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The purpose of this study was to quantify the benefits of maternal-neonatal zidovudine (ZDV) administration for the prevention of vertical human immunodeficiency virus (HIV) transmission against the potential risks of drug-induced complications in uninfected children. A decision analysis model was created with use of a Markov cohort simulation, for evaluating both survival and quality of life for two hypothetical cohorts of HIV-exposed neonates: one with in utero and neonatal exposure to preventive ZDV therapy and the other not exposed. The model included the probability of congenital HIV infection with and without ZDV treatment (estimates derived from AIDS Clinical Trials Group study 076), the yearly probability of death with and without congenital HIV infection, a range of probabilities of adverse effects from ZDV use, and a range of ages in life when any adverse effect would manifest. In a series of scenarios, the impact of different estimates for the quality-of-life decrement from any adverse ZDV effect in HIV-uninfected children was assessed, and threshold values for this estimate were established, i.e., critical values below which withholding ZDV would be the preferred choice. Across a wide range of estimates for multiple contingencies, ZDV use was associated with a greater number of quality-adjusted life years than was non-use. Only in implausible, pessimistic scenarios (i.e., a high incidence of profound adverse effects beginning early in life) would withholding ZDV be the rational choice for an asymptomatic HIV-infected pregnant woman.(ABSTRACT TRUNCATED AT 250 WORDS)
After mid-1987 fewer than the expected number of cases of AIDS were reported in the United States in some demographic and transmission groups but not in others. Gay men (regardless of intravenous drug use), adults with hemophilia, and transfusion recipients exhibited fewer cases than expected based on previously reliable models. These favorable trends could not be explained by assuming earlier cessation of human immunodeficiency virus (HIV) infection. Favorable AIDS incidence trends were not found in heterosexual intravenous drug users or in persons infected through heterosexual contact. White gay men from New York City, Los Angeles, and San Francisco experienced markedly favorable trends, whereas little changes was observed for nonwhite gay men from nonurban areas. AIDS incidence trends were quantitatively consistent with the fraction of AIDS-free persons with severe immunodeficiency who received zidovudine in three cohorts. Gay men in San Francisco used zidovudine more frequently than did adults with hemophilia, while little was used by intravenous drug users in New York City. Data describing the initial national distribution of zidovudine (March 31-September 18, 1987) indicated relatively high use by patients with severe immunodeficiency in those groups, such as urban white gay men, that subsequently experienced fewer cases of AIDS than expected. Available data suggest that zidovudine, perhaps in combination with other therapies, has been one factor contributing to favorable AIDS incidence trends in some groups. Broader application of therapy might further retard the incidence of AIDS, especially in intravenous drug users, persons infected through heterosexual contact, minorities, women, and persons diagnosed outside major metropolitan areas.
Although used widely, the effectiveness of zidovudine therapy and primary prophylaxis for Pneumocystis carinii pneumonia (PCP) in HIV-1-infected individuals, has not been assessed in a large cohort. We have done an observational study between October, 1986, and October, 1990, of a cohort of 2145 HIV-1-seropositive men and 371 who seroconverted during the study. A Markov chain transitional analysis was used to examine the effect of zidovudine and PCP prophylaxis on the probability of progression of HIV-1 infection to AIDS (after 6, 12, 18, and 24 months) after follow-up visits categorised into one of six disease states. The six starting states were based on CD4+ lymphocyte counts and the presence of HIV-related symptoms. Use of pre-AIDS zidovudine and PCP prophylaxis was associated with significant reductions in rates of progression to AIDS at 6, 12, 18, and 24 months for participants starting with less than 350 CD4+ lymphocytes/microliter. For those starting with 350 or more CD4+ lymphocytes/microliter, non-significant protective trends were seen during 12, 18, and 24 month intervals. In multivariate log-linear models virtually all the treatment effect was due to zidovudine. However, after adjusting for the effects of zidovudine, PCP prophylaxis reduced significantly the probability of progression to a first episode of PCP during 6, 12, 18, and 24 month intervals. This study suggests that early primary PCP prophylaxis is effective in preventing first episodes of PCP, and that the efficacy of zidovudine demonstrated in clinical trials can be translated to the population level.
Zidovudine use data were examined in the Multicenter AIDS Cohort Study to determine (i) if the proportion of pre-AIDS participants (i.e., CD4+ cells less than 200/mm3 or AIDS-related complex) taking zidovudine is high enough to explain a slower than expected rise in AIDS incidence in U.S. homosexual men since mid-1987; (ii) which factors are associated with starting zidovudine and clinical trials of zidovudine; and (iii) if pre-AIDS patients, as a group, are being undertreated. Data on zidovudine use, clinical trial participation, and sociodemographic, clinical, and hematologic variables were collected every 6 months from 1,195 AIDS-free HIV-1-seropositive homosexual men from April 1987 to September 1989. Overall prevalence of zidovudine use rose from 3.6% in mid-1987 (visit 7) to 23% in mid-1989 (visit 11). Of those with less than 200 CD4+ lymphocytes/mm3, the prevalence of zidovudine use rose from 23% (24% if those taking zidovudine or placebo as part of a clinical trial are included) at visit 7 to 58% (69%) at visit 11. Of those with ARC, 20% (23%) were using zidovudine at visit 7 and 55% (65%) at visit 11. Although numbers were small, the advanced ARC participants (CD4+ cells less than 200/mm3 and two or more symptoms) reported the highest treatment rates (50, 78, 80, 60, and 74% at visits 7-11, respectively). By September 1989, 42% (31%) of those with CD4+ lymphocyte levels less than 200/mm3 were still not receiving zidovudine, suggesting that many high-risk, pre-AIDS individuals are being undertreated. To explore this finding further, we examined a range of sociodemographic, hematologic, and clinical variables to determine which factors best predicted initiation of zidovudine therapy outside of clinical trials. In multivariate analyses, CD4+ lymphocyte number was the most consistent predictor of initiation of therapy over all four study visits. For each 100 cells/mm3 deficit, the odds ratios were 2.3 (95% C.I. of 1.7-3.1) at visit 7 and 1.7% (95% C.I. of 1.4-2.0) at visit 11. Symptom status and education level were also associated with starting zidovudine, but not at all visits. The relatively low predictive power of the clinical variables raises and the possibility that nonclinical factors not measured in the MACS (drug cost, third-party insurance restrictions, and individual preferences) may play an important role in predicting zidovudine use. Finally, comparisons were made between seropositive participants starting clinical trials of zidovudine and the rest of the study population. No important differences were found in demographic or major clinical variables between clinical trial participants and zidovudine nonusers in this study.
In a single decade, the pandemic of human immunodeficiency virus (HIV) infection has become an international health, social, and economic emergency. Early and effective intervention is urgently needed for both prevention of HIV infection and for the amelioration of clinical disease. Results of therapeutic trials have suggested expanding the population for which chemotherapy is indicated. In this paper, we first review the findings from selected recent drug trials, using zidovudine and pentamidine as examples. We then discuss six issues that we believe to be crucial for future epidemiologic research in the service of vaccine and drug development: 1. To identify which complications of HIV infection most urgently require development of new therapies, we must characterize the frequency and severity of specific medical events (outcomes) in persons taking a variety of treatments. 2. Currently, acquired immunodeficiency syndrome (AIDS) therapeutic trials gauge the effectiveness of new therapies by their impact on such clinical parameters as the time to development of AIDS or death. These approaches take too long to provide information. We urgently need to identify surrogate markers of clinical outcome that will be useful in the early assessment of treatment efficacy. 3. Progress in vaccine development is being retarded because we do not have enough data from natural history studies on host immunologic responses to suggest that a given response is protective. We therefore need to identify natural correlates of immunity, which can help set priorities in vaccine development. 4. Discovery that a therapy works in the setting of a clinical trial is only a first step in intervention. We must also assess the impact of new therapies on the health of the public, evaluating access to health care, compliance, and other barriers to treatment. 5. Clinical trials are usually associated with the effort to prevent disease in infected persons. However, other trials are needed to assess efforts to interrupt viral transmission through use of condoms, use of virucides, and treatment of sexually transmitted diseases, and by effecting specific behavioral changes. 6. Traditional methods of conducting clinical therapeutic research may not be adequate to address urgent questions in the AIDS/HIV epidemic. We must develop innovative clinical research methods, including better use of data from observational studies, to infer what we can about the effect of treatment on the clinical course.
We investigated the relationship of human papillomavirus (by cervicovaginal lavage and Southern blot), human immunodeficiency virus, and squamous intraepithelial lesions in 96 high-risk women in the Bronx, New York. Antibodies for human immunodeficiency virus were detected in 51 (53%) women. Of the 33 women with symptomatic human immunodeficiency virus infection, 23 (70%) had human papillomavirus infection compared with 4 of 18 (22%) asymptomatic women who were human immunodeficiency virus seropositive and 10 of 45 (22%) uninfected women (p less than 0.0001). The rate of squamous intraepithelial lesions was 52% (14 of 27) for women with both viruses detected, 18% (6 of 34) for women with either virus detected, and 9% (3 of 35) for uninfected women. Among symptomatic human immunodeficiency virus-infected women, a strong association between human papillomavirus infection and squamous intraepithelial lesions was demonstrated (odds ratio, 12; 95% confidence interval, 1.3 to 108). Risk was highest for younger women from ethnic or racial minority groups. Advanced human immunodeficiency virus-related disease, with its associated immunosuppression, seems to exacerbate human papillomavirus-mediated cervical cytologic abnormalities. Public health measures are needed to provide Papanicolaou smear screening and appropriate clinical follow-up and treatment for women at high risk for human immunodeficiency virus infection.
BACKGROUND - Zidovudine has been shown to prolong survival in patients with the acquired immunodeficiency syndrome (AIDS) and, in persons with human immunodeficiency virus (HIV) infection but not AIDS, to delay the progression to AIDS. However, it is still uncertain whether treatment before the development of AIDS prolongs survival.
METHODS - We analyzed data from a cohort of 2162 high-risk men who were already seropositive for HIV type 1 (HIV-1) and 406 men who seroconverted from October 1986 through April 1991. There were 306 deaths. The probabilities of death were compared among men at similar stages of disease who began zidovudine therapy before the diagnosis of AIDS and among those who did not. Relative risks of death were calculated for each of five initial disease states on the basis of CD4+ cell counts and clinical symptoms and signs appearing over follow-up periods of 6, 12, 18, and 24 months. Adjustments were also made for the use of prophylaxis against Pneumocystis carinii pneumonia (PCP).
RESULTS - After we controlled for CD4+ cell count and symptoms, the use of zidovudine with or without PCP prophylaxis before the development of AIDS significantly reduced mortality in all follow-up periods. The relative risks of death were 0.43 (95 percent confidence interval, 0.23 to 0.78) at 6 months, 0.54 (95 percent confidence interval, 0.38 to 0.78) at 12 months, 0.59 (95 percent confidence interval, 0.44 to 0.79) at 18 months, and 0.67 (95 percent confidence interval, 0.52 to 0.86) at 24 months. After we adjusted for the effects of PCP prophylaxis, zidovudine alone significantly reduced mortality at 6, 12, and 18 months (relative risks, 0.45, 0.59, and 0.70, respectively), but not at 24 months (relative risk, 0.81). Among zidovudine users, those who also used PCP prophylaxis before the development of AIDS had significantly lower mortality at 18 and 24 months than those who did not (relative risks, 0.62 and 0.60, respectively).
CONCLUSIONS - The results of this study support the hypothesis that in HIV-1 infection, early treatment with zidovudine and PCP prophylaxis improves survival in addition to slowing the progression to AIDS.