The Perils of Reductive Antiretroviral Therapy and Potential Promise
A number of trials, over the past 15 years, have evaluated the effectiveness of mono-ART or dual-ART in different stages of the HIV-1 treatment continuum. These studies were heterogeneous in design and participant population. The results have been mixed and none convincing enough to push the field to broadly agree on the role of reductive approaches. In fact, some studies were outright failures,[3,4] thus consolidating aversion towards mono-ART or dual-ART. However, in recent mono-ART or dual-ART trials, approximately three-quarters of the participants maintained viral suppression after reduction to fewer than three antiretroviral drugs (Table 1), suggesting that this approach is appropriate for some patients.[5–9] In general, trials evaluating PI/r monotherapy have shown the best results in patients who were virologically suppressed and without evidence of prior virologic failure. Concerns about PI/r monotherapy, however, include higher rates of virologic failure, low-level viremia and protease inhibitor resistance, and the possibility of limited central nervous system penetration in the case of atazanavir. Yet, the data should quell some of those concerns as protease inhibitor resistance early during failure of PI/r monotherapy is typically less than 5%, which is comparable to the standard therapy groups.[5,6,8] Furthermore, in the patients who failed reduction to PI/r, between 83 and 100% achieved virologic suppression with re-intensification of the regimen.[5,6,9]
A careful appraisal of lessons learned within the existing body of literature suggests that ideal patients and antiretroviral drugs for a reductive strategy may be identified if specific questions are rigorously addressed. For instance, would we see more positive results with monotherapy or dual therapy if patients had years rather than months of virologic suppression on three-drug cART prior to switch? Would a better understanding of the viral reservoirs and a selection of those patients with smaller or less active reservoirs on three-drug ART be better suited for a reduction strategy? It is plausible that patients on longer durations of cART and those with smaller reservoirs may coincide since viral reservoirs tend to diminish with increasing duration of effective cART. What is the ideal degree of plasma viremia prior to monotherapy or dual therapy? This question has become more relevant because it appears that virologic failure rates differ among patients who have different degrees of viral suppression below 50 copies/ml. HIV controllers exhibit an innate ability to maintain some viral control, but still experience harmful levels of immune activation. Would such patients be particularly suited for fewer antiretroviral drugs?
Do newer, more potent therapies with improved pharmacokinetic profiles and more robust barrier against resistance such as the integrase strand transfer inhibitors dolutegravir and S/GSK 1265744 (GSK 744) allow success with fewer drugs? The combination of dolutegravir and lamivudine or even dolutegravir monotherapy is an example regimen that may be worth evaluating in carefully designed clinical trials. Finally, optimal application of long-acting formulations of antiretroviral drugs also demands an in-depth understanding of the best patients for mono-ART or dual-ART. Desirable attributes of a long-acting agent include adequate and prolonged systemic exposure after a low-volume administration, a high barrier against resistance, and absence of late-onset severe adverse reaction or toxicity. The first-in-class long-acting antiretroviral drugs, non-nucleoside reverse transcriptase inhibitor, rilpivirine, and GSK 744, are in phase 2 clinical trials. It would be transformative if long-acting-based strategies were discovered that could be administered alone or in combination every 1–3 months. This may be a potential reductive strategy even for selected patients currently on STR daily therapy.
AIDS. 2014;28(7):943-947. © 2014 Lippincott Williams & Wilkins
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