HIV/AIDS: Antiretroviral Drugs

Abstract The last three decades have seen amazing progress in the treatment and prevention of HIV infection, with over 25 approved antiretrovirals and several experimental drugs in advanced development. Research in the basic science of HIV replication has enabled targeted drug discovery efforts, and these are, in turn, contributing to an improved understanding of the molecular biology of HIV infection. Refinement of therapeutic strategies continues, in pursuit of high virological efficacy, excellent safety and tolerability, convenience of administration and effective use of available resources. These aspirations now extend to the subset of patients who have experienced multiple antiretrovirals, for whom it is increasingly possible to construct optimised regimens that overcome drug resistance or poor tolerability. The next decade will test two‐drug combinations, most likely as a way of simplifying therapy once virological suppression is achieved with three‐drug regimens, whereas long‐acting injectable formulations will establish their role as a therapeutic and prophylactic option. Key Concepts Antiretroviral drugs target multiple steps of the HIV replication cycle, from the initial attachment to the target CD4 cell to the final step of maturation of a new virus particle. Treatment regimens usually consist of three drugs with two different mechanisms of action, which are often coformulated into a single tablet. Antiretroviral therapy is highly efficacious; most patients can expect to achieve long‐term HIV control, provided they maintain consistently good adherence. Antiretroviral therapy is not curative and must be taken for life to prevent viral rebound. Current antiretroviral drugs are generally safe and well tolerated. They have distinct profiles, however, and some pose safety and tolerability problems for some patients, whereas others are well tolerated but less efficacious. Many have unfavourable interactions with concomitant medications. Patients starting ART have a choice of treatment options. Most commonly, the initial regimen consists of two NRTIs that form the backbone and a third agent with a different mechanism of action, which may be an INSTI, an NNRTI or a PI/b. Whilst INSTIs are preferred, treatment selection is optimised based on HIV‐related clinical parameters, concurrent infectious and noninfectious comorbidities and concomitant medications, and considerations related to preference and life‐style, as well as cost. Treatment options and opportunities for tailoring the regimen are fewer in resource‐limited settings. Plasma viral load – that is, the quantity of circulating HIV RNA – provides the measure of the efficacy of antiretroviral therapy: the goal is to achieve a fully suppressed (undetectable) viral load. Studies have tested the hypothesis that once viral load suppression is achieved with triple ART, it may be possible to simplify treatment using fewer drugs. Results of maintenance monotherapy with PI/b or dolutegravir have been disappointing. More promising data have been obtained with two‐drug combinations where one of the two drugs is a PI/b, dolutegravir or cabotegravir. Patients who experience viraemia while on treatment require prompt management to avoid the emergence of drug resistance; the subsequent regimen is optimised according to the specific circumstances and may include three or more drugs chosen among those most likely to retain activity while continuing to meet the requirement for good safety and tolerability. Resource‐limited countries have few drugs for second‐line treatment and even fewer options for subsequent lines of therapy. Experimental agents in advanced development include drugs with new mechanisms of action such as novel entry inhibitors, NRTTIs, and capsid and maturation inhibitors, as well as new drugs within existing classes such as the recently approved bictegravir and doravirine. Some of the new agents hold promise that they may either prevent or overcome drug resistance. There is considerable interest in long‐acting injectables that allow infrequent dosing (e.g. monthly) and are intended for either treatment or prevention.