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Background: We aimed to describe the most frequently prescribed initial antiretroviral therapy (ART) regimens in recent years in HIV-positive persons in the Cohort of the Spanish HIV/AIDS Research Network (CoRIS) and to investigate factors associated with the choice of each regimen., Methods: We analyzed initial ART regimens prescribed in adults participating in CoRIS from 2014 to 2017. Only regimens prescribed in >5% of patients were considered. We used multivariable multinomial regression to estimate Relative Risk Ratios (RRRs) for the association between sociodemographic and clinical characteristics and the choice of the initial regimen., Results: Among 2874 participants, abacavir(ABC)/lamivudine(3TC)/dolutegavir(DTG) was the most frequently prescribed regimen (32.1%), followed by tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC)/elvitegravir(EVG)/cobicistat(COBI) (14.9%), TDF/FTC/rilpivirine (RPV) (14.0%), tenofovir alafenamide (TAF)/FTC/EVG/COBI (13.7%), TDF/FTC+DTG (10.0%), TDF/FTC+darunavir/ritonavir or darunavir/cobicistat (bDRV) (9.8%) and TDF/FTC+raltegravir (RAL) (5.6%). Compared with ABC/3TC/DTG, starting TDF/FTC/RPV was less likely in patients with CD4<200 cells/μL and HIV-RNA>100.000 copies/mL. TDF/FTC+DTG was more frequent in those with CD4<200 cells/μL and HIV-RNA>100.000 copies/mL. TDF/FTC+RAL and TDF/FTC+bDRV were also more frequent among patients with CD4<200 cells//μL and with transmission categories other than men who have sex with men. Compared with ABC/3TC/DTG, the prescription of other initial ART regimens decreased from 2014-2015 to 2016-2017 with the exception of TDF/FTC+DTG. Differences in the choice of the initial ART regimen were observed by hospitals' location., Conclusions: The choice of initial ART regimens is consistent with Spanish guidelines' recommendations, but is also clearly influenced by physician's perception based on patient's clinical and sociodemographic variables and by the prescribing hospital location., Competing Interests: IJ has received teaching fees from ViiV Healthcare and has been an external evaluator of scientific projects for GILEAD. ISG has received conference grants or speaker fees from Bristol-Myers Squibb, ViiV Healthcare, Merck Sharp & Dohme and Gilead. SM has been involved in speaking activities and has received grants for research from Abbott, Boehringer & Ingelheim, Bristol-Myers Squibb, Gilead, Glaxo Smith Kline, Janssen Cilag, Merck Sharp & Dohme, Pfizer, Roche, and Schering Plough. All other authors declare no conflict of interest. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Decisions about when to start or switch a therapy often depend on the frequency with which individuals are monitored or tested. For example, the optimal time to switch antiretroviral therapy depends on the frequency with which HIV-positive individuals have HIV RNA measured. This paper describes an approach to use observational data for the comparison of joint monitoring and treatment strategies and applies the method to a clinically relevant question in HIV research: when can monitoring frequency be decreased and when should individuals switch from a first-line treatment regimen to a new regimen? We outline the target trial that would compare the dynamic strategies of interest and then describe how to emulate it using data from HIV-positive individuals included in the HIV-CAUSAL Collaboration and the Centers for AIDS Research Network of Integrated Clinical Systems. When, as in our example, few individuals follow the dynamic strategies of interest over long periods of follow-up, we describe how to leverage an additional assumption: no direct effect of monitoring on the outcome of interest. We compare our results with and without the "no direct effect" assumption. We found little differences on survival and AIDS-free survival between strategies where monitoring frequency was decreased at a CD4 threshold of 350 cells/μl compared with 500 cells/μl and where treatment was switched at an HIV-RNA threshold of 1000 copies/ml compared with 200 copies/ml. The "no direct effect" assumption resulted in efficiency improvements for the risk difference estimates ranging from an 7- to 53-fold increase in the effective sample size., (© 2019 John Wiley & Sons, Ltd.)

Background: Most studies on hepatitis C virus (HCV)/HIV-coinfection do not account for the order and duration of these two infections. We aimed to assess the effect of incident HCV infection, and its timing relative to HIV seroconversion (HIVsc) in HIV-positive MSM on their subsequent CD4+ T-cell count and HIV RNA viral load trajectories., Methods: We included MSM with well estimated dates of HIVsc from 17 cohorts within the CASCADE Collaboration. HCV-coinfected MSM were matched to as many HIV monoinfected MSM as possible by HIV-infection duration and combination antiretroviral therapy (cART) use. We used multilevel random-effects models stratified by cART use to assess differences in CD4+ cell count and HIV RNA viral load trajectories by HCV-coinfection status., Findings: We matched 214 (ART-naive) and 147 (on cART) HCV-coinfected MSM to 5384 and 3954, respectively, matched controls. The timing of HCV seroconversion (HCVsc) relative to HIVsc had no demonstrable effect on HIV RNA viral load or CD4+ cell count trajectories. In the first 2-3 years following HCVsc CD4 cell counts were lower among HCV-coinfected MSM, but became comparable with HIV monoinfected MSM thereafter. In ART-naive MSM, during the first 2 years after HCVsc, HIV RNA viral load levels were lower or comparable with HIV monoinfected, tending to be higher thereafter. In MSM on cART, HCV had no significant effect on having a detectable HIV RNA viral load., Interpretation: Irrespective of the duration of HIV infection when HCV is acquired, CD4+ cell counts were temporarily lower following HCVsc, even when on cART. The clinical implications of our findings remain to be further elucidated.

Background: To analyze ultrasound findings of liver damage in alcohol use disorder (AUD) patients., Methods: A cross-sectional analysis of detoxification patients. Clinical and laboratory parameters were obtained at admission. Analytical liver injury (ALI) was defined as at least two of the following: aspartate aminotransferase (AST) levels ≥74 < 300 U/L, AST/alanine aminotransferase (ALT) ratio >2, and total bilirubin >1.2 mg/dL. Advanced liver fibrosis (ALF) was defined as a FIB-4 score ≥3.25. Abdominal ultrasound was used to identify steatosis, hepatomegaly, heterogeneous liver, and portal hypertension. Predictors of these findings were determined by logistic regression., Results: We included 301 patients (80% male) with a median age of 46 years (IQR: 39-51 years) and alcohol consumption of 180 g/day (IQR: 120-201 g). The prevalence of Hepatitis C virus (HCV) was 21.2%; AST and ALT serum levels were 42 U/L (IQR: 23-78 U/L) and 35 U/L (IQR: 19-60 U/L), respectively; 16% of patients had ALI and 24% ALF. Ultrasound findings were: 57.2% steatosis, 49.5% hepatomegaly, 17% heterogeneous liver, and 16% portal hypertension; 77% had at least one ultrasound abnormality, and 45% had ≥2. HCV infection was associated with heterogeneous liver (p = 0.046) and portal hypertension (p < 0.01). ALI and ALF were associated with steatosis (both p < 0.01) and hepatomegaly (both p < 0.01), ALI with portal hypertension (p = 0.08), and ALF with heterogeneous liver (p < 0.01). In logistic regression, ALI and ALF were associated with ≥2 abnormalities [OR (95%CI): 5.2 (2.1-12.8), p < 0.01 and 4.7 (2.2-9.7), p < 0.01; respectively]., Conclusions: Ultrasound findings of liver damage may facilitate clinical decisions and alcohol cessation in AUD patients., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Human Immunodeficiency Virus (HIV) infection affects 36.7 million people worldwide, it accounted for 1.1 million deaths in 2015. The advent of combined antiretroviral therapy (cART) has been associated with a decrease in HIV-related morbidity and mortality. However, there are increasing concerns about long-lasting effects of chronic inflammation and immune activation, leading to premature aging and HIV-related mortality. Cardiovascular diseases, especially coronary artery disease, are among the leading causes of death in HIV-infected patients, accounting for up to 15% of total deaths in high income countries. Furthermore, as cART availability expands to low-income countries, the burden of cardiovascular related mortality is likely to rise. Hence, over the next decade HIV-associated cardiovascular disease burden is expected to increase globally. In this review, we summarize our understanding of the pathogenesis and risk factors associated with HIV infection and cardiovascular disease, in particular coronary artery disease., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Cannabis is becoming increasingly present in our society. In recent years, the line between the natural (cannabis) and the synthetic (synthetic cannabinoids), the recreational (cannabis) and the medical (pharmaceutical cannabinoids and medical cannabis) has been crossed. In this paper we review some of the novel aspects of cannabis and cannabinoids in relation to their legal situation, changes in their composition and forms of cannabis use, the concept of medical cannabis, and synthetic cannabinoids as new psychoactive substances (NPS). We have also analyzed serious adverse reactions and intoxications associated with the use of synthetic cannabinoids, as well as the latest developments in the research of pharmaceutical cannabinoids., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.

Introduction: HCV infection is frequent in patients with alcohol use disorder (AUD). Ethanol and hepatitis C have a synergistic effect that increases the risk of end-stage liver disease. We aimed to assess fibrosis of the liver in patients admitted to treatment of AUD., Methods: Data were collected in two hospital units between 2000 and 2014. Liver fibrosis was assessed by serum biomarkers APRI, FIB-4 and Forns, and Advanced Liver Fibrosis (ALF) was defined if APRI > 1.5, FIB-4 > 3.25 or Forns > 6.9. Correlations were analyzed by Pearson's coefficients and logistic regression models were used., Results: 1313 patients (80% M) had complete data; age at admission was 45 years (IQR: 39-52 yrs), age of initial regular alcohol consumption was 20 years (IQR: 17-26 yrs) and the amount of alcohol consumed preceding admission was 200 g/day (IQR: 120-270 g/day). Prevalence of HCV infection was 18%. Prevalence of ALF in HCV positive patients was 40.6% by APRI, 30.6% by FIB-4, and 43.3% by Forns. Correlations were high for APRI vs. FIB-4 r = 0.906, APRI vs. Forns r = 0.710, and, FIB-4 vs. Forns r = 0.825. There was no significant difference in the APRI/FIB-4 correlation by HCV status (z = 1.35, p = 0.177). However, the APRI/Forns correlation was significantly higher in HCV positive patients (p < 0.001). Patients with HCV infection were two times more likely to present with ALF at admission (OR = 2.1, 95%CI:1.5-3.1)., Conclusions: HCV infection is associated with severity of fibrosis in patients with excessive alcohol consumption. In this context, APRI and FIB-4 are highly correlated which facilitates the assessment of liver damage., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Introduction: MDMA, 3,4-methylenedioxymethamphetamine, is a synthetic phenethylamine derivative with structural and pharmacological similarities to both amphetamines and mescaline. MDMA produces characteristic amphetamine-like actions (euphoria, well-being), increases empathy, and induces pro-social effects that seem to motivate its recreational consumption and provide a basis for its potential therapeutic use. Areas covered: The aim of this review is to present the main interindividual determinants in MDMA pharmacodynamics. The principal sources of pharmacodynamic variability are reviewed, with special emphasis on sex-gender, race-ethnicity, genetic differences, interactions, and MDMA acute toxicity, as well as possible therapeutic use. Expert opinion: Acute MDMA effects are more pronounced in women than they are in men. Very limited data on the relationship between race-ethnicity and MDMA effects are available. MDMA metabolism includes some polymorphic enzymes that can slightly modify plasma concentrations and effects. Although a considerable number of studies exist about the acute effects of MDMA, the small number of subjects in each trial limits evaluation of the different interindividual factors and does not permit a clear conclusion about their influence. These issues should be considered when studying possible MDMA therapeutic use.

The Alcohol Program of the Spanish Network on Addictive Disorders-RTA requires a longitudinal study to address different research questions related to alcoholism. The cohort study (CohRTA) focuses on patients seeking treatment for alcohol use disorder, as a multicentre, collaborative research project aimed to improve secondary prevention and early diagnosis of pathological processes associated with the disorder. Methods: multicentre cohort study in adults (>18 years) seeking their first treatment of the disorder. Patients sign an informed consent and data is collected in an online platform specifically designed for the study; patients are also requested to provide biological samples that are stored in a biobank. Baseline and prospective, socio-demographic, epidemiological, clinical and treatment data are collected. Currently there are 10 participating centres that expect to recruit more than 1,000 patients. Results: As of December 2015, 344 patients (77% men) were included. Median age at admission was 50 years (IQR: 43-55 years). Median age at the start of alcohol consumption was 15 years (IQR: 14-18 years) and 61% of cases reported antecedents of alcohol use disorder in the family. During the 30 days prior to admission, alcohol consumption amounted to 12.5 SDU/day (IQR: 7.1-20 SDU/day), 72% of the patients were tobacco smokers and 30% currently used cocaine. Organising an open cohort of patients with alcohol use disorder may be crucial to better understand the clinical consequences of alcoholism in Spain. This cohort may potentiate quantitative and qualitative research within the Spanish Network on Addictive Disorders-RTA/RETICS. Having a well-established, representative cohort of patients will increase translational research on consequences of alcoholism in our country.

Background: Observational studies have reported a high prevalence of obesity and diabetes in subjects on methadone therapy; there are, however, limited data about metabolic syndrome. The aim of the study was to evaluate the prevalence of metabolic syndrome and related factors in individuals with heroin use disorder on methadone therapy., Methods: A cross-sectional study in individuals with heroin use disorder on methadone therapy at a drug abuse outpatient center. Medical examinations and laboratory analyses after a 12-hour overnight fast were recorded. Metabolic syndrome was diagnosed according to the National Cholesterol Education Program Adult Treatment Panel III (ATP III) criteria., Results: One hundred and twenty-two subjects were included, with a mean age of 46.1 ± 9 years, a median body mass index (BMI) of 25.3 kg/m 2 (interquartile range [IQR]: 21.2-28), and 77.9% were men. Median exposure to methadone therapy was 13 years (IQR: 5-20). Overweight and obesity were present in 29.5% and 17.2% of the participants, respectively. Metabolic syndrome components were low high-density lipoprotein (HDL) cholesterol (51.6%), hypertriglyceridemia (36.8%), high blood pressure (36.8%), abdominal obesity (27.0%), and raised blood glucose levels (18.0%). Abdominal obesity was more prevalent in women (52% vs. 20%, P = >0.01) and high blood pressure more prevalent in men (41.1% vs. 22.2%, P = .07). Prevalence of metabolic syndrome was 29.5% (95% confidence interval [CI]: 16.6-31.8). In the multivariate logistic regression analysis, BMI (per 1 kg/m 2 increase odds ratio [OR]: 1.49, 95% CI: 1.27-1.76) and exposure time to methadone therapy (per 5 years of treatment increase OR: 1.38, 95% CI: 1.28-1.48) were associated with metabolic syndrome., Conclusions: Overweight and metabolic syndrome are prevalent findings in individuals with heroin use disorder on methadone therapy. Of specific concern is the association of methadone exposure with metabolic syndrome. Preventive measures and clinical routine screening should be recommended to prevent metabolic syndrome in subjects on methadone therapy.

Background: The differential effects of commonly prescribed combined antiretroviral therapy (cART) regimens on AIDS-defining neurological conditions (neuroAIDS) remain unknown., Setting: Prospective cohort studies of HIV-positive individuals from Europe and the Americas included in the HIV-CAUSAL Collaboration., Methods: Individuals who initiated a first-line cART regimen in 2004 or later containing a nucleoside reverse transcriptase inhibitor backbone and either atazanavir, lopinavir, darunavir, or efavirenz were followed from cART initiation until death, lost to follow-up, pregnancy, the cohort-specific administrative end of follow-up, or the event of interest, whichever occurred earliest. We evaluated 4 neuroAIDS conditions: HIV dementia and the opportunistic infections toxoplasmosis, cryptococcal meningitis, and progressive multifocal leukoencephalopathy. For each outcome, we estimated hazard ratios for atazanavir, lopinavir, and darunavir compared with efavirenz via a pooled logistic model. Our models were adjusted for baseline demographic and clinical characteristics., Results: Twenty six thousand one hundred seventy-two individuals initiated efavirenz, 5858 initiated atazanavir, 8479 initiated lopinavir, and 4799 initiated darunavir. Compared with efavirenz, the adjusted HIV dementia hazard ratios (95% confidence intervals) were 1.72 (1.00 to 2.96) for atazanavir, 2.21 (1.38 to 3.54) for lopinavir, and 1.41 (0.61 to 3.24) for darunavir. The respective hazard ratios (95% confidence intervals) for the combined end point were 1.18 (0.74 to 1.88) for atazanavir, 1.61 (1.14 to 2.27) for lopinavir, and 1.36 (0.74 to 2.48) for darunavir. The results varied in subsets defined by calendar year, nucleoside reverse transcriptase inhibitor backbone, and age., Conclusion: Our results are consistent with an increased risk of neuroAIDS after initiating lopinavir compared with efavirenz, but temporal changes in prescribing trends and confounding by indication could explain our findings.

Introduction: Harmful alcohol consumption may have an impact on the adaptive immune system through an imbalance in T cell subpopulations and changes in cell activation. We aimed to analyze profiles of CD4 and CD8T cell activation in patients with alcohol use disorder (AUD)., Methods: We used a cross-sectional study with patients seeking treatment of the disorder. Blood samples for immunophenotyping were obtained at admission. Profiles of T cell activation were defined: (I) CD38 + /HLA-DR + , (II) CD38 + /HLA-DR - , (III) CD38 - /HLA-DR + , (IV) CD38 - /HLA-DR - and compared with healthy controls. We calculated a CD8 + T cell activation indicator (AI) that was defined as the quotient of non-activated cells (CD38 - /HLA-DR - ) and activated cells (CD38 + /HLA-DR + )., Results: 60 patients were eligible (83%M); median age was 49 years [IQR: 44-54] and alcohol consumption was 145g/day [IQR: 90-205]. Mean±SD of CD38 + /HLA-DR - was 50.3±50.6 cells/μL in patients and 33.5±24.5 cells/μL in controls (p=0.03), for the CD38 - /HLA-DR + it was 61±62.2 cells/μL in patients and 21.2±17.3 cells/μL in controls (p<0.001) and for the CD38 + /HLA-DR + it was 20.2±15.6 cells/μL in patients and 10.8±10.3 cells/μL in controls (p<0.001). In patients, an inverse correlation was observed between absolute number and percentage of CD4 + T cells, and the percentage of CD38 + /HLA-DR + CD8 + T cells (r=0.37, p=0.003; r=0.2, p=0.086, respectively)., Conclusions: Patients with AUD have an increased expression of immune activation with respect to healthy individuals. This excess of activated CD8 + T cells correlates with the absolute CD4 + T cells., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Introduction: Nutritional deficiency is frequent in patients with an alcohol use disorder (AUD). We aimed to analyze serum and erythrocyte folate deficiency in a case series of patients that initiated treatment of AUD., Patients and Methods: A cross-sectional study in patients admitted for detoxification between 2007 and 2015 was performed. Sociodemographic characteristics, history of alcohol consumption, type of alcohol, and medical co-morbidity were assessed at admission. Blood samples for biochemistry and hematological parameters were collected at admission. Logistic regression models were used to establish predictors of folate deficiency., Results: 211 patients (79.1% men) were eligible; age at admission was 46 years [IQR:40-51], and the amount of alcohol consumption was of 160g/day [IQR:120-200]. Thirty four percent of patients had macrocytosis (MCV>100fL), 12.8% had anemia, 23% of cases presented with serum folate deficiency and 7% presented with erythrocyte folate deficiency. Most (69%) of the patients with serum folate deficiency had normal erythrocyte folate levels. In univariate analysis, macrocytosis (OR=3.4, 95%CI:1.7-6.6), alcohol-related liver disease (ARLD) (OR=2.5, 95%CI:1.0-6.1) and drinking alcoholic beverages other than beer (OR=3.3, 95%CI:1.5-7.3) were associated with folate deficiency. However, only macrocytosis was significantly associated with serum folate deficiency in multivariate analysis (OR=3.1, 95%CI:1.1-8.9). Macrocytosis (P<0.001), ARLD (P=0.01) and the type of alcohol consumption (P<0.001) were factors associated with erythrocyte folate deficiency in univariate analysis. In multivariate analysis only macrocytosis remained significantly associated to erythrocyte folate deficiency (P=0.037)., Conclusion: Folate deficiency is a relatively frequent finding in contemporary, middle-aged patients with AUD, and macrocytosis is significantly associated with the deficiency., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Clinical guidelines recommend immediate initiation of combined antiretroviral therapy for all HIV-positive individuals. However, those guidelines are based on trials of relatively young participants., Methods: We included HIV-positive antiretroviral therapy-naive, AIDS-free individuals aged 50-70 years after 2004 in the HIV-CAUSAL Collaboration. We used the parametric g-formula to estimate the 5-year risk of all-cause and non-AIDS mortality under (1) immediate initiation at baseline and initiation at CD4 count, (2) <500 cells/mm, and (3) <350 cells/mm. Results were presented separately for the general HIV population and for a US Veterans cohort with high mortality., Results: The study included 9596 individuals (28% US Veterans) with median (interquantile range) age of 55 (52-60) years and CD4 count of 336 (182-513) at baseline. The 5-year risk of all-cause mortality was 0.40% (95% confidence interval (CI): 0.10 to 0.71) lower for the general HIV population and 1.61% (95% CI: 0.79 to 2.67) lower for US Veterans when comparing immediate initiation vs initiation at CD4 <350 cells/mm. The 5-year risk of non-AIDS mortality was 0.17% (95% CI: -0.07 to 0.43) lower for the general HIV population and 1% (95% CI: 0.31 to 2.00) lower for US Veterans when comparing immediate initiation vs initiation at CD4 <350 cells/mm., Conclusions: Immediate initiation seems to reduce all-cause and non-AIDS mortality in patients aged 50-70 years.

Aims: To characterize a series of contemporary patients with alcohol-related Wernicke's encephalopathy (WE) or Korsakoff's syndrome (KS) and to update the current prognosis of disease., Methods: Retrospective and prospective study of patients diagnosed with an alcohol-related WE or KS between 2002 and 2011 in a tertiary hospital. Socio-demographic, alcohol use characteristics, signs and symptoms, co-morbidity and blood parameters were obtained at admission. Patients were followed up until 2013 and causes of death were ascertained through the review of charts., Results: Sixty-one patients were included (51 with WE and 10 with KS). Among patients with WE, 78% were men and age at diagnosis was 57 years (interquartile range (IQR): 49-66). Twenty-three percent fulfilled the classic WE triad. Regarding Caine's criteria for WE, 70.6% presented with at least two out of four signs or symptoms. Median follow-up of patients with WE syndrome was 5.3 years (IQR: 2.6-8.8), the cumulated mortality was 45% and death rate of 7.4 × 100 person-years (95% confidence interval (CI): 4.8-10.9). Overall, 50% of patients would be expected to die within 8 years of WE episode and main causes of death included serious bacterial infections (44.5%) and cancer (33.3%)., Conclusions: Survival of patients with an alcohol-related Wernicke-Korsakoff syndrome is poor; pursuing treatment of alcohol use disorder and early diagnosis of thiamine deficiency is a priority for improving clinical outcomes., (© The Author 2017. Medical Council on Alcohol and Oxford University Press. All rights reserved.)

Background: Clinical guidelines vary with respect to the optimal monitoring frequency of HIV-positive individuals. We compared dynamic monitoring strategies based on time-varying CD4 cell counts in virologically suppressed HIV-positive individuals., Methods: In this observational study, we used data from prospective studies of HIV-positive individuals in Europe (France, Greece, the Netherlands, Spain, Switzerland, and the UK) and North and South America (Brazil, Canada, and the USA) in The HIV-CAUSAL Collaboration and The Centers for AIDS Research Network of Integrated Clinical Systems. We compared three monitoring strategies that differ in the threshold used to measure CD4 cell count and HIV RNA viral load every 3-6 months (when below the threshold) or every 9-12 months (when above the threshold). The strategies were defined by the threshold CD4 counts of 200 cells per μL, 350 cells per μL, and 500 cells per μL. Using inverse probability weighting to adjust for baseline and time-varying confounders, we estimated hazard ratios (HRs) of death and of AIDS-defining illness or death, risk ratios of virological failure, and mean differences in CD4 cell count., Findings: 47 635 individuals initiated an antiretroviral therapy regimen between Jan 1, 2000, and Jan 9, 2015, and met the eligibility criteria for inclusion in our study. During follow-up, CD4 cell count was measured on average every 4·0 months and viral load every 3·8 months. 464 individuals died (107 in threshold 200 strategy, 157 in threshold 350, and 200 in threshold 500) and 1091 had AIDS-defining illnesses or died (267 in threshold 200 strategy, 365 in threshold 350, and 459 in threshold 500). Compared with threshold 500, the mortality HR was 1·05 (95% CI 0·86-1·29) for threshold 200 and 1·02 (0·91·1·14) for threshold 350. Corresponding estimates for death or AIDS-defining illness were 1·08 (0·95-1·22) for threshold 200 and 1·03 (0·96-1·12) for threshold 350. Compared with threshold 500, the 24 month risk ratios of virological failure (viral load more than 200 copies per mL) were 2·01 (1·17-3·43) for threshold 200 and 1·24 (0·89-1·73) for threshold 350, and 24 month mean CD4 cell count differences were 0·4 (-25·5 to 26·3) cells per μL for threshold 200 and -3·5 (-16·0 to 8·9) cells per μL for threshold 350., Interpretation: Decreasing monitoring to annually when CD4 count is higher than 200 cells per μL compared with higher than 500 cells per μL does not worsen the short-term clinical and immunological outcomes of virally suppressed HIV-positive individuals. However, more frequent virological monitoring might be necessary to reduce the risk of virological failure. Further follow-up studies are needed to establish the long-term safety of these strategies., Funding: National Institutes of Health., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Few individuals commencing antiretroviral therapy (ART) in primary HIV infection (PHI) maintain undetectable viremia after treatment cessation. Associated factors remain unclear given the importance of the phenomenon to cure research., Methods: Using CASCADE data of seroconverters starting ART in PHI (≤6 months from seroconversion), we estimated proportions experiencing viral blips (>400 copies followed by <400 copies HIV-RNA/mL without alteration of regimen) while on ART. We used Cox models to examine the association between time from ART stop to loss of control (2 consecutive measurements >1000 copies per milliliter) and magnitude and frequency of blips while on ART, time from seroconversion to ART, time on ART, adjusting for mean number of HIV-RNA measurements/year while on ART, and other confounders., Results: Seven hundred seventy-eight seroconverters started ART in PHI with ≥3 HIV-RNA measurements. Median interquartile range (IQR) ART duration was 16.2 (8.0-35.9) months, within which we observed 13% with ≥1 blip. Of 228 who stopped ART, 119 rebounded; time to loss of control was associated with longer interval between seroconversion and ART initiation [hazard ratio (HR) = 1.16 per month; 1.04, 1.28], and blips while on ART (HR = 1.71 per blip; 95% confidence interval = 0.94 to 3.10). Longer time on ART (HR = 0.84 per additional month; 0.76, 0.92) was associated with lower risk of losing control. Of 228 stopping ART, 22 (10%) maintained post treatment control (PTC), ie, HIV-RNA <50 copies per milliliter ≥24 months after ART cessation., Conclusion: HIV viral blips on therapy are associated with subsequent viral rebound on stopping ART among individuals treated in PHI. Longer duration on ART is associated with a greater chance of PTC., Competing Interests: All authors report no conflict of interest

Background: The health burden of cannabis use in patients with other substance dependencies is not fully understood., Objective: To assess the impact of cannabis use as secondary drug on mortality of patients with other major substance use disorders., Participants: Patients with opiate, cocaine, or alcohol dependence admitted to detoxification from 2001 to 2010 at a teaching hospital in Badalona, Spain., Main Measurements: Sociodemographic characteristics, drug use, medical comorbidities, and urine drug screens were obtained at admission. Deaths were ascertained through clinical records and a death registry. Mortality rates and Cox regression models were used to analyze the association between urinary cannabis and mortality., Results: A total of 474 patients (20% women) were admitted with a median age of 38 years (interquartile range: 32-44 years). The main substances that motivated admissions were opiates (27%), cocaine (24%), and alcohol (49%). Positive urinary cannabis was detected in 168 patients (35%). Prevalence of cannabis use among patients with opiate, cocaine, or alcohol dependence was 46.5%, 42.9%, and 25.5%, respectively. At admission, 110 (23.7%) patients had human immunodeficiency virus infection and 217 (46.5%) had hepatitis C virus infection. Patients were studied for a median of 5.6 years (interquartile range: 2.6-7.7 years) (2454.7 person-years), and at the end of the study, 50 patients (10.5%) had died, yielding a mortality rate of 2.04 × 100 patient-years (95% confidence interval: 1.53-2.66). There was no association between cannabis detection and overall mortality in the adjusted regression models [hazard ratio (95% confidence interval): 1.12 (0.60-2.00), P = 0.73], but acquired immune deficiency syndrome-related deaths were more frequent in those positive for cannabis (26% vs 2%, P = 0.03)., Conclusion: Positive urinary cannabis did not confer an increased risk of death in patients with severe opiate, cocaine or alcohol dependence.

4-Methyl-N-methylcathinone (mephedrone) is a popular new psychoactive substance (NPS) that is structurally related to the parent compound cathinone, the β-keto analogue of amphetamine. Mephedrone appeared on the street drug market as a substitute for 3,4-methylenedioxy-N-methylamphetamine (MDMA, ecstasy) and was subsequently banned due to the potential health risks associated with its use. Nevertheless, mephedrone continues to be widely consumed among specific populations, with unique patterns of misuse. To date, most information about the biological effects of mephedrone comes from user experiences, epidemiological data, clinical cases, toxicological findings, and animal studies, whilst there are very few data regarding its human pharmacodynamics and pharmacokinetics. This chapter reviews the available published data on patterns of mephedrone use, its acute and chronic effects, and its pharmacokinetic properties. More human research is needed to elucidate the safety, toxicity, and addiction potential of mephedrone and related NPS.

The provision of safely managed sanitation in informal settlements is a challenge, especially in schools that require durable, clean, sex-segregated facilities for a large number of children. In informal settlements in Nairobi, school sanitation facilities demand considerable capital costs, yet are prone to breakage and often unhygienic. The private sector may be able to provide quality facilities and services to schools at lower costs as an alternative to the sanitation that is traditionally provided by the government. We conducted a randomized trial comparing private sector service delivery (PSSD) of urine-diverting dry latrines with routine waste collection and maintenance and government standard delivery (GSD) of cistern-flush toilets or ventilated improved pit latrines. The primary outcomes were facility maintenance, use, exposure to fecal contamination, and cost. Schools were followed for one school year. There were few differences in maintenance and pathogen exposure between PSSD and GSD toilets. Use of the PSSD toilets was 128% higher than GSD toilets, as measured with electronic motion detectors. The initial cost of private sector service delivery was USD 2053 (KES 210,000) per school, which was lower than the average cost of rehabilitating the government standard flush-type toilets (USD 9306 (KES 922,638)) and constructing new facilities (USD 114,889 (KES 1,169,668)). The private sector delivery of dry sanitation provided a feasible alternative to the delivery of sewage sanitation in Nairobi informal settlements and might elsewhere in sub-Saharan Africa., Competing Interests: The authors declare no conflict of interest.

Introduction: Globally, pregnancy related complications contribute to more than half of the deaths among women annually. Antenatal care (ANC) is important for the prevention of maternal and fetal mortality and morbidity. This study identifies the socio-demographic and economic characteristics; knowledge and attitude and; health service provision for focused antenatal care (FANC) services., Methods: A cross-sectional comparative study conducted among 385 women of reproductive age who visited 5 public health facilities in Malindi and Magarini Sub Counties. Data collection was conducted between June 2013 and September 2013 through structured questionnaires, Key Informant Interviews (KIIs) and Focused Group Discussions (FGDs) and analyzed through descriptive summary statistics and test of associations of the various variables using chi square., Results: About 35% of women sought 1st and 2nd ANC services at the health facilities. These women went ahead to complete the recommended 4 minimum visits as recommended by World Health Organization (WHO). Compared to Catholics, Muslims were less likely to attend a rural health facility (Odds ratio (OR) = 0.25, 95% Confidence Interval (CI) 0.10, 0.62, p=0.003). According to education levels, those with secondary (OR=0.07, 95% CI 0.03, 0.18, p<0.001) or tertiary (OR=0.09, 95% CI 0.03-0.17, p<0.001) levels of education were less likely to seek FANC at rural facility. Women seeking rural ANC services started at 2nd or 3rd trimester (OR=5.40 95% CI 2.97-10.06, p<0.001) while those in urban setup start at 1st trimester. Among the women who were aware of FANC, only 27% utilized its services. Long waiting hours, unavailability of services, and departmental disharmony were major causes of dissatisfaction to mothers visiting the facilities., Conclusion: Utilization and awareness of FANC services in both rural and urban health facilities among women in Malindi and Magarini Sub Counties continues to be low which is associated by socio-demographic characteristics, and health facility inefficiencies. Thus there is need to standardize services across health facilities and increase awareness on FANC in both rural and urban., Competing Interests: The authors declare no competing interest.

Introduction: Estimated 236,548 People Living with HIV (PLHIV) were in Central-Eastern Kenya in 2013. Kiambu County had 46,656 PLHIV with 42,400 (91%) adults and 4,200(9%) children (1-14yrs). Amref Health Africa in Kenya, supported through USAID-APHIAplus KAMILI project, initiated two food banks to respond to poor nutritional status of the HIV infected children. Quality Improvement Teams were used to facilitate food-banking initiatives. The study aimed at assessing and demonstrating roles of community food-banking in improving nutrition status of HIV-infected children in food insecure regions., Methods: A pre and post-test study lasting 12 months (Oct 2013 to September 2014) conducted in Kiambu County, Kenya covering 103 HIV infected children. Two assessments were conducted before and after the food banking initiative and results compared. Child Status Index (CSI) and the Middle Upper Arm Circumference (MUAC) tools were used in data collection at households. Paired T-test and Wilcoxon test were applied for analysing MUAC and CSI scores respectively using the SPSS., Results: There was a significant improvement in the children's nutrition status from a rating of 'bad' in CSI Median (IQR) score 2(2-1) before food banking to a rating of 'fair' in CSI Median (IQR) score 3(4-3) after food banking intervention (p=<0.001) while MUAC increased from Mean (SD) of 5.6(2.6) before intervention to 7.2(2.8) after food banking (p=<0.001)., Conclusion: Food banking is a community-based nutritional intervention that can address factors of food access, affordability and availability. Food banking is a sustainable way to contribute to quality nutrition and reduced related deaths among HIV infected children., Competing Interests: The authors declare no competing interest.

Alcohol use disorder (AUD) and hepatitis C virus (HCV) infection frequently co-occur. AUD is associated with greater exposure to HCV infection, increased HCV infection persistence, and more extensive liver damage due to interactions between AUD and HCV on immune responses, cytotoxicity, and oxidative stress. Although AUD and HCV infection are associated with increased morbidity and mortality, HCV antiviral therapy is less commonly prescribed in individuals with both conditions. AUD is also common in human immunodeficiency virus (HIV) infection, which negatively impacts proper HIV care and adherence to antiretroviral therapy, and liver disease. In addition, AUD and HCV infection are also frequent within a proportion of patients with HIV infection, which negatively impacts liver disease. This review summarizes the current knowledge regarding pathological interactions of AUD with hepatitis C infection, HIV infection, and HCV/HIV co-infection, as well as relating to AUD treatment interventions in these individuals., Competing Interests: Conflict-of-interest statement: No potential conflicts of interest relevant to this article were reported.

Objective: To compare regimens consisting of either ritonavir-boosted atazanavir or efavirenz and a nucleoside reverse transcriptase inhibitor (NRTI) backbone with respect to clinical, immunologic, and virologic outcomes., Design: Prospective studies of human immunodeficiency virus (HIV)-infected individuals in Europe and the United States included in the HIV-CAUSAL Collaboration., Methods: HIV-positive, antiretroviral therapy-naive, and acquired immune deficiency syndrome (AIDS)-free individuals were followed from the time they started an atazanavir or efavirenz regimen. We estimated an analog of the "intention-to-treat" effect for efavirenz versus atazanavir regimens on clinical, immunologic, and virologic outcomes with adjustment via inverse probability weighting for time-varying covariates., Results: A total of 4301 individuals started an atazanavir regimen (83 deaths, 157 AIDS-defining illnesses or deaths) and 18,786 individuals started an efavirenz regimen (389 deaths, 825 AIDS-defining illnesses or deaths). During a median follow-up of 31 months, the hazard ratios (95% confidence intervals) were 0.98 (0.77, 1.24) for death and 1.09 (0.91, 1.30) for AIDS-defining illness or death comparing efavirenz with atazanavir regimens. The 5-year survival difference was 0.1% (95% confidence interval: -0.7%, 0.8%) and the AIDS-free survival difference was -0.3% (-1.2%, 0.6%). After 12 months, the mean change in CD4 cell count was 20.8 (95% confidence interval: 13.9, 27.8) cells/mm lower and the risk of virologic failure was 20% (14%, 26%) lower in the efavirenz regimens., Conclusion: Our estimates are consistent with a smaller 12-month increase in CD4 cell count, and a smaller risk of virologic failure at 12 months for efavirenz compared with atazanavir regimens. No overall differences could be detected with respect to 5-year survival or AIDS-free survival.

Water, Sanitation and Hygiene (WASH) programs in schools can increase the health, dignity and comfort of students and teachers. Understanding the costs of WASH facilities and services in schools is one essential piece for policy makers to utilize when budgeting for schools and helping to make WASH programs more sustainable. In this study we collected data from NGO and government offices, local hardware shops and 89 rural primary schools across three Kenyan counties. Current expenditures on WASH, from school and external (NGO, government, parent) sources, averaged 1.83 USD per student per year. After reviewing current expenditures, estimated costs of operations and maintenance for bringing schools up to basic WASH standards, were calculated to be 3.03 USD per student per year. This includes recurrent costs, but not the cost of installing or setting up WASH infrastructure, which was 18,916 USD per school, for a school of 400 students (4.92 USD per student, per year). These findings demonstrate the need for increases in allocations to schools in Kenya, and stricter guidance on how money should be spent on WASH inputs to enable all schools to provide basic WASH for all students.

Objective: To illustrate an approach to compare CD4 cell count and HIV-RNA monitoring strategies in HIV-positive individuals on antiretroviral therapy (ART)., Design: Prospective studies of HIV-positive individuals in Europe and the USA in the HIV-CAUSAL Collaboration and The Center for AIDS Research Network of Integrated Clinical Systems., Methods: Antiretroviral-naive individuals who initiated ART and became virologically suppressed within 12 months were followed from the date of suppression. We compared 3 CD4 cell count and HIV-RNA monitoring strategies: once every (1) 3 ± 1 months, (2) 6 ± 1 months, and (3) 9-12 ± 1 months. We used inverse-probability weighted models to compare these strategies with respect to clinical, immunologic, and virologic outcomes., Results: In 39,029 eligible individuals, there were 265 deaths and 690 AIDS-defining illnesses or deaths. Compared with the 3-month strategy, the mortality hazard ratios (95% CIs) were 0.86 (0.42 to 1.78) for the 6 months and 0.82 (0.46 to 1.47) for the 9-12 month strategy. The respective 18-month risk ratios (95% CIs) of virologic failure (RNA >200) were 0.74 (0.46 to 1.19) and 2.35 (1.56 to 3.54) and 18-month mean CD4 differences (95% CIs) were -5.3 (-18.6 to 7.9) and -31.7 (-52.0 to -11.3). The estimates for the 2-year risk of AIDS-defining illness or death were similar across strategies., Conclusions: Our findings suggest that monitoring frequency of virologically suppressed individuals can be decreased from every 3 months to every 6, 9, or 12 months with respect to clinical outcomes. Because effects of different monitoring strategies could take years to materialize, longer follow-up is needed to fully evaluate this question.

Background: Alcohol abuse impacts innate and adaptive immunity and predisposes to infections. However, prevalence and correlations of cellular immune alterations in large case series is underreported. We aimed to analyze quantitative alterations of T-lymphocyte subpopulations in patients with alcohol use disorder (AUD)., Methods: cross-sectional study in patients admitted for detoxification between January 1, 2002 and December 31, 2012. Socio-demographic and alcohol use characteristics and blood samples for biochemistry, hematology and immune phenotype was obtained at admission., Results: 238 patients (79.8%M) were eligible; age at admission was 43 years (interquartile range [IQR]: 38-51 years), the amount of alcohol consumption was 180 g/day (IQR: 120-200 g/day) and median duration of AUD was 18 years (IQR: 9-25 years). Compared to healthy individuals, 50% of patients had significantly fewer double-negative (DN) T-lymphocytes (<34 × 10(9)/L) and 23% had more double-positive (DP) T-cells (>52 × 10(9)/L). In addition, 24% of patients had high number of CD8(+) cells (>735 × 10(9)/L) and 13% had low CD4(+) cell counts (<600 × 10(9)/L). In multivariable analysis, age, sex, serum albumin, and current cocaine use were predictors of T-cell subpopulation alterations. Women were three-times (OR=3.5, 95%CI:1.3-9.5) more likely to present with higher DP T-lymphocytes than men., Conclusions: Quantitative alterations of T-cell subpopulations are frequent in patients seeking treatment of AUD. Assessment of cellular immunity in this population may help to identify those at increased risk of immune alterations., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Alcohol consumption in young women is a widespread habit that may continue during pregnancy and induce alterations in the fetus. We aimed to characterize prevalence of alcohol consumption in parturient women and to assess fetal ethanol exposure in their newborns by analyzing two direct metabolites of ethanol in meconium. This is a cross-sectional study performed in September 2011 and March 2012 in a series of women admitted to an obstetric unit following childbirth. During admission, socio-demographic and substance use (alcohol, tobacco, cannabis, cocaine, and opiates) during pregnancy were assessed using a structured questionnaire and clinical charts. We also recorded the characteristics of pregnancy, childbirth, and neonates. The meconium analysis was performed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) to detect the presence of ethyl glucuronide (EtG) and ethyl sulfate (EtS). Fifty-one parturient and 52 neonates were included and 48 meconium samples were suitable for EtG and EtS detection. The median age of women was 30 years (interquartile range (IQR): 26-34 years); EtG was present in all meconium samples and median concentration of EtG was 67.9 ng/g (IQR: 36.0-110.6 ng/g). With respect to EtS, it was undetectable (<0.01 ng/g) in the majority of samples (79.1%). Only three (6%) women reported alcohol consumption during pregnancy in face-to-face interviews. However, prevalence of fetal exposure to alcohol through the detection of EtG and EtS was 4.2% and 16.7%, respectively. Prevention of alcohol consumption during pregnancy and the detection of substance use with markers of fetal exposure are essential components of maternal and child health.

The role of sociocultural factors such as religion and ethnicity in aiding or hampering family planning (FP) uptake in rural Western Kenya, a region with persistently high fertility rates, is not well established. We explored whether attitudes towards FP can be attributed to religious affiliation and/or ethnicity among women in the region. Findings show that religion and ethnicity have no impact; the most significant factors are level of education and knowledge about the benefits of FP for the mother. FP interventions ought to include strategies aimed at enhancing women's knowledge about the positive impacts of family planning.

With 3-4 million of new infections occurring annually, hepatitis C virus (HCV) infection is a global Public Health problem. In fact, hepatitis C virus infection is one of the leading causes of liver disease in the world; in Western countries, two thirds of the new HCV infections are associated with injection drug use. The treatment of hepatitis C will change in the coming years with the irruption of new anti-HCV drugs, the so called Direct Antiviral Agents (DAA) that attack key proteins of the HCV life cycle. The new antiviral drugs are effective, safer and better tolerated. The 2014 WHO HCV treatment guidelines include some of them. The new DAA are used in combination and it is expected that Interferon will be not necessary in future treatment regimens against HCV infection. The irruption of new and potent antivirals mandate the review of the current standards of care in the HCV infected population. More inclusive and proactive treatment policies will be necessary in those individuals with substance use disorders.

Background: Current clinical guidelines consider regimens consisting of either ritonavir-boosted atazanavir or ritonavir-boosted lopinavir and a nucleoside reverse transcriptase inhibitor (NRTI) backbone among their recommended and alternative first-line antiretroviral regimens. However, these guidelines are based on limited evidence from randomized clinical trials and clinical experience., Methods: We compared these regimens with respect to clinical, immunologic, and virologic outcomes using data from prospective studies of human immunodeficiency virus (HIV)-infected individuals in Europe and the United States in the HIV-CAUSAL Collaboration, 2004-2013. Antiretroviral therapy-naive and AIDS-free individuals were followed from the time they started a lopinavir or an atazanavir regimen. We estimated the 'intention-to-treat' effect for atazanavir vs lopinavir regimens on each of the outcomes., Results: A total of 6668 individuals started a lopinavir regimen (213 deaths, 457 AIDS-defining illnesses or deaths), and 4301 individuals started an atazanavir regimen (83 deaths, 157 AIDS-defining illnesses or deaths). The adjusted intention-to-treat hazard ratios for atazanavir vs lopinavir regimens were 0.70 (95% confidence interval [CI], .53-.91) for death, 0.67 (95% CI, .55-.82) for AIDS-defining illness or death, and 0.91 (95% CI, .84-.99) for virologic failure at 12 months. The mean 12-month increase in CD4 count was 8.15 (95% CI, -.13 to 16.43) cells/µL higher in the atazanavir group. Estimates differed by NRTI backbone., Conclusions: Our estimates are consistent with a lower mortality, a lower incidence of AIDS-defining illness, a greater 12-month increase in CD4 cell count, and a smaller risk of virologic failure at 12 months for atazanavir compared with lopinavir regimens., (© The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Inflammation and intestinal permeability are believed to be paramount features in the development of alcohol-related liver damage. We aimed to assess the impact of 3 surrogate markers of inflammation (anemia, fibrinogen, and ferritin levels) on mid-term mortality of patients with alcohol dependence. This longitudinal study included patients with alcohol dependence admitted for hospital detoxification between 2000 and 2010. Mortality was ascertained from clinical charts and the mortality register. Associations between markers of inflammation and all-cause mortality were analyzed with mortality rates and Cox proportional hazards regression models. We also performed a subgroup analysis of mortality rates in patients with anemia, based on their mean corpuscular volume (MCV). We included 909 consecutive patients with alcohol dependence. Patients were mostly male (80.3%), had a median age of 44 years (interquartile range [IQR]: 38-50), and upon admission, their median alcohol consumption was 192 g/day (IQR: 120-265). At admission, 182 (20.5%) patients had anemia; 210 (25.9%) had fibrinogen levels >4.5 mg/dL; and 365 (49.5%) had ferritin levels >200 ng/mL. At the end of follow-up (median 3.8 years [IQR: 1.8-6.5], and a total of 3861.07 person-years), 118 patients had died (12.9% of the study population). Cox regression models showed that the presence of anemia at baseline was associated with mortality (hazard ratio [HR]: 1.67, 95% confidence interval [CI]: 1.11-2.52, P < 0.01); no associations were found between mortality and high fibrinogen or high ferritin levels. A subgroup of patients with anemia was analyzed and compared to a control group of patients without anemia and a normal MCV. The mortality ratios of patients with normocytic and macrocytic anemia were 3.25 (95% CI: 1.41-7.26; P < 0.01) and 3.39 (95% CI: 1.86-6.43; P < 0.01), respectively. Patients with alcohol dependence admitted for detoxification had an increased risk of death when anemia was present at admission. More accurate markers of systemic inflammation are needed to serve as prognostic factors for poor outcomes in this subset of patients.

Introduction: After achieving undetectable HIV-RNA on cART, on cessation, HIV-RNA rebounds to pre-treatment values for the majority due to the presence of an inaccessible viral reservoir. There is some evidence that cART during primary HIV infection (PHI) limits the reservoir size, optimizing the chance of maintaining viral control off cART. Data are required to predict possible viral controllers for treatment interruption following cART. This analysis aims to investigate the effect of cART duration and the rate of viral blips while on cART initiated in PHI, and other factors on maintaining viral control for those stopping cART., Material and Methods: Using CASCADE data on HIV seroconverters, we characterized virologic blip (viral suppression on cART followed by a single HIV-RNA above a blip threshold and a subsequent measure below the threshold without cART change) rates for those starting cART within six months of seroconversion (SC). Using Cox models, we examined the effect of the following factors on time to virologic rebound (HIV-RNA>1000) after cART stop: cART duration, severity/rate of blips on cART, time from SC to cART start, cART class, SC year, SC age, CD4 at cART start/stop, sex and HIV risk group., Results: The 660 individuals initiating cART in PHI were mostly male (91%), seroconverting between 1995 and 2012, with a median (IQR) age of 34 (29, 41) years mostly infected through sex between men (73%). Median cART duration was 14.8 (7.0, 31.7) months initiated at a median 1.9 (0.5, 3.9) months post SC. 13 (11, 16), 9 (7, 11), 6 (5, 9) and 7 (6, 10)% of individuals experienced blips >50, 100, 200 and 400 copies/mL, respectively. Of those who experienced blips, most (77-90%, depending on blip threshold) experienced just one. Among 250 individuals with undetectable HIV-RNA at cART stop, median time to rebound was 1.6 (0.30, 5.8) months. Time on cART was the only factor independently associated with control after stopping, HR for rebound=0.91 (0.86, 0.98) per extra six months spent on cART, HR for ever blipping >400 copies/mL while on cART=0.88 (0.40, 1.93)., Conclusions: Blips occur in about 10% of individuals who initiate cART in PHI, most of who experience only one blip, but was not predictive of subsequent virologic rebound. Increasing time spent on cART initiated in PHI could increase time of virological suppression after cART stop.

Introduction: Addressing inequities is a key role for international non-governmental organizations (INGOs) working in health and development. Yet, putting equity principles into practice can prove challenging. In-depth empirical research examining what influences INGOs' implementation of equity principles is limited. This study examined the influences on one INGO's implementation of equity principles in its HIV/AIDS programs., Methods: This research employed a case study with nested components (an INGO operating in Kenya, with offices in North America). We used multiple data collection methods, including document reviews, interviews (with staff, partners and clients of the INGO in Kenya), and participant observation (with Kenyan INGO staff). Participant observation was conducted with 10 people over three months. Forty-one interviews were completed, and 127 documents analyzed. Data analysis followed Auerbach and Silverstein's analytic process (2003), with qualitative coding conducted in multiple stages, using descriptive matrices, visual displays and networks (Miles and Huberman, 1994)., Results: There was a gap between the INGO's intent to implement equity principles and actual practice due to multiple influences from various players, including donors and country governments. The INGO was reliant on donor funding and needed permission from the Kenyan government to work in-country. Major influences included donor agendas and funding, donor country policies, and Southern country government priorities and legislation. The INGO privileged particular vulnerable populations (based on its reputation, its history, and the priorities of the Kenyan government and the donors). To balance its equity commitment with the influences from other players, the INGO aligned with the system as well as pushed back incrementally on the donors and the Kenyan government to influence these organizations' equity agendas. By moving its equity agenda forward incrementally and using its reputational advantage, the INGO avoided potential negative repercussions that might result from pushing too fast or working outside the system., Conclusions: The INGO aligned the implementation of equity principles in its HIV/AIDS initiatives by working within a system characterized by asymmetrical interdependence. Influences from the donors and Kenyan government contributed to an implementation gap between what the INGO intended to accomplish in implementing equity principles in HIV/AIDS work and actual practice.

Objectives: Improving school water, sanitation and hygiene (WASH) conditions reduces pupil absence and illness. However, these benefits may depend on the conditions of the latrines and availability of consumables. We sought to determine whether a low-cost, policy-relevant, environmental-level latrine cleaning intervention could improve latrine cleanliness, increase its use and reduce absenteeism., Methods: In a three-arm, cluster-randomized trial we assessed absence via periodical roll-call among 17 564 pupils in 60 schools that had previously received WASH improvements as part of the SWASH+ project. Latrine conditions and use were also assessed using structured observation. Latrine cleanliness increased significantly during the post-intervention period among schools receiving the latrine cleaning package compared to controls, as did handwashing with soap. We found no difference in latrine use and absence across arms., Conclusions: The additive impact of cleaning may not have been strong enough to impact absence above and beyond reductions attributable to the original WASH infrastructure improvements and basic hygiene education the schools previously received. Improving latrine conditions is important for the dignity and well-being of pupils, and investments and strategies are necessary to ensure that school toilets are clean and pupil-friendly., (© 2014 John Wiley & Sons Ltd.)

Background: Opioid substitution therapy has improved the survival of heroin users with and without HIV infection. We aimed to analyze sex differences in mortality rates and predictors of death among those admitted to a methadone treatment program (MTP)., Methods: Longitudinal study of patients enrolled in a MTP from 1992 to 2010. Socio-demographic and drug use characteristics, and markers of viral infections were assessed at entry. Vital status was ascertained by clinical charts and the mortality register. Four calendar periods were defined according to the introduction of preventive and treatment interventions in Spain. Predictors of death were analyzed by Cox regression models., Results: 1,678 patients (82.8% men) were included; age at first heroin use was 18.6 years (IQR: 16-23 years), and age at first entry into a MTP was 30.7 years (IQR: 26-36 years). A total of 441 (26.3%) deaths occurred during 15,124 person-years (p-y) of follow-up (median: 9.2 years, IQR: 4-13 years). HIV infection was the main predictor of death in men (HR = 3.5, 95% CI: 2.1-5.7) and women (HR = 3.2, 95% CI: 1.2-8.7 ) and main cause of death was HIV/AIDS. Overall mortality rate was 2.9 per 100 p-y (95% CI: 2.7-3.2 per 100 p-y) and death rates decreased over time: 7.4 per 100 p-y (95% CI: 6.3-8.8 per 100 p-y) for the 1992-1996 period to 1.9 per 100 p-y (95% CI: 1.6-2.4 per 100 p-y) for the 2007-2010 period. In women, a slightly increase in mortality was observed in recent periods specifically among HIV-positive women (3.7 per 100 p-y in period 2002-2006 and 4.5 per 100 p-y in 2007-2010)., Conclusions: Significant reductions in mortality of patients in MTP are observed after nineteen years of observation. However, HIV infection shows a great impact on survival, particularly among HIV-infected women.

Background: Antiretroviral therapy (ART) has reduced the rates and changed the causes of hospital admission. However, human immunodeficiency virus-positive intravenous drug users (HIV-IDU) continue to have increased hospitalizations and discharge diagnosis are less defined in the late ART era. Our aim was to examine ART use, HIV-1 RNA suppression, and hospital discharge diagnoses among HIV-IDU admitted to an urban hospital., Methods: A retrospective analysis was made of HIV-IDU admitted for medical causes for the first time (2006-2010). Surgical, obstetric, or mental (except HIV-associated neurocognitive disorder) diagnoses were excluded. Clinical characteristics, number of admissions, and primary discharge diagnoses were determined for each patient., Results: Three hundred and seventy-five admissions were recorded among 197 hospitalized HIV-IDU. Lifetime prevalence of ART use was 83.2% (164 of 197) and the rate of HIV-1 RNA <50 copies/mL was 38.1% (75 of 197). Primary discharge diagnosis groups were as follows: bacterial infections (59.2%), chronic end-organ damage (16.8%), complications derived from injected drug use (16.8%), malignancies (9.1%), and opportunistic infections (6.6%). Chronic end-organ damage was diagnosed more frequently in patients with HIV-1 RNA <50 copies/mL (36% vs 4.9%; P < .000), and complications derived from injected drug use (23.8% vs 5.3%; P < .0008) and acquired immune deficiency syndrome (AIDS) opportunistic infections (19.8% vs 1.3% P < .019) were usually diagnosed in patients with HIV-1 RNA detectable viral load., Conclusions: Human immunodeficiency virus-positive intravenous drug users are admitted to hospitals mainly for non-AIDS-related illnesses; however, sustained HIV-1 RNA viral load suppression is poor and determines hospital discharge diagnoses. Providers need to be aware of the management of HIV-related comorbidities and reinforce strategies to improve ART retention in this population.

Background: Mortality of alcohol and drug abusers is much higher than the general population. We aimed to characterize the role of the primary substance of abuse on the survival of patients admitted to treatment and to analyze changes in mortality over time., Methods: Longitudinal study analyzing demographic, drug use, and biological data of 5023 patients admitted to three hospital-based treatment units in Barcelona, Spain, between 1985 and 2006. Vital status and causes of death were ascertained from clinical charts and the mortality register. Piecewise regression models were used to analyze changes in mortality., Results: The primary substances of dependence were heroin, cocaine, and alcohol in 3388 (67.5%), 945 (18.8%), and 690 patients (13.7%), respectively. The median follow-up after admission to treatment was 11.6 years (IQR: 6.6-16.1), 6.5 years (IQR: 3.9-10.6), and 4.8 years (IQR: 3.1-7.8) for the heroin-, cocaine-, and alcohol-dependent patients, respectively. For heroin-dependent patients, mortality rate decreased from 7.3×100person-years (p-y) in 1985 to 1.8×100p-y in 2008. For cocaine-dependent patients, mortality rate decreased from 10.7×100p-y in 1985 to <2.5×100p-y after 2004. The annual average decrease was 2% for alcohol-dependent patients, with the lowest mortality rate (3.3×100p-y) in 2008., Conclusions: Significant reductions in mortality of alcohol and drug dependent patients are observed in recent years in Spain. Preventive interventions, treatment of substance dependence and antiretroviral therapy may have contributed to improve survival in this population., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Background and Objetive: Methadone is largely used as the primary opioid substitution therapy for the treatment of heroin addiction; the objective of the study was to describe the clinical characteristics of heroin abusers admitted into a methadone maintenance program (MMP) in metropolitan Barcelona., Method: Cross-sectional study in patients enrolled in MMP since its introduction in 1992 through December 2010. Socio-demographic data, drug use characteristics, prevalence of blood-borne infections (human immunodeficiency virus [HIV], and hepatitis B [HBV] and C [HCV]) and psychiatric co-morbidity were assessed at entry., Results: One thousand and six hundred seventy eight patients (82.8% male). A total of 608 (36.2%) patients were admitted during 1992-1996, 566 (33.7%) between 1997-2001, 305 (18.2%) between 2002-2006 and 199 (11.9%) in the last period. Age at admission to methadone increased significantly (28 years in period 1992-1996 vs. 37 years in the last period [P<.005]). The percentage of patients with a history of intravenous drug use decreased significantly (89.5% in first period vs. 56.4% in period 2007-2010 [P<.05]). Prevalence of HIV, HCV and HBV (HBcAb+) was 53.7, 73.6 and 61.3%, respectively. The prevalence of HIV decreased over time from 66.2% in first period to 43.5% in 2007-2010 (P<.05); the prevalence of HCV decreased significantly from 82.8% in 1992-1996 to 69.8% in last period (P<.05). Twenty five percent of patients had psychiatric co-morbidity at admission and the prevalence of psychiatric co-morbidity increased over time (21% in 1992-1996 and 32% in 2007-2010; P<.05)., Conclusion: Age at first opioid substitution therapy is increasing over time, as well as the proportion of patients with psychiatric co-morbidity. There were significant reductions in blood-borne infections., (Copyright © 2012 Elsevier España, S.L. All rights reserved.)

Background & Aims: Individuals with human immunodeficiency virus (HIV) infection frequently also are infected with hepatitis C virus (HCV) (co-infection), but little is known about its effects on the progression of HIV-associated disease. We aimed to determine the effects of co-infection on mortality from HIV and/or acquired immune deficiency syndrome (AIDS), and hepatitis or liver disease, adjusting for the duration of HIV infection., Methods: We analyzed data from the 16 cohorts of the Concerted Action on Seroconversion to AIDS and Death in Europe (CASCADE) collaboration, which included information on HCV infection and cause of death. A competing-risks proportional subdistribution hazards model was used to evaluate the effect of HCV infection on the following causes of death: HIV- and/or AIDS-related, hepatitis- or liver-related, natural, and non-natural., Results: Of 9164 individuals with HIV infection and a known date of seroconversion, 2015 (22.0%) also were infected with HCV. Of 718 deaths, 395 (55.0%) were caused by HIV infection and/or AIDS, and 39 (5.4%) were caused by hepatitis or liver-related disease. Among individuals infected with only HIV or with co-infection, the mortality from HIV infection and/or AIDS-related causes and hepatitis or liver disease decreased significantly after 1997, when combination antiretroviral therapy became widely available. However, after 1997, HIV and/or AIDS-related mortality was higher among co-infected individuals than those with only HIV infection in each risk group: injection drug use (adjusted hazard ratio [aHR], 2.43; 95% confidence interval [CI], 1.14-5.20), sex between men and women or hemophilia (aHR, 3.43; 95% CI, 1.70-6.93), and sex between men (aHR, 3.11; 95% CI, 1.49-6.48). Compared with individuals infected with only HIV, co-infected individuals had a higher risk of death from hepatitis or liver disease., Conclusions: Based on analysis of data from the CASCADE collaboration, since 1997, when combination antiretroviral therapy became widely available, individuals co-infected with HIV and HCV have had a higher risk of death from HIV and/or AIDS, and from hepatitis or liver disease, than patients infected with only HIV. It is necessary to evaluate the effects of HCV therapy on HIV progression., (Copyright © 2013 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Few data exist on tuberculosis (TB) incidence according to time from HIV seroconversion in high-income countries and whether rates following initiation of a combination of antiretroviral treatments (cARTs) differ from those soon after seroconversion., Methods: Data on individuals with well estimated dates of HIV seroconversion were used to analyse post-seroconversion TB rates, ending at the earliest of 1 January 1997, death or last clinic visit. TB rates were also estimated following cART initiation, ending at the earliest of death or last clinic visit. Poisson models were used to examine the effect of current and past level of immunosuppression on TB risk after cART initiation., Results: Of 19 815 individuals at risk during 1982-1996, TB incidence increased from 5.89/1000 person-years (PY) (95% CI 3.77 to 8.76) in the first year after seroconversion to 10.56 (4.83 to 20.04, p=0.01) at 10 years. Among 11 178 TB-free individuals initiating cART, the TB rate in the first year after cART initiation was 4.23/1000 PY (3.07 to 5.71) and dropped thereafter, remaining constant from year 2 onwards averaging at 1.64/1000 PY (1.29 to 2.05). Current CD4 count was inversely associated with TB rates, while nadir CD4 count was not associated with TB rates after adjustment for current CD4 count, HIV-RNA at cART initiation., Conclusions: TB risk increases with duration of HIV infection in the absence of cART. Following cART initiation, TB incidence rates were lower than levels immediately following seroconversion. Implementation of current recommendations to prevent TB in early HIV infection could be beneficial.

Background: The association between alcohol use disorders and increased risk of mortality is well known; however, there have been few systematic evaluations of alcohol-related organ damage and its impact on survival in younger alcoholics. Therefore, we assessed medical comorbidity with a clinical index to identify subgroups of alcoholic patients at high risk of premature death., Methods: Hospital-based cohort of alcohol-dependent patients admitted for detoxification between 1999 and 2008 in Barcelona, Spain. At admission, sociodemographic characteristics and a history of alcohol dependence and abuse of illegal drugs were obtained through clinical interviews and questionnaires. Medical comorbidity was assessed with the Cumulative Illness Rating Scale (Substance Abuse) (CIRS-SA). Dates and causes of death were obtained from clinical records and death registers. Survival was analyzed using Kaplan-Meier methods, and Cox regression models were used to analyze the risk factors for premature death., Results: Median age of the patients (686 total, 79.7% men) was 43.5 years (interquartile range [IQR], 37.8 to 50.4), average alcohol consumption was 200 g/d (IQR, 120 to 280 g/d), and duration of alcohol use disorder was 18 years (IQR, 11 to 24). Medical comorbidity by CIRS-SA at admission showed that the organs/systems most affected were liver (99%), respiratory (86%), and cardiovascular (58%). After median follow-up of 3.1 years (IQR, 1.5 to 5.1), 78 (11.4%) patients died with a mortality rate of 3.28 × 100 person-years; according to Kaplan-Meier estimates, 50% (95% confidence interval [95% CI], 24 to 69%) of patients with severe medical comorbidity died in the first decade after treatment. In multivariate analysis, severe medical comorbidity (hazard ratio [HR], 5.5; 95% CI, 3.02 to 10.07) and being treated with methadone at admission (HR, 2.60; 95% CI, 1.50 to 4.51) were independent risk factors for premature death., Conclusions: Systematic assessment of alcohol-related organ damage is relevant for the identification and treatment of those at increased risk of death., (Copyright © 2012 by the Research Society on Alcoholism.)

The factors associated with overall mortality and liver decompensation in HIV and hepatitis C virus (HCV)-coinfected patients who are evaluated to receive HCV antiviral therapy with a known liver histological fibrosis stage were evaluated in a prospective cohort study. A total of 387 consecutive HIV/HCV-coinfected patients attending an outpatient clinical unit between January 1997 and December 2007 who fulfilled criteria to be treated with interferon and to whom liver biopsy was performed were included and followed every 6 months from time of liver biopsy to death or to December 2008. The follow-up period was 6.2 years (IQR: 3.5-9.2). The median age at time of liver biopsy was 38 years. This included 73% men; 28% had advanced liver fibrosis (F3-F4) and a CD4 cell count of 556 cells/mm(3), 72% had HIV RNA <400 copies/ml and a mean CD4 nadir of 207 cell/mm(3), 21% had a previous diagnosis of AIDS, and 92% were on antiretroviral therapy. During follow-up 48% underwent HCV antiviral therapy, with a sustained virological response in 33%. The overall mortality rate and the incidence of liver decompensation or liver-related death were 1.17 and 0.72 per 100 patients-year, respectively. End stage liver disease (9/28 patients) and non-AIDS-related cancer (6/28) were the main causes of death. F3-F4 (HR: 3.74, 95% CI: 1.69-8.26, p=0.001) and previous AIDS diagnosis (HR: 3.04, 95% CI: 1.36-6.81) were the factors independently associated with death. Mortality rates in patients who received and who did not receive HCV antiviral therapy were 0.44 and 2.04 per 100 patients-year, respectively (p=0.003). In addition to the low mortality rate observed, HIV/HCV-coinfected patients with poor predictors of survival are candidates for intensive clinical management.

We analyse nine low-income and lower-middle-income countries in Africa and Asia that have implemented national health insurance reforms designed to move towards universal health coverage. Using the functions-of-health-systems framework, we describe these countries' approaches to raising prepaid revenues, pooling risk, and purchasing services. Then, using the coverage-box framework, we assess their progress across three dimensions of coverage: who, what services, and what proportion of health costs are covered. We identify some patterns in the structure of these countries' reforms, such as use of tax revenues to subsidise target populations, steps towards broader risk pools, and emphasis on purchasing services through demand-side financing mechanisms. However, none of the reforms purely conform to common health-system archetypes, nor are they identical to each other. We report some trends in these countries' progress towards universal coverage, such as increasing enrolment in government health insurance, a movement towards expanded benefits packages, and decreasing out-of-pocket spending accompanied by increasing government share of spending on health. Common, comparable indicators of progress towards universal coverage are needed to enable countries undergoing reforms to assess outcomes and make midcourse corrections in policy and implementation., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Objective: To compare regimens consisting of either efavirenz or nevirapine and two or more nucleoside reverse transcriptase inhibitors (NRTIs) among HIV-infected, antiretroviral-naive, and AIDS-free individuals with respect to clinical, immunologic, and virologic outcomes., Design: Prospective studies of HIV-infected individuals in Europe and the US included in the HIV-CAUSAL Collaboration., Methods: Antiretroviral therapy-naive and AIDS-free individuals were followed from the time they started an NRTI, efavirenz or nevirapine, classified as following one or both types of regimens at baseline, and censored when they started an ineligible drug or at 6 months if their regimen was not yet complete. We estimated the 'intention-to-treat' effect for nevirapine versus efavirenz regimens on clinical, immunologic, and virologic outcomes. Our models included baseline covariates and adjusted for potential bias introduced by censoring via inverse probability weighting., Results: A total of 15 336 individuals initiated an efavirenz regimen (274 deaths, 774 AIDS-defining illnesses) and 8129 individuals initiated a nevirapine regimen (203 deaths, 441 AIDS-defining illnesses). The intention-to-treat hazard ratios [95% confidence interval (CI)] for nevirapine versus efavirenz regimens were 1.59 (1.27, 1.98) for death and 1.28 (1.09, 1.50) for AIDS-defining illness. Individuals on nevirapine regimens experienced a smaller 12-month increase in CD4 cell count by 11.49 cells/μl and were 52% more likely to have virologic failure at 12 months as those on efavirenz regimens., Conclusions: Our intention-to-treat estimates are consistent with a lower mortality, a lower incidence of AIDS-defining illness, a larger 12-month increase in CD4 cell count, and a smaller risk of virologic failure at 12 months for efavirenz compared with nevirapine., (© 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins)

Objective: HIV-1-infected active drug users (ADU) obtain smaller clinical benefits with antiretroviral therapy (HAART) compared to non-ADU subjects with sexually-transmitted HIV-1 infection. Therefore treatment strategies are required to address the specific issues arising in this challenging scenario. We describe the effectiveness of HAART provided in a drug abuse outpatient treatment facility through a comprehensive integrated care that includes medical, drug dependence, and psychosocial support., Methods: We included all consecutive HIV-1-infected ADU admitted for drug dependency treatment and who started their first HAART. A comparator arm consisted of a control group of sexually transmitted HIV-1-infected subjects attended in a reference hospital under standard care. The strategy did not include directly observed treatment., Results: A total of 71 ADU and 48 matched subjects infected through sexual transmission were included. ADU had lower baseline CD4+ T-cell counts (196 vs 279 cells/μL, P=.001), and more advanced CDC stages (P=.001). The estimated probabilities of patients with virological response ( < 50 copies/mL) at weeks 48 and 96 were 92.9% (95%-CI: 87.1%-99.1%) and 87.3% (95%-CI: 78.7%-95.2% for ADU, and 93.7%(95%-CI: 84.1%-99.8%) and 87.5% (95%-CI: 77.5%-97.3%) for sexually-infected subjects (P= .1325 and .241). Kaplan-Meier estimates of time to loss of virological response did not show differences between groups (log rank test, P=.965)., Conclusions: An integrated multidisciplinary care of HIV-1-infected antiretroviral naïve ADU provided in a drug abuse treatment center obtains high rates of virological suppression, similar to those observed in a comparison group of sexually-transmitted HIV-1-infected subjects. This strategy should be further evaluated in public health programs and assessed in randomized trials.

Objectives: There has been increased attention to access to water, sanitation and hygiene (WASH) at schools in developing countries, but a dearth of empirical studies on the impact. We conducted a cluster-randomized trial of school-based WASH on pupil absence in Nyanza Province, Kenya, from 2007 to 2008., Methods: Public primary schools nested in three geographical strata were randomly assigned and allocated to one of three study arms [water treatment and hygiene promotion (WT & HP), additional sanitation improvement, or control] to assess the effects on pupil absence at 2-year follow-up., Results: We found no overall effect of the intervention on absence. However, among schools in two of the geographical areas not affected by post-election violence, those that received WT and HP showed a 58% reduction in the odds of absence for girls (OR 0.42, CI 0.21-0.85). In the same strata, sanitation improvement in combination with WT and HP resulted in a comparable drop in absence, although results were marginally significant (OR 0.47, 0.21-1.05). Boys were not impacted by the intervention., Conclusion: School WASH improvements can improve school attendance for girls, and mechanisms for gendered impacts should be explored. Incomplete intervention compliance highlights the challenges of achieving consistent results across all settings., (© 2011 Blackwell Publishing Ltd.)