An Update and Review of Antiretroviral Therapy

Abstract

The human immunodeficiency virus (HIV) was discovered in 1982, but treatment strategies were not introduced until 5 years later. Early regimens consisted of one or two drugs and often led to treatment failure. Since the advent in 1995 of highly active antiretroviral therapy (HAART), which consists of at least three agents, a dramatic improvement has been seen in the number of patients attaining undetectable viral loads, improved CD4 counts, and improved survival. However, early HAART often consisted of drugs with complex dosing schedules, strict food requirements, treatment-limiting adverse effects, and the need to take 16-20 pills/day. These treatment barriers often led to patient nonadherence, with subsequent treatment failure and development of resistant strains. The CD4 count and viral load are the most important surrogate markers used to determine if treatment is indicated. Current guidelines suggest starting treatment in patients who are symptomatic with an acquired immunodeficiency syndrome-defining illness regardless of CD4 count or viral load, as well as in asymptomatic patients with a CD4 count of 350 cells/mm(3) or below. In patients with CD4 counts above 350 cells/mm(3) and viral loads above 100,000 copies/ml, some clinicians prefer to defer treatment, whereas others will consider starting therapy; treatment is deferred in patients with CD4 counts above 350 cells/mm(3) and viral load s below 100,000 copies/ml. If therapy is started, the selection of appropriate agents is based on comorbidities (liver disease, depression, cardiovascular disease), pregnancy status, adherence potential (dosage regimen, pill burden, dosing frequency), food restrictions (dosing with regard to meals), adverse drug effects, and potential drug-drug interactions. Within the last 8 years, newer antiretroviral agents have focused on ways to improve adherence, such as convenient dosing (fewer pills), pharmacokinetic and formulation changes to reduce dosing frequency or pill burden, and coformulated dosage forms that contain two or three drugs in one convenient pill. Other improvements include increased potency of newer agents, agents sensitive to a highly resistant virus, improved adverse-effect profile (e.g., less gastrointestinal effects, improved lipid profiles), as well as protease inhibitor boosting with ritonavir, which takes advantage of the potent cytochrome P450 inhibitory action of ritonavir. This review focuses on the concepts of antiretroviral therapy, barriers to successful antiretroviral treatment, developments to limit treatment barriers, and new drug entities for the treatment of HIV.

Relevance of the Organic Cation Transporters 1 and 2 for Antiretroviral Drug Therapy in Human Immunodeficiency Virus Infection

“…Several classes of antiretroviral (ARV) drugs (ARDs) comprising nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), and protease inhibitors (PIs) are combined to the highly active ARV therapy in human immunodeficiency virus (HIV) (Piacenti, 2006). Long-term efficacy and avoidance of toxic effects are the main therapeutic challenges.…”

Trafficking through the Rev/RRE Pathway Is Essential for Efficient Inhibition of Human Immunodeficiency Virus Type 1 by an Antisense RNA Derived from the Envelope Gene

“…Current therapeutic strategies mainly use highly active antiretroviral therapy to control HIV-1 infection, typically using a triple-drug cocktail targeting reverse transcription and proteolytic processing (49,56). In spite of the successes using highly active antiretroviral therapy, drug resistance remains a problem, requiring changes in drugs and treatment strategies.…”

Adenovirus-Vectored Broadly Neutralizing Antibodies Directed Against gp120 Prevent Human Immunodeficiency Virus Type 1 Acquisition in Humanized Mice

“…Despite the improved quality of life, HAART has a number of limitations including high cost, drug toxicity and interactions, emergence of virus resistance, and the need for indefinite treatment, necessitating alternative therapeutic approaches. 3,4 Highly potent human monoclonal antibodies that recognize HIV envelope component gp120 or gp41 of a broad range of virus clades have been identified. These broadly neutralizing antibodies (bNAbs) have a number of unusual characteristics, including a high degree of somatic mutation, extended CDR H3 regions, and poly-and autoreactivity, making them difficult to elicit by immunization or natural infection.…”