Objectives: In the era of combination antiretroviral therapy (cART), vitamin D deficiency, low bone mineral density (BMD) and fractures have emerged as subjects of concern in HIV-positive patients. Testing for vitamin D deficiency has been widely adopted in clinical practice even though the benefits of vitamin D supplementation in this population remain uncertain. The objective of this review was to evaluate the evidence for such a strategy.
Design: Systematic review of the literature on vitamin D deficiency in HIV infection, the effects of cART on vitamin D status, and the effects of vitamin D deficiency and cART on parathyroid hormone (PTH), bone turnover, BMD and the incidence of fractures in HIV-positive patients.
Methods: PubMed was used to identify relevant articles up to September 2011.
Results: Vitamin D deficiency, secondary hyperparathyroidism and low BMD are common in HIV-positive patients. Efavirenz is associated with a reduction in 25-hydroxy vitamin D levels, tenofovir with secondary hyperparathyroidism, and cART with increased bone turnover and low BMD. The clinical significance of low BMD, however, remains unclear, especially in younger patients. Although the incidence of fractures may be increased in HIV-positive patients, the contribution of low BMD and vitamin D deficiency to these fractures is uncertain. Limited data on vitamin D supplementation in HIV-positive patients have shown transient, beneficial effects on PTH, but no effects on BMD.
Conclusion: The benefits of vitamin D supplementation in this population need to be demonstrated before widespread ‘test and treat’ policies can be recommended as part of routine clinical practice.
Objective: To determine whether the ability of primary myeloid dendritic cells (mDCs) to induce regulatory T cells (Treg) is affected by chronic simian immunodeficiency virus (SIV) infection.
Design: Modulation of dendritic cell activity with the aim of influencing Treg frequency may lead to new treatment options for HIV and strategies for vaccine development.
Methods: Eleven chronically infected SIV+ Rhesus macaques were compared with four uninfected animals. Immature and mature mDCs were isolated from mesenteric lymph nodes and spleen by cell sorting and cultured with purified autologous non-Treg (CD4+CD25- T cells). CD25 and FOXP3 up-regulation was used to assess Treg induction.
Results: The frequency of splenic mDC and plasmacytoid dendritic cell was lower in infected animals than in uninfected animals; their frequency in the mesenteric lymph nodes was not significantly altered, but the percentage of mature mDCs was increased in the mesenteric lymph nodes of infected animals. Mature splenic or mesenteric mDCs from infected animals were significantly more efficient at inducing Treg than mDCs from uninfected animals. Mature mDCs from infected macaques induced more conversion than immature mDCs. Splenic mDCs were as efficient as mesenteric mDCs in this context and CD103 expression by mDCs did not appear to influence the level of conversion.
Conclusions: Tissue mDCs from SIV-infected animals exhibit an enhanced capability to induce Treg and may contribute to the accumulation of Treg in lymphoid tissues during progressive infection. The activation status of dendritic cell impacts this process but the capacity to induce Treg was not restricted to mucosal dendritic cells in infected animals.
Objectives: Administration of synthetic long peptides (SLPs) derived from human papillomavirus to cervical cancer patients resulted in clinical benefit correlated with expansions of tumour-specific T cells. Because vaginal mucosa is an important port of entry for HIV-1, we have explored SLP for HIV-1 vaccination. Using immunogen HIVconsv derived from the conserved regions of HIV-1, we previously showed in rhesus macaques that SLP.HIVconsv delivered as a boost increased the breath of T-cell specificities elicited by single-gene vaccines. Here, we compared and characterized the use of electroporated pSG2.HIVconsv DNA (D) and imiquimod/montanide-adjuvanted SLP.HIVconsv (S) as priming vaccines for boosting with attenuated chimpanzee adenovirus ChAdV63.HIVconsv (C) and modified vaccinia virus Ankara MVA.HIVconsv (M).
Design: Prime-boost regimens of DDDCMS, DSSCMS and SSSCMS in rhesus macaques.
Methods: Animals’ blood was analysed regularly throughout the vaccination for HIV-1-specific T-cell and antibody responses.
Results: We found that electroporation spares DNA dose, both SLP.HIVconsv and pSG2.HIVconsv DNA primed weakly HIVconsv-specific T cells, regimen DDDCM induced the highest frequencies of oligofunctional, proliferating CD4+ and CD8+ T cells, and a subsequent SLP.HIVconsv boost expanded primarily CD4+ cells. DSS was the most efficient regimen inducing antibodies binding to regions of trimeric HIV-1 Env, which are highly conserved among the four major global clades, although no unequivocal neutralizing activity was detected.
Conclusion: The present results encourage evaluation of the SLP.HIVconsv vaccine modality in human volunteers along the currently trialled pSG2.HIVconsv DNA, ChAdV63.HIVconsv and MVA.HIVconsv vaccines. These results are discussed in the context of the RV144 trial outcome.
Objective: To compare fracture risk in persons with and without HIV infection and to examine the influence of highly active antiretroviral therapy (HAART) initiation on risk of fracture.
Design: Population-based nationwide cohort study using Danish registries.
Methods: Outcome measures were time to first fracture at any site, time to first low-energy and high-energy fracture in HIV-infected patients (n?=?5306) compared with a general population control cohort (n?=?26?530) matched by sex and age during the study period 1995–2009. Cox regression analyses were used to estimate incidence rate ratios (IRRs).
Results: HIV-infected patients had increased risk of fracture [IRR 1.5, 95% confidence interval (CI) 1.4–1.7] compared with population controls. The relative risk was lower in HIV-monoinfected patients (IRR 1.3, 95% CI 1.2–1.4) than in HIV/hepatitis C virus (HCV)-coinfected patients (IRR 2.9, 95% CI 2.5–3.4).
Both HIV-monoinfected and HIV/HCV-coinfected patients had increased risk of low-energy fracture, IRR of 1.6 (95% CI 1.4–1.8) and 3.8 (95% CI 3.0–4.9). However, only HIV/HCV-coinfected patients had increased risk of high-energy fracture, IRR of 2.4 (95% CI 2.0–2.9). Among HIV-monoinfected patients the risk of low-energy fracture was only significantly increased after HAART exposure, IRR of 1.8 (95% CI 1.5–2.1). The increased risk in HAART-exposed patients was not associated with CD4 cell count, prior AIDS, tenofovir or efavirenz exposure, but with comorbidity and smoking.
Conclusion: HIV-infected patients had increased risk of fracture compared with population controls. Among HIV-monoinfected patients the increased risk was observed for low-energy but not for high-energy fractures, and the increased risk of low-energy fracture was only observed in HAART-exposed patients.
Objective: Proteinuria occurs commonly among HIV-infected and uninfected injection drug users (IDUs) and is associated with increased mortality risk. Vitamin D deficiency, highly prevalent among IDUs and potentially modifiable, may contribute to proteinuria. To determine whether vitamin D is associated with proteinuria in this population, we conducted a cross-sectional study in the AIDS Linked to the IntraVenous Experience (ALIVE) Study.
Methods: 25(OH)-vitamin D levels were measured in 268 HIV-infected and 614 HIV-uninfected participants. The association between vitamin D deficiency (<10?ng/ml) and urinary protein excretion was evaluated by linear regression. The odds of persistent proteinuria (urine protein-to-creatinine ratio >200?mg/g on two occasions) associated with vitamin D deficiency was examined using logistic regression.
Results: One-third of participants were vitamin D-deficient. Vitamin D deficiency was independently associated with higher urinary protein excretion (P?
Objective: To evaluate the incidence and determinants of diabetes in a cohort of HIV-infected adults initiated with combination antiretroviral treatment (cART) in 1997–1999 and followed up to 2009.
Design: Prospective study of 1046 patients at 47 French clinical sites.
Methods: Potential determinants of diabetes occurrence, defined by confirmed increased glycemia and/or initiation of antidiabetic treatment, were assessed by a proportional hazards model, including time-updated metabolic parameters and ART exposure.
Results: Among the cohort, representing 7846 person-years of follow-up (PYFU), 54% received indinavir, 75% stavudine and 52% didanosine. Overall, 111 patients developed diabetes, with an incidence of 14.1/1000 PYFU (14.6 in men, 12.6 in women). Incidence peaked in 1999–2000 (23.2/1000 PYFU) and decreased thereafter. The incidence of diabetes was associated [adjusted hazard ratio (aHR), all P?30?kg/m2), waist-to-hip ratio (hazard ratio?=?3.87 for =0.97?male/0.92 female), time-updated lipoatrophy (hazard ratio?=?2.14) and short-term exposure to indinavir (0–1year: hazard ratio?=?2.53), stavudine (0–1year: hazard ratio?=?2.56, 1–2years: hazard ratio?=?2.65) or didanosine (2–3years: hazard ratio?=?3.16). Occurrence of diabetes was not associated with HIV-related markers, hepatitis C, hypertension or family history of diabetes. Insulin resistance was predictive for incident diabetes.
Conclusions: In this nationwide cohort, followed for 10 years after cART initiation, diabetes incidence peaked in 1990–2000, was markedly higher than that reported for European uninfected or other HIV-infected populations (4–6/1000 PYFU) and linked with age and adiposity. Adiposity and glycemic markers should be monitored in aging HIV-infected patients.
Background: Despite the known substantial benefits of combination antiretroviral therapy (cART), cumulative adverse effects could still limit the overall long-term treatment benefit. Therefore we investigated changes in the rate of death with increasing exposure to cART.
Methods: A total of 12 069 patients were followed from baseline, which was defined as the time of starting cART or enrolment into EuroSIDA whichever occurred later, until death or 6 months after last follow-up visit. Incidence rates of death were calculated per 1000 person-years of follow-up (PYFU) and stratified by time of exposure to cART (=3 antiretrovirals): less than 2, 2–3.99, 4–5.99, 6–7.99 and more than 8 years. Duration of cART exposure was the cumulative time actually receiving cART. Poisson regression models were fitted for each cause of death separately.
Results: A total of 1297 patients died during 70?613 PYFU [incidence rate 18.3 per 1000 PYFU, 95% confidence interval (CI) 17.4–19.4], 413 due to AIDS (5.85, 95% CI 5.28–6.41) and 884 due to non-AIDS-related cause (12.5, 95% CI 11.7–13.3). After adjustment for confounding variables, including baseline CD4 cell count and HIV RNA, there was a significant decrease in the rate of all-cause and AIDS-related death between 2 and 3.99 years and longer exposure time. In the first 2 years on cART the risk of non-AIDS death was significantly lower, but no significant difference in the rate of non-AIDS-related deaths between 2 and 3.99 years and longer exposure to cART was observed.
Conclusion: In conclusion, we found no evidence of an increased risk of both all-cause and non-AIDS-related deaths with long-term cumulative cART exposure.
Objective: Nevirapine and cotrimoxazole are associated with hematologic toxicities and skin-rash. Safety of their concurrent use for prophylaxis over extended periods among HIV-exposed uninfected infants has not been previously assessed.
Design: Secondary data analysis of the ‘HIV Prevention Trials Network-046 protocol’ (version 2.0), a phase-III, randomized, placebo-controlled trial that assessed efficacy and safety of nevirapine prophylaxis against breast milk transmission of HIV-1.
Methods: Trial infants received 6-month study nevirapine/placebo, and standard-of-care peripartum single-dose nevirapine+/- zidovudine ‘tail’, and cotrimoxazole prophylaxis from 6 weeks through breastfeeding cessation. Adverse events were monitored using United States Division of AIDS Toxicity Tables (2004). Risk of neutropenia, anemia and skin-rash in the cotrimoxazole?+?nevirapine and the cotrimoxazole?+?placebo groups were compared using negative-binomial regression.
Results: Incidence of neutropenia and/or anemia, and skin-rash was highest during the first 6 weeks of life and declined, thereafter, regardless of study group. Time to first adverse event after 6 weeks was similar in cotrimoxazole?+?nevirapine and cotrimoxazole?+?placebo groups: hazard ratio (95% confidence interval) was 1.26 (0.96–1.66) for neutropenia and/or anemia (all grades), 1.27 (0.80–2.03) for neutropenia and/or anemia (grade =3) and 1.16 (0.46–2.90) for skin-rash (grade =2). There were no statistically significant differences in immediate (6 weeks–6 months) and long-term (6–12 months) adverse event risk among infants on cotrimoxazole?+?nevirapine versus cotrimoxazole?+?placebo.
Conclusion: Extended nevirapine and cotrimoxazole prophylaxis through 6 months of age among HIV-exposed uninfected infants did not appear to increase the immediate or long-term risk of neutropenia, anemia or skin-rash. Concurrent use beyond 6 months, however, needs to be evaluated.
Background and objectives: Effective antiretroviral therapy (ART) has contributed greatly toward survival for people with HIV, yet many remain undiagnosed until very late. Our aims were to estimate the life expectancy of an HIV-infected MSM living in a developed country with extensive access to ART and healthcare, and to assess the effect of late diagnosis on life expectancy.
Methods: A stochastic computer simulation model of HIV infection and the effect of ART was used to estimate life expectancy and determine the distribution of potential lifetime outcomes of an MSM, aged 30 years, who becomes HIV positive in 2010. The effect of altering the diagnosis rate was investigated.
Results: Assuming a high rate of HIV diagnosis (median CD4 cell count at diagnosis, 432?cells/µl), projected median age at death (life expectancy) was 75.0 years. This implies 7.0 years of life were lost on average due to HIV. Cumulative risks of death by 5 and 10 years after infection were 2.3 and 5.2%, respectively. The 95% uncertainty bound for life expectancy was (68.0,77.3) years. When a low diagnosis rate was assumed (diagnosis only when symptomatic, median CD4 cell count 140?cells/µl), life expectancy was 71.5 years, implying an average 10.5 years of life lost due to HIV.
Conclusion: If low rates of virologic failure observed in treated patients continue, predicted life expectancy is relatively high in people with HIV who can access a wide range of antiretrovirals. The greatest risk of excess mortality is due to delays in HIV diagnosis.
Objectives: Recent data suggest that community viral load (CVL) can be used as a population-level biomarker for HIV transmission and its reduction may be associated with a decrease in HIV incidence. Given the magnitude of the HIV epidemic in Washington, District of Columbia, we sought to measure the District of Columbia's CVL.
Design: An ecological analysis was conducted.
Methods: Mean and total CVL were calculated using the most recent viral load for prevalent HIV/AIDS cases reported to District of Columbia HIV/AIDS surveillance through 2008. Univariate and multivariable analyses were conducted to assess differences in CVL availability, mean CVL, proportion of undetectable viral loads, and 5-year trends in mean CVL and new HIV/AIDS diagnoses. Geospatial analysis was used to map mean CVL and selected indicators of socioeconomic status by geopolitical designation.
Results: Among 15?467 HIV/AIDS cases alive from 2004 to 2008, 48.2% had at least one viral load reported. Viral load data completeness increased significantly over the 5 years (P?
Objective: To assess the cost-effectiveness of etravirine (INTELENCE), a novel nonnucleoside reverse transcriptase inhibitor, used in combination with a background regimen that included darunavir/ritonavir, from a Canadian Provincial Ministry of Health perspective.
Design: A Markov model with a 3-month cycle time and six health states based on CD4 cell count ranges was developed to follow a hypothetical cohort of treatment-experienced adults with HIV-1 infection through initial and subsequent treatment regimens.
Methods: Costs (in 2009 Canadian dollars), utilities, and HIV-related mortality data for each health state as well as non-HIV-related mortality data were estimated from Canadian sources and published literature. Transition probabilities between health states and first-year hospitalization and mortality rates were derived from clinical trial data. Incremental 1-year costs per additional adult with viral load less than 50?copies/ml at 48 weeks and incremental lifetime costs per quality-adjusted life-year (QALY) gained were estimated using a 5% discount rate. Sensitivity and variability analyses and model validation were performed.
Results: Etravirine was associated with an increased probability of achieving less than 50?copies/ml at 48 weeks of 0.205 and an estimated gain of 0.66 discounted (1.48 undiscounted) QALYs over a lifetime. The incremental 1-year cost per additional person with viral load less than 50?copies/ml was $23?862. The lifetime incremental cost per QALY gained was $49?120. For the uncertainty ranges and variability scenarios tested for the lifetime horizon, the cost-effectiveness ratio was between $28?859 and 66?249.
Conclusion: When compared with optimized standard of care including darunavir/ritonavir, adding etravirine represents a cost-effective option for treatment-experienced adults in Canada.
Objectives: To analyse mortality, loss to follow-up (LTFU) and retention on antiretroviral treatment (ART) in the first year of ART across all age groups in the Malawi national ART programme.
Design: Cohort study including all patients who started ART in Malawi's public sector clinics between 2004 and 2007.
Methods: ART registers were photographed, information entered into a database and merged with data from clinics with electronic records. Rates per 100 patient-years and cumulative incidence of retention were calculated. Subhazard ratios (sHRs) of outcomes adjusted for patient and clinic-level characteristics were calculated in multivariable analysis, applying competing risk models.
Results: A total of 117?945 patients contributed 85?246 person-years: 1.0% were infants below 2 years, 7.4% children 2–14, 7.5% young people 15–24, and 84.2% adults 25 years and above. Sixty percent of patients were female: women outnumbered men from age 14 to 35 years. Mortality and LTFU were higher in men from age 20 years. Infants and young people had the highest rates per 100 person-years for mortality (23.0 and 19.4) and LTFU (24.7 and 19.3), and the highest adjusted relative risks compared to age group 25–34 years: sHRs were 1.37 [95% confidence interval (CI) 1.17–1.60] and 1.17 (95% CI 1.10–1.25) for death and 1.37 (95% CI 1.18–1.59) and 1.27 (95% CI 1.19–1.35) for LTFU, respectively.
Conclusion: In this country-wide study patients aged 0–1 and 15–24 years had the highest risk of death and LTFU, and from age 20 men were at higher risk than women. Interventions to improve outcomes in these patient groups are required.
Objectives: To investigate the association between hormonal contraceptives and risk of HIV-1 seroconversion and prevalence of other sexually transmitted infections.
Design: Prospective cohort.
Methods: The study population was 2?236 HIV-negative women who were screened in a biomedical intervention trial in Durban, South Africa. The association between the use of hormonal contraceptives and risk of HIV-1 seroconversion was modeled using Cox proportional hazards regression analysis. Prevalence of Chlamydia trachomatis and Neisseria gonorrhoeae infections were assessed using logistic regression models.
Results: Hormonal injectables were the most common method of contraceptives (46.47%) followed by condom use (28.04%). Overall, compared with women who reported using condoms or other methods as their preferred form of contraceptive, those who reported using hormonal contraceptives (injectables and oral pills) were less likely to use condoms in their last sexual act. Using hormonal injectables during the study was significantly associated with increased risk for HIV-1 infection [adjusted hazard ratio 1.72, 95% confidence interval (CI) 1.19–2.49, P?=?0.005]; hormonal injectables were also significantly associated with higher prevalent of C. trachomatis infections (adjusted odds ratio 2.46, 95% CI 1.52–3.97, P?
Objective: To determine whether the proximate context of gender-unequal norms about violence against women undermines women's ability to negotiate condom use in sexual relationships.
Design: Secondary analysis of cross–sectional data pooled from 22 Demographic and Health Surveys conducted in sub-Saharan Africa.
Methods: Each of the 22 surveys employed a multistage stratified design with probabilistic sampling and was designed to be nationally representative of reproductive-age women. The outcome was self-reported condom use at last sexual intercourse. The primary explanatory variable of interest was a scale consisting of five questions about whether the respondent agreed with the appropriateness of wife beating under five different scenarios. To measure the proximate context of norms about violence against women, this scale was aggregated to the level of the primary sampling unit. We fit logistic regression models with cluster-correlated robust standard errors and adjustment for country-level fixed effects and sociodemographic characteristics.
Results: Our analysis sample included data from 198?806 sexually active women living in 22 sub-Saharan African countries. The wife-beating scale was internally consistent (Cronbach's a?=?0.84), and factor analysis confirmed the presence of a single factor. Condom use was associated with gender-unequal contextual norms about violence against women (adjusted odds ratio?=?0.88; 95% confidence interval, 0.85–0.92; P?
Objective: Although bacterial vaginosis is a known correlate of HIV infection, no previous studies have investigated whether women defined as HIV-exposed seronegative (HESN) are less likely to have bacterial vaginosis. Little is known about the effects of bacterial vaginosis on systemic immune activation associated with HIV+ serostatus.
Design: Cohort-based retrospective analysis of bacterial vaginosis in relation to HESN status, HIV+ serostatus and peripheral T-helper cells, with cross-sectional analysis of bacterial vaginosis in relation to peripheral T-regulatory cells (Tregs).
Methods: Bacterial vaginosis diagnosis by Gram stain and determination of systemic CD4+ and CD8+ T-helper cell frequency by flow cytometry for 3504 vaginal samples from 988 commercial sex workers over 4 years. Treg phenotyping by FoxP3 staining and multiparameter flow cytometry in peripheral blood of 97 women at a single time-point.
Results: No differences in bacterial vaginosis diagnosis were observed between HESN and other HIV-negative (HIV-N) controls; however, HIV+ women were more likely to be diagnosed with bacterial vaginosis compared to all HIV-negative women (HESN/HIV-N combined). HIV+ women with bacterial vaginosis had significantly higher CD4+/CD8+ T-helper cell counts and a lower CD4/CD8 ratio, as well as fewer Tregs as a proportion of total T-helper cells, compared to bacterial vaginosis-negative women. The number of bacterial vaginosis diagnoses in this cohort has decreased significantly over time.
Conclusion: Bacterial vaginosis is associated with HIV serostatus and shifts in distribution of T-cell subsets. A concomitant reduction in bacterial vaginosis and HIV infections over time suggests that the elucidation of bacterial vaginosis–HIV interactions will be critical to further understanding of HIV pathogenesis and prevention in this high-risk group.
