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Before the introduction of highly active antiretroviral therapy (HAART), HIV-infected persons were noted to have elevated triglyceride (TG) levels with low total cholesterol and low high-density lipoprotein cholesterol (HDL-C), presumably attributable to a persistent inflammatory state. Furthermore, elevation of serum lipids is a frequent and serious complication associated with the use of HAART.1-4 The most common lipid elevation observed is with the serum TG level.5 Although ritonavir is the antiretroviral drug (ARV) most commonly associated with this lipid change, other ARVs have also been associated with serum TG perturbations.6-8 There is mounting evidence that the observed metabolic syndrome characterized by elevated TGs, low HDL-C, glucose intolerance, and body fat changes may accelerate the development of atherosclerosis, leading to higher rates of cerebrovascular and coronary heart disease (CHD).9,10 HIV-infected patients with HAART-induced hypertriglyceridemia have been observed to have atherogenic dyslipidemia. Although there is not universal consensus, hypertriglyceridemia is increasingly being recognized as an independent risk factor in the development of CHD and is a secondary target for intervention in the most recent National Cholesterol Education Project (NCEP) Adult Treatment Panel III guidelines.11-14 In addition to increased CHD risks, high serum TG is associated with the development of pancreatitis. Thus, the identification of effective therapy for drug-induced hypertriglyceridemia is an important clinical concern. Presently, the recommended approaches to the treatment of serum hypertriglyceridemia consist of diet, exercise, and the use of drugs like fibrates or niacin.15 Neither diet nor exercise is consistently effective because of the difficulty in adhering to these lifestyle changes. Pharmacotherapy is somewhat effective, but in a large clinical trial in HIV-infected subjects with lipid abnormalities, fenofibrate alone reduced serum TG level to

Reduced energy intake is a primary factor in HIV-associated wasting. Megestrol acetate (MA) stimulates appetite and weight gain. However, much of the weight gained is fat, possibly as a result of MA-induced hypogonadism.The objective of the study was to determine whether coadministration of testosterone with MA could enhance lean body mass (LBM) accrual and evaluate the effects of MA, alone or combined with testosterone, on sexual functioning and the hypothalamic-pituitary-adrenal axis.This was a randomized, double-blind, placebo-controlled, multicenter trial.Fourteen AIDS Clinical Trials Units in the United States participated in the study.Seventy-nine HIV-positive men with 5% or more weight loss or body mass index less than 20 kg/m2 took part in the study.Subjects were randomized to receive MA (800 mg daily) plus testosterone enanthate (200 mg; MA/TE; n = 41) or placebo (MA/PL; n = 38) biweekly for 12 wk.Weight, body composition (bioelectric impedance analysis), adrenal and gonadal hormones, and sexual functioning (questionnaire) were measured.Both groups experienced robust increases in weight (median 5.3 and 7.3 kg in MA/TE and MA/PL, respectively), LBM (3.3 and 3.3 kg), and fat (3.0 and 3.8 kg). There were no significant differences between groups in the magnitude or composition of weight gain (P = 0.44, 0.90, and 0.11 for weight, LBM, and fat, respectively). Trough testosterone concentrations decreased to a greater extent in MA/PL (-12.3 vs. -6.1 nmol/liter in MA/TE; P = 0.04). Cortisol levels became nearly undetectable in subjects with plasma MA levels greater than 150 ng/ml. Sexual functioning was preserved with MA/TE but worsened in MA/PL.MA produced robust weight gain. Coadministration of testosterone preserved sexual functioning but did not enhance LBM accrual.

Purpose:To assess how patients with HIV who are enrolled in a clinical trials cohort rate their health and to compare their ratings with those of patients with HIV from 2 other cohorts: the HIV Cost and Services Utilization Study (HCSUS), and Adult AIDS Clinical Trials Group protocol 320 (ACTG 320). Methods: We analyzed baseline information for the 1649 subjects enrolled in the Adult AIDS Clinical Trials Group Longitudinal Linked Randomized Trials (ALLRT) study prior to March 2002 who had self-rated health data available. We compared those results with results from 2 other groups: HCSUS, the only nationally representative sample of people in care for HIV in the U.S., which conducted baseline interviews in 1996 and 1997, and ACTG 320, a randomized, double-blinded, placebo-controlled trial comparing a 3-drug antiretroviral regimen with a 2-drug combination, which enrolled subjects in the same general time frame as HCSUS. We used t tests, Pearson correlations, and linear regression to determine factors associated with self-rated health and z scores to compare results between cohorts. Results: The mean (SD) rating scale value on a 0–100 scale for ALLRT participants was 79.8 (16.8). Values were significantly lower for subjects who were older, had a history of injection drug use, had lower CD4 cell counts, or were beginning salvage antiretroviral therapy. Subjects in ALLRT reported significantly better self-rated health at baseline than those in HCSUS or ACTG 320 (11–12% higher rating scale values in ALLRT; p

Objective: To determine if particular components of antiretroviral drug regimens are associated with greater insulin resistance, dyslipidemia, and peripheral lipoatrophy. Methods: Metabolic and body composition variables were measured prospectively over 64 weeks in 334 antiretroviral-naive, HIV-infected subjects who were randomized to receive nelfinavir, efavirenz, or both, combined with zidovudine/lamivudine or didanosine/stavudine in a factorial design, multicenter trial. Subjects assigned to efavirenz (n = 110) were compared with those assigned to nelfinavir (n = 99); subjects assigned to zidovudine/lamivudine (n = 154) were compared with those assigned to didanosine/stavudine (n = 180). A subset of 157 subjects had serial dual-energy X-ray absorptiometry (DEXA) scans. Results: Lipid measures increased in all groups. Greater increases in high density lipoprotein (HDL) cholesterol occurred with efavirenz than with nelfinavir. Greater increases in total cholesterol, non-HDL cholesterol and HDL cholesterol occurred with stavudine and didanosine than with zidovudine/lamivudine. There were no differences in insulin resistance in the comparisons. After initial increases in the first 16 weeks, median limb fat decreased. Greater changes in percentage changes in limb fat occurred with didanosine/stavudine (-16.8%) than with zidovudine/lamivudine (+4.0%; P < 0.001 for overall change from baseline) and with nelfinavir (-13.1%) compared with efavirenz (+1.8%; P = 0.003). Conclusions: Over 64 weeks, all regimens were associated with increases in lipids but insulin resistance did not differ between groups. Regimens containing didanosine/ stavudine and regimens containing nelfinavir were associated with greater loss of limb fat.

There is a paucity of information on the safety and efficacy of lipid-lowering therapy for dyslipidemia associated with human immunodeficiency virus (HIV) and antiretroviral therapy. Our objective was to determine whether fenofibrate and pravastatin were equivalent for the treatment of combined dyslipidemia in HIV as measured by a composite of the National Cholesterol Education Project (NCEP) goals based on absolute values for low-density lipoprotein (LDL), triglycerides (TG), and high-density lipoprotein (HDL) and to compare the safety of these agents through 48 weeks. This was a randomized, open-label trial with subjects assigned to fenofibrate 200 mg (n = 88) or pravastatin 40 mg (n = 86) daily. Subjects who failed to reach the NCEP composite goal on monotherapy by week 12 received both drugs. The composite goal at week 12 was achieved in 1% of fenofibrate and 5% of pravastatin subjects. At week 16, 69/88 subjects on fenofibrate added pravastatin (FP) and 67/86 subjects on pravastatin added fenofibrate (PF). At week 48, 7% FP subjects and 3% PF subjects achieved the composite goal. Median changes in LDL/HDL/TG/non-HDL were -8/+5/-144/+50 and -14/+2/-66/+34 mg/dl in subjects receiving FP and PF, respectively. There were few adverse events and no rhabdomyolysis reported. Combination therapy with fenofibrate and pravastatin for HIV-related dyslipidemia provides substantial improvements in lipid parameters and appears safe, but is unlikely to achieve all NCEP targets for lipid levels.

Few studies have prospectively evaluated the impact of highly active antiretroviral therapy (HAART) on body weight and lean body mass (LBM) or explored the impact of baseline immunologic or virological changes on these parameters.Adult AIDS Clinical Trials Group (ACTG) protocol 892 was a prospective, 48-week, multisite observational study of body composition conducted during 1997-2000 among 224 antiretroviral-naive and antiretroviral-experienced subjects coenrolled into various adult ACTG antiretroviral studies. Assessments included human immunodeficiency virus type 1 (HIV-1) RNA load (by polymerase chain reaction); T lymphocyte subset analysis; Karnofsky score; height (baseline only); weight, LBM, and fat (by bioelectrical impedance analysis); and functional performance (by questionnaire).Overall, only modest median increases in body weight (1.9 kg) and LBM (0.6 kg) occurred after 16 weeks of therapy. Significantly greater median increases in body weight (2.1 vs. 0.5 kg; P=.045) occurred in subjects who achieved virological suppression (HIV-1 RNA load,500 copies/mL) at week 16 than in subjects who did not. Subjects who were antiretroviral naive at baseline gained more weight (median increase in body weight, 2.6 vs. 0.0 kg; P.001) and LBM (1.0 vs. 0.1 kg; P=.002) after 16 weeks of treatment than did subjects who were antiretroviral experienced. Subjects with lower baseline CD4 cell counts (200 cells/mm3) and subjects with higher baseline HIV-1 RNA loads (or =100,000 copies/mL) were more likely to show increases in LBM of1.5 kg (P=.013 and P=.005, respectively).HAART had modestly favorable effects on body composition, particularly in patients with greater pretreatment immunocompromise and virological compromise. The difference between antiretroviral-naive and antiretroviral-experienced subjects with regard to the ability to achieve increased body weight and LBM requires more study.

Background. Visual analog scale (VAS) scores are used as global quality-of-life indicators and, unlike true utilities (which assess the desirability of health states v. an external metric), are often collected in HIV-related clinical trials. The purpose of this study was to derive and evaluate transformations relating aggregate VAS scores to utilities for current health in patients with HIV/AIDS. Methods. HIV-specific transformations were developed using linear and nonlinear regression to attain models that best fit mean VAS and standard gamble (SG) utility values directly derived from 299 patients with HIV/AIDS participating in a multicenter study of health values. The authors evaluated the transformations using VAS and SG utility values derived directly from patients in other HIV/AIDS studies. Derived transformations were also compared with published transformations. Results. A simple linear transformation was derived (u = 0.44v + 0.49), as was the exponent for a curvilinear model (u = 1-[1- v ]1.6 ), where u = the sample mean utility and v the sample mean VAS score. The curvilinear transformation predicted values within 0.10 of the actual SG utility in 5 of 8 estimates and within 0.05 in 3 of 8 estimates (absolute error ranged from -0.01 to +0.21). The linear transformation performed some-what better, predicting within 0.10 of the actual SG value in 6 of 8 cases and within 0.05 in 5 of 8 estimates (absolute error ranged from -0.05 to +0.13). An alternative linear model (u =v + 0.018) derived from the literature performed similarly to our linear model (7 of 8 predictions within 0.10, 1 of 8 estimates within 0.05, and absolute error ranging from -0.15 to +0.10), whereas an alternative published curvilinear model (u = 1 - [1 - v ]2.3 ) performed the least well (2 of 8 estimates within 0.10 of the actual values and no estimates within 0.05). Conclusions. Predicted utilities are a reasonable alter-native for use in HIV/AIDS decision analyses and costeffectiveness analyses. Linear transformations performed better than curvilinear transformations in this context and can be used to convert aggregate VAS scores to aggregate SG values in large HIV/AIDS studies that collect VAS data but not utilities.

The advent of highly active antiretroviral therapy has greatly improved the long-term outcome of patients with human immunodeficiency virus (HIV) infection. This article reports successful cardiac transplantation in a patient infected with HIV type 1 (HIV-1) in whom heart failure had developed after daunorubicin therapy for Kaposi's sarcoma.

Objective: The relationship between HIV-1 viral load and the risk for opportunistic infection (OI) was examined in Adult AIDS Clinical Trial Group (AACTG) 722. a virology substudy of AACTG 323: a phase 4 randomized study designed to examine the use of chronic suppressive versus episodic fluconazole therapy. Methods: The primary analysis used a case-control sampling scheme with two controls per case (subjects that developed an OI) matched by gender, age, and time on study. Forty-five cases and matched controls were identified and used in the analysis. Results: Study 722 accrued 518 subjects between 5/97 and 11/99. Forty-five subjects developed serious Ols or refractory candidiasis. Median baseline CD4 count was 24 cell/mm 3 for cases and 46 for controls (p = .003). Median viral load (VL) was 5.02 loge 10 copies/mL for cases and 4.08 for controls (p = ,002). Multivariate analysis found four independent variables associated with time to OI: baseline VL and CD4 (RR = 2.2 per log increment and 6.0 per 50-cell increment, respectively), a one log increase in VL at any time (RR = 15), and history of an OI (RR = 5.2). Conclusions: VL and changes in VL were independently associated with risk of development of OIs in a prospective study and should be considered by clinicians when assessing patients for risk of OI.

OBJECTIVE To determine the efficacy and safety of amphotericin B oral suspension (ABOS) for the treatment of fluconazole refractory oral candidiasis in persons with HIV infection. DESIGN AND SETTING A prospective, multicenter, open label trial at 25 study centers within the AIDS Clinical Trials Group. PATIENTS AND METHODS Individuals with diffuse oral candidiasis after 14 days of treatment with 200 mg of fluconazole daily (more than five plaques or a single plaque > 3 cm largest length) were treated with ABOS, 100 mg/ml, 5 ml swish and swallow, four times daily for 14 days. Thereafter incomplete or non-responders received an additional 14 days of therapy and responders received maintenance ABOS twice daily for up to 6 months. Relapses during maintenance ABOS were treated by increasing the dose to four times daily. MAIN OUTCOME MEASURES To demonstrate an ABOS clinical response rate > 33% and a treatment-limiting toxicity rate < 50%. Clinical response was defined as the absence of mouth pain and the presence of less than five oral plaques, the largest being < 3 cm largest dimension. RESULTS Fifty-eight subjects with a median age of 39 years and a median CD4 count of 10 x 10(6) cells/l were enrolled. Four subjects were excluded from the analysis because of inadequate follow-up after randomization (n = 3) or the presence of active esophageal disease (n = 1). Of the remaining 54 subjects, 23 (42.6%; 95% lower confidence interval, 31.1%) were classified as responders after 28 days. Five subjects (9%) stopped treatment due to toxicity. Relapse occurred in 16 responders (70%). CONCLUSIONS Amphotericin B oral suspension is well tolerated but has limited efficacy for the treatment of fluconazole refractory oral candidiasis.

Virological measurement has become increasingly popular as an endpoint in the evaluation of new drugs to treat human immunodeficiency virus (HIV) diseases. A commonly used quantity to measure the viral load is the proportion of infected cells in a patient's blood. Although the literature suggests various patient-specific estimation procedures for such proportions based on a series of cell dilutions, the resulting estimates are highly unstable. Moreover, it seems inappropriate to use those estimates as raw data points to make inferences about the group differences in comparative studies. In this article, under a two-arm clinical trial setting, we propose semi-parametric methods to estimate the treatment difference with this particular quantity evaluated repeatedly over time. Our proposals are conceptually simple and implemented easily in practice. We also propose model checking techniques to examine the adequacy of the fitted model. Data from a recent trial conducted by the AIDS Clinical Trials Group to evaluate the relative merit of zidovudine (ZDV) and dideoxyinosine (ddI) illustrate the methods. Our analysis indicates that patients treated with high dose ddI tended to have significantly lower viral load than those treated with a low dose combination of ZDV and ddI. © 1997 by John Wiley & Sons, Ltd.

Cimetidine, widely used for peptic ulcer disease, blocks type 2 histamine receptors present on immune cells, including T cells, B cells, and monocytes. As an earlier published study showed evidence of increases in CD4 cell counts due to this drug, we conducted a randomized, placebo-controlled, 8-week trial of oral cimetidine (400 mg po t.i.d.) in a study involving 182 patients infected with human immunodeficiency virus (HIV). Overall, cimetidine-treated patients had a decline in CD4 + cell counts that was no different from the decline for placebo-treated persons, neither during the first 8 weeks of the trial (mean drop, 7.1% [standard error, 12.1-1.8] vs. 6.7% [standard error, 11.6-1.5]) nor during the subsequent 8 weeks of open-label administration of cimetidine. No differences were evident between the treatment groups in terms of the percentage reactive to p24 antigen at baseline, and p24 antigen concentrations did not change from baseline to the end of week 8. In summary, cimetidine is well tolerated by HIV-infected individuals but alters neither CD4 + cell counts nor at least one quantitative measure of viral load, HIV p24 antigen levels.

This article develops methods for estimating treatment effects in mixed-effects models using outcome data gathered from serial dilution assays. Our application allows us to estimate the viral burden of HIV infection before and after antiviral treatment from cell dilution assays. This assay is designed to determine the infectious units per patient peripheral blood mononuclear cell (PBMC). The infectious unit is the amount of virus required to produce detectable HIV infection in PBMC's from healthy, uninfected donors. At each dilution level of the patient cells, one observes whether or not it was possible for the virus from these cells to infect donor cells. Thus the assay result for each subject consists of a series of repeated binary outcomes. We propose an analytic approach in which patient-specific titers (measures of viral burden) are modeled as random effects from an unknown distribution, and treatment effects are modeled as fixed. This approach makes use of all assay results, even if many as...

OBJECTIVE To examine pretreatment factors associated with longer term (144 weeks) responses to antiretroviral therapy (ART). METHODS Of 1498 ART-naive subjects randomized to ART regimens, including > or =3 agents, 1083 patients who had plasma HIV RNA (vRNA) levels and CD4 cell counts at baseline and week 144 were analyzed. Primary baseline factors evaluated were CD4 cell count, vRNA level, gender, race, and age, using multivariable Cox, log-binomial, and linear regression models. RESULTS Shorter time to achieving a vRNA level

The impact of HIV infection and exposure to antiretroviral therapy on the development of subclinical atherosclerosis is incompletely understood.To compare intima-media thickness (IMT) of the carotid artery between HIV-infected subjects receiving protease inhibitor-containing regimens and subjects not receiving these regimens and to compare differences in the IMT of the carotid artery between HIV-infected subjects and HIV-uninfected subjects.A prospective matched cohort study in university-based outpatient clinics. Groups of three individuals (triads) matched on the following characteristics were enrolled: age, sex, race/ethnicity, smoking status, blood pressure and menopausal status. Group 1, HIV-infected subjects with continuous use of protease inhibitor (PI) therapy foror = 2 years; group 2, HIV-infected subjects without prior PI use; and group 3: HIV-uninfected. Ultrasonographers at six sites sent standardized ultrasound images to a central reading site for carotid IMT measurements. Carotid IMT was compared within the HIV-infected groups (1 and 2) and between the HIV-infected and uninfected groups in a matched analysis.One hundred and thirty-four individuals were enrolled in 45 triads. The median IMT in groups 1, 2 and 3 was 0.690, 0.712 and 0.698 mm, respectively. There were no statistically significant differences in IMT between groups 1 and 2, or in the combined HIV groups compared with the HIV uninfected group. Significant predictors of carotid IMT in a multivariate model included high-density lipoprotein (HDL) cholesterol, the interaction of HDL cholesterol and triglycerides, age and body mass index.We found no association between PI inhibitor exposure or HIV infection and carotid IMT.

Weight loss is associated with accelerated mortality and disease progression in patients with human immunodeficiency virus (HIV) infection. Although studies have examined a variety of anabolic therapies in HIV-infected men, the safety and efficacy of such treatments in women have not been adequately studied.In this randomized, double-blind, placebo-controlled, multicenter, phase I/II study, 38 HIV-infected women with documented weight loss of 5% or greater in the preceding year or a body mass index of less than 20 kg/m(2) were randomized to receive nandrolone decanoate (100 mg) or an equivalent volume of placebo every other week by intramuscular injection. Subjects received blinded treatment for 12 weeks, followed by open-label therapy for 12 weeks. Lean body mass and fat (bioelectrical impedance analysis) and weight were measured at baseline and at weeks 6, 12, 18, and 24. Biochemical assessments of safety (hematologic analyses, liver function tests, and sex hormone measurements) were performed at these same time points. Clinical signs and symptoms were monitored biweekly.Subjects randomized to receive nandrolone had significant increases in weight and lean body mass during blinded treatment (4.6 kg [9.0%] and 3.5 kg [8.6%], respectively; P.001 vs baseline and placebo in each case). Fat mass did not change statistically significantly in either group. Although there were no statistically significant differences between groups in biochemical measures, the number of grade 3 or greater toxicities, or reports of virilizing effects, a full assessment of safety cannot be made in a trial of this size.Nandrolone decanoate therapy may prove to be generally safe and beneficial in reversing weight loss and lean tissue loss in women with HIV infection and other chronic catabolic diseases.

Although initiation of potent antiretroviral therapy (ART) has significantly improved immune perturbations in individuals with AIDS, it is unclear which factors are most important in determining the degree of immune reconstitution.Whole blood was analyzed at baseline and week 12 in six groups of subjects (n = 81): those with acute or following immune reconstitution after Pneumocystis jirovecii (previously known as Pneumocystis carinii) pneumonia (PcP) (two groups) and cytomegalovirus (CMV) retinitis (two groups), HIV-infection without AIDS (one group), and healthy volunteers (one group). Absolute CD4+ and CD8+ T lymphocytes, naive (CD45RA+) and memory (CD45RO+) CD4+ T lymphocytes and percentages of activated CD8+ T lymphocytes (CD8+/CD38+/HLA-DR), and CD28 expression on CD4+ and CD8+ T lymphocytes were enumerated.The reconstituted CMV group, which had a history of a lower CD4+ T lymphocyte nadir compared to the reconstituted PcP group (15 cells/mm(3) versus 48 cells/mm(3); p = .013), had significantly lower absolute CD4+, CD8+ and naive CD4+ T lymphocytes and a trend toward lower memory CD4+ T lymphocytes compared to the reconstituted PcP group. Moreover, no difference was noted between the reconstituted groups in the proportion of subjects with undetected HIV-1 RNA. The reconstituted subjects had significantly lower absolute CD4+, memory CD4+ and naive CD4+ T lymphocytes than the HIV-positive controls and a significantly higher percentage of activated CD8+ T lymphocytes with a lower percentage of CD8+CD28 expression than the HIV-negative controls.The association of CD4+ T lymphocyte nadir with the extent of immune reconstitution in HIV-infected individuals suggests that HIV-1 may cause irreparable immune system damage despite potent ART.

Background: The prevalence of asymptomatic hyperlactatemia among HIV-infected individuals has been reported to be 4% to 36%. This variability may reflect differences in the definition of and risk factors for hyperlactatemia and/or techniques for venous lactate collection. Methods: We examined the prevalence of elevated venous lactate collected in accordance with Adult AIDS Clinical Trials Group (AACTG) guidelines among HIV-infected and nucleoside analogue-treated subjects with risk factors associated with hyperlactatemia. Sustained hyperlactatemia was defined as 2 consecutive levels ≥1.5 but ≤4 times the upper limit of normal (ULNI within 30 days. Results: Eighty-three subjects were enrolled. Two thirds had ≥2 risk factors, with 11% having >4 risk factors. The median entry venous lactate level was 1.2 mmol/L (range: 0.7-5.1 mmol/L). Two subjects had a lactate level >1.5 times the ULN: 1 with a value of 2.1 times the ULN at entry and a week 2 level of 1.2 times the ULN and a second subject with a week 2 value of 1.9 times the ULN but an entry level of 1.4 times the ULN. The latter subject developed symptomatic lactic acidosis 3 weeks following study discontinuation. Conclusions: Sustained asymptomatic hyperlactatemia among subjects with risk factors associated with hyperlactatemia was not observed when venous lactate was measured in a standardized fashion. One case of hyperlactatemia that evolved into symptomatic lactic acidosis was diagnosed soon after the completion of the study, however. Our findings indicate that asymptomatic hyperlactatemia is either very rare or an artifact of collection technique.

We performed a prospective observational study to assess the safety of stopping maintenance therapy for disseminated histoplasmosis among human immunodeficiency virus infected patients after response to antiretroviral therapy. All subjects received at least 12 months of antifungal therapy and 6 months of antiretroviral therapy before entry. Negative results of fungal blood cultures, urine and serum Histoplasma antigen level of4.1 units, and CD4+ T cell count of150 cells/mm3 were required for eligibility. Thirty-two subjects were enrolled; the median CD4+ T cell count at study entry was 289 cells/mm3. No relapses of histoplasmosis occurred after a median duration of follow-up of 24 months. This corresponded to an observed relapse rate of 0 cases per 65 person-years. The median CD4+ T cell count at final study visit was 338 cells/mm3. Discontinuation of antifungal maintenance therapy appears to be safe for patients with acquired immunodeficiency syndrome with previously treated disseminated histoplasmosis and sustained immunologic improvement in response to antiretroviral therapy.

Objectives (1) To document rates and patterns of adherence from enrollment until week 24 of an AIDS clinical trial; (2) to examine the association of adherence to clinical end-points including plasma HIV-1 RNA level and CD4 cell count; and (3) to identify predictors of adherence from clinical, behavioural, psychosocial and demographic factors. Design Sub-study of a multicentre, randomised, open-label, comparison-controlled trial; 21 collaborating units of the Adult AIDS Clinical Trials Group. Observational, prospective analysis. Methods Ninety-three subjects with baseline plasma HIV-1 RNA levels >500 copies/ml, who completed clinical assessment, plasma HIV-1 RNA titres and CD4 cell counts at study entry, weeks 2, 4 and every 4 weeks thereafter until week 24. All patients were antiretroviral-experienced but were naive to non-nucleoside reverse transcriptase inhibitors and protease inhibitors. Self-reported adherence to antiretroviral therapies prescribed as part of the trial was assessed every 4 weeks from trial, week 4 until week 24. Results Average adherence was high, with 63% of subjects reporting >95% adherence across the trial. However, there was a significant decline in adherence over time on trial. After controlling for potential confounding variables, patients who were less than 95% adherent to medications were 3.5-times more likely to have treatment failure (HIV-1 RNA >50 copies/ml) than subjects with adherence rates of 95–100%. The strongest predictor of adherence was adverse clinical events (for example, dermatological, gastrointestinal symptoms): patients with adverse events were 12.8-times less likely to have 95–100% adherence. Other clinical, demographic, psychosocial and behavioural factors were also significant predictors of adherence. Conclusions Adherence influences virological outcome even in AIDS clinical trials where overall adherence rates are high and should therefore be monitored in future trials. Intervention may be warranted to enhance adherence for subjects who have early toxicities, express concern about taking medications as directed, and for women and minorities.

BACKGROUND Macrolides have been reported to be effective for the prevention of cryptosporidiosis in persons with HIV infection. OBJECTIVE To evaluate the efficacy of clarithromycin and rifabutin for the prevention of cryptosporidiosis in persons with advanced HIV infection. DESIGN Cross-protocol analysis involving 2288 individuals with a history of a CD4 cell counts of < or = 100 x 10(6) cell/l who were enrolled in two prospective clinical trials to prevent Mycobacterium avium complex (MAC) infection and cytomegalovirus (CMV) end-organ disease. INTERVENTIONS Clarithromycin 500 mg twice daily, rifabutin 300-450 mg daily, the combination of the two or no MAC prophylaxis. MAIN OUTCOME MEASUREMENT Laboratory-confirmed cryptosporidiosis. Subjects were analyzed in an intent-to-treat and as-treated manner using time-to-event analyses (Cox proportional hazards models). RESULTS The median length of follow up was 463 days. The median CD4 count at entry was 29 x 10(6) cell/l (range 0-182). There were 60 cases of cryptosporidiosis during the prospective observational period, with an event rate of 2.2 per 100 person-years. In the intent-to-treat [relative risk (RR) 0.50; 95% confidence interval (CI) 0.26-0.96; P = 0.041 and as-treated (RR 0.42; 95% CI 0.20-0.91; P = 0.03) analyses, rifabutin alone was significantly associated with a lower rate of cryptosporidiosis. Clarithromycin alone was not protective in similar analyses (P = 0.98 and 0.90, respectively). CONCLUSIONS In doses used to prevent MAC infection, rifabutin but not clarithromycin decreases the risk of developing cryptosporidiosis in persons with advanced HIV infection who are not receiving potent combination antiretroviral therapy.

OBJECTIVE To describe factors predictive of >10% weight loss among enrolled participants in clinical trials of the AIDS Clinical Trial Group (ACTG). DESIGN A retrospective analysis of data from selected ACTG antiretroviral clinical trials completed prior to 1996 (ACTG 116, 117, 155, 175, and 241), which did not include protease inhibitors. METHODS Data were analyzed in Cox proportional hazards models to determine significant predictors for >10% weight loss while on study. Weight loss occurring within 30 days before or after an opportunistic infection (OI) was defined as "OI-associated." Both univariate and multivariate models were considered; gender-specific models were also analyzed to provide insight into potential gender differences in predictors of weight loss. RESULTS We found that substantial weight loss is a frequent occurrence among those enrolled in clinical trials of antiretroviral agents; approximately 15% of subjects in the studies considered experienced >10% weight loss. CD4 cell count and HIV-1 RNA at week 8, Karnofsky score, and injection drug use status were significant multivariate predictive markers for weight loss associated with an OI; baseline weight, hemoglobin, triglycerides, and gender were additional predictors for weight loss not associated with an OI. CONCLUSIONS This is the first study to characterize the association between baseline viral load and future weight loss. Baseline and week 8 immunologic parameters as well as measures of baseline symptomatology were significant predictors of weight loss associated and not associated with an OI.