Sharon Mannheimer

A randomized study of antiretroviral management based on plasma genotypic antiretroviral resistance testing in patients failing therapy

ObjectiveTo determine the short-term effects of using genotypic antiretroviral resistance testing (GART) with expert advice in the management of patients failing on a protease inhibitor and two nucleoside reverse transcriptase inhibitors. DesignProspective randomized controlled trial. SettingMulticenter community-based clinical trials network. PatientsOne-hundred and fifty-three HIV-infected adults with a threefold or greater rise in plasma HIV-1 RNA on at least 16 weeks of combination antiretroviral therapy. InterventionsRandomization was either to a GART group, where genotype interpretation and suggested regimens were provided to clinicians, or to a no-GART group, where treatment choices were made without such input. Main outcomes measuresPlasma HIV-1 RNA levels and CD4 cell counts were measured at 4, 8, and 12 weeks following randomization. The primary endpoint was change in HIV-1 RNA levels from baseline to the average of the 4 and 8 week levels. ResultsThe average baseline CD4 cell count was 230 × 106 cells/l and the median HIV-1 RNA was 28 085 copies/ml. At entry, 82 patients were failing on regimens containing indinavir, 51 on nelfinavir, 11 on ritonavir, and nine on saquinavir. HIV-1 RNA, averaged at 4 and 8 weeks, decreased by 1.19 log10 for the 78 GART patients and -0.61 log10 for the 75 no-GART patients (treatment difference: −0.53 log, 95% confidence interval, −0.77 to −0.29;P  = 0.00001). Overall, the best virologic responses occurred in patients who received three or more drugs to which their HIV-1 appeared to be susceptible. ConclusionIn patients failing triple drug therapy, GART with expert advice was superior to no-GART as measured by short-term viral load responses.

The Consistency of Adherence to Antiretroviral Therapy Predicts Biologic Outcomes for Human Immunodeficiency Virus—Infected Persons in Clinical Trials

We prospectively studied long-term antiretroviral adherence patterns and their impact on biologic outcomes for human immunodeficiency virus (HIV)-infected participants in 2 randomized, multicenter clinical trials. For the period from baseline to month 12 of the study, participants who reported adherence levels of 100%, 80%-99%, and 0%-79% had plasma HIV RNA levels that decreased by 2.77, 2.33, and 0.67 log(10) copies/mL, respectively (P<.001), whereas their CD4 counts increased by 179, 159, and 53 cells/mm(3), respectively (P<.001). Adherence predicted nondetectable HIV RNA levels (<50 copies/mL) at 12 months of follow-up (P<.001). The HIV RNA level was nondetectable in 72% of participants who reported 100% adherence at all 4 follow-up visits, compared with 66%, 41%, 35%, and 13% of participants who reported 100% adherence at 3, 2, 1, or 0 follow-up visits, respectively (P<.001). Nonwhite race was associated with poorer adherence (P<.001), and older age was associated with better adherence (P<.001).

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 ART adherence. 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.

Discontinuation of Prophylaxis against Mycobacterium avium Complex Disease in HIV-Infected Patients Who Have a Response to Antiretroviral Therapy

BACKGROUND Several agents are effective in preventing Mycobacterium avium complex disease in patients with advanced human immunodeficiency virus (HIV) infection. However, there is uncertainty about whether prophylaxis should be continued in patients whose CD4+ cell counts have increased substantially with antiviral therapy. METHODS We conducted a multicenter, double-blind, randomized trial of treatment with azithromycin (1200 mg weekly) as compared with placebo in HIV-infected patients whose CD4+ cell counts had increased from less than 50 to more than 100 per cubic millimeter in response to antiretroviral therapy. The primary end point was M. avium complex disease or bacterial pneumonia. RESULTS A total of 520 patients entered the study; the median CD4+ cell count at entry was 230 per cubic millimeter. In 48 percent of the patients, the HIV RNA value was below the level of quantification. The median prior nadir CD4+ cell count was 23 per cubic millimeter, and 65 percent of the patients had had an acquired immunodeficiency syndrome-defining illness. During follow-up over a median period of 12 months, there were no episodes of confirmed M. avium complex disease in either group (95 percent confidence interval for the rate of disease in each group, 0 to 1.5 episodes per 100 person-years). Three patients in the azithromycin group (1.2 percent) and five in the placebo group (1.9 percent) had bacterial pneumonia (relative risk in the azithromycin group, 0.60; 95 percent confidence interval, 0.14 to 2.50; P=0.48). Neither the rate of progression of HIV disease nor the mortality rate differed significantly between the two groups. Adverse effects led to discontinuation of the study drug in 19 patients assigned to receive azithromycin (7.4 percent) and in 3 assigned to receive placebo (1.1 percent; relative risk, 6.6; P=0.002). CONCLUSIONS Azithromycin prophylaxis can safely be withheld in HIV-infected patients whose CD4+ cell counts have increased to more than 100 cells per cubic millimeter in response to antiretroviral therapy.

Correlates of HIV acquisition in a cohort of black men who have sex with men in the United States: HIV prevention trials network (HPTN) 061

Background Black men who have sex with men (MSM) in the United States (US) are affected by HIV at disproportionate rates compared to MSM of other race/ethnicities. Current HIV incidence estimates in this group are needed to appropriately target prevention efforts. Methods From July 2009 to October 2010, Black MSM reporting unprotected anal intercourse with a man in the past six months were enrolled and followed for one year in six US cities for a feasibility study of a multi-component intervention to reduce HIV infection. HIV incidence based on HIV seroconversion was calculated as number of events/100 person-years. Multivariate proportional hazards modeling with time-dependent covariates was used to identify correlates of HIV acquisition. Results Of 1,553 Black MSM enrolled, 1,164 were HIV-uninfected at baseline and included in follow-up. Overall annual HIV incidence was 3.0% (95% confidence interval (CI): 2.0, 4.4%) and 5.9% among men ≤30 years old (95% CI: 3.6, 9.1%). Men ≤30 years old reported significantly higher levels of sexual risk and were more likely to have a sexually transmitted infection diagnosed during follow-up. Younger men also were more likely to not have a usual place for health care, not have visited a health care provider recently, and to have unmet health care needs. In multivariate analysis, age ≤30 years (hazard ratio (HR): 3.4; 95% CI: 1.4, 8.3) and unprotected receptive anal intercourse with HIV-positive or unknown status partners (HR: 4.1; 95% CI: 1.9, 9.1) were significantly associated with HIV acquisition. Conclusion In the largest cohort of prospectively-followed Black MSM in the US, HIV incidence was high, particularly among young men. Targeted, tailored and culturally appropriate HIV prevention strategies incorporating behavioral, social and biomedical based interventions are urgently needed to lower these rates.

Concomitant Socioeconomic, Behavioral, and Biological Factors Associated with the Disproportionate HIV Infection Burden among Black Men Who Have Sex with Men in 6 U.S. Cities

Background American Black men who have sex with men (MSM) are disproportionately affected by HIV, but the factors associated with this concentrated epidemic are not fully understood. Methods Black MSM were enrolled in 6 US cities to evaluate a multi-component prevention intervention, with the current analysis focusing on the correlates of being newly diagnosed with HIV compared to being HIV-uninfected or previously diagnosed with HIV. Results HPTN 061 enrolled 1553 Black MSM whose median age was 40; 30% self-identified exclusively as gay or homosexual, 29% exclusively as bisexual, and 3% as transgender. About 1/6th (16.2%) were previously diagnosed with HIV (PD); of 1263 participants without a prior HIV diagnosis 7.6% were newly diagnosed (ND). Compared to PD, ND Black MSM were younger (p<0.001); less likely to be living with a primary partner (p<0.001); more likely to be diagnosed with syphilis (p<0.001), rectal gonorrhea (p = 0.011) or chlamydia (p = 0.020). Compared to HIV-uninfected Black MSM, ND were more likely to report unprotected receptive anal intercourse (URAI) with a male partner in the last 6 months (p<0.001); and to be diagnosed with syphilis (p<0.001), rectal gonorrhea (p = 0.004), and urethral (p = 0.025) or rectal chlamydia (p<0.001). They were less likely to report female (p = 0.002) or transgender partners (p = 0.018). Multivariate logistic regression analyses found that ND Black MSM were significantly more likely than HIV-uninfected peers to be unemployed; have STIs, and engage in URAI. Almost half the men in each group were poor, had depressive symptoms, and expressed internalized homophobia. Conclusions ND HIV-infected Black MSM were more likely to be unemployed, have bacterial STIs and engage in URAI than other Black MSM. Culturally-tailored programs that address economic disenfranchisement, increase engagement in care, screen for STIs, in conjunction with safer sex prevention interventions, may help to decrease further transmission in this heavily affected community.

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.

The CASE adherence index: A novel method for measuring adherence to antiretroviral therapy

Abstract The Center for Adherence Support Evaluation (CASE) Adherence Index, a simple composite measure of self-reported antiretroviral therapy (ART) adherence, was compared to a standard three-day self-reported adherence measure among participants in a longitudinal, prospective cross-site evaluation of 12 adherence programs throughout the United States. The CASE Adherence Index, consisting of three unique adherence questions developed for the cross-site study, along with a three-day adherence self-report were administered by interviews every three months over a one-year period. Data from the three cross-site adherence questions (individually and in combination) were compared to three -day self-report data and HIV RNA and CD4 outcomes in cross-sectional analyses. The CASE Adherence Index correlated strongly with the three-day self-reported adherence data (p<0.001) and was more strongly associated with HIV outcomes, including a 1-log decline in HIV RNA level (maximum OR = 2.34; p<0.05), HIV RNA < 400 copies/ml (maximum OR = 2.33; p<0.05) and performed as well as the three-day self-report when predicting CD4 count status. Participants with a CASE Index score >10 achieved a 98 cell mean increase in CD4 count over 12 months, compared to a 41 cell increase for those with scores ≤10 (p<0.05). The CASE Adherence Index is an easy to administer instrument that provides an alternative method for assessing ART adherence in clinical settings.

Sustained benefit from a long-term antiretroviral adherence intervention. Results of a large randomized clinical trial.

Objective:To assess the efficacy of 2 adherence interventions, medication managers (MM) and medication alarms (ALR), among antiretroviral (ARV)-naive persons with HIV initiating ARV therapy. Methods:A multicenter, randomized, adherence intervention clinical trial was conducted among participants coenrolled in an HIV ARV strategy study for ARV-naive individuals. Sites were assigned by cluster randomization using a 2 × 2 factorial design to administer MM, ALR, MM + ALR, or neither (control). MM participants received individualized, structured, long-term adherence support from trained MMs. ALR participants received individually programmed ALR alarms for use throughout the study. Results:The 928 participants, followed a median of 30 months, included 22% women and 75% nonwhites; the median baseline CD4 count was 155 cells/mm3. First virologic failure was 13% lower in all MM versus no-MM groups (P = 0.13) and 28% lower in MM versus no-MM subgroups randomized to 2-class ARV arms in the parent ARV study (P = 0.01). MM (vs. no-MM) participants had significantly better CD4 cells count (P = 0.01) and adherence (P < 0.001) outcomes. ALR (vs. no-ALR) participants had worse virologic outcomes. Conclusion:This large randomized clinical trial demonstrated that interpersonal structured adherence support was associated with improved long-term medication adherence and virologic and immunologic HIV outcomes.

HIV Acquisition Among Women From Selected Areas of the United States: A Cohort Study

BACKGROUND Women account for 23% of newly diagnosed HIV infections in the United States, but there are few recent, well-characterized cohorts of U.S. women in whom behavior characteristics and HIV acquisition have been well-described. OBJECTIVE To evaluate HIV incidence and describe behaviors among U.S. women residing in areas of high HIV prevalence. DESIGN Multisite, longitudinal cohort of women who had HIV rapid testing and audio computer-assisted self-interviews at baseline and every 6 months for up to 12 months. (ClinicalTrials.gov: NCT00995176) SETTING 10 urban and periurban communities with high HIV prevalence and poverty rates, located in the northeastern and southeastern United States. PATIENTS Venue-based sampling was used to recruit women aged 18 to 44 years who recently had unprotected sex and had 1 or more additional personal or partner risk factors and no self-reported previous HIV diagnosis. MEASUREMENTS HIV prevalence and incidence, frequency of HIV risk behaviors, and health status perceptions. RESULTS Among 2099 high-risk women (85.9% black and 11.7% of Hispanic ethnicity), 32 (1.5%) were diagnosed with HIV infection at enrollment. Annual HIV incidence was 0.32% (95% CI, 0.14% to 0.74%). Older age, substance use, and knowing a partner had HIV were associated with HIV prevalence. Ten women died during the study (0.61% per year). LIMITATIONS Longitudinal assessment of risk behaviors was limited to a maximum of 12 months. There were few incident HIV infections, precluding identification of characteristics predictive of HIV acquisition. CONCLUSION This study enrolled a cohort of women with HIV incidence substantially higher than the Centers for Disease Control and Prevention national estimate in the general population of U.S. black women. Concerted efforts to improve preventive health care strategies for HIV and overall health status are needed for similar populations. PRIMARY FUNDING SOURCE National Institutes of Health.