Erna Milunka Kojic and Charles C.J. Carpenter
The acquired immunodeficiency syndrome (AIDS) was first identified as a distinct clinical entity in June 1981 when the CDC reported the occurrence of five cases of Pneumocystis pneumonia (PCP), accompanied by severe wasting, in young men who had sex with men (MSMs) in Los Angeles (1). This was quickly followed by reports of several cases of Kaposi's sarcoma, also associated with severe wasting, in 25 young MSMs in New York City and California (2). Of these cases, six developed pneumonia (confirmed in four cases as PCP), one had central nervous system (CNS) toxoplasmosis, and another had cryptococcal meningitis and extensive mucosal candidiasis. Since past experience with both Pneumocystis pneumonia and Kaposi's sarcoma in young individuals was almost entirely limited to persons with severe immunodeficiency, these observations suggested that immunodeficiency, of uncertain origin, provided the background for development of these usually fatal illnesses in previously healthy young men. Following the initial reports from Los Angeles and New York City, similar observations were reported in the MSM community in San Francisco, and extensive investigations were carried out to attempt to determine the basis for the immunodeficiency in these individuals.
Over the next 12 months, many additional cases of PCP pneumonia, Kaposi's sarcoma, and cryptococcal meningitis were identified in young MSMs, especially in major US cities on the East and West coasts. In most cases, the individuals had no prior indication of immunodeficiency, which provided the basis for nomenclature of AIDS that was applied to this syndrome by the CDC in 1982.
In September 1982, three men with hemophilia were observed to develop severe PCP, and immunological studies were similar to those in the MSM population with AIDS (3). Each of these men had received infusions of exogenous Factor VIII derived from plasma pools collected from up to 1,000 donors. These collective
Assistant Professor of Medicine, Brown University,164 Summit Ave, Providence, RI 02906, USA [email protected]
observations in MSM populations and in hemophiliacs suggested that the severe underlying insufficiency was caused by an infectious agent, which was transmitted both sexually and parenterally in a manner similar to that of the hepatitis B virus. The subsequent recognition of AIDS occurrence in both male and female intravenous drug users (13% of reported cases of AIDS by September 1982) added further credence to the concept that an infectious agent, most likely a virus, was responsible for the rapidly expanding epidemic of AIDS. The death in late 1982, from an AIDS-like illness, of a 20-month-old child who had received multiple blood transfusions, appeared to confirm transmission of an infectious agent by blood. Experience in Western Europe and Australia demonstrated that AIDS was also spreading, largely in the same population groups in which it had been recognized in the United States.
In late 1983, a viral agent, initially called human T lymphocyte virus III, was identified by Dr. Luc Montagner (4). This virus, now called HIV-1, was confirmed as the etiologic agent of AIDS by Dr. Robert Gallo in 1984 (5). These two investigators and their colleagues were independently successful in developing an enzyme-linked immunosorbent assay (ELISA), which could detect antibodies in persons infected by HIV-1. Application of this assay made it possible to identify individuals at an earlier, preclinical, state of HIV infection. Further studies of the commercial test (ELISA), in large numbers of "at-risk" individuals (intravenous drug users and MSMs) in 1985, indicated that the majority of persons who had been infected by the HIV virus were not yet symptomatic. Subsequent cohort observations, notably the Multicenter AIDS Cohort Study (MACS) initiated in 1984, have indicated that the average individual who acquires HIV infection remains asymptomatic, but at risk of transmitting the virus by either sexual or intravenous infection route, for an average of 9-10 years before developing distinctive infections or neoplasms associated with immunodeficiency.
With the development of the diagnostic test, it became clear that the HIV-1 infection was even more prevalent in sub-Saharan Africa, and that HIV-1 was the etiologic agent of "slim disease," a wasting illness that has been identified in Central and West Africa in the late 1970s. Epidemiologic observations in Africa, as well as increasing identification of HIV-1 infection in sexual partners of intravenous drug users in Europe and the United States, confirmed that the HIV virus could be transmitted heterosexually, and this has been the predominant route of HIV transmission worldwide.
Thus, by 1985, the etiologic agent for AIDS had been identified and persons living asymptomatically with the virus could be detected. This led to increasing major efforts by the pharmaceutical industry to develop effective antiretroviral agents.
The first potential antiretroviral agent to which the HIV virus showed in vitro susceptibility was the reverse transcriptase inhibitor (RTI) azidothymidine (AZT), subsequently known as zidovudine. Zidovudine, which has originally been developed as a potential chemotherapeutic agent for the treatment of cancer, was found to be effective in inhibiting the growth of HIV-1 in vitro. Extensive field trials of this agent were initiated in 1986 by the newly established NIH-supported AIDS
Clinical Trials Group (ACTG). Initial randomized controlled trials of this agent indicated a significant decrease in mortality in HIV-infected individuals who received this agent for 24 weeks (6). On this basis, and with additional support from subsequent studies by the ACTG, the FDA approved in 1989 the use of AZT for persons living with HIV infection who had a CD4 cell count of <500.
During the first 2 years this agent was employed (most often in doses of 600 mg but sometimes in doses as great as 1,500 mg/day), side effects, especially nausea, headache, and anemia, were common. Follow-up studies over several years demonstrated that the clinical benefit of monotherapy with zidovudine was transient. In 1990, a state-of-the-art panel convened by the NIH suggested that azidothymidine, because of the demonstrated short-term survival benefit, should be given in divided doses of 600 mg daily to all persons living with HIV infection who had CD4 counts <500/mm3. The recommendation of a CD4 count of 500 as the threshold for initiation of treatment was made on an arbitrary basis (7).
In 1992, second (didanosine, or ddI) and third (dideoxycitidine, or ddC) antiret-roviral drugs were approved by the FDA for administration to persons with CD4 counts <500. Each of these agents was approved for use as a single agent against HIV infection, on the basis of short-term benefit in clinical trials. Both didanosine and dideoxycitidine proved to have serious toxicities, of which the most frequent was severe, sometimes crippling, peripheral neuropathy.
In 1992, an NIH Advisory Panel recommended that the three available agents, AZT, ddI, and ddC be used in sequence, with discontinuation of an initial agent when either major toxicity occurred, or when CD4 count began to fall after an initial rise (8). The panel recommended that all HIV-infected individuals with CD4 T-cell counts below 500 be treated with such sequential monotherapy.
In 1992, trials of combination therapy with two of the above agents were initiated both in the United States and Western Europe. By 1995, two major clinical trials, the Delta trial in Europe (9) and an ACTG trial in the United States (10), indicated that combined use of AZT and ddI was more effective than AZT mono-therapy in preventing the progression of immunodeficiency and death in persons living with HIV infection. The toxicities of any two-drug combination of the three available drugs, however, proved to be major limiting factors. It became clear that the use of ddI and ddC together was prohibitive because of frequent neurotoxicity and occasional lactic acidosis.
Each of the initial three antiretroviral agents acted by the same mechanism, inhibition of reverse transcriptase, an enzyme essential to the replication of retroviruses.
While the early evaluations of HIV therapy were based on clinical endpoints (i.e., progression to clinical AIDS or death), extensive immunological and virologi-cal studies defined two precise laboratory determinations, the CD4 T-cell count (CD4) and the plasma HIV-RNA level (the plasma viral load, PVL), which, in concert, proved to be effective gauges of the rate of progression of HIV disease, and of the response to antiretroviral therapy. Most helpful were longitudinal studies obtained from the Multicenter AIDS Cohort Study, which was initiated in 1985, and included men either infected by, or at high risk for, HIV infection (11). The studies,
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