Grace Peng

Cd4+ count and risk of non-aids diseases following initial treatment for Hiv infection

Background:Reductions in AIDS-related morbidity and mortality following the advent of combination antiretroviral therapy have coincided with relative increases in chronic non-AIDS end-organ diseases among HIV+ patients. Objective:To examine the association of latest CD4+ counts with risk of non-AIDS diseases in a cohort of 1397 patients who initiate antiretroviral therapy. Methods:CD4+ counts and HIV RNA levels along with fatal, and non-fatal, AIDS and non-AIDS diseases (liver, cardiovascular, renal, and cancer) were assessed over a median follow-up of 5 years. Cox proportional regression models were used to study risk associations. Results:A total of 227 patients experienced an AIDS event and 80 patients developed a non-AIDS disease event. Both AIDS and non-AIDS diseases rates (events/100 person-years), respectively, declined with higher latest CD4+ counts: 13.8 and 2.1 with latest CD4+ counts less than 200 cells/μl; 2.0 and 1.7 for counts of 200–350 cells/μl; and 0.7 and 0.7 for counts greater than 350 cells/μl. After adjusting for baseline covariates and the latest HIV RNA level, risk of AIDS and non-AIDS diseases were lowered by 44% (95% confidence interval for hazard ratio 0.50–0.62, P < 0.01) and 14% (95% confidence interval for hazard ratio 0.77–0.96, P = 0.01), respectively, for each 100 cell/μl higher latest CD4+ count. Conclusion:Higher CD4+ counts on antiretroviral therapy are associated with lower rates of non-AIDS diseases and AIDS. These findings expand our understanding of the implications of HIV-related immunodeficiency and motivate randomized studies to evaluate the effects of antiretroviral therapy on a broad set of clinical outcomes at CD4+ counts greater than 350 cells/μl.

Continuous antiretroviral therapy decreases bone mineral density.

Objectives:To assess the effects of antiretroviral therapy (ART) on bone mineral density (BMD) Design:Randomized comparison of continuous ART (viral suppression group; VS) with intermittent ART (drug conservation group; DC) Setting:Outpatient clinics in the United States, Australia, and Spain. Participants:Participants in the Strategies for Management of Antiretroviral Therapy (SMART) Body Composition substudy. Main outcome measures:Annual hip and spine BMD by dual-energy radiographic absorptiometry (DXA) and spine BMD by quantitative computed tomography (qCT). Methods:Comparisons were by intention-to-treat analysis, using longitudinal models for change in BMD. Risk factors for BMD loss were evaluated. Results:The 214 participants (median 44 years, 19% female participants, 73% on ART; median T-scores −0.5 total hip, −0.7 spine DXA, −0.9 spine qCT; 98 randomized to VS and 116 to DC) were followed for a mean 2.4 years. With continuous ART, BMD declined per year by 0.8% (hip), 0.4% (spine DXA), and 2.4% (spine qCT). BMD declined significantly less with intermittent ART. Estimated DC minus VS group differences in mean BMD change through follow-up were 1.4% [hip; 95% confidence interval (CI) 0.6–2.3; P = 0.002], 1.3% (spine DXA; 95% CI 0.1–2.4, P = 0.03), and 3.0% (spine qCT; 95% CI 0.8–5.2, P = 0.007). No consistent drug-specific association with BMD decline was found. In the parent study, 10 of 2753 participants in the VS group and two of 2720 in the DC group reported serious fractures (hazard ratio 4.9; 95% CI 1.1–22.5; P = 0.04). Conclusion:Continuous ART is associated with decline in BMD and possibly more fractures relative to intermittent, CD4 cell count-guided ART.

A comparison of three highly active antiretroviral treatment strategies consisting of non-nucleoside reverse transcriptase inhibitors, protease inhibitors, or both in the presence of nucleoside reverse transcriptase inhibitors as initial therapy (CPCRA 058 FIRST Study): a long-term randomised trial

BACKGROUND Long-term data from randomised trials on the consequences of treatment with a protease inhibitor (PI), non-nucleoside reverse transcriptase inhibitor (NNRTI), or both are lacking. Here, we report results from the FIRST trial, which compared initial treatment strategies for clinical, immunological, and virological outcomes. METHODS Between 1999 and 2002, 1397 antiretroviral-treatment-naive patients, presenting at 18 clinical trial units with 80 research sites in the USA, were randomly assigned in a ratio of 1:1:1 to a protease inhibitor (PI) strategy (PI plus nucleoside reverse transcriptase inhibitor [NRTI]; n=470), a non-nucleoside reverse transcriptase inhibitor (NNRTI) strategy (NNRTI plus NRTI; n=463), or a three-class strategy (PI plus NNRTI plus NRTI; n=464). Primary endpoints were a composite of an AIDS-defining event, death, or CD4 cell count decline to less than 200 cells per mm3 for the PI versus NNRTI comparison, and average change in CD4 cell count at or after 32 months for the three-class versus combined two-class comparison. Analyses were by intention-to-treat. This study is registered ClinicalTrials.gov, number NCT00000922. FINDINGS 1397 patients were assessed for the composite endpoint. A total of 388 participants developed the composite endpoint, 302 developed AIDS or died, and 188 died. NNRTI versus PI hazard ratios (HRs) for the composite endpoint, for AIDS or death, for death, and for virological failure were 1.02 (95% CI 0.79-1.31), 1.07 (0.80-1.41), 0.95 (0.66-1.37), and 0.66 (0.56-0.78), respectively. 1196 patients were assessed for the three-class versus combined two-class primary endpoint. Mean change in CD4 cell count at or after 32 months was +234 cells per mm3 and +227 cells per mm3 for the three-class and the combined two-class strategies (p=0.62), respectively. HRs (three-class vs combined two-class) for AIDS or death and virological failure were 1.15 (0.91-1.45) and 0.87 (0.75-1.00), respectively. HRs (three-class vs combined two-class) for AIDS or death were similar for participants with baseline CD4 cell counts of 200 cells per mm3 or less and of more than 200 cells per mm3 (p=0.38 for interaction), and for participants with baseline HIV RNA concentrations less than 100 000 copies per mL and 100,000 copies per mL or more (p=0.26 for interaction). Participants assigned the three-class strategy were significantly more likely to discontinue treatment because of toxic effects than were those assigned to the two-class strategies (HR 1.58; p<0.0001). INTERPRETATION Initial treatment with either an NNRTI-based regimen or a PI-based regimen, but not both together, is a good strategy for long-term antiretroviral management in treatment-naive patients with HIV.

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.

Weekly Fluconazole for the Prevention of Mucosal Candidiasis in Women with HIV Infection: A Randomized, Double-Blind, Placebo-Controlled Trial

The demographic characteristics of the human immunodeficiency virus (HIV) epidemic in the United States have changed markedly in recent years. In 1994, 18% of new cases of acquired immunodeficiency syndrome (AIDS) occurred in women [1]; AIDS is now the third leading cause of death in women of reproductive age [2]. Candidiasis is a frequent complication of HIV infection [3-5]. The risk for oropharyngeal and esophageal candidiasis increases as the immune system becomes more suppressed. Vaginal candidiasis is also common in HIV-infected women [6, 7]. Because few HIV-infected women have been enrolled in clinical trials of therapy for and prophylaxis of fungal infections, few data have been recorded on the natural history, prevention, and treatment of mucosal candidiasis in women. Fluconazole, a broad-spectrum systemic antifungal agent, has been used effectively for the treatment of candidiasis in patients with HIV infection or AIDS and may result in a more rapid clinical and mycologic response than other azoles [8]. Although several regimens of fluconazole have been shown to prevent candidiasis (including recurrent episodes in persons with HIV infection), routine prophylaxis with fluconazole has not been recommended because of cost; the possible emergence of resistant Candida species; and drug interactions with non-sedating antihistamines, warfarin, phenytoin, oral hypoglycemic agents, rifampin or rifabutin, and hydrochlorothiazide [9-11]. The Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA) initiated this study in HIV-infected women to evaluate the effectiveness and safety of weekly fluconazole for the prevention of mucosal candidiasis and to detect alterations in vaginal colonization by Candida species [12]. A substudy was also done to investigate in vitro resistance to Candida organisms. Methods Study Sample Patients were enrolled in the Womens Fungal Study (CPCRA 010) at 14 sites that were participating in the CPCRA [12]. The CPCRA is a consortium of community-based sites that provide primary health care to patients who are infected with HIV. Potentially eligible patients were identified by physicians who were participating in the consortium. Female patients with HIV infection who were 13 years of age or older were eligible if their CD4+ cell count did not exceed 300 cells/mm3 or 20% of their total lymphocyte count. Patients were excluded if they had a history of Candida esophagitis, were receiving systemic antifungal agents, had a known intolerance of azoles, or were pregnant or lactating. The protocol was approved by the internal review board at each site. Informed consent was obtained from all patients before they were assigned to a study group. Study Design In this double-blind trial, patients were randomly assigned to receive weekly fluconazole or placebo using a permuted block scheme with randomly mixed block sizes of two and four. Randomization was stratified by CPCRA site and was done through the CPCRA statistical center. The target sample size (400 patients) and study duration (18 months) were chosen to ensure that there would be 80% power to detect a 50% difference in the rate of episodes of candidiasis between groups with a two-sided P value of 0.05. We extended the follow-up period to obtain more information on clinical and in vitro resistance. Treatment Regimens Fluconazole was provided in 100-mg capsules; patients received 200 mg of fluconazole per week or placebo. This dosage was used because pharmacologic studies by Houang and colleagues [13] indicated that therapeutic concentrations of fluconazole greater than the median minimal inhibitory concentration (MIC) of Candida albicans were found in vaginal secretions and tissues for 96 hours after a fluconazole dose of 150 mg. Open-label daily fluconazole for prophylaxis was permitted after two episodes of oropharyngeal or vaginal candidiasis or one episode of esophageal candidiasis (that is, prophylaxis failure). The relative severity of the candidiasis was considered in defining prophylaxis failure. Therapy with the study drug was continued during episodes of oropharyngeal and vaginal candidiasis but not during episodes of esophageal candidiasis. Ongoing use of systemic antifungal agents required withdrawal of the study drug. Topical antifungal agents were recommended for the treatment of oropharyngeal and vaginal candidiasis; fluconazole was recommended for esophageal candidiasis. End Points Episodes of candidiasis were reviewed by a committee that was blinded to treatment group. Several major clinical end points were specified: 1) first episode of confirmed vaginal candidiasis, confirmed oropharyngeal candidiasis, or confirmed or probable esophageal candidiasis; 2) prophylaxis failure, defined as the first episode of confirmed or probable esophageal candidiasis or the second episode of confirmed vaginal or oropharyngeal candidiasis; and 3) confirmed or probable clinical resistance to fluconazole. Esophageal candidiasis was confirmed by histologic or cytologic evidence on microscopy or evidence of candidiasis on gross endoscopic inspection or at autopsy. Patients were considered to have had a probable episode of esophageal candidiasis if they had recent onset of dysphagia or odynophagia and had either a confirmed diagnosis of oropharyngeal candidiasis or a response to antifungal therapy. Oropharyngeal or vaginal candidiasis was confirmed by a positive culture for Candida species in the presence of two or more clinical signs or symptoms. Patients were considered to have had a probable episode of mucosal candidiasis if 1) the culture was positive and they had one clinical sign or symptom [other than white exudates for oropharyngeal candidiasis], 2) a potassium hydroxide preparation was positive and they had two or more clinical signs or symptoms, or 3) they responded to antifungal therapy and had two or more signs or symptoms. Confirmation of clinical resistance to fluconazole required all of the following: 1) confirmed or probable esophageal candidiasis, confirmed vaginal candidiasis, or confirmed oropharyngeal candidiasis; 2) no response to a previous course of antifungal therapy and the need for high-dose therapy with systemic azoles or intravenous amphotericin B; and 3) no other identifiable cause of the symptoms. The patients were considered to have had probable clinical resistance if the first two criteria were met but other causes for the symptoms could not be ruled out. Adverse events were graded on a five-point scale (I through V). We recorded events that were at least grade IV, that were not caused by the progression of HIV infection, and that led to discontinuation of treatment while patients were receiving the study medication and for 8 weeks thereafter. Follow-up The trial ended on 30 November 1995, which was 22 months after the last patient was randomly assigned. The median length of follow-up was 29 months. Every 3 months, we ascertained symptoms of candidiasis, collected a vaginal specimen for yeast culture, and documented concomitant treatments and new HIV-related diagnoses. Liver function tests were done and CD4+ cell counts were measured every 6 months. Substudy of in Vitro Resistance to Fluconazole A substudy examining in vitro resistance to fluconazole (CPCRA 029) was started 1 year after the primary study began. After patients were enrolled, vaginal specimens that were obtained at scheduled follow-up visits every 3 months were analyzed for susceptibility to five antifungal agents. Isolates that had been obtained for other end points of the primary study were also analyzed. We used microtiter methods for in vitro susceptibility testing in accordance with National Committee for Clinical Laboratory Standards [14]. In vitro resistance to fluconazole was defined as an MIC of 16 g/mL or less at 48 hours. Statistical Analysis Participating investigators were blinded to interim results. Treatment groups were compared according to each patients original assignment (intention-to-treat analysis); the comparison groups consisted of patients who received weekly fluconazole and patients who received placebo until prophylaxis failure, at which time daily fluconazole could be prescribed at the clinicians discretion. Analyses were stratified by CPCRA site in accordance with the randomization method. Baseline comparability was assessed using the Mantel-Haenszel chi-square or stratified analysis of variance [15, 16]. For clinical end points and adverse events, time-to-event methods (including Kaplan-Meier estimation, log-rank tests, and proportional hazards regression models) were used to compare treatment groups [17-19]. We also compared two-sided P values and 95% CIs for relative risks (RRs) of fluconazole with those of placebo. Natural history analyses could be done because our control group received placebo. For such analyses, a proportional hazards regression model was used to investigate the independent influence of the following baseline variables on risk for candidiasis: ethnic group, injection drug use, CD4+ cell count, history of mucosal candidiasis, presence of AIDS, prophylaxis for Pneumocystis carinii pneumonia, antiretroviral treatment, and result of vaginal yeast culture at baseline. Vaginal specimens were collected every 3 months and analyzed for colonization by Candida species using a model for longitudinal binary data; findings are summarized with relative odds estimates for fluconazole compared with placebo [20]. All analyses were done using SAS software (SAS Institute, Cary, North Carolina). The National Institute of Allergies and Infectious Diseases (NIAID) supported the clinical sites and statistical center responsible for gathering and analyzing the data. Staff members from NIAID were also part of the protocol team but had no role in the decision to publish the results of the study. Results Study Sample Between May 1992 and January 1994, 323 patients were enrolled in CPCRA 010; 162 were randomly ass

Differential adherence to combination antiretroviral therapy is associated with virological failure with resistance

Objectives: To investigate the occurrence of differential adherence to components of combination antiretroviral therapy and assess its predictors and association with virological failure and antiretroviral medication resistance. Design: A secondary analysis of prospective clinical trial data. Methods: The Flexible Initial Retrovirus Suppressive Therapies study (Community Programs for Clinical Research on AIDS 058) was a randomized trial comparing non-nucleoside reverse transcriptase inhibitor (NNRTI) versus protease inhibitor (PI) versus NNRTI plus PI-based (three-class) antiretroviral therapy in treatment-naive HIV-1-infected individuals. Adherence was assessed at months 1 and 4, and then every 4 months. Differential adherence, defined as any difference in self-reported level of adherence to individual antiretroviral medications at the same timepoint, was evaluated as a binary time-updated variable in multivariate Cox regression analyses of time to initial virological failure (HIV-RNA > 1000 copies/ml) and initial virological failure with genotypic antiretroviral resistance. Results: Differential adherence was reported at least once by 403 of 1379 participants (29%), over 60 months median follow-up. Differential adherence was more commonly reported by participants randomly assigned to the three-class strategy (35%) than the NNRTI (28%) or PI (25%) strategies (P = 0.005), but was not associated with demographic or baseline disease-specific factors. Of those reporting differential adherence, 146 (36%) reported it before initial virological failure. These participants had an increased risk of initial virological failure and initial virological failure with antiretroviral resistance compared with participants without differential adherence before initial virological failure. Conclusion: Differential adherence was commonly reported and was associated with an increased risk of initial virological failure and initial virological failure with antiretroviral resistance.

Body composition and metabolic changes in antiretroviral-naive patients randomized to didanosine and stavudine vs. abacavir and lamivudine.

Comparisons of body composition and metabolic changes among antiretroviral-naive patients randomly assigned to didanosine and stavudine- (ddI + d4T) vs. abacavir and lamivudine- (ABC + 3TC) containing regimens were assessed in a nested substudy of an ongoing multicenter randomized trial. At baseline and every 4 months, body cell mass and total body fat were calculated, anthropometric measurements were performed, and fasting metabolic parameters were obtained. The rates of change (unit/mo) estimated using the slopes of regression lines and overall mean changes from baseline were compared by study assignment. Among 96 patients enrolled, 46 received ddI + d4T- and 50 received ABC + 3TC-containing regimens with a median follow-up of 32.4 months. For both study arms, an overall increase in the rates of change was seen for body cell mass. For ddI + d4T, after an initial increase, the rates of change declined for regional fat and total body fat compared with an increase for ABC + 3TC, with the 2 arms being significantly different (P < 0.05). For high-density lipoprotein cholesterol rates of change, ddI + d4T decreased, while ABC + 3TC increased. For both arms, low-density lipoprotein cholesterol decreased, while triglycerides increased. Early and sustained increases in insulin and insulin resistance were seen only for ddI + d4T. In this prospective study, metabolic and body composition changes varied according to whether subjects received ddI + d4T or ABC + 3TC.

Poor Initial CD4+ Recovery With Antiretroviral Therapy Prolongs Immune Depletion and Increases Risk for AIDS and Non-AIDS Diseases

Background:Low CD4+ increases risk for both AIDS- and non-AIDS-related morbidity and mortality. The magnitude of CD4+ recovery early after initial antiretroviral therapy (ART) is important in the ultimate duration of immune depletion. Methods:We examined CD4+ recovery among 850 participants in the Community Program for Clinical Research on AIDS Flexible Initial Retrovirus Suppressive Therapies study with virologic suppression (ie, achieved an HIV RNA level <400 copies/mL) with 8 months of initial ART and determined subsequent risk for AIDS, non-AIDS diseases (non-AIDS cancers and cardiovascular, end-stage renal, and liver diseases), or death using Cox regression during a median 5-year follow-up. Results:Mean pretreatment CD4+ was 221 cells/μL; 18% (n = 149) had a poor CD4+ recovery (<50 cells/μL) after 8 months of effective ART, resulting in lower CD4+ over 5 years. Older age (hazard ratio 1.34/10 yrs, P = 0.003) and lower screening HIV RNA (hazard ratio 0.65 per log10 copies/mL higher, P = 0.001), but not screening CD4+, were associated with a poor CD4+ recovery. After 8 months of effective ART, 30 patients experienced the composite outcome of AIDS, non-AIDS, or death among participants with a poor CD4+ recovery (rate = 5.8/100 person-years) and 74 patients among those with an adequate recovery (≥50 cells/μL; rate = 2.7/100 person-years) (adjusted hazard ratio = 2.24, P < 0.001). The risk of this composite outcome associated with a poor CD4+ recovery declined when ART was initiated at higher CD4+ counts (P < 0.01). Conclusions:Impaired immune recovery, despite effective ART, results in longer time spent at low CD4+, thereby increasing risk for a broad category of HIV-related morbidity and mortality conditions.

Long-term body composition and metabolic changes in antiretroviral naive persons randomized to protease inhibitor-, nonnucleoside reverse transcriptase inhibitor-, or protease inhibitor plus nonnucleoside reverse transcriptase inhibitor-based strategy

Objective:To assess changes in metabolic parameters and body composition among 422 antiretroviral-naive patients randomized to 3 antiretroviral therapy (ART) strategies: protease inhibitor (PI; n = 141)-, nonnucleoside reverse transcriptase inhibitor (NNRTI; n = 141)-, or PI + NNRTI (n = 140)-based strategies with a median follow-up of 5 years. Methods:At baseline and 1-month (metabolic parameters only) and 4-month follow-up intervals, fat-free mass (FFM) and total body fat were calculated, anthropometric measurements were performed, and fasting metabolic parameters were obtained. Rates of change and mean change were compared. Results:The PI + NNRTI strategy resulted in greater increases in triglycerides and low-density lipoprotein cholesterol compared with the PI and the NNRTI strategies (P < 0.005), with no differences between the PI and NNRTI strategies. High-density lipoprotein cholesterol increased significantly more in the NNRTI strategy than in the PI strategy (P < 0.005). Insulin and insulin resistance increased similarly with all 3 strategies. Changes in total and regional body composition (loss of subcutaneous tissue area and gains in FFM, nonsubcutaneous tissue area, and visceral tissue area) were observed but did not differ by strategy. Conclusions:Long-term follow-up of participants initiating 3 ART strategies demonstrated similar changes in total and regional fat, with no differences by ART strategy. The differential effects on lipid metabolism by strategy and the overall increases in insulin and insulin resistance with all 3 strategies necessitate close monitoring of patients on ART.

A prospective randomized trial of four three-drug regimens in the treatment of disseminated Mycobacterium avium complex disease in AIDS patients: Excess mortality associated with high-dose clarithromycin

The optimal regimen for treatment of Mycobacterium avium complex (MAC) disease has not been established. Eighty-five AIDS patients with disseminated MAC disease were randomized to receive a three-drug regimen of clarithromycin, rifabutin or clofazimine, and ethambutol. Two dosages of clarithromycin, 500 or 1,000 mg twice daily (b.i.d.), were compared. The Data and Safety Monitoring Board recommended discontinuation of the clarithromycin dosage comparison and continuation of the rifabutin vs. clofazimine comparison. After a mean follow-up of 4.5 months, 10 (22%) of 45 patients receiving clarithromycin at 500 mg b.i.d. had died (70 deaths per 100 person-years) compared with 17 (43%) of 40 patients receiving clarithromycin at 1,000 mg b.i.d. (158 deaths per 100 person-years) (relative risk, 2.43; 95% confidence interval, 1.11-5.34; P = .02). After 10.4 months, 20 (49%) of 41 patients receiving rifabutin had died (81 deaths per 100 person-years) compared with 23 (52%) of 44 patients receiving clofazimine (94 deaths per 100 person-years) (relative risk, 1.20; 95% confidence interval, 0.65-2.19; P = .56). Bacteriologic outcomes were similar among treatment groups. In treating MAC disease in AIDS patients, the maximum dose of clarithromycin should be 500 mg b.i.d.