Michael F. Para

Placebo-controlled phase 3 trial of a recombinant glycoprotein 120 vaccine to prevent HIV-1 infection.

BACKGROUND A vaccine is needed to prevent human immunodeficiency virus type 1 (HIV-1) infection. METHODS A double-blind, randomized trial of a recombinant HIV-1 envelope glycoprotein subunit (rgp120) vaccine was conducted among men who have sex with men and among women at high risk for heterosexual transmission of HIV-1. Volunteers received 7 injections of either vaccine or placebo (ratio, 2 : 1) over 30 months. The primary end point was HIV-1 seroconversion over 36 months. RESULTS A total of 5403 volunteers (5095 men and 308 women) were evaluated. The vaccine did not prevent HIV-1 acquisition: infection rates were 6.7% in 3598 vaccinees and 7.0% in 1805 placebo recipients; vaccine efficacy (VE) was estimated as 6% (95% confidence interval, -17% to 24%). There were no significant differences in viral loads, rates of antiretroviral-therapy initiation, or the genetic characteristics of the infecting HIV-1 strains between treatment arms. Exploratory subgroup analyses showed nonsignificant trends toward efficacy in preventing infection in the highest risk (VE, 43%; n=247) and nonwhite (VE, 47%; n=914) volunteers (P=.10, adjusted for multiple subgroup comparisons). CONCLUSIONS There was no overall protective effect. The efficacy trends in subgroups may provide clues for the development of effective immunization approaches.

Highly Active Antiretroviral Therapy Decreases Mortality and Morbidity in Patients with Advanced HIV Disease

The introduction of combination antiretroviral therapy for HIV infection revolutionized treatment of AIDS and HIV disease. Such treatment, which usually includes two nucleoside analogue inhibitors of HIV reverse transcriptase and at least one HIV protease inhibitor or non-nucleoside inhibitor of HIV reverse transcriptase, is called highly active antiretroviral therapy (HAART). Early cohort and registry-based studies showed a lower incidence of AIDS and decreased rates of AIDS-related mortality after the introduction of HAART in late 1995 in the United States (1-3), France (4), Australia (5), Germany (6), and Switzerland (7). However, ecologic studiesthose that measured use of HAART and mortality in groups rather than in individual patientsmay be subject to confounding by calendar period changes in other unmeasured variables. In addition, many studies that directly measured the effects of HAART on survival of patients with AIDS did not provide specific evidence of such effects in the patients with the most advanced cases (8-10), with the exception of small cohorts of patients with cytomegalovirus (CMV) retinitis (11) and progressive multifocal leukoencephalopathy (12). We therefore studied the effect of HAART in a large multicenter trial of blood transfusion in patients with advanced HIV disease who were also anemic, an indicator of poor prognosis (13, 14). Because the study spanned the period before and after the introduction of HAART, we could directly assess the effect of HAART status on subsequent death or opportunistic events. In addition, because our person-year analysis was controlled for calendar time, our estimates of the magnitude of the effect of HAART on mortality and morbidity are less likely to be confounded by changes in patient mix or medical practice compared with previously published studies. Methods Patients and Study Design The Viral Activation Transfusion Study (VATS) was a multicenter, randomized, double-blind clinical trial of leukoreduced versus nonleukoreduced red blood cell transfusion in HIV-infected patients who required a first transfusion for anemia. Details of the study design have been published elsewhere (15, 16). In brief, we enrolled patients who were HIV seropositive, were CMV seropositive or had a history of documented CMV disease, had an expected survival of at least 1 month, and required red blood cell transfusion for anemia. Data on clinical end points and prescribed medications were obtained by interview and medical record review at baseline and every 3 months thereafter. Ophthalmologic examinations to detect CMV retinitis were done at baseline and every 6 months thereafter. In patients who did not return for follow-up visits, vital status was ascertained by review of the medical record, a search for a death certificate, and tracing by using public databases. Of 528 patients, 58 were excluded before death or end of the study, including 29 for whom no follow-up information on opportunistic events was available and 3 for whom follow-up for death but not for opportunistic events was complete. The CD4+ lymphocyte count and plasma HIV RNA level were measured by using frozen blood specimens at the central study laboratory, as described elsewhere (15). The study protocol was approved by the institutional review boards of the 11 participating medical centers, and informed consent was obtained from all participants. Definitions of HAART and End Points The VATS did not dictate the choice of antiretroviral therapy for enrolled patients, except that prescription of new antiretroviral drugs was discouraged during the 2 weeks after the first two transfusion episodes. Highly active antiretroviral therapy was defined as prescription of at least three antiretroviral medications with activity against HIV, at least one of which was an HIV protease inhibitor or a non-nucleoside HIV reverse transcriptase inhibitor. Medication history collected at each quarterly visit included the names and start and stop dates of any HIV antiretroviral medications taken since the previous visit or in the 30 days before entry into the study. Patients taking no HIV antiretroviral medications and those taking HIV antiretroviral medications that did not fulfill our definition of HAART were classified as before HAART until the day that they began HAART. Once a patient initiated HAART, all of his or her subsequent follow-up time remained designated as after HAART even if they discontinued HAART, to approximate an intention-to-treat analysis. We made this conservative decision to avoid overestimating the effect of HAART, which would occur if patients who stopped HAART because of intolerance subsequently contributed outcomes to the before HAART person-years. Adherence to prescribed medications was not measured. End points of the current study were death, opportunistic events, and recurrent transfusions. Opportunistic events were defined a priori and confirmed by expert reviewers; they included clinical diagnoses corresponding to the Centers for Disease Control and Preventions AIDS-defining conditions (17), with some modifications. Presumptive diagnoses of central nervous system toxoplasmosis were allowed according to the Centers for Disease Control and Preventions definition. For CMV retinitis, progression of disease requiring initiation of or a change in anti-CMV medication counted as a clinical event. For analysis, end points were grouped as follows: CMV opportunistic events; non-CMV opportunistic events; all opportunistic events; death; and any end point, including death and all opportunistic events. We analyzed recurrent red blood cell transfusion (that is, occurring after the enrollment transfusion event) as a separate end point. Statistical Analysis We used a person-years approach to analyze event rates. The denominator for these rates was not the individual patient but was person-years of observation time, defined as study follow-up time for each patient classified as before or after initiation of HAART and summed over all patients. For example, patients who started HAART during the study contributed observation time to both the post-HAART and pre-HAART categories, in effect serving as their own controls. Patients who began HAART before study entry and those who never began HAART during the study period contributed only post-HAART or pre-HAART observation time, respectively. Observation time for a patient extended from the date of study entry to death or the end of follow-up. Because some patients had no follow-up information for opportunistic events and a few had less follow-up for opportunistic events than for mortality, the total observation time for opportunistic events was shorter than that for overall survival. Events were assigned to the time period during which they occurred, and incidence was reported as the number of events per person-year of observation time. A single patient could contribute multiple events (except for the mortality analysis) to the same or to different time periods. The association between HAART use and incidence rates was expressed as a rate ratio. Confidence intervals and P values were calculated from a Poisson regression model using generalized estimating equations with exchangeable correlation structure to adjust for correlated observations across time within the same patient (18, 19). All P values are two sided. Because the use of HAART increased dramatically over the 4 years of the study, the comparison of post-HAART and pre-HAART data is confounded with calendar time. In addition, the mixture of HIV risk groups, prevalence of prophylaxis against opportunistic infections, diagnostic testing accuracy, and physician experience may have changed over time. To evaluate and control for these and other calendar time effects, each patients observation time was further categorized as four 1-year calendar time periods, starting in July 1995. Similarly, a patients time since entering the study was divided into five study time periods (0 to 6, 7 to 12, 13 to 18, 19 to 24, or >24 months from randomization). The Poisson regression generalized estimating equations method was then used to calculate the rate ratios associated with CD4 T-cell count, plasma HIV RNA level, calendar time, and time on study and to adjust the comparisons of post-HAART and pre-HAART data for these covariates, both in pairs and combined with patient characteristics. Results Participants The VATS enrolled patients with anemia and HIV infection who received a first red blood cell transfusion between August 1995 and July 1998. Patients were followed until death or their last scheduled quarterly visit before 30 June 1999. Of 531 patients enrolled in VATS, we excluded 3 patients for whom no data on medication were available; thus, the sample for analysis in this study was 528 patients. Table 1 shows the baseline characteristics of the study sample. Most patients were 30 to 49 years of age and male, and equal proportions of patients were of white and nonwhite ethnicity. Half of the patients were men who reported sex with other men as their only HIV risk factor; 19% each were injection drug users or sexually active heterosexuals without other risk factors for HIV; and 12% had multiple or other risk factors. At baseline, the median CD4+ lymphocyte count was 0.015 109 cells/L, and 69% of patients had a CD4+ lymphocyte count less than 0.050 109 cells/L. The median HIV RNA level was 4.8 log10 copies/mL, and only 8% of patients had plasma levels of HIV RNA levels less than 200 copies/mL. Table 1. Baseline Characteristics of 528 Patients in the Viral Activation Transfusion Study At baseline, most patients had previously taken antiretroviral medication; more than half had taken such medication for 12 months or longer. The proportion of patients taking prophylaxis or treatment of Pneumocystis carinii pneumonia and Mycobacterium avium complex infection decreased from 95% and 49%, respectively, in 19951996 to 82% and 44% in 19

The Safety and Efficacy of Zidovudine (AZT) in the Treatment of Subjects with Mildly Symptomatic Human Immunodeficiency Virus Type 1 (HIV) Infection: A Double-Blind, Placebo-Controlled Trial

OBJECTIVE To evaluate the efficacy and safety of zidovudine early in the treatment of human immunodeficiency virus type 1 (HIV) infection. DESIGN A double-blind, randomized, placebo-controlled trial with subject stratification by pretreatment CD4 T lymphocyte counts. SETTING Multicenter trial at AIDS Clinical Trial units. SUBJECTS Seven hundred eleven subjects with mildly symptomatic HIV infection. INTERVENTION Three hundred fifty-one subjects were assigned to placebo and 360 to zidovudine, 200 mg orally every 4 hours. The median duration of follow-up was 11 months. MEASUREMENTS AND MAIN RESULTS Fifty-one subjects developed the acquired immunodeficiency syndrome (AIDS), advanced AIDS-related complex, or death as a first critical event. For the stratum of subjects with more than 200 but less than 500 CD4 T lymphocytes/mm3 before treatment, 34 events occurred in placebo recipients and 12 in zidovudine recipients (P = 0.0002; relative risk [RR] estimate, 3.23 [95% CI, 1.67 to 6.24]). For the stratum of subjects with 500 to 799 CD4 T lymphocytes/mm3 before treatment, 2 events occurred in placebo recipients and 3 in zidovudine recipients. Candidiasis at study entry independently increased the risk for having an event (P = 0.005; RR estimate, 2.3 [95% CI, 1.29 to 4.12]); HIV antigenemia at study entry also increased this risk (P = 0.01; RR estimate, 2.1 [95% CI, 1.2 to 3.8]). Significant differences between the treatment groups in CD4 T-lymphocyte counts occurred in subjects with more than 200 but less than 500 CD4 T lymphocytes/mm3 after 4 weeks of therapy (P = 0.002). Differences persisted through week 52. Less prominent changes occurred in subjects with 500 or more CD4 T lymphocytes/mm3. Serum levels of HIV antigen decreased significantly in zidovudine recipients. Serious anemia and neutropenia occurred in 5% and 4% of zidovudine recipients, respectively, and in 0% and 1% of placebo recipients, respectively. CONCLUSION Zidovudine delayed progression of HIV disease and produced little toxicity in subjects with mildly symptomatic HIV disease and less than 500 CD4 T lymphocytes/mm3.

Aerobic exercise: effects on parameters related to fatigue, dyspnea, weight and body composition in HIV-infected adults.

ObjectivesThe purpose of the study was to examine the effects of aerobic exercise on physiological fatigue (time on treadmill), dyspnea [rate of perceived exertion (RPE) and forced expiratory volume at 1 s (FEV1)], weight, and body composition in HIV-1-infected adults (200–499 × 106 CD4+ cells/l). DesignThe study was a randomized, wait-listed, controlled clinical trial of aerobic exercise in HIV-1-infected adults on signs and symptoms associated with HIV-1 infection or its treatment. MethodsSixty subjects were recruited and randomized to two groups. Experimental subjects completed a 12-week supervised exercise program. Control subjects continued usual activity from baseline to week 12 and were then were enrolled in the exercise program. ResultsAt baseline, the groups were similar in age, weight, body mass index [mean body mass index (BMI) > 27], time since diagnosis, number of symptoms, CD4+ cell count, and number on protease inhibitor therapy (n = 7). Despite disproportionate attrition from the exercise group (38%), exercise subjects were able to remain on the treadmill longer, lost weight, decreased BMI, subcutaneous fat, and abdominal girth when compared to controls. The improvement in weight and body composition occurred without a decrease in kilocalories consumed. Exercise did not seem to have an effect on RPE, a surrogate for dyspnea, and FEV1. There was no significant difference in either the change in CD4+ cell count, percentage or copies of plasma HIV-1 RNA between groups. ConclusionsWe conclude that supervised aerobic exercise training safely decreases fatigue, weight, BMI, subcutaneous fat and abdominal girth (central fat) in HIV-1-infected individuals. It did not appear to have an effect on dyspnea.

Nelfinavir, Efavirenz, or Both after the Failure of Nucleoside Treatment of HIV Infection

BACKGROUND The optimal antiretroviral treatment for patients who have human immunodeficiency virus (HIV) viremia despite treatment with nucleoside reverse-transcriptase inhibitors (nucleoside analogues) remains uncertain. We studied treatment with regimens that combined two nucleoside analogues, at least one of which was new, with the protease inhibitor nelfinavir, the nonnucleoside reverse-transcriptase inhibitor efavirenz, or both. METHODS The study included 195 patients who had been treated with nucleoside analogues only, and had a plasma HIV type 1 (HIV-1) RNA level of at least 500 copies per milliliter. Patients were randomly assigned to receive, in addition to two nucleoside analogues, nelfinavir, efavirenz, or nelfinavir plus efavirenz. The primary end point was a plasma HIV-1 RNA level of less than 500 copies per milliliter at week 16. A secondary end point was the composite of the HIV-1 RNA levels measured at weeks 40 and 48. RESULTS At week 16 and at weeks 40 and 48, the proportions of patients in whom a plasma HIV-1 RNA level of less than 500 copies per milliliter was achieved were, respectively, 81 percent and 74 percent in the nelfinavir-plus-efavirenz group, 69 percent and 60 percent in the efavirenz group, and 64 percent and 35 percent in the nelfinavir group. Quadruple therapy resulted in a higher rate of viral suppression in both the short term (P=0.03) and the long term (P=0.001) than did triple therapy with nelfinavir. Triple therapy with efavirenz conferred a higher rate of long-term suppression than triple therapy with nelfinavir (P=0.004). Quadruple therapy also achieved a higher rate of virologic suppression than triple therapy with efavirenz (P=0.008). CONCLUSIONS In HIV-infected patients previously treated with nucleoside analogues, treatment with nelfinavir plus efavirenz and at least one new nucleoside analogue achieves a higher rate of viral suppression than do regimens with nucleoside analogues and nelfinavir or efavirenz alone.

Psychopathology in human immunodeficiency virus infection : lifetime and current assessment

The present study determined lifetime and current psychiatric functioning in a sample of homosexual or bisexual men at various stages of human immunodeficiency virus (HIV) infection in order to address several questions regarding the relationship between psychopathology and HIV infection. HIV+ asymptomatic or symptomatic and HIV- homosexual or bisexual men completed self-report measures of psychological and health functioning and participated in structured diagnostic interviews. Additional information regarding HIV-related life events and their potential relationship to onset of disorder and family history of psychiatric disorder were obtained. A high lifetime prevalence of affective and substance use disorder was found, with almost one half of the sample meeting criteria for both disorders. Lifetime affective disorder diagnosis was associated with a positive family history of affective disorder. HIV-related events were most closely associated with onset or recurrence of affective disorder compared with other disorders. Low current rates of psychiatric disorder and levels of emotional distress were found, with no differences in degree of psychiatric adjustment across stage of infection. We conclude that the lifetime prevalence of certain categories of psychiatric disorder is high in both HIV+ and HIV- homosexual samples. Increased rates of psychiatric disorders do not appear to be a consequence of HIV infection. However, episodes of illness, particularly affective disorder, may develop following an HIV-related event such as confirmation of infection. Although symptomatic subjects have more somatic difficulties, there appears to be no relationship between stage of illness and level of emotional distress.

Neuropsychological performance in symptomatic and asymptomatic HIV infection.

OBJECTIVE To examine cognitive function in patients at various stages of HIV infection, and to determine the nature and severity associated with stage of illness. DESIGN Subjects were administered an extensive battery of neuropsychological tests. SUBJECTS Two hundred and thirty-three HIV-1-infected homosexual/bisexual men and 77 HIV-negative control subjects who had been screened for previous neurological illness. All subjects were volunteers in a longitudinal study of neurobehavioral complications of HIV infection. RESULTS Patients with symptomatic infection differed from controls on a large number of measures, and asymptomatic patients had a more circumscribed pattern of deficit. On a summary measure of cognitive impairment, there was a twofold increase in the prevalence of impairment in asymptomatic patients relative to controls, and a fourfold increase in symptomatic patients. Memory and dexterity problems appear to be early features of neurobehavioral dysfunction, and frontal lobe deficits were found in patients with symptomatic infection. CONCLUSION These data indicate that there is a steady increase in the prevalence of neurobehavioral abnormalities associated with stage of infection. The pattern of abnormality also varies with disease stage.

HIV sexual risk behavior over 36 months of follow-up in the World's first HIV vaccine efficacy trial

Increased risk behavior among participants in HIV vaccine efficacy trials has been a concern. This study evaluated HIV sexual risk behavior among 5095 HIV-negative men who have sex with men (MSM) and 308 women enrolled in a randomized, double-blind, placebo-controlled efficacy trial of a bivalent rgp120 vaccine at 61 sites, primarily in North America. Sexual risk behavior data were collected at baseline and semiannually for 36 months. Overall, sexual risk behavior did not exceed baseline levels during the trial. Among MSM, younger age (≤30 years), perceived assignment to vaccine, and nonblack race were associated with an increased probability of unprotected anal sex. Among women, unprotected vaginal sex initially decreased but was statistically equivalent to baseline by 24 months, whereas unprotected vaginal sex with HIV-infected partners decreased from baseline, where it remained throughout the trial. HIV sexual risk behavior did not increase among trial participants; however, it was substantial throughout the trial. Consistently high levels of risk behavior and the association of these behaviors to perceived assignment and demographic variables underscore the need for vigilant HIV risk reduction counseling, informed consent, and educational processes in the context of HIV vaccine efficacy trials.

Delavirdine Susceptibilities and Associated Reverse Transcriptase Mutations in Human Immunodeficiency Virus Type 1 Isolates from Patients in a Phase I/II Trial of Delavirdine Monotherapy (ACTG 260)

ABSTRACT The development of human immunodeficiency virus type 1 resistance to delavirdine (DLV) was studied in subjects receiving DLV monotherapy. Phenotypic resistance developed in 28 of 30 subjects within 8 weeks. K103N and Y181C, which confer nonnucleoside reverse transcriptase inhibitor (NNRTI) cross-resistance, were the predominant reverse transcriptase mutations. P236L, which confers DLV resistance but hypersensitivity to other NNRTIs, developed in <10% of isolates.

Methods for Investigation of the Relationship between Drug-Susceptibility Phenotype and Human Immunodeficiency Virus Type 1 Genotype with Applications to AIDS Clinical Trials Group 333

Use of human immunodeficiency virus (HIV) drug-resistance testing in therapeutic decision making may be aided by understanding the relationship between results of genotypic and drug-susceptibility phenotypic assays. We investigated this relationship by applying 3 different statistical methods-cluster analysis, recursive partitioning, and linear discriminant analysis-to results for 72 patients followed in the Adult AIDS Clinical Trials Group (ACTG) protocol 333. ACTG 333 was a multicenter, randomized trial comparing 2 formulations of saquinavir (SQV) to indinavir (IDV) in patients with extensive hard-gel SQV experience. Data include protease amino acid sequences and 50% inhibitory concentrations for SQV and IDV at baseline. The 3 methods give similar results showing the association of mutations at codons 10, 63, 71, and 90 with in vitro resistance to IDV and SQV. Recursive partitioning is especially useful because it can identify interactions among mutations at different codons and accommodates many types of data as well as missing observations.