Faculty Bibliography

To determine the effect of active tuberculosis on survival and the incidence of opportunistic infections in HIV-infected patients, we performed a retrospective cohort study at four U.S. medical centers to compare the survival and incidence rate of opportunistic infections in 106 HIV-infected patients with active tuberculosis (cases) with that of 106 HIV-infected patients without tuberculosis (control subjects) but with a similar level of immunosuppression (measured by the absolute CD4+ lymphocyte count) as the cases. Cases and control subjects were similar with regard to age, sex, race, previous opportunistic infection, and use of antiretroviral therapy, but they were more likely than control subjects to have a history of intravenous drug use (49 versus 19%). The mean CD4+ counts were similar for cases and control subjects (154 versus 153 cells/microliters, respectively). The incidence rate of new AIDS-defining opportunistic infections in cases was 4.0 infections per 100 person-months compared with 2.8 infections per 100 person-months in control subjects for an incidence rate ratio (RR) of 1.42 (95% confidence interval: 0.94-2.11). Cases also had a shorter overall survival than did controls subjects (p = 0.001). Active tuberculosis was associated with an increased risk for death (odds ratio = 2.17), even when controlling for age, intravenous drug use, previous opportunistic infection, baseline CD4+ count, and antiretroviral therapy. Although active tuberculosis may be an independent marker of advanced immunosuppression in HIV-infected patients, it may also act as a cofactor to accelerate the clinical course of HIV infection.

Delayed-type hypersensitivity (DTH) testing was evaluated as a predictor of human immunodeficiency virus (HIV) disease progression in 336 symptomatic patients with baseline CD4 cell counts of 200-500/mm3 who were participating in a randomized trial of early versus late therapy with zidovudine. Patients with a response of > 2 mm to any of seven antigens were categorized as reactive; those without were anergic. Anergic patients were significantly more likely than reactive patients to have HIV disease progression as evidenced by decrease in CD4 cell count (52% vs. 27%), development of AIDS (33% vs. 17%), or death (18% vs. 9%) (P < or = .02), irrespective of time of zidovudine initiation. By multivariate analysis, DTH results were an independent predictor of HIV progression separate from CD4 cell count, p24 antigen positivity, or level of beta 2-microglobulin. DTH skin tests are an independent predictor of HIV disease progression and may be of value in the evaluation of a patient's immune status

The likelihood that subjects in human immunodeficiency virus (HIV) vaccine efficacy trials will alter their behavioral risks for HIV infection over time must be considered in evaluating the feasibility of such trials and in estimating the necessary sample sizes to be enrolled. Potential subjects for future vaccine efficacy trials include injecting drug users (IDUs) and others who may be difficult to retain in studies and who may alter HIV-risk-related behaviors substantially over time. We have investigated behavior change, retention, and HIV seroconversion among 577 New York City resident IDUs and sexual partners of IDUs enlisted between July 1 and December 31, 1992. We attempted to see all subjects every 3 months for interviews, blood donation and HIV testing. We were able to retain 68% of subjects in the study through the third scheduled recall at 7.5-10.5 months after enlistment. HIV seroconversion through March 1, 1994, was 1.33/100 person-years at risk. There was a significant inverse relationship between HIV seroconversion and retention at the 9-month recall after adjusting for age, gender, and the amount of locator information provided by subjects at enlistment. Among subjects seen at each of the scheduled visits at 3, 6, and 9 months after enrollment, modest but statistically significant behavior changes that reduced risk were observed in self-reported drug injection frequency, heroin injection frequency, sexual contact with IDUs, and sharing of needles/syringes. The magnitude of these changes in risk, however, was small and may be transient. The behavior changes observed to date do not appear to be large enough to substantially alter calculations of sample sizes needed in future HIV vaccine efficacy trials

Streptococcus pneumoniae (pneumococcus) is an important pathogen that causes pneumonia, bacteremia, and meningitis in adults. In recent years, pneumococcal isolates resistant to penicillin have become increasingly prevalent in the U.S. For these reasons, wide use of the pneumococcal vaccine has been advocated. Pneumococcal vaccines have been proven to be effective in preventing the invasive complications of S pneumoniae infection. The efficacy of pneumococcal vaccines in preventing non-bacteremic pneumonia in high-risk subjects, however, has not been proven. The current pneumococcal vaccine is limited because it includes the antigens of the serotypes known to be associated with invasive infection, and it elicits a thymus-independent, B-cell response that evokes no memory and a poor immunologic response in many of the patients at greatest risk for pneumococcal infection. In the absence of data concerning efficacy of the pneumococcal vaccine against pneumonia, it is difficult to argue that it is cost-effective for this purpose. I concur with the recommendations for use of pneumococcal vaccine to prevent bacteremia, but I am skeptical about the vaccine's efficacy against pneumonia. More data and an improved vaccine are necessary

A case-control study of patients with progressive (cases) or nonprogressive (controls) disease was designed to determine the association among disease progression, zidovudine sensitivity, and syncytium-inducing phenotype. Viral isolates were screened for sensitivity to zidovudine using a peripheral blood mononuclear cell-based assay and for syncytium-inducing (SI) phenotype in MT2 cell culture. Thirty-four patients, whose disease progressed to AIDS or whose CD4 cell numbers fell < 200 cells/mm3, were matched with 34 patients whose conditions had not progressed or whose CD4 cell numbers remained > 200 cells/mm3. Virus was successfully cultured from both the progressor and the nonprogressor in 17 of these 34 matched case-control pairs. In six of the 17 pairs, virus isolated from the progressor had an IC50 (50% inhibitory concentration) for zidovudine > 1 microM and at least threefold greater than the IC50 of virus isolated from the matched nonprogressor (p = 0.04). In 16 of these 17 pairs the virus isolated from the progressor had the SI phenotype, indicative of high cytopathogenicity, while the virus from the matched nonprogressor had a non-syncytium-inducing phenotype (p < 0.0001). Zidovudine therapy did not appear to select for the SI phenotype in this patient population. A statistically significant association between high-level zidovudine resistance and clinical disease progression was demonstrated. A statistically significant association between the SI phenotype and disease progression was demonstrated. The results suggest that disease progression while being treated with zidovudine therapy may be more closely associated with the SI phenotype than with zidovudine resistance

Ethical dilemmas caused by external events and an interim subset analysis raised concerns about continuing a long-term VA clinical trial comparing early with later zidovudine therapy for symptomatic human immunodeficiency virus (HIV) infection. The first external event was the early termination of other, apparently similar, trials conducted by the AIDS Clinical Trials Group (ACTG) and the announced clear benefits for the zidovudine-treated patients. Interim analysis of the VA trial at this time did not show similar benefits. Subset analyses were performed to explore factors that might explain the different results. These suggested a difference in response to zidovudine in white and minority groups. The Data Monitoring Board and a special advisory panel reviewed these data and concluded that, since the VA results were neutral overall and the subset analyses based on small numbers, the trial should continue. By conference call, the study cochairmen and biostatistician discussed this decision with study personnel without revealing interim results, and study personnel passed the information on to patients at the participating centers. The second event was in March 1990, when the Food and Drug Administration (FDA) approved earlier use of zidovudine, which applied to patients still in the VA trial. Patients were asked to reaffirm their participation by signing a new informed consent that explained the findings reported by the ACTG, the FDA-approved revised recommendations, and the rationale for continuation of the VA trial. The consent form emphasized that continued masked therapy was optional and that unmasked treatment and follow-up would be provided to patients requesting it. Seventy-four percent of the participants chose to continue masked therapy. We conclude that when new external data are announced, informed participation in a long-term clinical trial may require a revised consent form and that it is ethical and practical to present this without disclosure of interim study results

Major surgical procedures, especially when performed under general anesthesia, can depress immunological parameters measured in vitro. Therefore concern has been expressed that operation might have an adverse effect on the immune status of individuals infected with the human immunodeficiency virus (HIV). Four HIV-positive patients without symptoms of HIV disease underwent cardiac valve replacement in consequence of infective endocarditis. After up to 15 months postoperatively, 3 patients are alive and well without signs of progressive immunodeficiency or recurrent endocarditis. One patient died of recurrent endocarditis without evidence of HIV-related disease on autopsy. Cardiac operation does not seem to accelerate HIV-related immunodeficiency