to switching to DTG/3TC (n = 246) vs. continuing their regimen (n = 247), and at 48 weeks, non-inferiority was met, 94% in the two-drug arm vs. 93% in the three- or four-drug arm [15]. These studies supported a favorable side effect and tolerability profile for DTG/3TC. These drugs are co-formulated as the single-tablet regimen (STR) Dovato®. The use of DTG/3TC or DTG/RPV for simplification in virologically suppressed patients is recommended by the DHHS, EACS, and GeSIDA guidelines [16–18]. These guidelines also contain recommendations for dual-drug therapies as alternatives in various situations. DTG/3TC is also recommended by these guideline committees as an option for treatment-naïve patients who are Hepatitis B surface antigen negative, have a baseline viral HIV viral load of <500,000 copies/ml, and a CD4 count of >200 cells/mm3. Addressing the feasibility of starting a regimen of DTG/3TC in patients with a new diagnosis of HIV infection whose baseline laboratories are pending, data on the STAT study was recently published [19]. This is a single-arm, open-label study of DTG/3TC for patients newly diagnosed with HIV who are initiated on ART prior to receiving laboratory confirmation of hepatitis B status, viral load, or HIV-1 genotype. The primary analysis of HIV-RNA <50 copies/ml at week 24 showed 78% of all patients and 92% of patients with available data reached this target.

2.1.4. LongActing Intramuscular 2DR

One additional category of dual-drug therapy has entered the market in the novel form of long-acting injectable therapy. Long-acting cabotegravir (CAB-LA), which is an INSTI with a similar structure to DTG, has been studied in combination with a novel formulation of rilpivirine, long-acting rilpivirine (RPV-LA) as injections given intramuscularly on a monthly or every-other-month basis. LATTE-2 was the initial randomized, open-label phase 2b clinical trial that compared CAB + RPV LA as a two-drug HIV-1 maintenance therapy, administered every 4 or 8 weeks to virologically suppressed patients. The injectable regimen was similar to a daily three-drug oral therapy of CAB/abacavir(ABC)/3TC in maintaining viral suppression 20]. Together, these results supported phase 3 investigations of CAB + RPV LA in both the FLAIR and ATLAS trials. In FLAIR, patients naïve to antiretroviral therapy (ART) received an induction phase of DTG/ABC/3TC for 20 weeks, and then were randomized to either continue DTG/ABC/3TC or switch to first an oral phase of CBG/RPV and then intramuscular (IM) CAB+RPV-LA monthly [21]. ATLAS enrolled treatment experienced patients who were on 2NTRIs and a 3rd drug and virologically suppressed; patients were then randomly assigned to either continue this oral regimen or switch to an initial oral phase of CAB/RPV as a safety measure and then start CAB-RPV-LA IM monthly [22]. FLAIR and ATLAS combined results showed non-inferiority between the two-drug IM and the three-drug oral arms in ITT analysis at 48 weeks: 93% of 591 patients on the two-drug regimen and 94% of patients on the three-drug regimen had viral loads <50 copies/mL. ATLAS-2M has further extended the analysis of these patients to compare monthly vs. every-other-month injections [23]. At 96 weeks, the monthly and every-other-month injections were non-inferior. Side effects for the injectable regimens have demonstrated a high rate of injection site reactions (ISR), but the majority of these reactions are grade 1 or 2, and treatment discontinuations due to ISRs make up less than 3% across all of these studies. Patient satisfaction surveys have shown that the patients enrolled in these trials overwhelmingly preferred the injectable regimen compared to their former oral regimen, but selection bias may be a factor. Resistance-associated mutations developed in 10 of 522 (1.9%) patients on the every-other-month regimen in ATLAS-2M as opposed to 2 of 523 (<1%) patients on the monthly regimen. Further studies will help to clarify the potential risk for the development of treatment related resistance for monthly vs. every-other-month CAB+RPV-LA regimens.

2.2. Potential Benefits and Risks of 2D Regimens

When considering the potential benefits of fewer drugs in a treatment regimen, the endpoints to consider would be fewer adverse events (AEs) or lower discontinuation rates, favorable renal or metabolic profiles, or differences in weight gain. Two possible other benefits that are difficult to measure are the reduction in future possible drug–drug interactions or the avoidance of as-yet-unrecognized side effects from a drug that is now removed from a regimen. Potential drawbacks must be considered as well. The durability of suppression is one concern, and the data reviewed above support the non-inferiority of the virologic response for certain two-drug regimens compared to three-drug regimens as far out as 144 weeks. Additional concerns include the possibility of treatment-emergent resistance mutations, low-level viremia, or variability in controlling inflammation
and immune activation [3].

2.2.1. Adverse Events and Discontinuation Rates for 2D vs. 3D Regimens

Overall, the 2D regimens discussed above have shown the same rates of the comparison 3D arm in reported AEs, serious AEs, and rates of discontinuation [3]. With regard to more specific endpoints such as changes in metabolic parameters, measurements of renal function, or changes from baseline in weight, the findings are mixed and depend on the particular regimens assessed. However, differences have been small overall and the clinical significance is currently unclear.

2.2.2. Emergence of Resistance Associated Mutations

To protect against the development of treatment-emergent resistance in dual-drug regimens, initial trials were designed as switch trials and recruited patients on suppressive antiretroviral therapy with no history of resistance to the drugs in the regimen. Among several trials evaluating protease inhibitors in dual-drug regimens, the development of resistance mutations to either drug in the regimen was rare, in particular to the protease inhibitor [3]. Regarding the combination of DTG/3TC, in the GEMINI 1 and 2, TANGO, and SALSA trials combined, only one patient developed treatment emergent virologic resistance [12,13,15]. In these trials, patients with a history of resistance to either drug in the regimen were excluded; however, archive genotypes were not performed on virologically suppressed patients. Two open-label studies are investigating DTG/3TC as a simplification regimen for patients with prior detection of the M184V mutation: the ART-PRO study and the ongoing SOLAR 3D study. The former was a pilot study that enrolled 21 patients with and 21 without a history of prior M184V mutation who were virologically suppressed and naïve to integrase inhibitors, who were then switched to DTG/3TC. At 48 weeks, the virologic response was the same in both groups [24]. The SOLAR 3D study is an open-label prospective trial evaluating the switch to DTG/3TC from a stable baseline two-, three-, or four-drug regimen in patients with historic M184V/I mutation and virologic failure. At 48 weeks by ITT analysis, there were no differences in viral suppression between the arm with prior M184V/I detection or without [25]. Regarding the development of confirmed virologic failure (CVF) for the long-acting combination of CAB-LA and RPV-LA, the overall rate in combined studies of this two-drug therapy as recently presented was about 1% [26]. In individuals with CVF on the every-other-month regimen, 9 of 10 failed with NNRTI RAMs, and 6 of 10 failed with INSTI RAMs, while on the monthly regimen, 2 of 2 patients with CVF had NNRTI and INSTI RAMs at time of failure. A multivariable analysis across Atlas, Flair, and Atlas -2M phase 3 studies revealed that the presence of two or more of four factor was associated with the development of CVF. These four factors were: RPV-resistance-associated mutation(s) at baseline, baseline HIV-1 subtype A6/A1, week 8 RPV trough concentration, and BMI at baseline [26].

2.2.3. LowLevel Viremia and Immune Activation

The analysis for low-level viremia and the presence of inflammation and inflammatory biomarkers have been areas of intense research recently, and multiple studies have been published to try and assess the impact of low-level viremia as well as immune activation [3,27]. However, there is a lack of consensus regarding what constitutes low-level viremia and which biomarkers are validated as indicative of immune activation [27]. Data recently presented from GEMINI 1 and 2 showed no differences in low-level viremia in patients on DTG/3TC compared to a three-drug regimen [28]. It is clear that additional as well as long-term data are needed to better answer these concerns. Unanswered questions due to insufficient or lacking data still remain regarding certain patient populations such as HIV-infected pregnant patients, people co-infected with hepatitis B, or the performance of these regimens in patients with severe immune depletion or very high viral loads. For these populations, the option of two-drug therapy cannot be recommended without additional clinical trials.

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Table 1:

2 Drug Regimen vs 3 Drug Regimen Comparator Trials