The evolution of three decades of antiretroviral therapy: challenges, triumphs and the promise of the future

Abstract

The evolution of human immunodeficiency virus (HIV) treatment has improved our understanding and management of complex pharmacological issues that have driven improved outcomes and quality of life of the HIV-infected patient. These issues include adherence, long- and short-term toxicities, pharmacoenhancement, pharmacogenomics, therapeutic drug monitoring, differential penetration of drugs into sanctuary sites, such as the central nervous system, genital tract and small bowel, and drug-drug and drug-food interactions related to cytochrome P450 drug-metabolizing enzymes, uridine diphosphate glucuronyltransferases and drug transporters, to name a few. There is future promise, as an increased understanding of the immunopathogenesis of HIV and global public health initiatives are driving novel treatment approaches with goals to prevent, control and, ultimately, eradicate HIV.

Keywords: adherence; antiretroviral; drug interactions; human immunodeficiency virus; pharmacogenomics; therapeutic drug monitoring.

Figure 1

Time lines of antiretroviral development. The time course of development of >25 drugs across five different classes over the last 27 years is highlighted according to the US Food and Drug Administration (FDA) approval date. Those that are no longer in use or available are illustrated with an ‘X’ through them

Figure 2

Convergence of human immunodeficiency virus (HIV) treatment guidelines in the developed and developing world. Changes in recommendations on when to start antiretroviral therapy (ART) in asymptomatic HIV-infected individuals based on CD4+ count criteria are shown. The Department of Health and Human Services (DHHS), European and World Health Organization (WHO) guidelines over time showing the fluctuations in recommendations which, in the developed world, represented a change from the initial optimism of ‘hit hard, hit early’ in 1998 to the reality of challenging high pill burden combinations. In the developing world, the trend has moved upwards, largely based on increased availability of ART and HIV care. The DHHS guidelines have now moved to an evidence-based approach, where treatment is recommended in all asymptomatic individuals but with various grades of evidence. The European guidelines have been more conservative, awaiting the results of the START study, a randomized double-blinded study of treatment initiation in treatment-naïve asymptomatic HIV-infected individuals with CD4+ T-cell count ≥500 or <500 mm⁻³. Although there are differences between guidelines, all agree and recommend earlier ART initiation regardless of CD4+ count in high-risk patient groups, such as those with co-morbidities such as co-infection with hepatitis B or C, HIV-associated nephropathy, rapid decline in CD4+, pregnancy and in sero-discordant partner situations. , DHHS (US); , WHO; , EACS (European). ART, antiretroviral therapy; DHHS, Department of Health and Human Services; EACS, European AIDS Clinical Society; HIV, human immunodeficiency virus; WHO, World Health Organization