In 1991, medical researchers at Merck Laboratories announced the first clinically promising protease inhibitor for the treatment of patients infected with HIV. This and similar compounds formed the basis for highly active antiretroviral therapy, which dramatically improved the life expectancy of persons with HIV/AIDS.
By the time acquired immunodeficiency syndrome (AIDS) became recognized as a major public health problem in the mid-1980’s, the science of molecular genetics had progressed to levels at which gene sequencing of a virus and complete characterization, at the molecular level, of all the steps involved in pathogenesis had become almost routine. Once Robert Gallo and other virologists had isolated the virus that causes AIDS, grown it in cell culture, and determined both the molecular structure of key enzymes and the underlying gene sequence coding for them, research biochemists employed by pharmaceutical companies were able to predict, synthesize, and test compounds capable of pinpointing virus replication without disrupting critical aspects of human metabolism.
Human immunodeficiency virus (HIV) consists of a single strand of ribonucleic acid (RNA) surrounded by a protein coat. It is a retrovirus, meaning that the viral RNA serves as a template for assembling deoxyribonucleic acid (DNA), which then attaches itself to the genome of a host cell, a reversal of the process in which host-cell DNA codes for RNA, which in turn serves as a template for the proteins forming the building blocks of cells.
The first drug designed specifically for HIV-1 infection, AZT
The search for a more effective therapeutic agent proceeded simultaneously in the research laboratories of a number of pharmaceutical firms—notably Merck,
The research programs involved synthesizing literally hundreds of extremely complex organic chemicals in sufficient quantities for testing their antiviral activity against HIV in cell culture. In late 1990, a team at Hoffmann-La Roche reported and obtained a patent for saquinavir (trade name Invirase), the first such compound to be later approved for clinical use. This was followed shortly by Merck’s announcement of indinavir
Between identification of a potential therapeutic agent in the laboratory and its release on the open market lies a long and costly road of animal testing, controlled clinical testing, testing to determine the best way to administer the drug, and development of a manufacturing process to ensure the quantities needed. In the early 1990’s there was widespread sentiment on the part of the drug companies, the medical community, and advocates for persons with HIV/AIDS that the situation at the time demanded some means of shortening this process. In response to this pressure and recommendations from David A. Kessler, commissioner of the FDA, the U.S. Congress authorized an accelerated approval process for drugs used to treat life-threatening diseases. Drug companies were required to continue clinical trials following FDA approval. Some years later, when the multiple side effects of protease inhibitors began surfacing, AIDS advocates accused the pharmaceutical companies of failing to provide adequate follow-up testing.
As a result of the accelerated approval process, the first protease inhibitor, Merck’s Crixivan, developed by biochemist Joseph P. Vacca and his colleagues, became available on a limited basis in mid-1995. Because demand far exceeded initial supplies, Merck conducted a lottery to determine who would receive the drug. For another year, the company closely controlled access to Crixivan through a single supplier. Saquinavir
The problem of resistant strains of HIV-1 surfaced almost at the outset. The AIDS virus has a high mutation rate, and because neither AZT nor protease inhibitors completely eliminate the virus from an infected person, emergence of a strain resistant to a particular drug is virtually inevitable, especially if a patient ceases taking prescribed medication for a period of time and then resumes it. This was one reason for Merck’s limiting access to a defined number of patients for whom adequate stocks were available. Combining lower doses of several protease inhibitors reduces the chance that viral resistance to any one of them will develop. The spread of Crixivan-resistant strains of HIV-1 in the United States and Europe led to disuse of this agent in the developed world; this helped convince Merck to allow indinavir’s release as a generic in Africa and Asia, although Merck’s patent remained in force.
HAART combining HIV protease inhibitors, AZT, and prophylaxis for secondary infections is credited with transforming HIV/AIDS from a sentence of death into a chronic, manageable condition. When administered late in pregnancy, HAART greatly reduces the chance of intergenerational HIV infection during childbirth. Such therapy is not a cure, however, and it carries high physical, social, and monetary costs.
Protease inhibitors exact a heavy toll in side effects, some of them potentially lethal in their own right. The oral medications must be taken at precisely timed intervals, because the compounds are rapidly metabolized once ingested. Although considerable improvements in delivery were made in the years after the drugs were introduced in 1995, in the early twenty-first century HAART remains a time-consuming occupation requiring a great deal of self-discipline on the part of the patient. Consequently, many HIV/AIDS patients fail to adhere to their treatment regimens and relapse, facilitating the spread of drug-resistant viral strains.
The annual cost of drugs alone for an HIV-positive patient on HAART in the United States exceeds twenty thousand dollars. Since passage of the Ryan White Comprehensive AIDS Resources Emergency Act of 1990,
The development and adoption of protease inhibitors as standard therapy for HIV/AIDS illustrated the mismatch between science and technology on one hand and social reality on the other. If a molecular knowledge of a biological process affecting human health and the tools required to use that knowledge to synthesize an agent for regulating that process were all that were required to combat a scourge such as AIDS, the outlook for human happiness would be rosy indeed. In reality, the main benefit of HAART has been to prolong the useful lives of HIV patients who, unless an actual cure is developed, will eventually succumb to AIDS. Moreover, to the extent that infected people who fail to adhere to treatment protocols also engage in risky behavior and uninfected people use the availability of therapy as an excuse for not taking precautions against exposure (both of which are known to occur), HAART has actually served to amplify the AIDS epidemic.
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Dutta, A. S., ed. Small Peptides: Chemistry, Biology, and Clinical Studies. New York: Elsevier, 1993. Includes two chapters on inhibitors of aspartyl proteases, with an overview and structures of HIV protease inhibitors being developed. -
Feldman, Douglas A., and Julia Wang Miller, eds. The AIDS Crisis: A Documentary History. Westport, Conn.: Greenwood Press, 1998. Collection of essays on the AIDS crisis includes source documents on drug development and the logistical and financial barriers to drug therapy. -
Roberts, Noel A., J. Charles Craig, and Jonathan Sheldon. “Resistance and Cross-Resistance with Saquinavir and Other HIV Protease Inhibitors: Theory and Practice.” AIDS 12 (March 26, 1998): 453-460. Provides a good account of efforts to prevent emergence of drug-resistant HIV strains. -
Vacca, Joseph P. “Design of Tight-Binding Human Immunodeficiency Virus Type-1 Protease Inhibitors.” In Retroviral Proteases, edited by Lawrence C. Kuo and Jules M. Shafer. San Diego, Calif.: Academic Press, 1994. Presents a comprehensive, highly technical description of the development of anti-AIDS drugs and the functioning of these drugs at the molecular level.
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