Journal of acquired immune deficiency syndromes and human retrovirology : official publication of the International Retrovirology Association最新文献

Objectives: To compare, in a community-based therapeutic setting, the safety, tolerance, and efficacy of combination therapy with recombinant interferon-alpha2b (rIFN-alpha2b) and zidovudine (ZDV) to ZDV monotherapy.

Design: Open-label, two-armed, randomized study.

Patients and methods: Asymptomatic or minimally symptomatic HIV-infected adults without an AIDS-defining illness, a CD4 count of 200 to 500 cells/microl, and < or = 6 months of prior ZDV therapy received ZDV 100 mg orally five times daily. Patients randomized to rIFN-alpha2b received 3 million IU subcutaneously three times weekly for 2 weeks and 5 million IU three times weekly thereafter. The groups were compared with respect to adverse events (AEs), dosing modifications, treatment discontinuation, clinical endpoints and changes in CD4 count. A virology substudy compared the treatments with respect to HIV viral load and development of ZDV resistance.

Results: Between October, 1991 and January, 1993, 139 patients were randomized to combination therapy and 117 to ZDV alone. Of AEs reported at any grade, fatigue, myalgias, and sweating occurred significantly more often with combination therapy (p < .001). Study subjects receiving combination therapy showed modest but significantly greater weight loss (p = .0001), a significantly higher frequency of any abnormal laboratory test result (p = .002), neutropenia (p = .002), and leukopenia (p = .02), and also required dosage reduction for hematologic toxicity significantly more often (p < .05) than those in the ZDV monotherapy arm. No statistically significant differences were found between the groups with respect to development of specific AIDS-defining events, overall event rate, time to events, or change in performance status or CD4+ counts, or percentages or development of ZDV resistance. Viral burden, reflected by serum p24 antigen and quantitative peripheral blood mononuclear cell (PBMC) microcultures, was greater at baseline in the combination therapy group. Baseline SI phenotype predicted progression to AIDS (p = .004, chi2), whereas intermediate susceptibility to ZDV predicted development of ZDV resistance (p < .005, chi2). The annual rate of development of phenotypic resistance to ZDV was 16.8% and was not affected by administration of rIFN-alpha2b.

Conclusions: At the doses and schedule used in this study, the combination of ZDV with rIFN-alpha2b was not therapeutically superior to ZDV alone and was less well tolerated. The addition of rIFN-alpha2b to ZDV did not prevent or delay the development of ZDV resistance.

Objective: To compare the rate of HIV disease progression in a sample of polydrug injectors (AIDS Link to Intravenous Experiences [ALIVE] study) with that in a sample of predominantly opiate injectors (Italian Seroconversion Study [ISS]).

Design: Prospective cohort studies of HIV-positive individuals whose date of seroconversion (SC) is known with a good degree of precision. The ALIVE study involves a community-based cohort of injection drug users (IDU) in the United States and the ISS reports on a clinic-based cohort of seroconverters in Italy with different exposure modalities to HIV.

Methods: Data from the two cohorts were combined. The date of SC was estimated as the midpoint in time between the last negative and the first positive HIV test. Time-to-event (i.e., AIDS or death from an infectious disease) statistical methods were used. Relative hazards (RH) of progression to event were adjusted by age at SC, gender, and year of SC.

Results: Of the 1003 IDUs (251 from ALIVE and 752 from ISS), 226 progressed to AIDS, and 146 died after AIDS or from an infectious disease; of these, 10 were without an AIDS diagnosis. The two groups of IDUs differed in terms of age at SC (median, 35 years for ALIVE and 25 years for ISS), proportion of women (24% versus 31%), race (7.6% versus 100% white), and year of seroconversion (i.e., ISS participants seroconverted, on average, earlier than ALIVE participants). Although the univariate analysis suggested possible differences for progression to AIDS, or to death from infectious disease between cohorts, multivariate analyses that adjusted for age showed no significant differences by cohort, gender, race, or time of seroconversion. The median time to AIDS for 25-year-old persons was 12.3 years for ALIVE and 11.8 years for ISS; for 35-year-old persons, it was 8.5 and 8.2 years, respectively. These estimates were similar to those for non-IDUs observed in the ISS and to those from large cohort of homosexual men.

Conclusion: Our results confirm the importance of accounting for age when considering the incubation period for HIV infection. Despite differences in drug use characteristics, the similar median times to AIDS, for each age, between the two cohorts of IDUs and between the IDUs and the non-IDUs suggest a negligible effect of injection drug use on HIV progression.

Objective: To determine the incidence and determinants for discontinuation of initial highly active antiretroviral therapy (HAART).

Design: In this retrospective follow-up study from hospital files and pharmacy dispensing data, a standard dataset was collected including patient characteristics, therapy characteristics, and HIV-monitoring parameters (e.g., CD4+ lymphocyte counts, viral load determinations). Kaplan-Meier estimates of the cumulative probability of discontinuation of initial HAART were calculated. Cox proportional hazard analysis was used to identify determinants for discontinuation of initial HAART.

Patients: All patients starting HAART (n = 99) during June 1996 to February 1997 at our regional AIDS center.

Main outcome measures: Incidence and determinants for discontinuation of HAART.

Results: During the mean follow-up of 450+/-10 days, 27 patients switched initial HAART, 3 patients stopped any antiretroviral therapy. Reasons for switching were increasing viral load (18x), insufficient decrease of viral load (3x), and adverse events (6x). Nonnaivete for antiretroviral therapy and a lower CD4+ lymphocyte count at start were identified as determinants for discontinuation of initial HAART.

Conclusions: The overall incidence density for discontinuation of initial HAART was 25 per 100 patients/year. The main reason for switching was an increasing viral load. CD4+ lymphocyte counts at start and nonnaivete for antiretroviral therapy were identified as determinants for discontinuation.

Clinical trial endpoints based on magnitude of reduction in HIV-1 RNA levels provide an important complement to endpoints based on percentage of patients achieving complete virologic suppression. However, interpretation of magnitude of reduction can be biased by measurement limitations of virologic assays, particularly lower and upper limits of quantification. Using data from two AIDS Clinical Trials Group (ACTG) studies, widely used crude methods of analyzing HIV-1 RNA reductions were compared with methods that take into account censoring of HIV-1 RNA measurements. Such methods include Kaplan-Meier and censored regression analyses. It was found that standard crude methods of analysis consistently underestimated treatment effects. In some cases, the bias induced by crude methods masked statistically significant differences between treatment arms. Although statistically significant, adjustment for baseline HIV-1 RNA levels had little effect on estimated treatment differences. Furthermore, convenient parametric analyses performed as well as more complex nonparametric analyses. It is concluded that conveniently implemented censored data analyses should be conducted in preference to widely used crude analyses of magnitude of HIV-1 RNA reduction. To obtain complete information about virologic response to antiretroviral therapy, such analyses of magnitude of virologic response should be used to complement analyses of the percentage of patients having complete virologic suppression.

To assess the kinetics of viral replication and decay in cerebrospinal fluid (CSF), we studied the short-term effects of highly active antiretroviral therapy (HAART) on CSF HIV-1 RNA concentrations. In 15 HIV-positive patients, HIV RNA concentrations were measured in paired CSF and plasma/serum samples. Samples were obtained prior to and 5 to 24 days after initiation or change of HAART. The short-term effects of interruption of HAART were tested in 2 patients. Viral load was measured by the Roche Amplicor assay. During HAART, in 12 of 15 patients a significant reduction of CSF HIV RNA concentration was observed, ranging from 0.55 to 2.77 log10 (median, 1.37 log10). This was paralleled by a reduction of blood viremia ranging from 0.12 to 3.0 log10 (median, 1.65 log10). The median half-life, as calculated from the slopes of the two time-point measurements, for CSF and blood viral load was 2.66 and 2.36 days, respectively. In 2 patients, CSF viral load remained essentially unchanged despite substantial reduction of plasma viral load. In 1 patient, after interruption of HAART, a rapid increase of HIV RNA in the CSF and blood was seen. No correlation was found between the CSF:blood albumin ratio as a measure of the functional integrity of the blood-CSF barrier and the ratio of CSF:blood RNA concentration, which suggests that no major passive influx of HIV RNA moves from the blood into the CSF compartment. However, a correlation existed between the CSF cell count and the CSF viral load (r = 0.74; p < .003). We conclude that, in most HIV-infected individuals, the decay of viral load in the CSF is similarly rapid as that seen in plasma. The rapid kinetics of virus found in the CSF suggest that it may be produced by rapidly proliferating cells, such as lymphocytes.

Objective: Recent studies have documented alterations in body fat distribution that have been associated with protease inhibitor therapy. We compared body composition, including measurements of fat distribution, in 96 HIV-infected subjects studied since January 1996 (current HIV), subjects seen prior to January 1996 (previous HIV), and healthy controls.

Design: Retrospective cross-sectional studies of subjects matched by gender, race, age, and height.

Methods: Body weight, height, body cell mass by whole-body counting of 40K plus fat, fat-free mass, and body fat distribution by anthropometry were measured.

Results: Current HIV men weighed more (p = .025) and had more body cell mass than previous HIV men, but less than controls (p < .001). In women, the between group differences in fat were greater than the differences in body cell mass. Current and previous HIV study subjects had lower indices of subcutaneous and higher indices of visceral fat than controls. In current HIV subjects, body fat distribution was significantly associated with log plasma HIV RNA content but not with antiretroviral or protease inhibitor usage, nor with CD4+ lymphocyte counts. In 7 of 9 current HIV subjects studied, 24-hour urinary free cortisol excretion was abnormally high.

Conclusions: Alterations in body fat distribution are a characteristic feature in HIV infection. The occurrence of increased visceral fat content and decreased subcutaneous fat content preceded the era of combination antiretroviral therapy. The alteration in fat distribution may be affected by plasma HIV RNA content rather than antiretroviral or protease-inhibitor therapy. The body composition alterations might be associated with endogenous hypercortisolism.

Objective: Tuberculosis (TB) is the commonest HIV-related opportunistic infection in many developing countries and is thought to be a frequent underlying cause of HIV-associated wasting. We have used reference water dilution methods to examine the body composition changes associated with TB and to assess the severity and pattern of wasting.

Methods: The study was conducted at a charitable support house for poor and homeless HIV-infected people in Rio de Janeiro, Brazil. Male patients who were HIV-positive and receiving treatment for active TB (HIVTB+) and HIV-infected controls without TB (HIVTB-) were studied. Total body water (TBW) and extracellular water (ECW) were measured by giving oral doses of deuterium oxide and sodium bromide, respectively, and determining enrichment in plasma after 4 hours. Intracellular water (ICW), body cell mass (BCM), lean body mass (LBM) and fat mass were calculated from these parameters using standard equations.

Results: HIVTB+ (n = 11) and HIVTB- (n = 12) groups were similar in age, height, CD4 count and HIV risk factors. HIVTB+ men had significantly lower mean ICW (13.2 versus 16.6 kg; p = .02) and BCM (18.4 versus 23.0 kg; p = .02), a relative expansion of ECW (35.0 versus 30.0 L/kg body weight; p = .04), and small and nonsignificant reductions in total body weight (58.0 versus 62.1 kg; p = .26), LBM (45.5 versus 47.7 kg; p = .33) and fat mass (12.5 versus 14.4 kg; p = .51) compared with HIVTB- controls. BCM in the HIVTB+ group was similar to reference values for severe malnutrition. The relative depletion of BCM appeared excessive in comparison with reference values for uncomplicated starvation.

Conclusion: The nutritional status of HIVTB+ patients was significantly worse than HIVTB- patients. Body weight and LBM underestimated the nutritional deficit, and measurement of BCM is therefore necessary to appreciate the extent of malnutrition in such patients. Malnutrition in HIVTB+ patients is severe and may therefore contribute to decreased survival. Hypermetabolism appears to play a role in the wasting process in patients coinfected with HIV and TB.

Heterosexual transmission of HIV-1 is widespread in Southern Africa. Heteroduplex mobility assays (HMA) and phylogenetic analyses of V3-V5 envelope (env) gene sequences demonstrate that subtype C predominates in Zimbabwe. To elucidate factors contributing to the epidemic in Zimbabwe, clinical and virologic characteristics of recently acquired subtype C HIV-1 infection among 21 men and 1 woman were determined. In 12 of 19 men providing clinical histories, a sexually transmitted infection preceded serologic evidence of HIV-1, and 14 of 19 men complained of rash or fever before seroconversion. Quantitative p24 antigen levels, reverse transcriptase activity, and HIV RNA levels of 22 viral isolates correlated with in vitro infectivity in peripheral blood mononuclear cells (p < .05). Biologic phenotype assessed in MT-2 cells demonstrated that 3 of 22 isolates (14%) were syncytia inducing (SI) and the remaining 19 nonsyncytium inducing (NSI). Early growth of virus in culture was associated with increased plasma HIV RNA levels, decreased CD4 cell levels, and SI virus. Recent subtype C HIV-1 infection through heterosexual transmission in Zimbabwe demonstrated clinical and virologic features consistent with reports of seroconversion to subtype B viruses.

Given their high seroincidence, young gay men will be targeted for recruitment into HIV vaccine trials but many challenges stand in the way of enlisting their cooperation. This study examined factors associated with young gay men's willingness to participate in vaccine trials and identified reasons for agreeing or not agreeing to participate. The data come from the Young Men's Survey, a cohort of western U.S. young gay men aged 18 to 29 years, surveyed using mail-back questionnaires. Participants who reported being HIV-negative or who had not been tested for HIV (n = 390) were asked to rate their desire to be given an HIV vaccine and their degree of willingness to participate in a vaccine trial. They also responded to open-ended questions regarding their reasons for participating or not participating. Of these respondents, 91% wanted to be given an HIV vaccine, yet many had serious reservations about participating in a vaccine trial. Men who had engaged in HIV risk behavior reported greater willingness to participate. The most common reasons for wanting to participate were desires to contribute to ending the AIDS epidemic and desire to help others; however, fears for one's own health and safety made many reluctant to participate.