Michelle A. Kendall

Timing of Antiretroviral Therapy for HIV-1 Infection and Tuberculosis

BACKGROUND Antiretroviral therapy (ART) is indicated during tuberculosis treatment in patients infected with human immunodeficiency virus type 1 (HIV-1), but the timing for the initiation of ART when tuberculosis is diagnosed in patients with various levels of immune compromise is not known. METHODS We conducted an open-label, randomized study comparing earlier ART (within 2 weeks after the initiation of treatment for tuberculosis) with later ART (between 8 and 12 weeks after the initiation of treatment for tuberculosis) in HIV-1 infected patients with CD4+ T-cell counts of less than 250 per cubic millimeter and suspected tuberculosis. The primary end point was the proportion of patients who survived and did not have a new (previously undiagnosed) acquired immunodeficiency syndrome (AIDS)-defining illness at 48 weeks. RESULTS A total of 809 patients with a median baseline CD4+ T-cell count of 77 per cubic millimeter and an HIV-1 RNA level of 5.43 log(10) copies per milliliter were enrolled. In the earlier-ART group, 12.9% of patients had a new AIDS-defining illness or died by 48 weeks, as compared with 16.1% in the later-ART group (95% confidence interval [CI], -1.8 to 8.1; P=0.45). Among patients with screening CD4+ T-cell counts of less than 50 per cubic millimeter, 15.5% of patients in the earlier-ART group versus 26.6% in the later-ART group had a new AIDS-defining illness or died (95% CI, 1.5 to 20.5; P=0.02). Tuberculosis-associated immune reconstitution inflammatory syndrome was more common with earlier ART than with later ART (11% vs. 5%, P=0.002). The rate of viral suppression at 48 weeks was 74% and did not differ between the groups (P=0.38). CONCLUSIONS Overall, earlier ART did not reduce the rate of new AIDS-defining illness and death, as compared with later ART. In persons with CD4+ T-cell counts of less than 50 per cubic millimeter, earlier ART was associated with a lower rate of new AIDS-defining illnesses and death. (Funded by the National Institutes of Health and others; ACTG A5221 ClinicalTrials.gov number, NCT00108862.).

Carotid artery intima–media thickness and Hiv infection: traditional risk factors overshadow impact of protease inhibitor exposure

Context:The impact of HIV infection and exposure to antiretroviral therapy on the development of subclinical atherosclerosis is incompletely understood. Objective: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. Methods: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 for ≥ 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. Results: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. Conclusions:We found no association between PI inhibitor exposure or HIV infection and carotid IMT.

Alendronate with calcium and vitamin D supplementation is safe and effective for the treatment of decreased bone mineral density in HIV

Background:Decreased bone mineral density (BMD) is prevalent in HIV-infected patients. Bisphosphonates are currently the mainstay of treatment for postmenopausal and male osteoporosis in HIV-uninfected individuals; however, their efficacy and safety in HIV-infected patients remains unclear. Methods:In this prospective, randomized, placebo-controlled multicenter trial, we studied the effectiveness of calcium and vitamin D supplementation with or without alendronate in improving BMD in HIV-infected subjects receiving stable antiretroviral therapy. Subjects with secondary causes of osteoporosis were excluded. The study was powered to detect differences of 3.5% between arms and to detect a moderate sex effect in percentage change in lumbar spine BMD. All dual-energy X-ray absorptiometry scans were analysed centrally, blinded by arm. Results:The 82 subjects enrolled were 71% men, 77% white, with a baseline median age of 48 years, CD4 cell count of 469 cells/μl, and lumbar spine t-score of less than 2.1; 91% had HIV-RNA levels less than 400 copies/ml, and 99% were taking antiretroviral drugs. Compared with calcium/vitamin D alone, alendronate plus calcium/vitamin D resulted in significant improvements in BMD at the lumbar spine, total hip, and trochanter, but not at the femoral neck, compared with baseline. There were trends towards significant increases in BMD values in the calcium/vitamin D group at the lumbar spine, total hip, and femoral neck. There were no apparent sex differences in the responses to therapy. Alendronate was well tolerated, without significant adverse events. Conclusion:Once-weekly alendronate is safe and effective in the treatment of decreased BMD in HIV-infected patients.

Biomarkers of Microbial Translocation and Macrophage Activation: Association With Progression of Subclinical Atherosclerosis in HIV-1 Infection

BACKGROUND The relationships between soluble CD14 (sCD14), endotoxin (lipopolysaccharide [LPS]), and progression of atherosclerosis have not been defined in human immunodeficiency virus (HIV) infection. METHODS We retrospectively assessed serum sCD14 and LPS levels of 91 subjects in a prospective 3-year study of carotid artery intima-media thickness (CIMT) (AIDS Clinical Trials Group [ACTG] 5078), where subjects were enrolled as risk factor-controlled triads of HIV-uninfected (n = 36) and HIV-infected individuals with (n = 29) or without (n = 26) protease inhibitor (PI)-based therapy for ≥2 years. The primary end point was the yearly rate of change of CIMT (ΔCIMT). RESULTS In multivariate analysis of the HIV-infected subjects, each 1 µg/mL above the mean of baseline serum sCD14 corresponded to an additional 1.52 µm/y (95% confidence interval, .07-2.98; P = .04) in the ΔCIMT. Every 100 pg/mL above the mean of baseline serum LPS corresponded to an additional 0.49 µm/y (95% confidence interval, .18-.81; P = .003) in the ΔCIMT. However, in univariate analysis in the HIV-uninfected group sCD14 (P = .33) and LPS (P = .27) levels were not associated with higher ΔCIMT. HIV infection and PI therapy were not associated with baseline serum LPS and sCD14 levels (P > .1). CONCLUSIONS Our data are among the first to suggest that serum biomarkers of microbial translocation (LPS) and macrophage activation (sCD14) predict subclinical atherosclerosis progression in HIV-infected persons.

Progression of carotid artery intima-media thickening in HIV-infected and uninfected adults.

Objectives:To compare the rate of change in intima–media thickness (IMT) of the carotid artery among uninfected subjects and HIV-infected subjects receiving or not receiving protease inhibitor (PI) regimens over a 144 week period. Design:This prospective, matched cohort study enrolled 133 subjects into 45 triads (groups of three subjects matched by age, sex, race/ethnicity, smoking status, blood pressure, and menopause) from university based outpatient HIV clinics. Each triad consisted of one subject from each of the following groups: 1, HIV-infected subjects with continuous use of PI therapy for ≥ 2 years; 2, HIV-infected subjects without prior PI use; 3, HIV-uninfected subjects. Methods:Standardized ultrasound images of carotid IMT were collected at weeks 0, 2, 24, 48, 72, 96, and 144. The main outcome was the yearly progression rate of carotid IMT (mm/year). Results:The median yearly IMT progression rate in groups 1, 2, and 3 was 0.0096, 0.0058, and 0.0085 mm/year, respectively. There were no statistically significant differences in progression between groups 1 and 2, or between the combined HIV-positive groups and the HIV-negative control group. A multicovariate model examining predictors of progression in carotid IMT among all subjects contained low density lipoprotein cholesterol and homocysteine. Among HIV subjects, predictors included nadir CD4 cell count and ritonavir use. Conclusions:HIV infection and PI use did not contribute substantially to the rate of carotid IMT progression in our matched study.

Pharmacokinetic interactions between indinavir plus ritonavir and calcium channel blockers.

Hypertension is an important modifiable cardiac risk factor in human immunodeficiency virus (HIV)‐infected patients. Calcium channel blockers are substrates of cytochrome P450 3A and are commonly prescribed for hypertension. We evaluated potential bidirectional pharmacokinetic interactions between calcium channel blockers and coadministered indinavir and ritonavir.

Fractures after antiretroviral initiation.

Background:Bone mineral density declines by 2–6% within 1–2 years after initiation of antiretroviral therapy (ART); however, it is uncertain whether this results in an immediate or cumulative increase in fracture rates. Methods:We evaluated the incidence and predictors of fracture in 4640 HIV-positive participants from 26 randomized ART studies followed in the AIDS Clinical Trials Group (ACTG) Longitudinal-Linked Randomized Trial study for a median of 5 years. Fragility and nonfragility fractures were recorded prospectively at semiannual visits. Incidence was calculated as fractures/total person-years. Cox proportional hazards models evaluated effects of traditional fracture risks, HIV disease characteristics, and ART exposure on fracture incidence. Results:Median (interquartile range) age was 39 (33, 45) years; 83% were men, 48% white, and median nadir CD4 cell count was 187 (65, 308) cells/&mgr;l. Overall, 116 fractures were reported in 106 participants with median time-to-first fracture of 2.3 years. Fracture incidence was 0.40 of 100 person-years among all participants and 0.38 of 100 person-years among 3398 participants who were ART naive at enrollment into ACTG parent studies. Among ART-naive participants, fracture rates were higher within the first 2 years after ART initiation (0.53/100 person-years) than subsequent years (0.30/100 person-years). In a multivariate analysis of ART-naive participants, increased hazard of fracture was associated with current smoking and glucocorticoid use but not with exposure to specific antiretrovirals. Conclusion:Fracture rates were higher within the first 2 years after ART initiation, relative to subsequent years. However, continuation of ART was not associated with increasing fracture rates in these relatively young HIV-positive individuals.

Vaginal 5-fluorouracil for high-grade cervical dysplasia in human immunodeficiency virus infection: a randomized trial.

OBJECTIVE To compare the efficacy and toxicity of topical vaginal 5-fluorouracil (5-FU) maintenance therapy against the effects of observation after standard treatment for high-grade cervical dysplasia in human immunodeficiency virus (HIV)-infected women and to evaluate the association between baseline CD4 count and time to recurrence. METHODS In a phase III unmasked, randomized, multicenter, outpatient clinical trial, 101 HIV-positive women either received 6 months of biweekly treatment with vaginal 5-FU cream (2 g) or underwent 6 months of observation after standard excisional or ablative cervical treatment for cervical intraepithelial neoplasia (CIN). Papanicolaou smears and colposcopy were scheduled at regular intervals during the ensuing 18 months, with the primary end point being the time at which CIN of any grade recurred. RESULTS Thirty-eight percent of women developed recurrence: 14 (28%) of 50 in the 5-FU therapy group and 24 (47%) of 51 in the observation group. Treatment with 5-FU was significantly associated with prolonged time to CIN development (P = .04). Observation subjects were more likely to have high-grade recurrences, with 31% developing CIN 2-3 compared with 8% in the 5-FU treatment arm (P = .014), and disease recurred more quickly in observation subjects as well. Baseline CD4 count was related significantly to time to recurrence (P = .04), with 46% of subjects with CD4 counts less than 200 cells/mm3 developing recurrence compared with 33% of subjects with CD4 counts at least 200 cells/mm3. Disease recurred more slowly in subjects who had received antiretroviral therapy than in antiretroviral therapy-naive subjects. There were no instances of grade 3 or 4 toxicity, and compliance with 5-FU treatment was generally good. CONCLUSION Adjunctive maintenance intravaginal 5-FU therapy after standard surgery for high-grade lesions safely and effectively reduced recurrence of cervical intraepithelial neoplasia in HIV-infected women.

Cytomegalovirus (CMV) and Human Immunodeficiency Virus (HIV) Burden, CMV End-Organ Disease, and Survival in Subjects with Advanced HIV Infection (AIDS Clinical Trials Group Protocol 360)

We undertook a prospective study to analyze cytomegalovirus (CMV) end-organ disease (EOD) in subjects with advanced human immunodeficiency virus (HIV) infection. Of 403 individuals without prior CMV EOD who were followed up for a median of 151 weeks, 56 died and 21 developed CMV EOD. Twenty of the subjects with CMV EOD had CD4 cell counts of < or =50 cells/mm3 and HIV RNA level of >10,000 copies/mL of plasma at baseline; in these 20 subjects, an increase of CMV DNA level to greater than the quantification limits was associated with CMV EOD. A CD4 cell count of < or =100 cells/mm3 and an HIV RNA level of >10,000 copies/mL of plasma at baseline, a CMV DNA level of >200 copies/mL of blood during follow-up, or development of CMV EOD were all associated with decreased survival. HIV-infected subjects with CD4 cell counts of < or =50 cells/mm3 and HIV RNA levels of >10,000 copies/mL of plasma should have blood fractions screened for CMV DNA; if CMV DNA is detected, CMV prophylaxis might be considered.

Tuberculosis immune reconstitution inflammatory syndrome in A5221 STRIDE: Timing, Severity, and Implications for HIV-TB Programs

Rationale and Objectives:Earlier initiation of antiretroviral therapy (ART) in HIV–tuberculosis (TB) is associated with increased immune reconstitution inflammatory syndrome (IRIS). The severity, frequency, and complications of TB IRIS were evaluated in A5221, a randomized trial of earlier ART (within 2 weeks after TB treatment initiation) vs. later ART (8–12 weeks after TB treatment) in HIV-infected patients starting TB treatment. Methods and Measurements:In 806 participants, TB IRIS was defined using published clinical criteria. Cases were classified as severe (hospitalization/death), moderate (corticosteroid use/invasive procedure), or mild (no hospitalization/procedures/steroids). Fisher exact, Wilcoxon, and log-rank tests were used for comparisons. Main Results:TB IRIS occurred in 61 (7.6%) patients: 10.4% in earlier vs. 4.7% in later ART, 11.5% with CD4+ <50 vs. 5.4% with CD4+ ≥50 cells per cubic millimeter. The CD4+/ART arm interaction was significant, P = 0.014, with 44.3% of TB IRIS occurring with CD4+ <50 and earlier ART. TB IRIS occurred sooner with earlier vs. later ART initiation, at a median of 29 vs. 82 days after TB treatment initiation (P < 0.001). IRIS manifestations included lymphadenopathy (59.0%), constitutional symptoms (54.1%), and radiographic changes (41.0%); central nervous system TB IRIS was uncommon (6.6%). TB IRIS was mild in 27.9%, moderate in 41.0%, and severe in 31.1%. No TB IRIS–associated deaths occurred. IRIS management required ≥1 invasive procedures in 34.4%, hospitalization in 31.1%, and corticosteroids in 54.1%. Conclusions:TB IRIS was more frequent with earlier ART initiation and CD4+ <50 cells per cubic millimeter. As ART is implemented earlier in HIV–TB coinfection, programs will require the diagnostic capabilities, clinical resources, and training necessary to manage TB IRIS.