The development of antiretroviral therapy and its impact on the HIV-1/AIDS pandemic

Abstract

In the last 25 years, HIV-1, the retrovirus responsible for the acquired immunodeficiency syndrome (AIDS), has gone from being an "inherently untreatable" infectious agent to one eminently susceptible to a range of approved therapies. During a five-year period, starting in the mid-1980s, my group at the National Cancer Institute played a role in the discovery and development of the first generation of antiretroviral agents, starting in 1985 with Retrovir (zidovudine, AZT) in a collaboration with scientists at the Burroughs-Wellcome Company (now GlaxoSmithKline). We focused on AZT and related congeners in the dideoxynucleoside family of nucleoside reverse transcriptase inhibitors (NRTIs), taking them from the laboratory to the clinic in response to the pandemic of AIDS, then a terrifying and lethal disease. These drugs proved, above all else, that HIV-1 infection is treatable, and such proof provided momentum for new therapies from many sources, directed at a range of viral targets, at a pace that has rarely if ever been matched in modern drug development. Antiretroviral therapy has brought about a substantial decrease in the death rate due to HIV-1 infection, changing it from a rapidly lethal disease into a chronic manageable condition, compatible with very long survival. This has special implications within the classic boundaries of public health around the world, but at the same time in certain regions may also affect a cycle of economic and civil instability in which HIV-1/AIDS is both cause and consequence. Many challenges remain, including (1) the life-long duration of therapy; (2) the ultimate role of pre-exposure prophylaxis (PrEP); (3) the cardiometabolic side-effects or other toxicities of long-term therapy; (4) the emergence of drug-resistance and viral genetic diversity (non-B subtypes); (5) the specter of new cross-species transmissions from established retroviral reservoirs in apes and Old World monkeys; and (6) the continued pace of new HIV-1 infections in many parts of the world. All of these factors make refining current therapies and developing new therapeutic paradigms essential priorities, topics covered in articles within this special issue of Antiviral Research. Fortunately, there are exciting new insights into the biology of HIV-1, its interaction with cellular resistance factors, and novel points of attack for future therapies. Moreover, it is a short journey from basic research to public health benefit around the world. The current science will lead to new therapeutic strategies with far-reaching implications in the HIV-1/AIDS pandemic. This article forms part of a special issue of Antiviral Research marking the 25th anniversary of antiretroviral drug discovery and development, Vol. 85, issue 1, 2010.

Figure 1

Trends in annual age-adjusted rate of death due to HIV disease in the USA. Data were compiled from death certificates from all 50 states and the District of Columbia by the National Center for Health Statistics. See Centers for Disease Control and Prevention (CDC): HIV Mortality. http://www.cdc.gov/hiv/topics/surveillance/resources/slides/mortality/

Figure 2

Proportion of persons surviving, by number of months after AIDS diagnosis, by year of diagnosis—USA and dependent areas See Centers for Disease Control and Prevention (CDC): AIDS Surveillance - General Epidemiology http://www.cdc.gov/hiv/topics/surveillance/resources/slides/epidemiology

Figure 3

A patient with AIDS and disseminated Kaposi's sarcoma (KS) undergoing evaluation and therapy by my group at NCI early in the pandemic. One of the most striking features of the early HIV-1/AIDS pandemic was the emergence of an unusual tumor, KS, as a common malignancy among infected individuals. Following the introduction of highly active antiretroviral therapy, its incidence dropped precipitously in nine population-based cancer registries sponsored by the NCI's Surveillance, Epidemiology and End Results (SEER) program.

Figure 4

Patient number 1 in the first study of Retrovir® (AZT) at the NIH Clinical Center in the summer of 1985. The patient, who had a CD4⁺ T cell count of 33/microL and was anergic at entry, developed a six-fold increase in absolute CD4⁺ count, and as shown in the figure, displayed a strongly positive delayed hypersensitivity skin reaction to 5 TU PPD approximately two weeks after starting the experimental antiretroviral agent.