Sean B. Rourke

Effect of Early versus Deferred Antiretroviral Therapy for HIV on Survival

BACKGROUND The optimal time for the initiation of antiretroviral therapy for asymptomatic patients with human immunodeficiency virus (HIV) infection is uncertain. METHODS We conducted two parallel analyses involving a total of 17,517 asymptomatic patients with HIV infection in the United States and Canada who received medical care during the period from 1996 through 2005. None of the patients had undergone previous antiretroviral therapy. In each group, we stratified the patients according to the CD4+ count (351 to 500 cells per cubic millimeter or >500 cells per cubic millimeter) at the initiation of antiretroviral therapy. In each group, we compared the relative risk of death for patients who initiated therapy when the CD4+ count was above each of the two thresholds of interest (early-therapy group) with that of patients who deferred therapy until the CD4+ count fell below these thresholds (deferred-therapy group). RESULTS In the first analysis, which involved 8362 patients, 2084 (25%) initiated therapy at a CD4+ count of 351 to 500 cells per cubic millimeter, and 6278 (75%) deferred therapy. After adjustment for calendar year, cohort of patients, and demographic and clinical characteristics, among patients in the deferred-therapy group there was an increase in the risk of death of 69%, as compared with that in the early-therapy group (relative risk in the deferred-therapy group, 1.69; 95% confidence interval [CI], 1.26 to 2.26; P<0.001). In the second analysis involving 9155 patients, 2220 (24%) initiated therapy at a CD4+ count of more than 500 cells per cubic millimeter and 6935 (76%) deferred therapy. Among patients in the deferred-therapy group, there was an increase in the risk of death of 94% (relative risk, 1.94; 95% CI, 1.37 to 2.79; P<0.001). CONCLUSIONS The early initiation of antiretroviral therapy before the CD4+ count fell below two prespecified thresholds significantly improved survival, as compared with deferred therapy.

Comparisons of disparities and risks of HIV infection in black and other men who have sex with men in Canada, UK, and USA: a meta-analysis

BACKGROUND We did a meta-analysis to assess factors associated with disparities in HIV infection in black men who have sex with men (MSM) in Canada, the UK, and the USA. METHODS We searched Embase, Medline, Google Scholar, and online conference proceedings from Jan 1, 1981, to Dec 31, 2011, for racial comparative studies with quantitative outcomes associated with HIV risk or HIV infection. Key words and Medical Subject Headings (US National Library of Medicine) relevant to race were cross-referenced with citations pertinent to homosexuality in Canada, the UK, and the USA. Data were aggregated across studies for every outcome of interest to estimate overall effect sizes, which were converted into summary ORs for 106,148 black MSM relative to 581,577 other MSM. FINDINGS We analysed seven studies from Canada, 13 from the UK, and 174 from the USA. In every country, black MSM were as likely to engage similarly in serodiscordant unprotected sex as other MSM. Black MSM in Canada and the USA were less likely than other MSM to have a history of substance use (odds ratio, OR, 0·53, 95% CI 0·38-0·75, for Canada and 0·67, 0·50-0·92, for the USA). Black MSM in the UK (1·86, 1·58-2·18) and the USA (3·00, 2·06-4·40) were more likely to be HIV positive than were other MSM, but HIV-positive black MSM in each country were less likely (22% in the UK and 60% in the USA) to initiate combination antiretroviral therapy (cART) than other HIV-positive MSM. US HIV-positive black MSM were also less likely to have health insurance, have a high CD4 count, adhere to cART, or be virally suppressed than were other US HIV-positive MSM. Notably, despite a two-fold greater odds of having any structural barrier that increases HIV risk (eg, unemployment, low income, previous incarceration, or less education) compared with other US MSM, US black MSM were more likely to report any preventive behaviour against HIV infection (1·39, 1·23-1·57). For outcomes associated with HIV infection, disparities were greatest for US black MSM versus other MSM for structural barriers, sex partner demographics (eg, age, race), and HIV care outcomes, whereas disparities were least for sexual risk outcomes. INTERPRETATION Similar racial disparities in HIV and sexually transmitted infections and cART initiation are seen in MSM in the UK and the USA. Elimination of disparities in HIV infection in black MSM cannot be accomplished without addressing structural barriers or differences in HIV clinical care access and outcomes. FUNDING None.

Risk of Anal Cancer in HIV-Infected and HIV-Uninfected Individuals in North America

BACKGROUND Anal cancer is one of the most common cancers affecting individuals infected with human immunodeficiency virus (HIV), although few have evaluated rates separately for men who have sex with men (MSM), other men, and women. There are also conflicting data regarding calendar trends. METHODS In a study involving 13 cohorts from North America with follow-up between 1996 and 2007, we compared anal cancer incidence rates among 34 189 HIV-infected (55% MSM, 19% other men, 26% women) and 114 260 HIV-uninfected individuals (90% men). RESULTS Among men, the unadjusted anal cancer incidence rates per 100 000 person-years were 131 for HIV-infected MSM, 46 for other HIV-infected men, and 2 for HIV-uninfected men, corresponding to demographically adjusted rate ratios (RRs) of 80.3 (95% confidence interval [CI], 42.7-151.1) for HIV-infected MSM and 26.7 (95% CI, 11.5-61.7) for other HIV-infected men compared with HIV-uninfected men. HIV-infected women had an anal cancer rate of 30/100 000 person-years, and no cases were observed for HIV-uninfected women. In a multivariable Poisson regression model, among HIV-infected individuals, the risk was higher for MSM compared with other men (RR, 3.3; 95% CI, 1.8-6.0), but no difference was observed comparing women with other men (RR, 1.0; 95% CI, 0.5-2.2). In comparison with the period 2000-2003, HIV-infected individuals had an adjusted RR of 0.5 (95% CI, .3-.9) in 1996-1999 and 0.9 (95% CI, .6-1.2) in 2004-2007. CONCLUSIONS Anal cancer rates were substantially higher for HIV-infected MSM, other men, and women compared with HIV-uninfected individuals, suggesting a need for universal prevention efforts. Rates increased after the early antiretroviral therapy era and then plateaued.

Evaluation of cognitive function associated with chemotherapy: a review of published studies and recommendations for future research.

PURPOSE There is evidence that some cancer survivors suffer cognitive impairment after chemotherapy. Determining if a patient has cognitive impairment is challenging, especially because impairment is usually subtle. PATIENTS AND METHODS We assessed the design of studies evaluating cognitive function during or after chemotherapy in adult patients with solid tumors. We also reviewed methods used to evaluate cognitive function in subjects with other diseases and make recommendations for future studies. RESULTS We identified 22 studies that met our criteria: 82% included women with breast cancer. Eight studies were longitudinal, 12 were cross-sectional, and two were follow-ups of cross-sectional studies. Sixteen studies used a battery of neuropsychological (NP) tests to assess subjects, and 13 included a control group. Ten studies (45%) had no explicit definition of cognitive impairment; most others used z scores or T scores and defined impairment based on standard deviations below the mean, but there was no consistency in for the cutoff point used or the number of tests required. CONCLUSION There is no consistency in defining cognitive impairment, in the NP batteries used, or in statistical methods in studies of cognitive function of cancer patients. We suggest guidelines to define criteria for cognitive impairment. Use of summary scores and control groups is recommended. Practice effect should be adjusted for in longitudinal studies. A balance is needed between comprehensive batteries and briefer tests, which still need to be sensitive to mild impairment.

Late Presentation for Human Immunodeficiency Virus Care in the United States and Canada

BACKGROUND. Initiatives to improve early detection and access to human immunodeficiency virus (HIV) services have increased over time. We assessed the immune status of patients at initial presentation for HIV care from 1997 to 2007 in 13 US and Canadian clinical cohorts. METHODS. We analyzed data from 44,491 HIV-infected patients enrolled in the North American-AIDS Cohort Collaboration on Research and Design. We identified first presentation for HIV care as the time of first CD4(+) T lymphocyte (CD4) count and excluded patients who prior to this date had HIV RNA measurements, evidence of antiretroviral exposure, or a history of AIDS-defining illness. Trends in mean CD4 count (measured as cells/mm(3)) and 95% confidence intervals were determined using linear regression adjusted for age, sex, race/ethnicity, HIV transmission risk, and cohort. RESULTS. Median age at first presentation for HIV care increased over time (range, 40-43 years; P < .01), whereas the percentage of patients with injection drug use HIV transmission risk decreased (from 26% to 14%; P < .01) and heterosexual transmission risk increased (from 16% to 23%; P < .01). Median CD4 count at presentation increased from 256 cells/mm(3) (interquartile range, 96-455 cells/mm(3)) to 317 cells/mm(3) (interquartile range, 135-517 cells/mm(3)) from 1997 to 2007 (P < .01). The percentage of patients with a CD4 count > or = 350 cells/mm(3) at first presentation also increased from 1997 to 2007 (from 38% to 46%; P < .01). The estimated adjusted mean CD4 count increased at a rate of 6 cells/mm(3) per year (95% confidence interval, 5-7 cells/mm(3) per year). CONCLUSION. CD4 count at first presentation for HIV care has increased annually over the past 11 years but has remained <350 cells/mm(3), which suggests the urgent need for earlier HIV diagnosis and treatment.

Cognitive Complaints, Depression, Medical Symptoms, and Their Association With Neuropsychological Functioning in HIV Infection: A Structural Equation Model Analysis

The main objective of this study was to use structural equation modeling (SEM) to clarify the relationship between subjective cognitive complaints and neuropsychological functioning in 160 adults with HIV infection. Participants completed questionnaires assessing cognitive complaints, symptoms of depression, and HIV-related medical symptoms. Neuropsychological tests included measures of attention, verbal fluency, psychomotor skills, learning, memory, and executive skills. SEM was used to test models of the relationships among cognitive complaints, mood, and medical symptoms with neuropsychological functioning. The model indicated that although depressed mood (beta = 0.32, p < .01) and medical symptoms (beta = 0.31, p < .01) influenced cognitive complaints, cognitive complaints were independently associated with poorer neuropsychological performance (beta = 0.39, p < .01). Mood and medical symptoms were significantly correlated but were not significantly associated with neuropsychological skills.

Systematic Review of HIV Transmission between Heterosexual Serodiscordant Couples where the HIV-Positive Partner Is Fully Suppressed on Antiretroviral Therapy

Background The risk of sexual HIV transmission in serodiscordant couples when the HIV-positive partner has full virologic suppression on combination antiretroviral therapy (cART) is debated. This study aims to systematically review observational studies and randomized controlled trials (RCTs), evaluating rates of sexual HIV transmission between heterosexual serodiscordant couples when the HIV-positive partner has full suppression on cART. Methods and Findings We searched major bibliographic databases to November 2012 for relevant observational studies and RCTs without language restrictions. Conference proceedings, key journals and bibliographies were also searched. Studies reporting HIV transmission rates, cART histories and viral loads of the HIV-positive partners were included. Two reviewers extracted methodologic characteristics and outcomes. Of 20,252 citations, 3 studies met all eligibility criteria with confirmed full virologic suppression in the HIV-positive partner. We included 3 additional studies (2 cohort studies, 1 RCT) that did not confirm viral suppression in the HIV-positive partner at transmission in a secondary meta-analysis. Methodologic quality was reasonable. The rate of transmission in the 3 studies confirming virologic suppression was 0 per 100 person-years (95% CI = 0–0.05), with low heterogeneity (I2 = 0%). When we included the 3 studies that did not confirm virologic suppression, the rate of transmission was 0.14 per 100 person-years (95%CI = 0.04–0.31) (I2 = 0%). In a sensitivity analysis including all 6 studies, the rate of transmission was 0 per 100 person-years (95%CI = 0–0.01) after omitting all transmissions with known detectable or unconfirmed viral loads, as full suppression in these cases was unlikely. Limitations included lack of data on same-sex couples, type of sexual intercourse (vaginal vs. anal), direction of HIV transmission, exact viral load at the time of transmission, sexually transmitted infections (STI) rates, and extent of condom use. Conclusions Our findings suggest minimal risk of sexual HIV transmission for heterosexual serodiscordant couples when the HIV-positive partner has full viral suppression on cART with caveats regarding information on sexual intercourse type, STIs, and condom use. These findings have implications when counseling heterosexual serodiscordant couples on sexual and reproductive health. More research is needed to explore HIV transmission risk between same-sex couples.

Employment status is associated with both physical and mental health quality of life in people living with HIV

Abstract To evaluate the relationship between employment status and health-related quality of life (HRQOL) in HIV/AIDS. A total of 361 participants provided baseline data in the context of an ongoing cohort study examining the natural history of neurobehavioral functioning and its effects on HRQOL. We administered tests and collected laboratory data to determine demographic status, HIV disease markers, psychosocial symptom burden, neurocognitive function and HRQOL (MOS-HIV). We performed regression analyses to evaluate the contribution of employment status to the physical and mental health components of quality of life (QOL). Multivariate analyses showed that employment status was strongly related to better physical and mental health QOL after controlling for potential confounders. We found, however, that employment status had a greater impact on physical health than mental health QOL [physical health (β = 6.8, 95% CI 4.6 to 9.1) and mental health QOL (β = 3.3, 95% CI 0.93 to 5.7)]. The effect of employment for physical health QOL was stronger than that observed for ethnicity, social support, or having an AIDS diagnosis and was comparable to that observed with having many HIV-related symptoms. This cross-sectional study suggests that there may be physical and mental health benefits associated with obtaining or keeping employment, or more likely that both selection and causation mechanisms comprise an interactional and reinforcing process.

Assessment, Diagnosis, and Treatment of HIV-Associated Neurocognitive Disorder: A Consensus Report of the Mind Exchange Program

Many practical clinical questions regarding the management of human immunodeficiency virus (HIV)-associated neurocognitive disorder (HAND) remain unanswered. We sought to identify and develop practical answers to key clinical questions in HAND management. Sixty-six specialists from 30 countries provided input into the program, which was overseen by a steering committee. Fourteen questions were rated as being of greatest clinical importance. Answers were drafted by an expert group based on a comprehensive literature review. Sixty-three experts convened to determine consensus and level of evidence for the answers. Consensus was reached on all answers. For instance, good practice suggests that all HIV patients should be screened for HAND early in disease using standardized tools. Follow-up frequency depends on whether HAND is already present or whether clinical data suggest risk for developing HAND. Worsening neurocognitive impairment may trigger consideration of antiretroviral modification when other causes have been excluded. The Mind Exchange program provides practical guidance in the diagnosis, monitoring, and treatment of HAND.

Predictive accuracy of the veterans aging cohort study index for mortality with HIV infection: A north american cross cohort analysis

Background:By supplementing an index composed of HIV biomarkers and age (restricted index) with measures of organ injury, the Veterans Aging Cohort Study (VACS) index more completely reflects risk of mortality. We compare the accuracy of the VACS and restricted indices (1) among subjects outside the Veterans Affairs Healthcare System, (2) more than 1–5 years of prior exposure to antiretroviral therapy (ART), and (3) within important patient subgroups. Methods:We used data from 13 cohorts in the North American AIDS Cohort Collaboration (n = 10, 835) limiting analyses to HIV-infected subjects with at least 12 months exposure to ART. Variables included demographic, laboratory (CD4 count, HIV-1 RNA, hemoglobin, platelets, aspartate and alanine transaminase, creatinine, and hepatitis C status), and survival. We used C-statistics and net reclassification improvement (NRI) to test discrimination varying prior ART exposure from 1 to 5 years. We then combined Veterans Affairs Healthcare System (n = 5066) and North American AIDS Cohort Collaboration data, fit a parametric survival model, and compared predicted to observed mortality by cohort, gender, age, race, and HIV-1 RNA level. Results:Mean follow-up was 3.3 years (655 deaths). Compared with the restricted index, the VACS index showed greater discrimination (C-statistics: 0.77 vs. 0.74; NRI: 12%; P < 0.0001). NRI was highest among those with HIV-1 RNA <500 copies per milliliter (25%) and age ≥50 years (20%). Predictions were similar to observed mortality among all subgroups. Conclusions:VACS index scores discriminate risk and translate into accurate mortality estimates over 1–5 years of exposure to ART and for diverse patient subgroups from North American.