A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults.

BACKGROUND: The incidence and severity of herpes zoster and postherpetic neuralgia increase with age in association with a progressive decline in cell-mediated immunity to varicella-zoster virus (VZV). We tested the hypothesis that vaccination against VZV would decrease the incidence, severity, or both of herpes zoster and postherpetic neuralgia among older adults. METHODS: We enrolled 38,546 adults 60 years of age or older in a randomized, double-blind, placebo-controlled trial of an investigational live attenuated Oka/Merck VZV vaccine ("zoster vaccine"). Herpes zoster was diagnosed according to clinical and laboratory criteria. The pain and discomfort associated with herpes zoster were measured repeatedly for six months. The primary end point was the burden of illness due to herpes zoster, a measure affected by the incidence, severity, and duration of the associated pain and discomfort. The secondary end point was the incidence of postherpetic neuralgia. RESULTS: More than 95 percent of the subjects continued in the study to its completion, with a median of 3.12 years of surveillance for herpes zoster. A total of 957 confirmed cases of herpes zoster (315 among vaccine recipients and 642 among placebo recipients) and 107 cases of postherpetic neuralgia (27 among vaccine recipients and 80 among placebo recipients) were included in the efficacy analysis. The use of the zoster vaccine reduced the burden of illness due to herpes zoster by 61.1 percent (P<0.001), reduced the incidence of postherpetic neuralgia by 66.5 percent (P<0.001), and reduced the incidence of herpes zoster by 51.3 percent (P<0.001). Reactions at the injection site were more frequent among vaccine recipients but were generally mild. CONCLUSIONS: The zoster vaccine markedly reduced morbidity from herpes zoster and postherpetic neuralgia among older adults.

Using the national registry of HIV-infected veterans in research: lessons for the development of disease registries.

Disease-specific registries have many important applications in epidemiologic, clinical and health services research. Since 1989 the Department of Veterans Affairs has maintained a national HIV registry. VA's HIV registry is national in scope, it contains longitudinal data and detailed resource utilization and clinical information. To describe the structure, function, and limitations of VA's national HIV registry, and to test its accuracy and completeness. The VA's national HIV registry contains data that are electronically extracted from VA's computerized comprehensive clinical and administrative databases, called Veterans Integrated Health Systems Technology and Architecture (VISTA). We examined the number of AIDS patients and the number of new patients identified to the registry, by year, through December 1996. We verified data elements against information obtained from the medical records at five VA sites. By December 1996, 40,000 HIV-infected patients had been identified to the registry. We encountered missing data and problems with data classification. Missing data occurred for some elements related to the computer programming that creates the registry (e.g., pharmacy files), and for other elements because manual entry is required (e.g., ethnicity). Lack of a standardized data classification system was a problem, especially for the pharmacy and laboratory files. In using VA's national HIV registry we have learned important lessons, which, if taken into account in the future, could lead to the creation of model disease-specific registries.

Clinical and socioeconomic determinants of health care use among HIV-infected patients in the Department of Veterans Affairs.

This study estimates the impact of clinical and socioeconomic characteristics on health care use for HIV-infected patients. Data come from the Department of Veterans Affairs (VA) HIV Registry, which electronically extracts data from patients' automated medical records, and from patient interviews. Unlike prior studies, this analysis includes a staging system incorporating CD4 count and AIDS-defining diagnoses. Results showed that clinical factors were the most important determinants of health care use; socioeconomic variables were seldom significant. These findings were expected, since the VA is an equal access system, providing care regardless of socioeconomic status.

Surrogate marker of preclinical tuberculosis in human immunodeficiency virus infection: antibodies to an 88-kDa secreted antigen of Mycobacterium tuberculosis.

Antibodies to purified, size-fractionated secreted proteins of Mycobacterium tuberculosis in sera from patients with human immunodeficiency virus (HIV) infection and active tuberculosis (HIV/TB patients), and in stored sera obtained from the same patients prior to clinical manifestation of TB, were evaluated by ELISA, and the repertoire of antigens recognized was analyzed by immunoblotting. Compared with non-HIV/TB patients, HIV/TB patients had lower levels of anti-mycobacterial antibodies, and these were directed toward a restricted set of antigens. Antibodies to an 88-kDa secreted antigen were present in the sera of 74% of HIV/TB patients during the years (1.5-6) prior to manifestation of active, clinical tuberculosis, although only 66% were positive by the time tuberculosis was diagnosed. The presence of antibodies to the 88-kDa antigen can serve as a surrogate marker for identifying HIV-infected persons with active, subclinical disease who are at a high risk of developing clinical tuberculosis.

Changes in plasma HIV RNA levels and CD4+ lymphocyte counts predict both response to antiretroviral therapy and therapeutic failure. VA Cooperative Study Group on AIDS.

BACKGROUND: Markers are needed for assessing response to antiretroviral therapy over time. The CD4+ lymphocyte count is one such surrogate, but it is relatively weak. OBJECTIVE: To assess the association of changes in plasma human immunodeficiency virus (HIV) RNA level and CD4+ lymphocyte count with progression to the acquired immunodeficiency syndrome (AIDS). DESIGN: Analysis of data from a subset of patients in a multicenter, randomized, clinical trial. SETTING: Six Veterans Affairs medical centers and one U.S. Army medical center. PATIENTS: 270 symptomatic HIV-infected patients from the Veterans Affairs Cooperative Study on AIDS. INTERVENTION: Patients were randomly assigned to receive zidovudine or placebo initially; a cross-over protocol was established for patients receiving placebo who had disease progression. MEASUREMENTS: Reverse transcriptase polymerase chain reaction on cryopreserved plasma samples, previously obtained CD4+ lymphocyte counts, and clinical events. RESULTS: For each decrease of 0.5 log10 copies/mL in plasma HIV RNA level, averaged over the 6 months after randomization, the relative risk (RR) for progression to AIDS was 0.67 (P < 0.001). In a subset of 70 treated patients with long-term follow-up, a return to baseline plasma HIV RNA levels within 6 months of randomization was associated with progression to AIDS (RR, 4.28; P = 0.004). Plasma HIV RNA levels or CD4+ lymphocyte counts over time were more strongly associated with progression to AIDS than were baseline levels or counts. CONCLUSIONS: An adequate virologic response after initiation of antiretroviral therapy seems to require a decrease in plasma HIV RNA level of at least 0.5 log10 copies/mL that is sustained for at least 6 months. The independent relation between plasma HIV RNA level and CD4+ lymphocyte count over time and clinical outcome suggests that the measurement of plasma HIV RNA level, in addition to the CD4+ lymphocyte count, has a role in guiding the management of antiretroviral therapy.

Bacterial infections.

Non-opportunistic bacterial infections are an important cause of morbidity and mortality for HIV-infected adults and children. Factors associated with increased risk of these include altered B- and T-cell function; altered phagocytic cell function; skin and mucous membrane defects; and use of indwelling vascular catheters, antibiotics, or cytotoxic agents. The pathogens encountered most frequently are S. aureus, S. pneumoniae, H. influenzae, Salmonella sp., and Pseudomonas aeruginosa. Less commonly encountered organisms include Rhodococcus equi, Listeria monocytogenes, Shigella sp., and Nocardia asteroides, Strategies for prevention as well as diagnosis and treatment of these are discussed.

Prevention of community-acquired and nosocomial pneumonia.

Pneumonia is an important cause of morbidity and mortality in the United States. The provision of effective prophylaxis for pneumonia has become a major goal for both public health officials and individual physicians. Prophylaxis for community-acquired pneumonia is pathogen-specific and is directed toward the most common microorganisms that cause it. The 23-valent pneumococcal polysaccharide vaccine; the trivalent influenza vaccine; the Haemophilus b conjugate vaccine; and either trimethoprim-sulfamethoxazole, dapsone, or aerosolized pentamidine are recommended to prevent Streptococcus pneumoniae, influenza viruses, H. influenzae type b, and Pneumocystis carinii respectively. Except for the microorganisms listed above, the prevention of nosocomial pneumonia is not pathogen-specific. Rather, prevention of nosocomial pneumonia requires the use of infection control procedures, including patient and staff education; isolation of patients with highly contagious respiratory pathogens; vigorous hand washing; cleaning and sterilizaton of respiratory equipment; and use of sterile water in nebulizers and humidifiers. It also requires procedures to limit pooling and aspiration of secretions, such as positioning and rotation of the bed-bound patient; frequent suctioning of respiratory secretions using gloves and sterile suction catheters; and limiting enteral alimentation. Finally, selective decontamination of the digestive tract may be considered for intubated patients.

Changes in plasma HIV-1 RNA and CD4+ lymphocyte counts and the risk of progression to AIDS. Veterans Affairs Cooperative Study Group on AIDS.

BACKGROUND: Clinical trials of antiretroviral drugs can take years to complete because the outcomes measured are progression to the acquired immunodeficiency syndrome (AIDS) or death. Trials could be accelerated by the use of end points such as changes in CD4+ lymphocyte counts and plasma levels of human immunodeficiency virus type 1 (HIV-1) RNA and beta 2-microglobulin, but there is uncertainty about whether these surrogate measures are valid predictors of disease progression. METHODS: We analyzed data from the Veterans Affairs Cooperative Study on AIDS, which compared immediate with deferred zidovudine therapy. Patients' plasma levels of HIV-1 RNA and beta 2-microglobulin were measured in stored plasma. RESULTS: Among the 129 patients in the immediate-treatment group, 34 had disease that progressed to AIDS, as compared with 57 of the 141 patients in the deferred-treatment group (P = 0.03). Progression to AIDS correlated strongly with base-line CD4+ lymphocyte counts (P = 0.001) and plasma levels of HIV-1 RNA (P < 0.001), but not with base-line levels of beta 2-microglobulin (P = 0.14). A decrease of at least 75 percent in the plasma level of HIV-1 RNA over the first six months of zidovudine therapy accounted for 59 percent of the benefit of treatment, defined as the absence of progression to AIDS (95 percent confidence interval, 13 to 112 percent). Plasma beta 2-microglobulin levels and CD4+ lymphocyte counts explained less of the effect of treatment. A 75 percent decrease in the plasma HIV-1 RNA level plus a 10 percent increase in the CD4+ lymphocyte count could explain 79 percent of the treatment effect (95 percent confidence interval, 27 to 145 percent). CONCLUSIONS: Treatment-induced changes in the plasma HIV-1 RNA level and the CD4+ lymphocyte count, taken together, are valid predictors of the clinical progression of HIV-related disease and can be used to assess the efficacy of zidovudine and possibly other antiretroviral drugs as well.

Long-term follow-up of symptomatic HIV-infected patients originally randomized to early versus later zidovudine treatment; report of a Veterans Affairs Cooperative Study. VA Cooperative Study Group on AIDS Treatment.

Following a 4-year controlled trial comparing early and later zidovudine treatment, we conducted an additional 3-year follow-up. Of the original 338 patients, 275 participated. Clinical outcome measures were AIDS and death. In the early therapy group (n = 170), 67 patients progressed to AIDS compared with 85 in the later therapy group (n = 168); the relative risk (RR) comparing early with later therapy was 0.72% (95% confidence interval [CI] 0.52-0.99; p = 0.044). The early therapy group had 74 deaths compared with 73 in the later therapy (RR = 0.98; 95% CI, 0.71-1.36; p = 0.91). The early group had a peak CD4+ count increase at 1-2 months and a delay of 1 year before CD4+ counts fell below baseline. For patients who received zidovudine for more than the median duration (20.3 months) before their first AIDS diagnosis, the RR for death was 2.08 (95% CI, 1.36-3.19, p = 0.001). Additional factors independently associated with poor prognosis following AIDS were a CD4+ count of < 100 cells/mm3 and increased severity of the first AIDS diagnosis, whereas use of another antiretroviral agent was associated with improved survival. We conclude that early zidovudine therapy delays progression to AIDS but does not affect survival. Patients who progress to AIDS while on prolonged zidovudine monotherapy many benefit from a change to other antiretroviral therapy(ies).

Amphotericin B lipid complex compared with amphotericin B in the treatment of cryptococcal meningitis in patients with AIDS.

The study objective was to obtain preliminary information regarding the safety and efficacy of amphotericin B (AmB) lipid complex (ABLC) in the treatment of AIDS-associated cryptococcal meningitis. Of 55 patients randomly assigned to 6 weeks of therapy with ABLC (1.2-5.0 mg/[kg.d], with ascending doses for three sequential cohorts) or AmB (0.7-1.2 mg/[kg.d]), 46 received > or = 12 doses. Transfusion requirements, mean decreases in hemoglobin level, and mean increases in creatinine level were significantly greater with AmB than with ABLC. The total number of adverse events, infusion-related events, and occurrences of hypomagnesemia and hypokalemia associated with each form of therapy were similar. Among 21 recipients of ABLC at a dosage of 5 mg/kg (daily for 2 weeks and then thrice weekly for 4 weeks), symptoms and signs resolved for 18 (86%). Of those receiving > or = 12 doses of ABLC, cultures converted to negative for 8 (42%), were undeterminable for 3 (16%), and remained positive for 8 (42%) despite resolution of symptoms. Although preliminary, these data suggest ABLC has significant activity in patients with AIDS-associated cryptococcal meningitis. Because this formulation has less hematologic and renal toxicity than does AmB, further evaluation of ABLC is warranted.

Empirically treated Pneumocystis carinii pneumonia in Los Angeles, Chicago, and Miami: 1987-1990.

Many patients infected with the human immunodeficiency virus (HIV) with symptoms suggestive of pneumonia are treated empirically for Pneumocystis carinii pneumonia (PCP), although other bacterial infections (e.g., tuberculosis) and pulmonary Kaposi's sarcoma may cause identical symptoms. Empiric treatment for PCP may result in misdiagnosis and mistreatment. When the outcomes of cytologically confirmed versus empirically treated PCP cases were evaluated, the most important predictors of in-hospital mortality were severity of illness and use of bronchoscopy. Persons who did not undergo bronchoscopy had higher mortality rates than patients negative by bronchoscopy or cytologically confirmed as positive for PCP (22% vs. 11% vs. 14%, P < .01), although severity of illness and timing of anti-PCP medications did not differ significantly. Compared with cytologically confirmed cases, persons who did not have bronchoscopy were more likely to die than were bronchoscopy-negative patients (P < .05), after adjusting for severity of illness. Bronchoscopy use may have contributed to better outcomes for persons treated for HIV-related PCP.

Delayed-type hypersensitivity skin tests are an independent predictor of human immunodeficiency virus disease progression. Department of Veterans Affairs Cooperative Study Group.

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.

Pneumococcal vaccine in the prevention of community-acquired pneumonia: a skeptical view of cost-effectiveness.

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.

Zidovudine resistance, syncytium-inducing phenotype, and HIV disease progression in a case-control study. The VA Cooperative Study Group.

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 in continuing a zidovudine trial after early termination of similar trials.

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.

Cardiac valve replacement in patients infected with the human immunodeficiency virus.

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.

Tuberculous abscesses in patients with AIDS.

Five cases of large tuberculous abscesses in patients with AIDS were observed over a 2-year period at the New York Veterans Affairs Medical Center. These cases represent 11.6% of the 43 cases of tuberculosis diagnosed in patients with AIDS during that period. The abscesses were located in the liver, abdominal wall, psoas muscle, mediastinum, and peripancreatic area. All patients presented with localized pain or swelling, and four of five patients had fever. The diagnosis was made on the basis of detection of abscesses on computed tomography (CT) and the results of culture of abscess material obtained by CT-guided aspiration. CT-guided therapeutic drainage was performed in two cases. Despite administration of therapy, two of five patients died of tuberculous infection. Formation of tuberculous abscesses appears to be a common complication of tuberculosis in patients with AIDS. This diagnosis should be considered for patients with AIDS who have fever and localized pain or swelling.