Generics for AIDS

    Entering its fourth decade of known existence, human immunodeficiency virus (HIV) remains a formidable foe. Without an effective vaccine available, the global incidence of AIDS cases continues to rise, prompting dire predictions from both local and international officials on the human and economic tolls exacted by this virus. An estimated 38 million individuals are now infected with HIV worldwide; yet recent reports suggest this number may be an underestimate: new infections are rising rapidly in parts of Eastern Europe, India and parts of Asia. One in eight South Africans, 5.6 million individuals, is HIV positive. Women between the ages of 20 and 40 are now the fastest-growing population at risk for HIV. The delivery of low-cost anti-HIV generic drugs will be critical for combatting AIDS and to the success of the World Health Organization (WHO) initiative to treat 3 million AIDS patients by 2005 (the '3 by 5' initiative).

    One positive effect of the AIDS threat has been the convening of international collaborative efforts to organize and fund HIV education, prevention and treatment programs. These programs are directed mainly at developing countries that are most at risk to the AIDS epidemic and yet are most ill prepared to deal with this public health crisis. On top of the direct costs associated with caring for patients living with AIDS and their surviving dependents, these countries must deal with the lost financial productivity of individuals in their prime. Donors for these efforts include the United Nations Global Fund for HIV/AIDS, Tuberculosis and Malaria; UNICEF; the World Bank; the William J. Clinton Foundation; and the Bill & Melinda Gates Foundation. To much fanfare, the Bush administration announced in 2003 a 5-year, $15 billion, US government–sponsored effort, the President's Emergency Plan for AIDS Relief (PEPFAR), to assist 15 underdeveloped countries deal with AIDS.

    A chief goal is the purchase of low-cost antiretroviral drugs. In response to the AIDS threat, the World Trade Organization (WTO) issued a clause in intellectual property agreements in August 2003 to allow developing countries under public health emergency conditions to import cheaper generic versions of antiretrovirals, without violating existing patents covering these drugs. Several companies, mainly in India and Brazil, now produce a few generic fixed-dose combination antiretrovirals (essentially 'three-in-one' pills) for export to countries that lack domestic production facilities, as allowed by the WTO exemption. Fixed-dose combination antiretrovirals are advocated by Médecins Sans Frontières (Doctors without Borders) and the WHO for use in developing countries. Such drug formulations promote better compliance, as fewer pills need to be taken daily, and reduce the potential for resistant viruses to develop, a key concern, given HIV's potential to mutate. Former US president Bill Clinton has played a key role in negotiating low prices for generic combination antiretrovirals and HIV diagnostic tests for use in poorer countries. A clinical trial testing the efficacy of one such generic combination antiretroviral, Triomune, produced by the Indian pharmaceutical Cipla, was conducted by French researchers in Cameroon, and the drug was reported in the 3 July 2004 issue of The Lancet to be safe, tolerable and effective in reducing viral load.

    Despite these positive results, controversies continue to swirl around these efforts. At the July 2004 AIDS conference in Bangkok, Thailand, protesters criticized the US for its policy that requires US-donated funds be used only toward the purchase of antiretrovirals whose 'safety, efficacy and quality' can be assured. Critics, however, maintain that the Bush administration's motivation is protection of the American pharmaceutical industry, which hold patents on many of the antiretrovirals. This policy means US money can not be used to purchase the lower-cost generic antiretrovirals unless bioequivalence with the patented brand name drug has been established. The Bush administration claims that such approval requires action by regulatory agencies such as the US Food and Drug Administration (FDA), which in May 2004 announced a fast-track program to analyze generic and combination antiretrovirals. At present, the WHO 'prequalification' process uses manufacturer-supplied bioequivalence data and outside inspectors to verify the biosafety and efficacy of generic drugs.

    The Office of the US Global AIDS Coordinator released a report on 14 September 2004 defending US actions, stating that WHO pre-qualification lacks a stringent regulatory review process comparable to the criteria in place at the US FDA. In support of this contention, the report points to several generic antiretrovirals made by Cipla and Ranbaxy Laboratories, another Indian pharmaceutical firm, that in the past 6 months have had their prequalifications revoked. However, in those cases the efficacy of the antiretrovirals was not questioned; instead, it was the companies conducting the bioequivalence tests that were found noncompliant with standard good clinical research and laboratory practice. Both companies have since contacted other bioequivalence testing facilities in an effort to regain WHO certification and are planning to apply for US FDA approval. Nevertheless, these questions may prompt officials to stop prescribing three-in-one generics, which would have serious public health implications.

    The stringent US bioequivalency requirement forces recipient countries to set up separate purchasing and delivery programs to document the source of all funds used to buy generic antiretrovirals. Demonstrating safety and efficacy is, of course, of the utmost importance for the patients' sake. Yet as more time goes by, we must not lose sight of the ultimate goal: staving off an epidemic of epic proportions. While new rules are promulgated, more people are dying. The distribution of generic antiretrovirals to AIDS-ravaged developing countries is critical to stemming the tide. The additional burden of maintaining separate accounts will no doubt complicate an already difficult situation and result in a measurable human toll. Given that 8,000 individuals die from AIDS every day, this is not the time to quibble.

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    Generics for AIDS. Nat Immunol 5, 1089 (2004).

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