New ART Strategies: Where Are We Heading?

Abstract

Highly Active Antiretroviral Therapy (HAART) was developed as a combination of drugs in 1996, and, since then, it has been the standard of care in all treatment guidelines due to its extraordinary impact on the reduction of HIV/AIDS-related morbimortality.

The first combinations were difficult to take and tolerate for patients. The first generations of persons living with HIV and treating professionals had to deal with dosage schedules of up to 24 daily tablets, taken three times a day, with severe adverse effects associated both to first- generation Nucleotide Reverse Transcriptase Inhibitors (NRTIs) (zidovudine, stavudine, and didanosine) and protease inhibitors (saquinavir, ritonavir, nelfinavir, and indinavir). Nowadays, there are more efficient, better- tolerated, simpler triple therapy regimens based on the intake of one, or at most two, daily tablets indicated at treatment initiation, as well as for virologically suppressed patients under more complex regimes.

Regimens recommended by local and international guidelines have shown, as evidenced by the studies that served as the basis for their approval, virological suppression levels greater than 90%. It is hard to think of new drugs that could achieve greater levels. Remaining toxicities under current regimens (although significantly less common and severe than those described in the above paragraph) pose an obstacle to treatment adherence in certain cases (1).

To date, HAART is a lifelong treatment. And as a result of it, the life expectancy of a person living with HIV (PLHIV) is similar to that of a HIV-negative person, as long as viral replication remains suppressed, which means that chronic viral infection coexists with comorbidities associated with old age and the resulting polypharmacy, with potential risk of drug-drug interactions.

Based on the foregoing, investigation of new strategies in recent years has been aimed at identifying simpler options, seeking to achieve either reduction of drug load (dual therapy) or intermittent administration regimens, via IM or SC route, implants, or extended-release oral drugs.

Accordingly, simplification of ARV treatment using two, instead of three, drugs was analyzed through various studies. Initial studies, based on reducing regimens of two NRTIs plus one PI suppressing the third drug failed to demonstrate non-inferiority. Other attempts associating two drugs (PI + NRTI; PI + maraviroc, among others) also proved unsuccessful. Moreover, the association of two excellent drugs like raltegravir and darunavir/ritonavir (2) failed to demonstrate non-inferiority in the group of patients having a baseline viral load above 100,000 copies or CD4 below 200 cells/mm3. Based on what has been observed so far, including a reverse transcriptase inhibitor seems to be crucial for a successful dual therapy regimen.

Observation of a high percentage of viral suppression with a PI monotherapy (although insufficient to demonstrate non-inferiority) led to consideration of the following research question: what would happen if a PI was associated with lamivudine (3TC) for treatment initiation.

This hypothesis is based on 3TC excellent tolerability, convenient dosage, low cost, and its particular residual activity, even in the presence of M184V/I mutation due to its impact on HIV replication capacity (3).

This led to the development of the GARDEL study (4), the first multicenter, randomized study with statistical power to demonstrate non-inferiority of the lopinavir/ ritonavir plus 3TC regimen compared to the same PI plus two NRTIs in patients initiating treatment. Non-inferiority was demonstrated at 48 weeks and confirmed at 96 weeks, including the group of patients with a baseline viral load above 100,000 copies/mL.

Later, these findings were confirmed by the ANDES study using the darunavir/ritonavir 800/100 mg co-formulation associated with 3TC.

In parallel, based on the observed power, convenient dosage, and tolerability of second-generation integrase inhibitors (INSTI) (dolutegravir and bictegravir), a dual therapy of dolutegravir and 3TC was assessed in the PADDLE study, a pilot with 20 patients that demonstrated 90% of viral suppression at 48 and 96 weeks in the intent- to-treat analysis and 95% in the per-protocol analysis. This study was followed by ACTG 5353, which included 120 patients, with similar results. Both studies provided the basis for the phase 3, randomized, multicenter, double-blind GEMINI studies (5), which included more than 1400 participants, confirming non-inferiority of the dolutegravir+3TC association versus the dolutegravir +Tenofovir/FTC regimen.

As a result, a new alternative for initiation of ART was established in different treatment guidelines (6), including those by the Argentine Society of Infectious Diseases (SAD) and the Argentine Department of Health.

As early as in 2017, the US Food and Drug Administration (FDA) had approved the first combination of dual therapy for simplification of treatment in patients with undetectable viral load, consisting of dolutegravir and rilpivirine, a regimen that was not available in Argentina.

The indication of Dolutegravir+3TC is limited by certain guidelines to patients having a viral load below 500,000 copies/mL and/or CD4 counts below 200 cells/mL, although the latter has not been established by the FDA or the European Medicines Agency (EMA).

The TANGO and SALSA studies demonstrated non- inferiority of DTG/3TC in simplification for virologically suppressed patients versus 3-drug TAF-based therapy (TANGO) or under any 3-drug regime (SALSA). This dual therapy option was also included in the above-mentioned guidelines.

New compounds such as lenacapavir (viral capsid inhibitor) and islatravir (translocation inhibitor) are being tested in dual therapy strategies, although Islatravir trials have been put on hold due to an unexpected negative impact on limphocyte and CD4 cell counts.

Does this mean that 3-drug therapy should be replaced with 2-drug therapy in all cases? The answer is no. Dual therapy has not been tested in children, pregnant women, or TBC cases treated with rifampicin, and is contraindicated in case of active hepatitis B infection, as well as in cases of previous treatment failure. However, it certainly represents a new alternative for treatment initiation and simplification. While a search for a cure persists, the development of new strategies is focused on regimens with less drug load, whether by reducing the number of drugs or through extended release strategies to avoid daily intake of ART. That is where we are heading.