HIV-1 Transmission During Recent Infection and During Treatment Interruptions as Major Drivers of New Infections in the Swiss HIV Cohort Study.

BACKGROUND  Reducing the fraction of transmissions during recent human immunodeficiency virus (HIV) infection is essential for the population-level success of "treatment as prevention". METHODS  A phylogenetic tree was constructed with 19 604 Swiss sequences and 90 994 non-Swiss background sequences. Swiss transmission pairs were identified using 104 combinations of genetic distance (1%-2.5%) and bootstrap (50%-100%) thresholds, to examine the effect of those criteria. Monophyletic pairs were classified as recent or chronic transmission based on the time interval between estimated seroconversion dates. Logistic regression with adjustment for clinical and demographic characteristics was used to identify risk factors associated with transmission during recent or chronic infection. FINDINGS  Seroconversion dates were estimated for 4079 patients on the phylogeny, and comprised between 71 (distance, 1%; bootstrap, 100%) to 378 transmission pairs (distance, 2.5%; bootstrap, 50%). We found that 43.7% (range, 41%-56%) of the transmissions occurred during the first year of infection. Stricter phylogenetic definition of transmission pairs was associated with higher recent-phase transmission fraction. Chronic-phase viral load area under the curve (adjusted odds ratio, 3; 95% confidence interval, 1.64-5.48) and time to antiretroviral therapy (ART) start (adjusted odds ratio 1.4/y; 1.11-1.77) were associated with chronic-phase transmission as opposed to recent transmission. Importantly, at least 14% of the chronic-phase transmission events occurred after the transmitter had interrupted ART. CONCLUSIONS  We demonstrate a high fraction of transmission during recent HIV infection but also chronic transmissions after interruption of ART in Switzerland. Both represent key issues for treatment as prevention and underline the importance of early diagnosis and of early and continuous treatment.

Comparative effectiveness of immediate antiretroviral therapy versus CD4-based initiation in HIV-positive individuals in high-income countries: observational cohort study.

BACKGROUND Recommendations have differed nationally and internationally with respect to the best time to start antiretroviral therapy (ART). We compared effectiveness of three strategies for initiation of ART in high-income countries for HIV-positive individuals who do not have AIDS: immediate initiation, initiation at a CD4 count less than 500 cells per μL, and initiation at a CD4 count less than 350 cells per μL. METHODS We used data from the HIV-CAUSAL Collaboration of cohort studies in Europe and the USA. We included 55 826 individuals aged 18 years or older who were diagnosed with HIV-1 infection between January, 2000, and September, 2013, had not started ART, did not have AIDS, and had CD4 count and HIV-RNA viral load measurements within 6 months of HIV diagnosis. We estimated relative risks of death and of death or AIDS-defining illness, mean survival time, the proportion of individuals in need of ART, and the proportion of individuals with HIV-RNA viral load less than 50 copies per mL, as would have been recorded under each ART initiation strategy after 7 years of HIV diagnosis. We used the parametric g-formula to adjust for baseline and time-varying confounders. FINDINGS Median CD4 count at diagnosis of HIV infection was 376 cells per μL (IQR 222-551). Compared with immediate initiation, the estimated relative risk of death was 1·02 (95% CI 1·01-1·02) when ART was started at a CD4 count less than 500 cells per μL, and 1·06 (1·04-1·08) with initiation at a CD4 count less than 350 cells per μL. Corresponding estimates for death or AIDS-defining illness were 1·06 (1·06-1·07) and 1·20 (1·17-1·23), respectively. Compared with immediate initiation, the mean survival time at 7 years with a strategy of initiation at a CD4 count less than 500 cells per μL was 2 days shorter (95% CI 1-2) and at a CD4 count less than 350 cells per μL was 5 days shorter (4-6). 7 years after diagnosis of HIV, 100%, 98·7% (95% CI 98·6-98·7), and 92·6% (92·2-92·9) of individuals would have been in need of ART with immediate initiation, initiation at a CD4 count less than 500 cells per μL, and initiation at a CD4 count less than 350 cells per μL, respectively. Corresponding proportions of individuals with HIV-RNA viral load less than 50 copies per mL at 7 years were 87·3% (87·3-88·6), 87·4% (87·4-88·6), and 83·8% (83·6-84·9). INTERPRETATION The benefits of immediate initiation of ART, such as prolonged survival and AIDS-free survival and increased virological suppression, were small in this high-income setting with relatively low CD4 count at HIV diagnosis. The estimated beneficial effect on AIDS is less than in recently reported randomised trials. Increasing rates of HIV testing might be as important as a policy of early initiation of ART. FUNDING National Institutes of Health.

Self-reported nonadherence to antiretroviral therapy as a predictor of viral failure and mortality.

OBJECTIVE To determine the effect of nonadherence to antiretroviral therapy (ART) on virologic failure and mortality in naive individuals starting ART. DESIGN Prospective observational cohort study. METHODS Eligible individuals enrolled in the Swiss HIV Cohort Study, started ART between 2003 and 2012, and provided adherence data on at least one biannual clinical visit. Adherence was defined as missed doses (none, one, two, or more than two) and percentage adherence (>95, 90-95, and <90) in the previous 4 weeks. Inverse probability weighting of marginal structural models was used to estimate the effect of nonadherence on viral failure (HIV-1 viral load >500 copies/ml) and mortality. RESULTS Of 3150 individuals followed for a median 4.7 years, 480 (15.2%) experienced viral failure and 104 (3.3%) died, 1155 (36.6%) reported missing one dose, 414 (13.1%) two doses and, 333 (10.6%) more than two doses of ART. The risk of viral failure increased with each missed dose (one dose: hazard ratio [HR] 1.15, 95% confidence interval 0.79-1.67; two doses: 2.15, 1.31-3.53; more than two doses: 5.21, 2.96-9.18). The risk of death increased with more than two missed doses (HR 4.87, 2.21-10.73). Missing one to two doses of ART increased the risk of viral failure in those starting once-daily (HR 1.67, 1.11-2.50) compared with those starting twice-daily regimens (HR 0.99, 0.64-1.54, interaction P = 0.09). Consistent results were found for percentage adherence. CONCLUSION Self-report of two or more missed doses of ART is associated with an increased risk of both viral failure and death. A simple adherence question helps identify patients at risk for negative clinical outcomes and offers opportunities for intervention.

Essentials from the 2015 European AIDS Clinical Society (EACS) guidelines for the treatment of adult HIV-positive persons.

BACKGROUND The European AIDS Clinical Society (EACS) guidelines are intended for all clinicians involved in the care of HIV-positive persons, and are available in print, online, and as a free App for download for iPhone and Android. GUIDELINE HIGHLIGHTS The 2015 version of the EACS guidelines contains major revisions in all sections; antiretroviral treatment (ART), comorbidities, coinfections and opportunistic diseases. Among the key revisions is the recommendation of ART for all HIV-positive persons, irrespectively of CD4 count, based on the Strategic Timing of AntiRetroviral Treatment (START) study results. The recommendations for the preferred and the alternative ART options have also been revised, and a new section on the use of pre-exposure prophylaxis (PrEP) has been added. A number of new antiretroviral drugs/drug combinations have been added to the updated tables on drug-drug interactions, adverse drug effects, dose adjustment for renal/liver insufficiency and for ART administration in persons with swallowing difficulties. The revisions of the coinfection section reflect the major advances in anti-hepatitis C virus (HCV) treatment with direct-acting antivirals with earlier start of treatment in individuals at increased risk of liver disease progression, and a phasing out of interferon-containing treatment regimens. The section on opportunistic diseases has been restructured according to individual pathogens/diseases and a new overview table has been added on CD4 count thresholds for different primary prophylaxes. CONCLUSIONS The diagnosis and management of HIV infection and related coinfections, opportunistic diseases and comorbidities continue to require a multidisciplinary effort for which the 2015 version of the EACS guidelines provides an easily accessable and updated overview.

Low Risk of Death, but Substantial Program Attrition, in Pediatric HIV Treatment Cohorts in Sub-Saharan Africa

BACKGROUND: To date, an estimated 10% of children eligible for antiretroviral treatment (ART) receive it, and the frequency of retention in programs is unknown. We evaluated the 2-year risks of death and loss to follow-up (LTFU) of children after ART initiation in a multicenter study in sub-Saharan Africa. METHODS: Pooled analysis of routine individual data from 16 participating clinics produced overall Kaplan-Meier estimates of the probabilities of death or LTFU after ART initiation. Risk factors analysis used Weibull regression, accounting for between-cohort heterogeneity. RESULTS: The median age of 2405 children at ART initiation was 4.9 years (12%, younger than 12 months), 52% were male, 70% had severe immunodeficiency, and 59% started ART with a nonnucleoside reverse transcriptase inhibitor. The 2-year risk of death after ART initiation was 6.9% (95% confidence interval [CI]: 5.9 to 8.1), independently associated with baseline severe anemia (adjusted hazard ratio [aHR]: 4.10 [CI: 2.36 to 7.13]), immunodeficiency (adjusted aHR: 2.95 [CI: 1.49 to 5.82]), and severe clinical status (adjusted aHR: 3.64 [CI: 1.95 to 6.81]); the 2-year risk of LTFU was 10.3% (CI: 8.9 to 11.9), higher in children with severe clinical status. CONCLUSIONS: Once on treatment, the 2-year risk of death is low but the LTFU risk is substantial. ART is still mainly initiated at advanced disease stage in African children, reinforcing the need for early HIV diagnosis, early initiation of ART, and procedures to increase program retention.

Qualitative Distinction of Autotrophic and Heterotrophic Processes at the Leaf Level by Means of Triple Stable Isotope (C–O–H) Patterns

Foliar samples were harvested from two oaks, a beech, and a yew at the same site in order to trace the development of the leaves over an entire vegetation season. Cellulose yield and stable isotopic compositions (δ13C, δ18O, and δD) were analyzed on leaf cellulose. All parameters unequivocally define a juvenile and a mature period in the foliar expansion of each species. The accompanying shifts of the δ13C-values are in agreement with the transition from remobilized carbohydrates (juvenile period), to current photosynthates (mature phase). While the opponent seasonal trends of δ18O of blade and vein cellulose are in perfect agreement with the state-of-art mechanistic understanding, the lack of this discrepancy for δD, documented for the first time, is unexpected. For example, the offset range of 18 permil (oak veins) to 57 permil (oak blades) in δD may represent a process driven shift from autotrophic to heterotrophic processes. The shared pattern between blade and vein found for both oak and beech suggests an overwhelming metabolic isotope effect on δD that might be accompanied by proton transfer linked to the Calvin-cycle. These results provide strong evidence that hydrogen and oxygen are under different biochemical controls even at the leaf level.

Influence of noninjecting and injecting drug use on mortality, retention in the cohort, and antiretroviral therapy, in participants in the Swiss HIV Cohort Study.

OBJECTIVES We studied the influence of noninjecting and injecting drug use on mortality, dropout rate, and the course of antiretroviral therapy (ART), in the Swiss HIV Cohort Study (SHCS). METHODS Cohort participants, registered prior to April 2007 and with at least one drug use questionnaire completed until May 2013, were categorized according to their self-reported drug use behaviour. The probabilities of death and dropout were separately analysed using multivariable competing risks proportional hazards regression models with mutual correction for the other endpoint. Furthermore, we describe the influence of drug use on the course of ART. RESULTS A total of 6529 participants (including 31% women) were followed during 31 215 person-years; 5.1% participants died; 10.5% were lost to follow-up. Among persons with homosexual or heterosexual HIV transmission, noninjecting drug use was associated with higher all-cause mortality [subhazard rate (SHR) 1.73; 95% confidence interval (CI) 1.07-2.83], compared with no drug use. Also, mortality was increased among former injecting drug users (IDUs) who reported noninjecting drug use (SHR 2.34; 95% CI 1.49-3.69). Noninjecting drug use was associated with higher dropout rates. The mean proportion of time with suppressed viral replication was 82.2% in all participants, irrespective of ART status, and 91.2% in those on ART. Drug use lowered adherence, and increased rates of ART change and ART interruptions. Virological failure on ART was more frequent in participants who reported concomitant drug injections while on opiate substitution, and in current IDUs, but not among noninjecting drug users. CONCLUSIONS Noninjecting drug use and injecting drug use are modifiable risks for death, and they lower retention in a cohort and complicate ART.

Prevention of vascular dysfunction and arterial hypertension in mice generated by assisted reproductive technologies by addition of melatonin to culture media.

Assisted reproductive technologies (ART) induce vascular dysfunction in humans and mice. In mice, ART-induced vascular dysfunction is related to epigenetic alteration of the endothelial nitric oxide synthase (eNOS) gene, resulting in decreased vascular eNOS expression and nitrite/nitrate synthesis. Melatonin is involved in epigenetic regulation, and its administration to sterile women improves the success rate of ART. We hypothesized that addition of melatonin to culture media may prevent ART-induced epigenetic and cardiovascular alterations in mice. We, therefore, assessed mesenteric-artery responses to acetylcholine and arterial blood pressure, together with DNA methylation of the eNOS gene promoter in vascular tissue and nitric oxide plasma concentration in 12-wk-old ART mice generated with and without addition of melatonin to culture media and in control mice. As expected, acetylcholine-induced mesenteric-artery dilation was impaired (P = 0.008 vs. control) and mean arterial blood pressure increased (109.5 ± 3.8 vs. 104.0 ± 4.7 mmHg, P = 0.002, ART vs. control) in ART compared with control mice. These alterations were associated with altered DNA methylation of the eNOS gene promoter (P < 0.001 vs. control) and decreased plasma nitric oxide concentration (10.1 ± 11.1 vs. 29.5 ± 8.0 μM) (P < 0.001 ART vs. control). Addition of melatonin (10(-6) M) to culture media prevented eNOS dysmethylation (P = 0.005, vs. ART + vehicle), normalized nitric oxide plasma concentration (23.1 ± 14.6 μM, P = 0.002 vs. ART + vehicle) and mesentery-artery responsiveness to acetylcholine (P < 0.008 vs. ART + vehicle), and prevented arterial hypertension (104.6 ± 3.4 mmHg, P < 0.003 vs. ART + vehicle). These findings provide proof of principle that modification of culture media prevents ART-induced vascular dysfunction. We speculate that this approach will also allow preventing ART-induced premature atherosclerosis in humans.

Determinants of Weight Evolution Among HIV-Positive Patients Initiating Antiretroviral Treatment in Low-Resource Settings.

BACKGROUND In resource-limited settings, clinical parameters, including body weight changes, are used to monitor clinical response. Therefore, we studied body weight changes in patients on antiretroviral treatment (ART) in different regions of the world. METHODS Data were extracted from the "International Epidemiologic Databases to Evaluate AIDS," a network of ART programmes that prospectively collects routine clinical data. Adults on ART from the Southern, East, West, and Central African and the Asia-Pacific regions were selected from the database if baseline data on body weight, gender, ART regimen, and CD4 count were available. Body weight change over the first 2 years and the probability of body weight loss in the second year were modeled using linear mixed models and logistic regression, respectively. RESULTS Data from 205,571 patients were analyzed. Mean adjusted body weight change in the first 12 months was higher in patients started on tenofovir and/or efavirenz; in patients from Central, West, and East Africa, in men, and in patients with a poorer clinical status. In the second year of ART, it was greater in patients initiated on tenofovir and/or nevirapine, and for patients not on stavudine, in women, in Southern Africa and in patients with a better clinical status at initiation. Stavudine in the initial regimen was associated with a lower mean adjusted body weight change and with weight loss in the second treatment year. CONCLUSIONS Different ART regimens have different effects on body weight change. Body weight loss after 1 year of treatment in patients on stavudine might be associated with lipoatrophy.

Incidence of AIDS-Defining and Other Cancers in HIV-Positive Children in South Africa: Record Linkage Study.

BACKGROUND Little is known on the risk of cancer in HIV-positive children in sub-Saharan Africa. We examined incidence and risk factors of AIDS-defining and other cancers in pediatric antiretroviral therapy (ART) programs in South Africa. METHODS We linked the records of five ART programs in Johannesburg and Cape Town to those of pediatric oncology units, based on name and surname, date of birth, folder and civil identification numbers. We calculated incidence rates and obtained hazard ratios (HR) with 95% confidence intervals (CI) from Cox regression models including ART, sex, age, and degree of immunodeficiency. Missing CD4 counts and CD4% were multiply imputed. Immunodeficiency was defined according to World Health Organization 2005 criteria. RESULTS Data of 11,707 HIV-positive children were included in the analysis. During 29,348 person-years of follow-up 24 cancers were diagnosed, for an incidence rate of 82 per 100,000 person-years (95% CI 55-122). The most frequent cancers were Kaposi Sarcoma (34 per 100,000 person-years) and Non Hodgkin Lymphoma (31 per 100,000 person-years). The incidence of non AIDS-defining malignancies was 17 per 100,000. The risk of developing cancer was lower on ART (HR 0.29, 95%CI 0.09-0.86), and increased with age at enrolment (>10 versus <3 years: HR 7.3, 95% CI 2.2-24.6) and immunodeficiency at enrolment (advanced/severe versus no/mild: HR 3.5, 95%CI 1.1-12.0). The HR for the effect of ART from complete case analysis was similar but ceased to be statistically significant (p=0.078). CONCLUSIONS Early HIV diagnosis and linkage to care, with start of ART before advanced immunodeficiency develops, may substantially reduce the burden of cancer in HIV-positive children in South Africa and elsewhere.

Retention in care during the first 3 years of antiretroviral therapy for women in Malawi's option B+ programme: an observational cohort study

Background Studies of Malawi's option B+ programme for HIV-positive pregnant and breastfeeding women have reported high loss to follow-up during pregnancy and at the start of antiretroviral therapy (ART), but few data exist about retention during breastfeeding and after weaning. We examined loss to follow-up and retention in care in patients in the option B+ programme during their first 3 years on ART. Methods We analysed two data sources: aggregated facility-level data about patients in option B+ who started ART between Oct 1, 2011, and June 30, 2012, at 546 health facilities; and patient-level data from 20 large facilities with electronic medical record system for HIV-positive women who started ART between Sept 1, 2011, and Dec 31, 2013, under option B+ or because they had WHO clinical stages 3 or 4 disease or had CD4 counts of less than 350 cells per μL. We used facility-level data to calculate representative estimates of retention and loss to follow-up. We used patient-level data to study temporal trends in retention, timing of loss to follow-up, and predictors of no follow-up and loss to follow-up. We defined patients who were more than 60 days late for their first follow-up visit as having no follow-up and patients who were more than 60 days late for a subsequent visit as being lost to follow-up. We calculated proportions and cumulative probabilities of patients who had died, stopped ART, had no follow-up, were lost to follow-up, or were retained alive on ART for 36 months. We calculated odds ratios and hazard ratios to examine predictors of no follow-up and loss to follow-up. Findings Analysis of facility-level data about patients in option B+ who had not transferred to a different facility showed retention in care to be 76·8% (20 475 of 26 658 patients) after 12 months, 70·8% (18 306 of 25 849 patients) after 24 months, and 69·7% (17 787 of 25 535 patients) after 36 months. Patient-level data included 29 145 patients. 14 630 (50·2%) began treatment under option B+. Patients in option B+ had a higher risk of having no follow-up and, for the first 2 years of ART, higher risk of loss to follow-up than did patients who started ART because they had CD4 counts less than 350 cells per μL or WHO clinical stage 3 or 4 disease. Risk of loss to follow-up during the third year was low and similar for patients retained for 2 years. Retention rates did not change as the option B+ programme matured. Interpretation Our data suggest that pregnant and breastfeeding women who start ART immediately after they are diagnosed with HIV can be retained on ART through the option B+ programme, even after many have stopped breastfeeding. Interventions might be needed to improve retention in the first year on ART in option B+. Funding Bill & Melinda Gates Foundation, Partnerships for Enhanced Engagement in Research Health, and National Institute of Allergy and Infectious Diseases.

CD4 count at antiretroviral therapy initiation and the risk of loss to follow-up: results from a multicentre cohort study.

BACKGROUND Antiretroviral therapy (ART) initiation is now recommended irrespective of CD4 count. However data on the relationship between CD4 count at ART initiation and loss to follow-up (LTFU) are limited and conflicting. METHODS We conducted a cohort analysis including all adults initiating ART (2008-2012) at three public sector sites in South Africa. LTFU was defined as no visit in the 6 months before database closure. The Kaplan-Meier estimator and Cox's proportional hazards models examined the relationship between CD4 count at ART initiation and 24-month LTFU. Final models were adjusted for demographics, year of ART initiation, programme expansion and corrected for unascertained mortality. RESULTS Among 17 038 patients, the median CD4 at initiation increased from 119 (IQR 54-180) in 2008 to 257 (IQR 175-318) in 2012. In unadjusted models, observed LTFU was associated with both CD4 counts <100 cells/μL and CD4 counts ≥300 cells/μL. After adjustment, patients with CD4 counts ≥300 cells/μL were 1.35 (95% CI 1.12 to 1.63) times as likely to be LTFU after 24 months compared to those with a CD4 150-199 cells/μL. This increased risk for patients with CD4 counts ≥300 cells/μL was largest in the first 3 months on treatment. Correction for unascertained deaths attenuated the association between CD4 counts <100 cells/μL and LTFU while the association between CD4 counts ≥300 cells/μL and LTFU persisted. CONCLUSIONS Patients initiating ART at higher CD4 counts may be at increased risk for LTFU. With programmes initiating patients at higher CD4 counts, models of ART delivery need to be reoriented to support long-term retention.