A Decade of HAART: Historical Perspective, Successes, Failures, and Future Considerations

Anthony Fauci, MD, Director of the National Institute of Allergy and Infectious Diseases, National Institutes of Health in Bethesda, Maryland, provided a historical review of HIV infection and its treatment in 3 phases: "the dark ages" (1981-1986), "pre-highly active antiretroviral therapy (HAART)" (1987-1996), and "HAART" (1997-2006).

The "dark ages" was just that: desperate attempts to find something -- anything -- that would slow disease progression. There was little or no logic to the approach that included isoprinosine, suramin, AL721, HPA-23, ribavirin, thymosin, alpha interferon, interleukin-2, thymic implants, leukocyte transfer, bone marrow transplantation, and dinitrochlorobenzene (DNCB). By 1986, there were 5833 AIDS cases in the United States and the 1-year mortality was 51%.

The pre-HAART era represented the first step into rational drug design. The scientific discovery that opened the door to drug discovery was the work of Luc Montagnier and Robert Gallo^[1] to describe HIV as the putative agent; what followed were studies of the virus with cloning, sequencing, analysis of the replication cycle, and analysis of the 6 regulatory genes, among other investigations. The seminal discovery for the first class of anti-HIV drugs was that reverse transcriptase was central to viral replication, and agents were then screened to find candidate drugs that inhibited this process. Drs. Robert Yarchoan, Hiroaki Mitsuya, and Sam Broder^[2] found that zidovudine (AZT) had this property, and it was then quickly placed in a placebo-controlled clinical trial in patients with late-stage disease. The first review of data by the Data and Safety Monitoring Board in September 1986 showed 19 deaths in the placebo group compared with 1 death in the AZT treatment group^[3]; the study was stopped and the US Food and Drug Administration (FDA) approved the drug in record time. It was 21 months from trial initiation to drug approval -- an FDA record that has never been beaten.

The destiny of AZT monotherapy is well known. Viral load decreased about 0.5 log₁₀ copies/mL and resistance then quickly terminated benefit.^[4] The second nucleoside was didanosine (ddI), which was approved in 1991; combination therapy with ddI reduced viral load a median of 1.1 log₁₀ copies/mL, but again, the benefit was temporary.

The HAART era came about with the advent of the protease inhibitors (PIs), the first "designer drugs" that were developed on the basis of structural and functional analysis.^[5,6,7] The introduction of triple combinations of 2 NRTIs plus PIs in 1995-96 began the third phase of HIV treatment: the "Decade of HAART." This made a sudden and dramatic impact, with a decrease in annual deaths in the United States from about 52,000 in 1995 to about 18,000 by 1998. The total impact of this "triple therapy" was a life extension averaging 13 years for the individual and a cumulative total of nearly 3 million life-years saved by 2004.^[8] (The study by Walensky and colleagues^[8] is presented in detail in a separate review of Medscape's "Decade of HAART" conference coverage; see "Survival Benefits of Medical Interventions for HIV/AIDS in the United States.") This benefit substantially exceeded other advances in medicine, and it also proved cost-effective.^[9] Another major advance was simplification of the treatment regimens, which culminated in the recent single pill combining efavirenz + tenofovir + emtricitabine (Atripla) for once-daily administration.

But these advances did not come without a cost: There were the short- and long-term drug toxicities, emergence of drug resistance, persistence of viral reservoirs, inability to achieve viral eradication, issues of cost and access, and a need for new therapeutic targets.

There are 2 other challenges that remain. Ninety-five percent of the world's HIV infections are found in resource-limited areas. The first challenge is to make available across the world the therapeutic advances that are now customary treatment in the United States and Europe. To address this issue, funding is now available from 3 major sources: PEPFAR; the Global Fund for AIDS, Tuberculosis, and Malaria; and philanthropies plus nongovernmental organizations (NGOs). Progress in this effort is good, but it is not enough. In 2002, there were 300,000 people in low- and middle-income countries who were receiving antiretrovirals; this increased to 1.6 million in June 2006. Nevertheless, this represents only 24% of persons in these settings who need treatment for HIV.

The second major challenge is prevention, which has been largely unsuccessful in most of the world. The methods that are currently available and/or under study include:

• Education and behavior change;
  
  

• Interruption of mother-to-child HIV transmission;
  
  

• Treatment/prevention of drug/alcohol abuse;
  
  

• Clean needles;
  
  

• Circumcision;
  
  

• Condoms and other barrier methods;
  
  

• Topical microbicides;
  
  

• Treatment of sexually transmitted diseases;
  
  

• Prophylactic antiretroviral therapy; and
  
  

• Vaccination.

In conclusion, Dr. Fauci provided what may have been the conference's most notable quote: "History will judge us as a global society by how well we address the next 25 years of HIV/AIDS, as much as by what we have done in the first 25 years."

1. Gallo RC, Montagnier L. The discovery of HIV as the cause of AIDS. N Engl J Med. 2003;349:2283-2285. Abstract

2. Yarchoan R, Klecker RW, Weinhold KJ, et al. administration of 3'-azido-3'-deoxythymidine, an inhibitor of HTLV-III/LAV replication, to patients with AIDS or AIDS-related complex. Lancet. 1986;1:575-580. Abstract

3. Fischl MA, Richman DD, Grieco MH, et al. The efficacy of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex. A double-blind, placebo-controlled trial. N Engl J Med. 1987;317:185-191. Abstract

4. Larder BA, Darby G, Richman DD. HIV with reduced sensitivity to zidovudine (AZT) isolated during prolonged therapy. Science. 1989;243:1731-1734. Abstract

5. Miller M, Schneider J, Sathyanarayana BK, et al. Structure of complex of synthetic HIV-1 protease with a substrate-based inhibitor at 2.3 A resolution. Science. 1989;246:1149-1152. Abstract

6. Erickson J, Neidhart DJ, VanDrie J, et al. Design, activity, and 2.8 A crystal structure of a C2 symmetric inhibitor complexed to HIV-1 protease. Science. 1990;249:527-533. Abstract

7. Navia MA, Fitzgerald PM, McKeever BM, et al. Three-dimensional structure of aspartyl protease from human immunodeficiency virus HIV-1. Nature. 1989;337:615-720. Abstract

8. Walensky RP, Paltiel AD, Losina E, et al. The survival benefits of AIDS treatment in the United States. J Infect Dis. 2006;194:11-19. Abstract

9. Chen RY, Accortt NA, Westfall AO, et al. Distribution of health care expenditures for HIV-infected patients. Clin Infect Dis. 2006;42:1003-1010. Abstract

Medscape HIV/AIDS © 2006 

Cite this: John G Bartlett. A Decade of HAART: Historical Perspective, Successes, Failures, and Future Considerations - Medscape - Nov 17, 2006.