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PubMed1999

Randomized, controlled trial of caloric supplements in HIV infection. Terry Beirn Community Programs for Clinical Research on AIDS.

OBJECTIVE: To compare the efficacy of three nutritional regimens in the prevention of weight loss. DESIGN: A three-arm randomized controlled trial with primary outcome measure percent change in weight over four months. PATIENTS: A total of 536 patients with CD4 count <200 cells/mm3 and stable weight, defined as <5% weight loss as determined by a weight measurement 3 to 6 months before randomization were recruited at fourteen administrative units in the United States, each unit consisting of multiple primary care sites. INTERVENTION: The three arms were 500 kcal daily of caloric supplement with peptides and medium-chain triglycerides plus a multivitamin and mineral supplement, 500 kcal of a caloric supplement with whole protein and long-chain triglycerides plus a multivitamin and mineral supplement, and a multivitamin and mineral supplement only. RESULTS: There were no significant differences among the three regimens in the percent change in weight (p = .74) and body cell mass (p = .63). On average, 65% of the recommended 500 kcal/day of caloric supplements containing peptides with medium-chain triglycerides and 82% of the 500 kcal/day of the caloric supplement containing whole protein and long-chain triglycerides were consumed. CONCLUSIONS: Caloric supplements do not promote increases in average weight or body cell mass in weight-stable, HIV-infected adults beyond that offered by a multivitamin and mineral supplement.

Adult↗
PubMed1999

Predictors for multidrug-resistant tuberculosis among HIV-infected patients and response to specific drug regimens. Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA) and the AIDS Clinical Trials Group (ACTG), National Institutes for Health.

SETTING: Mortality associated with human immunodeficiency virus (HIV) related multidrug-resistant tuberculosis (MDR-TB) is reduced with effective early therapy. Identifying predictors of, and effective regimens for, MDR-TB is critical. OBJECTIVE: A multicenter prospective study was initiated to 1) determine the demographic, behavioral, clinical and geographic risk factors associated with the occurrence of MDR-TB among HIV-infected patients, and 2) to evaluate the overall survival and clinical response of MDR-TB patients treated with specific drug regimens. METHODS: Patients were prospectively evaluated for MDR-TB. Information included history of prior treatment for tuberculosis, close contact with a known case of MDR-TB, and residence in a facility with known or suspected MDR-TB transmission. Patients with known MDR-TB, or those suspected to be at high risk, were offered enrollment in a treatment pilot study. Study drugs included levofloxacin and at least two additional drugs to which the patient's isolate was known, or most likely, to be susceptible. Survival was the primary endpoint. RESULTS: Complete data are available for 156 HIV-infected patients with confirmed tuberculosis. Sixteen (10%) had MDR-TB. Only a history of prior tuberculosis treatment was associated with MDR-TB in multivariate analysis (OR = 4.4, P < 0.02). Twelve patients with MDR-TB enrolled in the treatment pilot had a median CD4 cell count of 51/mm3. The cumulative probability of survival at one year was 75% (95% CI 50.5-99.5) and at 18 months, 65.6% (95% CI 38.1-93.1). Toxicity requiring discontinuation of medications occurred in two patients. CONCLUSIONS: A history of treatment for tuberculosis was the only predictor for MDR-TB in a cohort of HIV-infected patients with tuberculosis. In addition, this prospective study supports the results of prior retrospective studies that effective treatment impacts on mortality. Current second-line treatment, including high dose levofloxacin, appears to be reasonably well tolerated.

AIDS-Related Opportunistic Infections↗
PubMed2000

Frequency of antiretroviral drug resistance mutations in HIV-1 strains from patients failing triple drug regimens. The Terry Beirn Community Programs for Clinical Research on AIDS.

The frequency of protease and reverse transcriptase (RT) gene mutations was determined in HIV-1 strains from 153 patients entering the CPCRA 046 (GART) study who were failing triple-drug regimens consisting of one protease inhibitor (PI) and two RT inhibitors. Population-based sequence analyses showed that nearly all patients had similar RT gene mutations regardless of prior drug exposure, although the M184V mutation was significantly less prevalent in patients not recently treated with lamivudine. Whilst typical inhibitor-specific ('signature') protease gene mutations were found in patients failing their first PI, these mutations were significantly less likely to be found in patients exposed to two or more PIs. Protease gene mutations associated with multi-PI resistance were more likely to be observed in patients treated with more than one PI. These results suggest sequential treatment with PIs select for a relatively limited number of protease gene mutations that likely originated during early PI therapy. These protease gene mutations and a similarly limited set of RT gene mutations appear to be responsible for treatment failure in antiretroviral therapy.

Anti-HIV Agents↗
PubMed1989

AIDS--challenges to basic and clinical biomedical research.

The epidemic of acquired immune deficiency syndrome (AIDS) presents unusual challenges to basic and clinical biomedical research. The issues of clinical trials and access to therapeutic drugs pose dilemmas for researchers, physicians, and AIDS patients and their families. Clinical trials are conducted for two related but separate purposes: definitive identification of which experimental drugs work and which do not (in scientifically controlled trials performed by clinical researchers); and to provide data as to whether drugs are safe and effective so that they can be licensed and made available (determined by the Federal Drug Administration). The public must be made aware of the distinction between the two processes and of the need for strict control of the procedures in each. The National Institute of Allergy and Infectious Diseases, recognizing the need for greater access to clinical trials of investigational drugs by a broader spectrum of the infected population, is establishing the Community Programs for Clinical Research on AIDS. This national program will involve greater participation by community physicians and patients in the design and implementation of AIDS-related research projects. Further, the institute is committed to addressing the implications of the disproportionate representation of blacks and Hispanics among people with AIDS. More minority patients, researchers, and physicians must be brought into the clinical trials of AIDS therapies.

Acquired Immunodeficiency Syndrome↗
PubMed1999

Use of observational databases to evaluate the effectiveness of antiretroviral therapy for HIV infection: comparison of cohort studies with randomized trials. EuroSIDA, the French Hospital Database on HIV and the Swiss HIV Cohort Study Groups.

OBJECTIVES: It is important to assess the extent of bias when comparing the clinical efficacy of antiretroviral regimens in observational databases because, with the current lack of planned large trials, such analyses may represent the only means of assessing the risk of serious clinical events associated with new regimens. We aimed to compare the results from observational databases with those from randomized trials. METHODS: Three treatment comparisons from randomized trials [Delta, AIDS Clinical Trials Group (ACTG) 175, Community Programs for Clinical Research on AIDS (CPCRA) 007 and ACTC 320] were mimicked in cohorts: (i) zidovudine monotherapy versus combination regimens of two nucleoside analogues; (ii) zidovudine combined with either didanosine or zalcitabine; and (iii) a dual combination versus a triple regimen including a protease inhibitor. Data for over 10 000 patients from the French Hospital Database on HIV, the EuroSIDA study and the Swiss HIV cohort study were analysed for each of the comparisons. Progression to AIDS disease or death was analysed in Cox models, adjusting for baseline differences, and results compared with randomized trials. RESULTS: For comparison (i) the adjusted relative risk estimates from cohorts were between 0.61 and 0.84, favouring combinations over monotherapy, compared with 0.57 to 0.63 for trials. For comparison (ii) relative risk estimates from cohorts ranged from 0.81 to 1.01 compared with 0.77 to 0.92 for trials. For comparison (iii), two of the cohorts showed similar results to the ACTG 320 trial but one indicated a higher risk of progression on triple therapy [relative risk 1.20, 95% confidence interval (CI) 1.01-1.441, in direct contrast to the trial result (relative risk 0.50, 95% CI 0.33-0.76). CONCLUSION: Serious biases can be present when comparing outcomes from the use of antiretroviral regimens in observational studies. However, such bias is not inevitable and careful interpretation of the results from several observational studies considered together is likely to be informative, guiding the design of new trials.

Anti-HIV Agents↗
PubMed2005

Eligibility criteria for HIV clinical trials and generalizability of results: the gap between published reports and study protocols.

OBJECTIVE: Applicability of randomized controlled clinical trial (RCT) results to 'real world' situations is dependent on the comparability of trial participants to general patient populations. A full disclosure of criteria employed for trial enrollment is necessary for clinicians to assess generalizability. We sought to assess both the impact on generalizability and the disclosure rate of enrollment criteria for 32 major HIV RCTs in the AIDS Clinical Trial Group (ACTG) and Community Programs for Clinical Research on AIDS (CPCRA) trial networks. DESIGN AND METHODS: Eligibility criteria were compared in complete protocols to criteria listed in publications from these 32 NIH-funded HIV RCTs. We then applied these criteria to the Women's Interagency HIV Study (WIHS), the largest cohort study of HIV-infected women in the US. RESULTS: When applied to WIHS, eligibility criteria from protocols excluded 0-67.6% (median 42%) of WIHS participants (50.6% excluded from ACTG trials). Eligibility criteria in publications excluded 0-62% (median 19.6%) of WIHS (21.2% excluded from ACTG trials). The number of women in WIHS seemingly ineligible for trial participation per enrollment criteria listed in publications averaged only 60% of those actually excluded based on the protocols. CONCLUSIONS: We found that HIV RCT eligibility criteria excluded a large proportion of a representative cohort of HIV-infected women from trial participation. Furthermore, trial publications are not fully reflective of protocols in terms of disclosing eligibility criteria. Standardization and full disclosure of trial methodology will allow clinicians and researchers to more fully assess the generalizability of findings to their patient populations.

Clinical Protocols↗
PubMed1991

Clinical programs for clinical research on AIDS: description of a randomized prospective study of clindamycin versus pyrimethamine for prevention of Toxoplasma gondii infection.

The risk of toxoplasmic encephalitis complicating AIDS appears largely limited to those HIV-infected patients with serologic evidence of past Toxoplasma gondii infection and low CD4 lymphocyte counts. The Community Programs for Clinical Research on AIDS has initiated a randomized, placebo-controlled trial to determine if clindamycin or pyrimethamine prophylactic regimens are effective and safe in preventing toxoplasmic encephalitis.

Acquired Immunodeficiency Syndrome↗
PubMed1998

Clinical trials update in human immunodeficiency virus wasting.

The major acquired immunodeficiency syndrome (AIDS) clinical trials groups in the Division of AIDS of the National Institutes of Health have been investigating weight loss and wasting in persons with the human immunodeficiency virus (HIV) and AIDS. Both the AIDS Clinical Trials Group (ACTG) and the Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA) have developed research projects to study the pathogenesis, diagnosis, prevention, and treatment of HIV-related malnutrition and wasting. This article reviews multicenter trials concerning HIV-related malnutrition and wasting conducted by the AIDS clinical trials groups. CPCRA trials will examine the effects of caloric supplements and triglycerides, or the use of megestrol acetate, oxandrolone, and progressive resistance training, on weight loss in patients with HIV-associated wasting. Planned ACTG trials will study the effects of the combination of megestrol acetate and testosterone, the testosterone derivative nandrolone decanoate, or highly active antiretroviral therapy on weight loss. Results from these studies may also have relevance to clinical oncologists who are treating patients with cancer-related cachexia.

Anabolic Agents↗
PubMed2005

Quality of life in HIV-infected individuals receiving antiretroviral therapy is related to adherence.

This study assesses changes in quality of life (QoL) over time among HIV-infected individuals receiving antiretroviral therapy (ART) and evaluates how this relates to ARTadherence. Prospective, longitudinal data were examined from 1050 participants in two large, randomized, multi-centre antiretroviral clinical trials. QoL was assessed by the SF-12; adherence by the Terry Beirn Community Programs for Clinical Research on AIDS Antiretroviral Medication Self-report. Participants included 20% women, 53% African Americans, 16% Latinos; mean age was 39 years; mean baseline CD4+ cell count 230 cells/mm3; 89% were ART-naïve at entry. Baseline physical and mental health summary QoL scores were 45.4 and 42.9, comparable to scores reported in other advanced HIV populations. Significant improvements in mean QoL scores were seen for the group as a whole after 1 to 4 months on new ART regimens, and persisted for 12 months. Participants reporting 100% ART adherence achieved significantly higher QoL scores at 12 months compared to those with poorer adherence, particularly if 100% adherence was consistent (p < 0.001). Those with at least 80% ART adherence had smaller gains in QoL at 12 months when compared to baseline, while those with < 80% adherence had worsening of QoL. In this analysis, ART adherence was associated with improved QoL, particularly if adherence was sustained.

Adult↗
PubMed2003

Nadir CD4+ T cell count predicts response to subcutaneous recombinant interleukin-2.

Community Program for Clinical Research on AIDS 059 was a multicenter study conducted among human immunodeficiency virus (HIV)-infected individuals with CD4+ cell counts > or =300 cells/mm3 who were randomly assigned to receive antiretroviral therapy with or without intermittent subcutaneously administered recombinant interleukin-2 (rIL-2). To identify factors associated with a response to IL-2, a secondary analysis was performed that included the subset of rIL-2 recipients who were able to complete all 3 initial treatment cycles. Predictors of a change in CD4+ cell count between baseline and 1 month after the start of treatment cycle 3 were examined in a multivariate model that included sex, race, body surface area, rIL-2 dose, HIV load, and both baseline and nadir CD4+ cell count. The combination of race and sex (P=.027) and the nadir CD4+ cell count (P=.005) were significant predictors of mean CD4+ cell count response. Baseline CD4+ cell count had no significant effect. The strong association between nadir CD4+ cell count and CD4+ cell count response suggests that immunologic losses resulting from HIV-mediated CD4+ cell depletion may be irreversible.

Adult↗
PubMed1993

Drug abuse treatment programs as centers for HIV-related research and treatment.

The Observational Data Base (ODB) is a multicenter, longitudinal effort of the Community Programs for Clinical Research in AIDS (CPCRA) designed to collect HIV-related data on a large number of HIV-infected patients receiving primary care from community based physicians and health care groups. Over 400 patients from the Addiction Research and Treatment Corporation have enrolled in the ODB. Compared to the remainder of the CPCRA, ARTC ODB enrollees are more likely to be female, African American or Hispanic and to have injectable drug use and heterosexual contact with an injectable drug user as risk factors. The ARTC ODB patient profile closely resembles the fastest growing segments of the AIDS epidemic.

Adolescent↗
PubMed1995

Issues of recruitment, retention, and compliance in community-based clinical trials with traditionally underserved populations.

Site-specific sociodemographic recruitment, retention, and compliance (RRC) data were solicited at two points in time from the 18 National Institutes of Health-funded Community Programs for Clinical Research on AIDS (CPCRA). Based on their experiences delivering primary care to human immunodeficiency virus-infected individuals, nurses at each site identified organizational and client-centered factors functioning as barriers to protocol participation. In addition, the clinicians described the nature, frequency, and relative success of strategies used to enhance recruitment, retention, and protocol compliance. CPCRA units where nurses had clearly identified RRC barriers related to protocol design also were the sites that had accrued the most research participants. This study suggests that as the CPCRA units evolve, the most successful programs will be those in which the clinical and research staff can identify and develop innovative strategies that will successfully overcome RRC barriers.

Acquired Immunodeficiency Syndrome↗
PubMedDate not supplied

Data analysis issues for protocols with overlapping enrollment.

Many persons with HIV require and take several medications. The efficacy and safety of many of these medications are uncertain. Usually limited data on drug interactions are available. Thus simultaneous and sequential enrolment of patients into multiple studies is desired for reasons of science and efficiency. This paper discusses the analysis of data arising from coenrolment in multiple studies sponsored by the Community Programs for Clinical Research on AIDS (CPCRA). Factorial designs and those in which patients are sequentially instead of simultaneously randomized are compared. Approaches to data analysis, based on intention-to-treat, for individual and pairs of trials are described. An antiretroviral trial and a trial for prophylaxis of Pneumocystis carinii pneumonia (PCP) are used for illustration. We conclude that such analyses may yield useful information on drug interactions and that a more vigorous coenrolment policy should be pursued in AIDS research.

AIDS-Related Opportunistic Infections↗
PubMed1999

Cross-study hierarchical modeling of stratified clinical trial data.

Hierarchical random-effects models can be used to estimate treatment or other covariate effects in single-study analyses coordinated over multiple clinical units and can also be extended to a wide variety of cross-study applications. After reviewing the single-study case, we use data from five trial protocols to look for units that tend to have treatment effects consistently above or below the study-specific grand mean across several studies. As a first step, we summarize the patient-level data as study-specific and unit-specific estimated treatment effects and standard errors using independent Cox regression models. We then compare the results of a hierarchical model using these data summaries as input to those produced by a more fully Bayesian method that uses the actual patient-level survival data. We also compare various different models using a deviance information criterion, a recent extension of the Akaike information criterion designed for hierarchical models. Our procedure appears to be effective at answering the question whether certain clinical units of the Terry Beirn Community Programs for Clinical Research on AIDS are better than others at identifying treatment effects where they exist.

AIDS-Related Opportunistic Infections↗
PubMed1996

Response of CD4 lymphocytes and clinical consequences of treatment using ddI or ddC in patients with advanced HIV infection.

The value of CD4 lymphocyte counts as a surrogate marker in persons with advanced human immunodeficiency virus infection during antiretroviral treatment was assessed using longitudinal models and data from the Terry Beirn Community Programs for Clinical Research on AIDS didanosine/zalcitabine trial of 467 HIV-infected patients. Patients with AIDS or two CD4 counts of < or = 300 who fulfilled specific criteria for zidovudine intolerance or failure were randomized to receive either 500 mg didanosine (ddl) daily or 2.25 mg zalcitabine (ddC) per day. Absolute CD4 counts were recorded at study entry and at as many as four visits. Patients were followed for clinical disease progression and survival. At 2 months, the difference in mean CD4 count from baseline was +15.4 cells/mm3 in the ddI group but -1.3 cells/mm3 in the ddC group. Patients assigned to ddI had a greater chance of a CD4 response at 2 months than those on ddC, yet only those in the ddC group with a response showed significant improvement in progression of disease or survival compared with ddC nonresponders, ddI responders, and ddI nonresponders (p = 0.03). We conclude that a CD4 response does not necessarily correlate with improved outcome and is therefore not a useful surrogate marker in these patients.

Antiviral Agents↗
PubMed2006

Disadvantages of structured treatment interruption persist in patients with multidrug-resistant HIV-1: final results of the CPCRA 064 study.

BACKGROUND: We report the final results of Community Programs for Clinical Research on AIDS (CPCRA-064) study, a multicenter, prospective, randomized, controlled trial that determines the long-term clinical impact of structured treatment interruption (STI) in patients with multidrug-resistant (MDR) HIV-1. METHODS AND RESULTS: Two hundred seventy-four patients on stable antiretroviral therapy with MDR HIV-1 treatment failure were randomized to a 4-month STI, followed by an optimized antiretroviral regimen (STI arm, n = 140) or an immediate change to an optimized antiretroviral regimen (control arm, n = 134). Main outcome measures were progression of disease or death and changes from baseline in HIV RNA levels (log copies/mL) and CD4 cell counts (cells/mm). The median baseline HIV RNA level was 5.0 log copies/mL, the median CD4 count was 147 cells/mm, and the nadir CD4 count was 32 cells/mm. The median follow-up was 37 months. After the STI period, there were no differences in HIV RNA level responses between treatment arms. Differences in CD4 count responses always favored the control arm, with an advantage of 84 cells from 0 to 4 months (P < 0.0001), 50 cells from 4 to 12 months (P < 0.0001), 45 cells from 12 to 24 months (P = 0.006), and 43 cells after 24 months (P = 0.07). Rates in the STI and control arms for first progression-of-disease event or death were 17.5 and 14.3, respectively (hazard ratio = 1.28; P = 0.22). CONCLUSION: STI before changing regimens in patients with MDR HIV-1 treatment failure has a prolonged negative impact on CD4 cell count recovery and does not confer progression of disease or virologic benefits.

Adult↗
PubMed2005

Prevalence of antiretroviral drug resistance mutations in chronically HIV-infected, treatment-naive patients: implications for routine resistance screening before initiation of antiretroviral therapy.

BACKGROUND: The prevalence of drug resistance among persons with newly acquired human immunodeficiency virus (HIV) infection is well documented. However, it is unclear to what extent these mutations persist in chronically infected, treatment-naive patients. METHODS: Prevalence of and factors associated with genotypic drug resistance were analyzed retrospectively in a subset of 491 chronically HIV-infected, antiretroviral-naive patients enrolled at 25 cities in the Terry Beirn Community Programs for Clinical Research on Acquired Immune Deficiency Syndrome (AIDS) Flexible Initial Retrovirus Suppressive Therapies trial during 1999-2001. Resistance was defined on the basis of the International AIDS Society 2003 definition, as well as the presence of additional mutations at codons 215 (C/D/E/S) and 69 (A/N/S) in the pol gene. Prevalence of mutations was estimated by use of techniques for stratified random samples. Logistic regression models were used to determine factors associated with resistance. RESULTS: Among the 491 chronically HIV-infected patients (mean CD4 cell count, 269 cells/mm(3); 31% of patients had a prior AIDS diagnosis), 57 (11.6%) had >or=1 resistance mutation, resulting in an estimated prevalence for the cohort of 10.8% (95% confidence interval [CI], 9.5%-12.1%). The prevalence was 8.8% if the 118I mutation was excluded. By drug class, the estimated prevalence of mutations conferring resistance to nucleoside reverse-transcriptase inhibitors was 7.8%, and the prevalence was 3.0% for nonnucleoside reverse-transcriptase inhibitors and 0.7% for protease inhibitors. In a multiple logistic regression analysis, non-Hispanic white subjects were twice as likely than African American subjects to have resistance (odds ratio [OR], 2.1; 95% CI, 1.1-4.1; P=.03), and there was a 40% increase per year in prevalence of mutations by later year of enrollment (OR, 1.4; 95% CI, 1.0-2.1; P=.05). CONCLUSIONS: These results demonstrate the persistence of drug resistance mutations in chronically HIV-infected patients and an increasing prevalence of resistance over time, and they support genotyping of virus at baseline for chronically HIV-infected patients.

Adult↗