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Objectives There is increasing evidence to suggest that people living with HIV (PLWH) have significant morbidity from alcohol, recreational drug use and cigarette smoking. Our aim was to report associations of these factors with antiretroviral therapy (ART) non-adherence, viral non-suppression and subsequent viral rebound in PLWH. Methods The Antiretroviral Sexual Transmission Risk and Attitudes (ASTRA) study recruited PLWH attending eight outpatient clinics in England between February 2011 and December 2012. Data included self-reported excessive drinking (estimated consumption of > 20 units of alcohol/week), alcohol dependency (CAGE score ≥ 2 with current alcohol consumption), recreational drug use (including injection drug use in the past 3 months), and smoking status. Among participants established on ART, cross-sectional associations with ART non-adherence [missing ≥2 consecutive days of ART on ≥2 occasions in the past three months] and viral-non suppression [viral load (VL) > 50 copies/mL] were assessed using logistic regression. In participants from one centre, longitudinal associations with subsequent viral rebound (first VL > 200 copies/mL) in those on ART with VL ≤ 50 copies/mL at baseline were assessed using Cox regression during a 7-year follow-up. Results Among 3258 PLWH, 2248 (69.0%) were men who have sex with men, 373 (11.4%) were heterosexual men, and 637 (19.6%) were women. A CAGE score ≥ 2 was found in 568 (17.6%) participants, 325 (10.1%) drank > 20 units/week, 1011 (31.5%) currently smoked, 1242 (38.1%) used recreational drugs and 74 (2.3%) reported injection drug use. In each case, prevalence was much more common among men than among women. Among 2459 people on ART who started at least 6 months previously, a CAGE score ≥ 2, drinking > 20 units per week, current smoking, injection and non-injection drug use were all associated with ART non-adherence. After adjusting for demographic and socioeconomic factors, CAGE score ≥ 2 [adjusted odds ratio (aOR) = 1.52, 95% confidence interval (CI): 1.09-2.13], current smoking (aOR = 1.58, 95% CI: 1.10-2.17) and injection drug use (aOR = 2.11, 95% CI: 1.00-4.47) were associated with viral non-suppression. During follow-up of a subset of 592 people virally suppressed at recruitment, a CAGE score ≥ 2 [adjusted hazard ratio (aHR) = 1.66, 95% CI: 1.03-2.74], use of 3 or more non-injection drugs (aHR = 1.82, 95% CI: 1.12-3.57) and injection drug use (aHR = 2.73, 95% CI: 1.08-6.89) were associated with viral rebound. Conclusions Screening and treatment for alcohol, cigarette and drug use should be integrated into HIV outpatient clinics, while clinicians should be alert to the potential for poorer virological outcomes.

Background Increased understanding of whether individuals who have recovered from COVID-19 are protected from future SARS-CoV-2 infection is an urgent requirement. We aimed to investigate whether antibodies against SARS-CoV-2 were associated with a decreased risk of symptomatic and asymptomatic reinfection. Methods A large, multicentre, prospective cohort study was done, with participants recruited from publicly funded hospitals in all regions of England. All health-care workers, support staff, and administrative staff working at hospitals who could remain engaged in follow-up for 12 months were eligible to join The SARS-CoV-2 Immunity and Reinfection Evaluation study. Participants were excluded if they had no PCR tests after enrolment, enrolled after Dec 31, 2020, or had insufficient PCR and antibody data for cohort assignment. Participants attended regular SARS-CoV-2 PCR and antibody testing (every 2–4 weeks) and completed questionnaires every 2 weeks on symptoms and exposures. At enrolment, participants were assigned to either the positive cohort (antibody positive, or previous positive PCR or antibody test) or negative cohort (antibody negative, no previous positive PCR or antibody test). The primary outcome was a reinfection in the positive cohort or a primary infection in the negative cohort, determined by PCR tests. Potential reinfections were clinically reviewed and classified according to case definitions (confirmed, probable, or possible) and symptom-status, depending on the hierarchy of evidence. Primary infections in the negative cohort were defined as a first positive PCR test and seroconversions were excluded when not associated with a positive PCR test. A proportional hazards frailty model using a Poisson distribution was used to estimate incidence rate ratios (IRR) to compare infection rates in the two cohorts. Findings From June 18, 2020, to Dec 31, 2020, 30 625 participants were enrolled into the study. 51 participants withdrew from the study, 4913 were excluded, and 25 661 participants (with linked data on antibody and PCR testing) were included in the analysis. Data were extracted from all sources on Feb 5, 2021, and include data up to and including Jan 11, 2021. 155 infections were detected in the baseline positive cohort of 8278 participants, collectively contributing 2 047 113 person-days of follow-up. This compares with 1704 new PCR positive infections in the negative cohort of 17 383 participants, contributing 2 971 436 person-days of follow-up. The incidence density was 7·6 reinfections per 100 000 person-days in the positive cohort, compared with 57·3 primary infections per 100 000 person-days in the negative cohort, between June, 2020, and January, 2021. The adjusted IRR was 0·159 for all reinfections (95% CI 0·13–0·19) compared with PCR-confirmed primary infections. The median interval between primary infection and reinfection was more than 200 days. Interpretation A previous history of SARS-CoV-2 infection was associated with an 84% lower risk of infection, with median protective effect observed 7 months following primary infection. This time period is the minimum probable effect because seroconversions were not included. This study shows that previous infection with SARS-CoV-2 induces effective immunity to future infections in most individuals. Funding Department of Health and Social Care of the UK Government, Public Health England, The National Institute for Health Research, with contributions from the Scottish, Welsh and Northern Irish governments.

Background A rapid, accurate, non-invasive diagnostic screen is needed to identify people with SARS-CoV-2 infection. We investigated whether organic semi-conducting (OSC) sensors and trained dogs could distinguish between people infected with asymptomatic or mild symptoms, and uninfected individuals, and the impact of screening at ports-of-entry. Methods Odour samples were collected from adults, and SARS-CoV-2 infection status confirmed using RT-PCR. OSC sensors captured the volatile organic compound (VOC) profile of odour samples. Trained dogs were tested in a double-blind trial to determine their ability to detect differences in VOCs between infected and uninfected individuals, with sensitivity and specificity as the primary outcome. Mathematical modelling was used to investigate the impact of bio-detection dogs for screening. Results About, 3921 adults were enrolled in the study and odour samples collected from 1097 SARS-CoV-2 infected and 2031 uninfected individuals. OSC sensors were able to distinguish between SARS-CoV-2 infected individuals and uninfected, with sensitivity from 98% (95% CI 95–100) to 100% and specificity from 99% (95% CI 97–100) to 100%. Six dogs were able to distinguish between samples with sensitivity ranging from 82% (95% CI 76–87) to 94% (95% CI 89–98) and specificity ranging from 76% (95% CI 70–82) to 92% (95% CI 88–96). Mathematical modelling suggests that dog screening plus a confirmatory PCR test could detect up to 89% of SARS-CoV-2 infections, averting up to 2.2 times as much transmission compared to isolation of symptomatic individuals only. Conclusions People infected with SARS-CoV-2, with asymptomatic or mild symptoms, have a distinct odour that can be identified by sensors and trained dogs with a high degree of accuracy. Odour-based diagnostics using sensors and/or dogs may prove a rapid and effective tool for screening large numbers of people. Trial Registration NCT04509713 (clinicaltrials.gov).

Background Protease inhibitors (PI) have relatively low penetration into the genital tract, raising concerns about the potential for genital HIV RNA shedding in patients taking PI-based regimens, particularly PI monotherapy (PI-mono). Methods We measured HIV RNA and PI drug concentrations in samples of semen, cervicovaginal and rectal mucosa secretions, and plasma in patients after 48–96 weeks on PI-mono or standard triple therapy. Results A total of 85 participants were recruited. Of the 43 participants on PI-mono (70% on darunavir [DRV]/ ritonavir [r]), 3 had detectable virus in semen or vaginal secretions (all below quantification limit), and none in rectal mucosa or plasma. Among those taking triple therapy, five had detectable virus in semen or vaginal secretions (HIV RNA >50 copies/ml in one), none in rectal mucosa and one in plasma. The median (IQR) concentration of DRV and atazanavir in semen (659.7 [339–1,089] and 128.8 [63–368] ng/ml, respectively) and cervico-vaginal samples (2,768 [312–7,879] and 1,836 [359–3,314] ng/ml, respectively) exceeded their protein adjusted median inhibition concentration (MIC50). DRV concentration in rectal secretions showed higher variability compared with concentration in the other sites, with particularly high rectal secretion/blood ratios (median 8.4, IQR 2.6–68.7:1). Conclusions We found no substantive evidence of HIV shedding in patients taking PI-mono, suggesting that PIs provide adequate control of virus in the genital compartment and are unlikely to lead to ongoing sexual transmission.

Learning and memory are important for successful education and career progression. We assess these functions in young people (YP) with perinatal HIV (PHIV) (with or without a previous AIDS-defining illness) and a comparable group of HIV-negative YP. 234 PHIV and 68 HIV-negative YP completed 9 tests; 5 National Institutes of Health (NIH) Toolbox tests (2 executive function, 1 speed of information processing, 2 memory); 2 Hopkins Verbal Learning Test Revised (HVLT-R) (learning (L), delayed recall (R)), and 2 verbal application measures. Z-scores for each test were calculated using normative data and averaged by domain where appropriate. The effect of predictors on test scores in the three domains with the lowest z-scores were analysed using linear regression. 139(59%) and 48(71%) PHIV and HIV-negative YP were female, 202(86%) and 52(76%) Black, and median age was 19 [17, 21] and 18 [16, 21] years respectively. 55(24%) PHIV had a previous Center for Disease Control and Prevention (CDC) class C AIDS-defining diagnosis (PHIV/C). For HVLT-R, there was a trend towards PHIV/C YP having the lowest mean z-scores (L -1.5 (95% CI -1.8,-1.2), R -1.7 (-2.0,-1.4)) followed by PHIV without a CDC C diagnosis (L -1.3 (-1.4,-1.1), R -1.4 (-1.5,-1.2)) and then the HIV-negative group (L -1.0 (-1.3,-0.7), R -1.1 (-1.3,-0.8)); all were greater than 1 SD below the reference mean. The same trend was seen for verbal application measures; however, z-scores were within 1 SD below the reference mean. NIH Toolbox tests were similar for all groups. In multivariable analyses PHIV/C and Black ethnicity predicted lower HVLT-R scores. Black ethnicity also predicted lower executive function scores, however each year increase in age predicted higher scores. In conclusion, cognitive performance in verbal learning and recall fell below population normative scores, and was more pronounced in PHIV/C, supporting wider findings that earlier antiretroviral therapy initiation, before the occurrence of AIDS-defining conditions, may protect aspects of cognitive development.

OBJECTIVES: We performed a network meta-analysis of PEP randomized clinical trials to evaluate the best regimen. METHODS: After MEDLINE/Pubmed search, studies were included if: (1) were randomized, (2) comparing at least 2 PEP three-drug regimens and, (3) reported completion rates or discontinuation at 28 days. Five studies with 1105 PEP initiations were included and compared ritonavir-boosted lopinavir (LPV/r) vs. atazanavir (ATV) (one study), cobicistat-boosted elvitegravir (EVG/c) (one study), raltegravir (RAL) (one study) or maraviroc (MVC) (two studies). We estimated the probability of each treatment of being the best based on the evaluation of five outcomes: PEP non-completion at day 28, PEP discontinuation due to adverse events, PEP switching due to any cause, lost to follow-up and adverse events. RESULTS: Participants were mostly men who have sex with men (n = 832, 75%) with non-occupational exposure to HIV (89.86%). Four-hundred fifty-four (41%) participants failed to complete their PEP course for any reason. The Odds Ratio (OR) for PEP non-completion at day 28 in each antiretroviral compared to LPV/r was: ATV 0.95 (95% CI 0.58-1.56; EVG/c: OR 0.65 95% CI 0.30-1.37; RAL: OR 0.68 95% CI 0.41-1.13; and MVC: OR 0.69 95% CI 0.47-1.01. In addition, the rankogram showed that EVG/c had the highest probability of being the best treatment for the lowest rates in PEP non-completion at day 28, switching, lost to follow-up or adverse events and MVC for PEP discontinuations due to adverse events. CONCLUSIONS: Our study shows the advantages of integrase inhibitors when used as PEP, particularly EVG as a Single-Tablet Regimen.

Objectives We performed a network meta-analysis of PEP randomized clinical trials to evaluate the best regimen. Methods After MEDLINE/Pubmed search, studies were included if: (1) were randomized, (2) comparing at least 2 PEP three-drug regimens and, (3) reported completion rates or discontinuation at 28 days. Five studies with 1105 PEP initiations were included and compared ritonavir-boosted lopinavir (LPV/r) vs. atazanavir (ATV) (one study), cobicistat-boosted elvitegravir (EVG/c) (one study), raltegravir (RAL) (one study) or maraviroc (MVC) (two studies). We estimated the probability of each treatment of being the best based on the evaluation of five outcomes: PEP non-completion at day 28, PEP discontinuation due to adverse events, PEP switching due to any cause, lost to follow-up and adverse events. Results Participants were mostly men who have sex with men (n = 832, 75%) with non-occupational exposure to HIV (89.86%). Four-hundred fifty-four (41%) participants failed to complete their PEP course for any reason. The Odds Ratio (OR) for PEP non-completion at day 28 in each antiretroviral compared to LPV/r was: ATV 0.95 (95% CI 0.58-1.56; EVG/c: OR 0.65 95% CI 0.30-1.37; RAL: OR 0.68 95% CI 0.41-1.13; and MVC: OR 0.69 95% CI 0.47-1.01. In addition, the rankogram showed that EVG/c had the highest probability of being the best treatment for the lowest rates in PEP non-completion at day 28, switching, lost to follow-up or adverse events and MVC for PEP discontinuations due to adverse events. Conclusions Our study shows the advantages of integrase inhibitors when used as PEP, particularly EVG as a Single-Tablet Regimen.

There are currently no cures for coronavirus infections, making the prevention of infections the only course open at the present time. The COVID-19 pandemic has been difficult to prevent, as the infection is spread by respiratory droplets and thus effective, scalable and safe preventive interventions are urgently needed. We hypothesise that preventing viral entry into mammalian nasal epithelial cells may be one way to limit the spread of COVID-19. Here we show that N-palmitoyl-N-monomethyl-N,N-dimethyl-N,N,N-trimethyl-6-O-glycolchitosan (GCPQ), a positively charged polymer that has been through an extensive Good Laboratory Practice toxicology screen, is able to reduce the infectivity of SARS-COV-2 in A549ACE2+ and Vero E6 cells with a log removal value of − 3 to − 4 at a concentration of 10–100 μg/ mL (p p 50/mL) showed a trend for nasal GCPQ (20 mg/kg) to inhibit viral load in the respiratory tract and brain, although the study was not powered to detect statistical significance. GCPQ’s electrostatic binding to the virus, preventing viral entry into the host cells, is the most likely mechanism of viral inhibition. Radiolabelled GCPQ studies in mice show that at a dose of 10 mg/kg, GCPQ has a long residence time in mouse nares, with 13.1% of the injected dose identified from SPECT/CT in the nares, 24 h after nasal dosing. With a no observed adverse effect level of 18 mg/kg in rats, following a 28-day repeat dose study, clinical testing of this polymer, as a COVID-19 prophylactic is warranted.

There are currently no cures for coronavirus infections, making the prevention of infections the only course open at the present time. The COVID-19 pandemic has been difficult to prevent, as the infection is spread by respiratory droplets and thus effective, scalable and safe preventive interventions are urgently needed. We hypothesise that preventing viral entry into mammalian nasal epithelial cells may be one way to limit the spread of COVID-19. Here we show that N-palmitoyl-N-monomethyl-N,N-dimethyl-N,N,N-trimethyl-6-O-glycolchitosan (GCPQ), a positively charged polymer that has been through an extensive Good Laboratory Practice toxicology screen, is able to reduce the infectivity of SARS-COV-2 in A549ACE2+ and Vero E6 cells with a log removal value of −3 to −4 at a concentration of 10 – 100 μg/ mL (p < 0.05 compared to untreated controls) and to limit infectivity in human airway epithelial cells at a concentration of 500 μg/ mL (p < 0.05 compared to untreated controls). GCPQ is currently being developed as a pharmaceutical excipient in nasal and ocular formulations. GCPQ’s electrostatic binding to the virus, preventing viral entry into the host cells, is the most likely mechanism of viral inhibition. Radiolabelled GCPQ studies in mice show that at a dose of 10 mg/ kg, GCPQ has a long residence time in mouse nares, with 13.1% of the injected dose identified from SPECT/CT in the nares, 24 hours after nasal dosing. With a no observed adverse effect level of 18 mg/ kg in rats, following a 28-day repeat dose study, clinical testing of this polymer, as a COVID-19 prophylactic is warranted.

OBJECTIVE The aim of the current study is to assess the effect of tenofovir alafenamide (TAF) and tenofovir disoproxil fumarate (TDF) on lipids in patients switching from TDF to TAF and back. METHODS Retrospective data collection on patients who were initially switched from TDF to TAF and switched back to TDF after generics of TDF became available. RESULTS In total, 385 patients were included. Median duration of TDF exposure before switch was 317 weeks (interquartile range 172-494). After switching from TDF to TAF, mean total cholesterol (TC) increased from 186 ± 37 mg/dl at baseline to 206 ± 43 and 204 ± 43 mg/dl at weeks 12 and 24 (P

Alcohol misuse has been associated with negative consequences among HIV-positive patients. Data on real prevalence of risky alcohol consumption among the HIV-positive population in the UK are lacking. A cross-sectional questionnaire study using standardised validated instruments among HIV-positive (n = 227) and HIV-negative (n = 69) patients was performed. The prevalence of risky alcohol consumption (AUDIT) and associations with depressive symptoms (PHQ-9), problematic drug use (DUDIT), adherence to ART (CASE Adherence Index), sexual behaviour and demographic characteristics were assessed among both patient groups independently. A quarter (25.1%) of HIV-positive patients and 36.1% of HIV-negative patients reported risky alcohol consumption (AUDIT-score ≥ 8). In the multivariable analysis among HIV-positive patients depressive symptoms (p = 0.03) and problematic drug use (p = 0.007) were associated with risky alcohol consumption. Among HIV-negative patients these associations were not present. Risky alcohol consumption among HIV-positive patients is prevalent, and together with depressive symptoms and problematic drug use, may influence HIV-disease progression and patients’ wellbeing. Electronic supplementary material The online version of this article (10.1007/s10461-019-02714-2) contains supplementary material, which is available to authorized users.

Adolescents with perinatal HIV (PHIV) may be at higher risk of anxiety and depression than HIV negative young people. We investigated the prevalence of symptoms of anxiety and depression in PHIV and HIV-affected (siblings of PHIV and/or had an HIV positive mother) young people in England. Symptoms were measured using the Hospital Anxiety and Depression Scale (HADS) scores. A cross-sectional analysis was conducted of data from 283 young people with PHIV aged 13-21 years and 96 HIV-affected young people aged 13-23 years in the Adolescents and Adults Living with Perinatal HIV (AALPHI) cohort. Linear regression investigated factors associated with higher (worse) anxiety and depression scores.115 (41%) and 29 (30%) PHIV and HIV-affected young people were male, median age was 16 [interquartile range 15,18] and 16 [14,18] years and 241 (85%) and 71 (74%) young people were black African, respectively. There were no differences in raw or z-scores of anxiety and depression, or self-esteem, between PHIV and HIV-affected participants (all p values >0.1). Across both PHIV and HIV-affected groups, factors associated with higher anxiety scores were having more carers in childhood, speaking a language other than English at home, lower self-esteem, and ever thinking life was not worth living and lower social functioning. Factors associated with higher depression scores were male sex, death of one or both parents, ever excluded from school, lower self-esteem and lower social functioning. This study found anxiety and depression scores were similar among PHIV and HIV-affected young people and similar to that of population norms. Other studies have found an association between poorer mental health and worse health outcomes in young people with PHIV, highlighting the need to identify young people at increased risk and provide timely support.

IMPACT: Our findings could potentially identify CVD at-risk persons living with HIV who might benefit from aggressive risk-reduction. OBJECTIVES/GOALS: PWH have higher rates of CVD than the general population yet CVD risk prediction models rely on traditional risk factors and fail to capture the heterogeneity of CVD risk in PWH. Here we identify protein biomarkers that are able to discriminate between CVD cases and controls in PWH, and we assess their added benefit beyond traditional risk factors. METHODS/STUDY POPULATION: We analyzed 459 baseline protein expression levels from five OLINK panels in a matched CVD (MI, coronary revascularization, stroke, CVD death) case-control study with 390 PWH from INSIGHT trials (131 cases, 259 controls). We formed 200 datasets via bootstrap. For each bootstrap set, a two-component partial least squares discriminant model (PLSDA) was fit. The importance of each variable in the discrimination of cases and controls in the PLSDA projection was assessed by the variable importance in projection (VIP) score. Proteins with average VIP scores > 1 were used in penalized logistic regression models with elastic net penalty, and proteins were ranked based on the number of times the protein had a nonzero coefficient. Proteins in the top 25th percentile were considered to have high discrimination. RESULTS/ANTICIPATED RESULTS: Participants had mean age 47 years, 13% were females, 4.9% had CVD at baseline and 69% were on ART at baseline. Eight proteins including the hepatocyte growth factor and interleukin-6 were identified as able to distinguish between CVD cases and controls within PWH. A protein score (PS) of the top-ranked proteins was developed using the bootstrap (for weights) and the entire data. The PS was found to be predictive of CVD independent of established CVD and HIV factors (Odds ratio: 2.17 CI: 1.58-2.99). A model with the PS and traditional risk factors had a 5.9% improvement in AUC over the baseline model (AUC=0.731 vs 0.69), which is an increase in model predictive power of 18%. Individuals with a PS above the median score were 3.1 (CI: 1.83- 5.41) times more likely to develop CVD than those with a protein score below the median score. DISCUSSION/SIGNIFICANCE OF FINDINGS: A protein score developed improved discrimination of PWH with CVD and those without, and helped identify PWH with high risk for developing CVD. If validated, this score and/or the individual proteins could be used in addition with established factors to identify CVD at-risk individuals who might benefit from aggressive risk-reduction.

Background: Mapping of health-related quality-of-life measures to health utility values can facilitate cost-utility evaluation. Regression-based methods tend to lead to shrinkage of variance. This study aims to map the Medical Outcomes Study HIV Health Survey (MOS-HIV) to EuroQoL 5 Dimensions (EQ-5D-3 L) utility index, and to characterize the performance of three mapping methods, including ordinary least squares (OLS), equi-percentile method (EPM), and a recently proposed method called Mean Rank Method (MRM). Methods: This is a secondary analysis of data from a randomized HIV treatment trial. Baseline data from 421 participants were used to develop mapping functions. Follow-up data from 236 participants was used to validate the mapping functions. Results: In the training dataset, MRM and OLS, but not EPM, reproduced the observed mean utility (0.731). MRM, OLS and EPM under-estimated the standard deviation by 0.3, 26.6 and 1.7%, respectively. MRM had the lowest mean absolute error (0.143) and highest intraclass correlation coefficient (0.723) with the observed utility values, whereas OLS had the lowest mean squared error (0.038) and highest R-squared (0.542). Regressing the MRM- and OLS-mapped utility values upon body mass index and log-viral load gave covariate associations comparable to those estimated from the observed utility data (all P > 0.10). EPM did not achieve this property. Findings from the validation data were similar. Conclusions: Functions are available for mapping the MOS-HIV to the EQ-5D-3 L utility values. MRM and OLS were comparable in terms of agreement with the observed utility values at the individual level. MRM had better performance at the group level in terms of describing the utility distribution. Trial registration: NCT00988039. Registered 30 September 2009., The EARNEST trial was funded by the European and Developing Countries Clinical Trials Partnership (EDCTP, Grant Code: IP.2007.33011.003) with contributions from the Medical Research Council, UK; Institito de Salud Carlos III, Spain (Grant A107/90015); Irish Aid, Ireland; Swedish International Development Cooperation Agency (SIDA), Sweden; Instituto Superiore di Sanita (ISS), Italy; The World Health Organisation; and Merck, USA. Substantive in-kind contributions were made by the Medical Research Council Clinical Trials Unit, UK [MC_UU_12023/23], CINECA, Bologna, Italy, Janssen Diagnostics, Beerse, Belgium; GSK/ViiV Healthcare Ltd., UK; Abbott Laboratories, USA. Trial medication was donated by AbbVie, Merck, Pfizer, GSK and Gilead. The Malawi-Liverpool-Wellcome Trust Clinical Research Programme, University of Malawi

Background. There is limited evidence about the cognitive performance of older adolescents with perinatally acquired human immunodeficiency virus (HIV) compared with HIV-negative (HIV−) adolescents.\ud \ud Methods. A total of 296 perinatally HIV-infected (PHIV+) and 97 HIV− adolescents (aged 12–21 and 13–23 years, respectively) completed 12 tests covering 6 cognitive domains. The HIV− participants had PHIV+ siblings and/or an HIV-infected mother. Domain-specific and overall (NPZ-6) z scores were calculated for PHIV+ participants, with or without Centers for Disease Control and Prevention (CDC) stage C disease, and HIV− participants. Linear regression was performed to explore predictors of NPZ-6.\ud \ud Results. One hundred twenty-five (42%) of the PHIV+ and 31 (32%) of the HIV− participants were male; 251 (85%) and 69 (71%), respectively, were black African; and their median ages (interquartile range) were 16 (15–18) and 16 (14–18) years, respectively. In PHIV+ participants, 247 (86%) were receiving antiretroviral therapy, and 76 (26%) had a previous CDC C diagnosis. The mean (standard deviation) NPZ-6 score was −0.81 (0.99) in PHIV+ participants with a CDC C diagnosis (PHIV+/C), −0.45 (0.80) in those without a CDC C diagnosis (PHIV+/no C), and −0.32 (0.76) in HIV− participants (P < .001). After adjustment, there was no difference in NPZ-6 scores between PHIV+/no C and HIV− participants (adjusted coefficient, −0.01; 95% confidence interval, −.22 to .20). PHIV+/C participants scored below the HIV− group (adjusted coefficient, −0.44; −.70 to −.19). Older age predicted higher NPZ-6 scores, and black African ethnicity and worse depression predicted lower NPZ-6 scores. In a sensitivity analysis including PHIV+ participants only, no HIV-related factors apart from a CDC C diagnosis were associated with NPZ-6 scores.\ud \ud Conclusions. Cognitive performance was similar between PHIV+/no C and HIV− participants and indicated relatively mild impairment compared with normative data. The true impact on day-to-day functioning needs further investigation.

Summary Background Standard-of-care antiretroviral therapy (ART) uses a combination of drugs deemed essential to minimise treatment failure and drug resistance. Protease inhibitors are potent, with a high genetic barrier to resistance, and have potential use as monotherapy after viral load suppression is achieved with combination treatment. We aimed to assess clinical risks and benefits of protease inhibitor monotherapy in long-term clinical use: in particular, the effect on drug resistance and future treatment options. Methods In this pragmatic, parallel-group, randomised, controlled, open-label, non-inferiority trial, we enrolled adults (≥18 years of age) positive for HIV attending 43 public sector treatment centres in the UK who had suppressed viral load (

The role of antiretroviral therapy (ART) in reducing or contributing to liver fibrosis in persons with human immunodeficiency virus (HIV) is unclear. We evaluated participants in the Strategic Timing of AntiRetroviral Treatment (START) trial for liver fibrosis using the AST to Platelet Ratio Index (APRI) and Fibrosis-4 Index (FIB-4), and assessed for a benefit of early versus delayed ART on liver fibrosis progression. ART-naive persons with high CD4 counts (>500 cells/µL) from 222 clinical sites in 35 countries were randomized to receive ART either at study enrollment (immediate treatment arm) or when their CD4 count fell below 350 cells/µL (deferred treatment arm). The following outcomes were evaluated: fibrosis (APRI > 0.5 or FIB-4 > 1.45), significant fibrosis (APRI > 1.5 or FIB-4 > 3.25), hepatic flare, and resolution of elevated APRI and FIB-4 scores. Of the 4,684 enrolled into the START study, 104 did not have APRI or FIB-4 results and were excluded. Among 4,580 participants (2,273 immediate treatment; 2,307 deferred treatment), the median age was 36 years, 26.9% were female, and 30.4% were black. Three percent had an alcoholism or substance abuse history, 6.4% had hepatitis B and/or C, and 1.1% had significant fibrosis at baseline. The median CD4 count was 651, and 5.3% had HIV RNA ≤ 200. Immediate arm participants were at lower risk of developing increased fibrosis scores than deferred arm participants (hazard ratio [HR] = 0.66; 95% confidence interval [CI] = 0.57-0.78; P < 0.001) and more likely to have resolution of elevated baseline scores (HR 1.6; 95% CI 1.3-1.9; P < 0.001). Conclusions: Significant liver fibrosis was rare among ART-naive HIV-positive persons with high CD4 counts. Our findings suggest a benefit of early ART in preventing the development of liver fibrosis.

OBJECTIVE To compare the effect of immediate versus deferred antiretroviral treatment (ART) on neuropsychological test performance in treatment-naive HIV-positive adults with more than 500 CD4 cells/μl. DESIGN Randomized trial. METHODS The START parent study randomized participants to commence immediate versus deferred ART until CD4 less than 350 cells/μl. The START Neurology substudy used eight neuropsychological tests, at baseline, months 4, 8, 12 and annually, to compare groups for changes in test performance. Test results were internally standardized to z-scores. The primary outcome was the average of the eight test z-scores (QNPZ-8). Mean changes in QNPZ-8 from baseline were compared by intent-to-treat using longitudinal mixed models. Changes from baseline to specific time points were compared using ANCOVA models. RESULTS The 592 participants had a median age of 34 years; median baseline CD4 count was 629 cells/μl; the mean follow-up was 3.4 years. ART was used for 94 and 32% of accrued person-years in the immediate and deferred groups, respectively. There was no difference between the immediate and deferred ART groups in QNPZ-8 change through follow-up [-0.018 (95% CI -0.062 to 0.027, P = 0.44)], or at any visit. However, QNPZ-8 scores increased in both arms during the first year, by 0.22 and 0.24, respectively (P

BACKGROUND Protease inhibitor monotherapy (PIM) for human immunodeficiency virus (HIV) may exert suboptimal viral control in the central nervous system. We determined whether cerebral blood flow (CBF) and regional brain volumes were associated with PIM, and whether specific cognitive domains were associated with imaging biomarkers. METHODS Cognitive assessments and brain magnetic resonance imaging were performed after the final visit of a randomized HIV-treatment strategy trial. Participants were virologically suppressed on triple therapy at trial entry and followed for 3-5 years. We studied 37 patients randomized to ongoing triple therapy and 39 randomized to PIM. Resting CBF and normalized volumes were calculated for brain regions of interest, and correlated with treatment strategy and neuropsychological performance. RESULTS Mean age was 48.1 years (standard deviation 8.6 years), 63 male (83%), and 64 white (84%). Participants had median 8.1 years (interquartile range 6.4, 10.8) of antiretroviral therapy experience and CD4+ counts of median 640 cells/mm3 (interquartile range 490, 780). We found no difference between treatment arms in CBF or regional volumes. Regardless of treatment arm, poorer fine motor performance correlated with lower CBF in the caudate nucleus (P = .01), thalamus (P = .04), frontal cortex (P = .01), occipital cortex (P = .004), and cingulate cortex (P = .02), and was associated with smaller supratentorial white matter volume (decrease of 0.16 in Z-score per -1% of intracranial volume, 95% confidence interval 0.02-0.29; P = .023). CONCLUSIONS PIM does not confer an additional risk of neurological injury compared with triple therapy. There were correlations between fine motor impairment, grey matter hypoperfusion, and white matter volume loss. CLINICAL TRIALS REGISTRATION ISRCTN-04857074.

Objectives Liver disease is increasingly recognized in HIV-positive individuals, even among those without viral hepatitis, partly as a result of the recent availability of noninvasive methods of liver fibrosis assessment. The objective of this substudy is to compare the effects of early versus deferred antiretroviral therapy (ART) on liver fibrosis progression. Methods Sites in the Strategic Timing of AntiRetroviral Treatment (START) study with access to FibroScan® were invited to participate in the Liver Fibrosis Progression Substudy. All substudy participants underwent FibroScan® at baseline, and two noninvasive serum algorithms, APRI and FIB-4, were calculated. Demographic and liver-related information was collected for all START participants at baseline. Results A total of 230 participants were enrolled in the substudy (11.5% with hepatitis B or C virus coinfection), of whom 221 had a valid transient elastography (TE) result. The median TE score was 4.9 kPa [interquartile range (IQR) 4.3–6.0 kPa]. Seventeen patients (7.8%) [95% confidence interval (CI) 5.1–12.1%] had a TE score of > 7.2 kPa, indicating significant liver fibrosis. Baseline factors associated with higher TE scores in multivariate analysis were higher alanine aminotransferase (ALT) per 10 U/L (P = 0.045), higher log10 HIV RNA (P

Background Lactic acidosis (LA) and severe hyperlactataemia (HL) are infrequent but serious complications of antiretroviral therapy that have been associated with a high fatality rate. Methods In a multinational retrospective cohort study, LA was defined as arterial blood pH5 mmol/l. Logistic regression was used to identify factors associated with fatality. Sensitivity and specificity of different case definitions as predictors of death were compared. Results The overall case-fatality rate was 19/110 (17.3%), but among acidotic patients it was 33% (16/49 cases). There were 10 asymptomatic patients and none of them died as a consequence of the event. The median lactate for fatal, non-fatal and all patients was 8.3 mmol/l (IQR 7.2–13.1), 6.4 mmol/l (IQR 5.4–7.8) and 6.7 mmol/l (IQR 5.5–8.1), respectively. After adjusting for age and current CD4+ T-cell count, lactate >7 mmol/l (OR 6.27, 95% CI 1.13–34.93), blood bicarbonate 18 mmol/l, 95% CI 1.33–75.65) and concurrent opportunistic infections (OR 8.69, 95% CI 1.45–52.22) were independently associated with case fatality. Blood lactate >7 mmol/l showed a sensitivity of 84% for fatality with a specificity of 60%, whereas bicarbonate Conclusions Our data suggest that blood lactate >7 mmol/l and blood bicarbonate

Background Randomized trials have shown increased risk of suicidality associated with efavirenz (EFV). The START (Strategic Timing of Antiretroviral Treatment) trial randomized treatment-naive human immunodeficiency virus (HIV)-positive adults with high CD4 cell counts to immediate vs deferred antiretroviral therapy (ART). Methods The initial ART regimen was selected prior to randomization (prespecified). We compared the incidence of suicidal and self-injurious behaviours (suicidal behavior) between the immediate vs deferred ART groups using proportional hazards models, separately for those with EFV and other prespecified regimens, by intention to treat, and after censoring participants in the deferred arm at ART initiation. Results Of 4684 participants, 271 (5.8%) had a prior psychiatric diagnosis. EFV was prespecified for 3515 participants (75%), less often in those with psychiatric diagnoses (40%) than without (77%). While the overall intention-to-treat comparison showed no difference in suicidal behavior between arms (hazard ratio [HR], 1.07, P = .81), subgroup analyses suggest that initiation of EFV, but not other ART, is associated with increased risk of suicidal behavior. When censoring follow-up at ART initiation in the deferred group, the immediate vs deferred HR among those who were prespecified EFV was 3.31 (P = .03) and 1.04 (P = .93) among those with other prespecified ART; (P = .07 for interaction). In the immediate group, the risk was higher among those with prior psychiatric diagnoses, regardless of prespecified treatment group. Conclusions Participants who used EFV in the immediate ART group had increased risk of suicidal behavior compared with ART-naive controls. Those with prior psychiatric diagnoses were at higher risk.

Background A strategy of protease inhibitor (PI) mono-therapy with re-introduction of triple therapy in those who rebound has been shown to be a safe and effective treatment simplification approach for long-term management. We sought evidence for cerebrospinal fluid (CSF) virological escape in patients on long-term PI monotherapy. Methods We performed lumbar puncture in asymptomatic participants with suppressed plasma HIV RNA after 96 weeks on the PI monotherapy arm (PI-mono) of the PIVOT trial. We also report CSF HIV RNA concentration in trial participants who were investigated for neurological/ neurocognitive symptoms during the trial regardless of study arm allocation. Results All 11 asymptomatic participants on PI-mono who were tested had undetectable CSF HIV RNA at week 96. One of the three symptomatic participants on PI-mono had CSF HIV RNA of 1,895 copies/ml (undetectable in plasma) and neither of two symptomatic participants on triple therapy had CSF HIV RNA detected. Conclusions CSF virological escape appears rare in asymptomatic patients on PI monotherapy and may not warrant routine CSF monitoring, but patients with symptoms merit more concern.

Background: HIV prevention for men who have sex with men (MSM) hastypically focused on behaviour change at the individual-level, rather than aspart of a couple. However, recent research has highlighted the role of primarysexual partners in the transmission of HIV among young MSM in the US,estimating that as many as 84% of new transmissions were from men’s mainpartner. This suggests that work with couples could contribute to preventionefforts.Methods: We conducted qualitative in-depth interviews with 30 young MSM(aged 18-29) in Scotland, recruited via a number of strategies; onlineadvertisements, through voluntary sector organisations working with MSM,and snowballing. Thematic data analysis focused on identifying how menunderstand HIV risk management strategies in the context of relationships,specifically the role of ‘safer sex’ practices, HIV testing, and expectationsaround monogamy and/or sexual exclusivity.Results: At the time of interview, nine men reported being in a relationship,and the majority (n=28) discussed their aspirations for sex in long-termrelationships. Participants’ demonstrated varying levels of HIV literacy (i.e.HIV-related knowledge and an individual’s capacity to apply this), andalthough all discussed condom use as part of ‘safer sex’ and their individualmanagement of HIV risk, a recurring theme was desire to discontinue condomuse in the context of a committed relationship. Over a third of the men (n=22)discussed discontinuing condom use in this context. Of those in relationships,six had discontinued condom use, but not all tested for HIV prior to this, norexplicitly discussed expectations for monogamy and/or sexual exclusivity withtheir partners. Agreeing to testing and discussing expectations of fidelity werecomplicated by issues of trust and intimacy.Conclusion: How MSM understand and manage HIV risk in relationships hasimplications for future HIV prevention. Knowledge of their own (and partner’s)HIV status - particularly where serodiscordant relationships are identified -could enable men to make decisions around prevention, and whereappropriate, open up the possibility of accessing biomedical prevention. Ourresearch suggests young MSM in relationships continue to base safer sexdecisions on perceptions of fidelity and trust in their partners. Young MSMaccessing testing in clinical settings could be targeted for interventions toencourage HIV status disclosure and informed safer sex negotiation.

OBJECTIVES: Post-exposure prophylaxis (PEP) for HIV is often poorly tolerated and not completed. Alternative PEP regimens may improve adherence and completion, aiding HIV prevention. We conducted a randomized controlled trial of a maraviroc-based PEP regimen compared with a standard-of-care regimen using ritonavir-boosted lopinavir. METHODS: Patients meeting criteria for PEP were randomized to tenofovir disoproxil/emtricitabine (200/245 mg) once daily plus ritonavir-boosted lopinavir (Kaletra ® 400/100 mg) or maraviroc 300 mg twice daily. The composite primary endpoint was completion of 28 days of the allocated PEP regimen without grade 3 or 4 clinical or laboratory adverse events (AEs) related to the PEP medication. RESULTS: Two hundred and thirteen individuals were randomized (107 to maraviroc; 106 to Kaletra ® arm). Follow-up rates were high in both groups. There was no difference in the primary endpoint; 70 (71%) in the maraviroc and 64 (65%) in the Kaletra ® arm ( P = 0.36) completed PEP without grade 3 or 4 AEs. Discontinuation of PEP was the same (18%) in both groups. There were no grade 3 or 4 clinical AEs in either arm, but more grade 1 or 2 clinical AEs in the Kaletra ® arm (91% versus 70%; P

OBJECTIVE The Protease Inhibitor Monotherapy Versus Ongoing Triple Therapy (PIVOT) trial found that protease inhibitor monotherapy as a simplification strategy is well tolerated in terms of drug resistance but less effective than combination therapy in suppressing HIV viral load. We sought to identify factors associated with the risk of viral load rebound in this trial. METHODS PIVOT was a randomized controlled trial in HIV-positive adults with suppressed viral load for at least 24 weeks on combination therapy comparing a strategy of physician-selected ritonavir-boosted protease inhibitor monotherapy versus ongoing triple therapy. In participants receiving monotherapy, we analysed time to confirmed viral load rebound and its predictors using flexible parametric survival models. RESULTS Of 290 participants initiating protease inhibitor monotherapy (80% darunavir, 14% lopinavir, and 6% other), 93 developed viral load rebound on monotherapy. The risk of viral load rebound peaked at 9 months after starting monotherapy and then declined to approximately 5 per 100 person-years from 18 months onwards. Independent predictors of viral load rebound were duration of viral load suppression before starting monotherapy (hazard ratio 0.81 per additional year

Objective: To fully define cytotoxic T-lymphocyte (CTL) escape variants of an HLA-B*51-restricted integrase epitope in early HIV-1 infection. Design: Ninety-four longitudinally sampled acute/early HIV-1 subtype B-infected participants were assessed to determine HLA-B*51-restricted LPPVVAKEI (LI9) escape variants. Methods: LI9 was sequenced at baseline and subsequent time points. Interferon-γ (IFNγ) ELISpot assays were performed using serial log dilutions of variant LI9 peptides to determine the cellular response and functional avidity. Results: There is a significant association between HLA-B*51 expression and an evolving LI9 sequence from baseline to year 1 (P

BACKGROUND: To determine whether treatment with ritonavir-boosted protease inhibitor (PI) monotherapy is associated with detrimental effects on neurocognitive function or brain imaging markers compared to standard antiretroviral therapy (ART). METHODS: Neuropsychological assessment and brain magnetic resonance imaging were performed at the last study visit in a subset of participants randomized to PI monotherapy (PI-mono group) or ongoing triple ART (OT group) in the PIVOT trial. We calculated a global z-score (NPZ-7) from the average of the individual test z-scores and the proportion of participants with symptomatic neurocognitive impairment (score >1 standard deviation below normative means in ≥2 cognitive domains and neurocognitive symptoms). In a subgroup, white matter hyperintensities, bicaudate index, global cortical (GCA) and medial temporal lobe atrophy scores and single voxel (basal ganglia) N-acetylaspartate (NAA)/Choline, NAA/Creatine and myo-inositol/Creatine ratios were measured. RESULTS: 146 participants (75 PI-mono) had neurocognitive testing (median time after randomization 3.8 years), of whom 78 were imaged. We found no difference between arms in NPZ-7 score (median -0.4 (interquartile range [IQR] = -0.7; 0.1) vs -0.3 (IQR = -0.7; 0.3) for the PI-mono and OT groups respectively, P = .28), the proportion with symptomatic neurocognitive impairment (13% and 18% in the PI-mono and OT groups respectively; P = .41), or any of the neuroimaging variables (P > .05). Symptomatic neurocognitive impairment was associated with higher GCA score (OR = 6.2 per additional score; 95% confidence interval, 1.7-22.3 P = .005) but no other imaging variables. CONCLUSIONS: Based on a comprehensive neuropsychological assessment and brain imaging, PI monotherapy does not increase the risk of neurocognitive impairment in stable human immunodeficiency virus-positive patients.

Background: Protease inhibitor (PI) monotherapy can maintain virological suppression in the majority of patients once it has been established on triple therapy and may also have the potential for substantial cost savings arising from the use of fewer drugs. However, the cost effectiveness of PI monotherapy has yet to be demonstrated. Objectives: In this study we examine the cost effectiveness of PI monotherapy with prompt return to combination therapy in the event of viral load rebound compared with ongoing triple therapy (OT) in patients with suppressed viral load on combination antiretroviral therapy (ART) in the UK. Methods: The analysis used data from the PIVOT trial in which HIV-positive adults with suppressed viral load for ≥24 weeks on combination ART were randomised to maintain OT or to a strategy of PI monotherapy with prompt return to combination therapy if viral load rebounded. A cost-effectiveness analysis including long-term modelling was conducted. Main outcomes included UK National Health Service (NHS) costs and quality-adjusted life-years (QALYs) with comparative results presented as incremental cost-effectiveness ratios. Results: PI monotherapy was cost saving as a result of large savings in ART drug costs while being no less effective in terms of QALYs in the within-trial analysis and marginally less effective with lifetime modelling. In the base-case analysis over 3 years, the incremental total cost per patient was −£6424.11 (95 % confidence interval −7418.84 to −5429.38) and incremental QALYs were 0.0051 (95 % CI −0.0479 to 0.0582), resulting in PI monotherapy ‘dominating’ OT. Multiple scenario analyses found that PI monotherapy was cost saving with no marked differences in QALYs. Modelling of lifetime costs and QALYs showed that PI monotherapy was associated with significant cost savings and was marginally less effective; PI monotherapy was cost effective at accepted cost-effectiveness thresholds in all but one scenario analysis. Conclusions: Under most assumptions, PI monotherapy appears to be a cost-effective treatment strategy compared with OT for HIV-infected patients who have achieved sustained virological suppression.

BACKGROUND AND OBJECTIVES: Tuberculosis (TB) is a leading cause of death in HIV-infected patients worldwide. We aimed to study clinical characteristics and outcome of 1075 consecutive patients diagnosed with HIV/TB from 2004 to 2006 in Europe and Argentina. METHODS: One-year mortality was assessed in patients stratified according to region of residence, and factors associated with death were evaluated in multivariable Cox models. RESULTS: At TB diagnosis, patients in Eastern Europe had less advanced immunodeficiency, whereas a greater proportion had a history of intravenous drug use, coinfection with hepatitis C, disseminated TB, and infection with drug-resistant TB (P < 0.0001). In Eastern Europe, fewer patients initiated TB treatment containing at least rifamycin, isoniazid, and pyrazinamide or combination antiretroviral therapy (P < 0.0001). Mortality at 1 year was 27% in Eastern Europe, compared with 7, 9 and 11% in Central/Northern Europe, Southern Europe, and Argentina, respectively (P < 0.0001). In a multivariable model, the adjusted relative hazard of death was significantly lower in each of the other regions compared with Eastern Europe: 0.34 (95% confidence interval 0.17-0.65), 0.28 (0.14-0.57), 0.34 (0.15-0.77) in Argentina, Southern Europe and Central/Northern Europe, respectively. Factors significantly associated with increased mortality were CD4 cell count less than 200 cells/μl [2.31 (1.56-3.45)], prior AIDS [1.74 (1.22-2.47)], disseminated TB [2.00 (1.38-2.85)], initiation of TB treatment not including rifamycin, isoniazid and pyrazinamide [1.68 (1.20-2.36)], and rifamycin resistance [2.10 (1.29-3.41)]. Adjusting for these known confounders did not explain the increased mortality seen in Eastern Europe. CONCLUSION: The poor outcome of patients with HIV/TB in Eastern Europe deserves further study and urgent public health attention. © 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Background Peripheral neuropathy (PN) in HIV-infected individuals is thought be due to a toxic effect on mitochondria induced by some nucleoside reverse transcriptase inhibitors (NRTI). Methods A time-to-event analysis was performed using data from the Delta trial to study the incidence of PN in HIV-infected individuals receiving zidovudine (AZT) alone or in combination with didanosine (ddI) or zalcitabine (ddC). In an on-treatment analysis, changes in the incidence of PN by duration of treatment were directly estimated using a flexible parametric survival model. Results A total of 3,195 patients (total follow-up 4,593 person-years) were included in the analysis. AZT+ddC was associated with a higher incidence of PN (6.2 cases/100 person-years) compared with AZT monotherapy (3.0 cases/100 person-years) and AZT+ddI (2.2 cases/100 person-years). The risk of PN peaked around day 90 following randomization (at 8.9 events/100 person-years in the AZT+ddC arm). PN was also associated with age at entry (hazard ratio (HR)=2.35 for those aged 35–44 years compared with + T-cell count (HR=2.27 for CD4+ T-cell counts 3 compared with >350). Conclusion Our findings challenge the common supposition that PN arises from cumulative exposure to NRTIs. We found that patients who developed PN tended to do so shortly after exposure to antiretroviral therapy. Therefore, our results support the hypothesis of a susceptibility in a subgroup of patients. These results will be of direct interest to those working in resource-limited countries where potentially neurotoxic dideoxynucleosides are still widely used.

Severe hyperlactataemia and lactic acidosis are rare serious complications of antiretroviral therapy (ART).Lactic acidosis was defined as pH7.35, bicarbonate20 mmol/l and raised lactate; hyperlactataemia as two consecutive lactates5 mmol/l. The case-control study of 110 cases and 220 controls(two randomly selected from treated patients by centre and calendar year) from centres in 10 countries included 40 (36.4%) female cases and 40 female controls (18.2%) (P0.001). Median age was 42.4 years [interquartile range (IQR, 36.0-52.5] for cases and 40 (IQR, 35.0-47.1) for controls (P = 0.013). More cases were nonwhite (41.9%) than controls (31.2%) (P = 0.032). Cases had a shorter duration of exposure to dideoxynucleosides.After adjusting for age, gender and current CD4 cell count, hyperlactataemia/lactic acidosis remained associated with exposure to didanosine in every category of exposure duration but was most strongly associated with exposure12 months. In a separate multivariable model, apart from exposure to stavudine, didanosine, or even more strongly both, age above 40 years [odds ratio (OR), 2.6; 95% confidence interval (CI), 1.08-6.29], female gender (OR, 5.97; 95% CI, 1.92-18.5) and advanced immunosuppression were independent associations (CD4 cell count 200-349, 100-199 and100 cells/mul: OR, 3.89, 7.58 and 8.11, respectively).Hyperlactataemia/lactic acidosis was associated with exposure to dideoxynucleosides, female gender, advanced immunosuppression and possibly ethnicity. This has important consequences for choice of ART in resource-limited settings. The association with shorter duration of exposure may support the hypothesis of susceptibility in a small proportion of patients.

BACKGROUND: Data from randomized trials are lacking on the benefits and risks of initiating antiretroviral therapy in patients with asymptomatic human immunodeficiency virus (HIV) infection who have a CD4+ count of more than 350 cells per cubic millimeter.METHODS: We randomly assigned HIV-positive adults who had a CD4+ count of more than 500 cells per cubic millimeter to start antiretroviral therapy immediately (immediate-initiation group) or to defer it until the CD4+ count decreased to 350 cells per cubic millimeter or until the development of the acquired immunodeficiency syndrome (AIDS) or another condition that dictated the use of antiretroviral therapy (deferred-initiation group). The primary composite end point was any serious AIDS-related event, serious non-AIDS-related event, or death from any cause.RESULTS: A total of 4685 patients were followed for a mean of 3.0 years. At study entry, the median HIV viral load was 12,759 copies per milliliter, and the median CD4+ count was 651 cells per cubic millimeter. On May 15, 2015, on the basis of an interim analysis, the data and safety monitoring board determined that the study question had been answered and recommended that patients in the deferred-initiation group be offered antiretroviral therapy. The primary end point occurred in 42 patients in the immediate-initiation group (1.8%; 0.60 events per 100 person-years), as compared with 96 patients in the deferred-initiation group (4.1%; 1.38 events per 100 person-years), for a hazard ratio of 0.43 (95% confidence interval [CI], 0.30 to 0.62; PCONCLUSIONS: The initiation of antiretroviral therapy in HIV-positive adults with a CD4+ count of more than 500 cells per cubic millimeter provided net benefits over starting such therapy in patients after the CD4+ count had declined to 350 cells per cubic millimeter. (Funded by the National Institute of Allergy and Infectious Diseases and others; START ClinicalTrials.gov number, NCT00867048.).

Sensory peripheral neuropathy (PN) remains a common complication in HIV-positive patients despite effective combination anti-retroviral therapy (ART). Data on PN on second-line ART is scarce. We assessed PN using a standard tool in patients failing first-line ART and for 96 weeks following a switch to PI-based second-line ART in a large Randomised Clinical Trial in Sub-Saharan Africa. Factors associated with PN were investigated using logistic regression. Symptomatic PN (SPN) prevalence was 22% at entry (N = 1,251) and was associated (p

Liver disease is increasingly recognized in HIV-positive individuals, even among those without viral hepatitis, partly as a result of the recent availability of noninvasive methods of liver fibrosis assessment. The objective of this substudy is to compare the effects of early versus deferred antiretroviral therapy (ART) on liver fibrosis progression.Sites in the Strategic Timing of AntiRetroviral Treatment (START) study with access to FibroScan® were invited to participate in the Liver Fibrosis Progression Substudy. All substudy participants underwent FibroScan® at baseline, and two noninvasive serum algorithms, APRI and FIB-4, were calculated. Demographic and liver-related information was collected for all START participants at baseline.A total of 230 participants were enrolled in the substudy (11.5% with hepatitis B or C virus coinfection), of whom 221 had a valid transient elastography (TE) result. The median TE score was 4.9 kPa [interquartile range (IQR) 4.3-6.0 kPa]. Seventeen patients (7.8%) [95% confidence interval (CI) 5.1-12.1%] had a TE score of 7.2 kPa, indicating significant liver fibrosis. Baseline factors associated with higher TE scores in multivariate analysis were higher alanine aminotransferase (ALT) per 10 U/L (P = 0.045), higher log10 HIV RNA (P 0.001) and Hispanic/Latino ethnicity (P = 0.01). TE correlated weakly with noninvasive markers.At baseline, significant liver fibrosis was observed in approximately 8% of participants, with higher ALT and HIV RNA the only clinical factors associated with increasing TE score. TE will be used annually to monitor fibrosis and evaluate the role of ART in further fibrosis progression.

A cross-sectional study was undertaken to determine the prevalence of cryptosporidiosis and its clinical and laboratory pattern in Venezuelan HIV-infected patients (N = 397). At enrollment, they underwent thorough clinical history and physical examination and provided stool specimens for the identification of Cryptosporidium sp. and other parasites. Cryptosporidium sp. was identified in 59 subjects (15%). This infection was strongly associated with acute and chronic diarrhea, weight loss, CD4(+) counts below 100 cells/mm(3), older age in patients with leukopenia, and more than 5 stools per day when CD4(+) counts were below 100 cells/mm(3). In addition, patients with Cryptosporidium infection were less likely to be coinfected with Isospora belli (OR = 0.05, P = 0.001). In fact, results of the current study confirm the worldwide importance of cryptosporidiosis as a clinically significant opportunistic infection associated with an advanced stage of immunosuppression.

A cross-sectional study was undertaken to determine the prevalence of isosporiasis and its clinical and laboratory pattern in Venezuelan patients infected with human immunodeficiency virus (HIV) (n = 397). At enrollment, they underwent a thorough clinical history and physical examination, and provided stool specimens for the identification of Isospora belli and other parasites. Isospora belli was identified in 56 subjects (14%) and diarrhea, either acute or chronic, was present in 98% of these cases (P < 0.001). Eosinophilia was strongly associated with isosporiasis (P = 0.01). It was also found that the presence of eosinophilia was more common in I. belli-infected patients without weight loss (P < 0.001). Twenty-six (81.25%) subjects with I. belli infection had CD4+ cell counts < 200 cells/mm3 (P = 0.03). In addition, the data and its description shows the association to be < 100 cells/mm3. This infection seems to be seasonal because the recovery of oocysts occurred mainly in months with significant rainfall. In fact, isosporiasis should be suspected in HIV-infected patients from tropical countries with diarrhea, weight loss, eosinophilia, and low CD4+ cell counts.

Objective: To describe the clinical, epidemiological, and biochemical characteristics of published cases of lactic acidosis (LA) and to generate hypotheses concerning risk factors associated with this complication. Methods: Systematic review of cases reported in the medical literature. Results: 217 published cases were identified, 90 of which fulfilled the study definition and had sufficient individual data on potential risk factors to be included. The 90 patients had a mean age of 40.1 years (range 16–69) and 53% were female. All 90 patients were taking nucleoside reverse transcriptase inhibitors (NRTI) at the time of the episode. Among the 83 patients with details of their antiretroviral therapy (ART) regimen 51 patients were taking stavudine, 29 zidovudine, 27 didanosine, and 25 lamivudine. Around 50% of the patients had abdominal pain, nausea, or vomiting. Hepatic steatosis was consistently reported (53/90) and in 36 (68%) there was histological evidence. The case fatality rate was 48%. Six cases were rechallenged with NRTI and three developed a further LA episode. Using data on the numbers of HIV infected individuals receiving care in the United States, we estimate that the risk of LA could be 2.5 times higher for women than men. Conclusions: NRTI use and female sex appear to be risk factors for the development of LA. What other factors are involved is still not clear but might include duration of NRTI therapy, specific drug use, and genetic predisposition. A case-control study is needed to better define risk factors for severe LA.

Background Increased levels of markers of systemic inflammation have been associated with serious non-AIDS events even in patients on fully suppressive antiretroviral therapy. We explored residual viremia and systemic inflammation markers in patients effectively treated with ritonavir-boosted protease inhibitor monotherapy (PImono). Methods HIV-infected adults with persistent HIV-RNA 3 mg/l (21% vs 20% in the PImono and cART groups respectively; p = 0.577) or SAA >6.4 mg/l (38% vs 22% in the PImono and cART groups respectively; P = 0.172). In a univariate analysis IL6 and IL8 levels were associated with SAA >6.4 mg/l (OR = 1.74 and 1.46; 95% CI = 1.00 – 3.03 and 1.06 – 2.01; p = 0.051 and 0.02 respectively) and hsCRP >3 mg/l in (OR = 2.00 and 1.37; 95% CI = 1.09 – 3.69 and 1.02 – 1.85; p = 0.026 and 0.039 respectively). Conclusions We found no evidence of increased levels of inflammatory biomarkers or higher prevalence of residual viraemia in patients effectively suppressed on PImono as compared with patients on standard cART.

Background Genetic predisposition to dideoxynucleoside-induced mitochondrial dysfunction might be related to mitochondrial DNA (mtDNA) polymorphisms. Severe hyperlactataemia is probably the best model to assess such a predisposition. Methods For this exploratory study in White European and Black African HIV-infected adults, hypervariable region 1 of mtDNA samples from peripheral blood mono-nuclear cells or buccal smears of patients who have developed confirmed severe hyperlactataemia was sequenced. Additionally, 21 single nucleotide polymorphisms and a 9 bp deletion were genotyped to assign mtDNA haplogroups. Finally, entire mtDNA sequencing was performed in a subset of European samples. Samples were obtained from Black African cases and controls recruited from a single centre in Johannesburg, South Africa and from white European cases from Amsterdam, London and Zurich. Results A total of 40 cases and 38 controls from Johannesburg were included. All of the cases and 33 controls were receiving stavudine-based therapy at the time of the index date ( P=0.024). The distribution of mtDNA haplotypes was not different between cases and controls ( P=0.137), and neither were the predicted haplogroups ( P=0.751). In total, 11 of the 12 European cases were on stavudine and/or didanosine at the time of the event. No hypervariable region 1 haplotype was consistently found in the European cases. Sequencing of the entire mtDNA from three of these cases supported the absence of any shared mutations other than major alleles frequently seen in the mtDNA database. Conclusions We did not find an association between homoplasmic inherited mtDNA polymorphisms and severe hyperlactataemia. Our data do not support the existence of non-synonymous mtDNA mutations that explain an increased predisposition to dideoxynucleoside-induced mitochondrial dysfunction.

Objective— The purpose of this study was to investigate the mechanism by which the nonnucleoside reverse transcriptase inhibitor (NNRTI) nevirapine (NVP) increases high-density lipoprotein cholesterol (HDLc) in treatment-experienced human immunodeficiency virus-1 (HIV-1)–infected patients. Methods and Results— Twelve HIV-1 infected patients, with stably suppressed HIV-1 viral load using AZT/3TC/abacavir for ≥6 months, added NVP to their current antiretroviral regimen. Patients received a primed bolus infusion of the stable isotope L-[1- 13 C]-valine for 12 hours before, as well as 6 and 24 weeks after, the addition of NVP to study apolipoprotein A-I (apoA-I) kinetics. Absolute production rate (APR) and fractional catabolic rate (FCR) of apoA-I were calculated using SAAM-II modeling. Major HDLc-modulating enzymes were assessed. Plasma apoA-I and HDLc levels increased significantly after 24 weeks of treatment by, respectively, 13±4% ( P =0.01) and 16±6% ( P =0.015). Concomitantly, apoA-I production rate at 24 weeks increased by 17±7% ( P =0.04). ApoA-I catabolism did not change. A modest increase of lecithin:cholesterol acyltransferase and cholesteryl ester transfer protein activity was observed. Conclusions— NVP increases apoA-I production, which contributes to the HDLc increase after introduction of NVP-containing regimens. In view of the potent antiatherogenic effects of apoA-I, the observed increase may contribute to the favorable cardiovascular profile of NVP.

Background: the prevalence of risky alcohol consumption, associated factors and its impact on the brain is not well established in clinically stable HIV-patients. Materials and methods: Within the PIVOT neurocognitive sub-study, effectively suppressed HIV-infected adults on either standard cART or ritonavir-boosted PI monotherapy completed the Alcohol Use Disorders Identification Test (AUDIT) designed to detect risky alcohol consumption. They also completed a brief neuropsychological assessment (NPZ 5) composed by five measures. For this cross-sectional analysis, we calculated rates of hazardous (AUDIT=8-15) or harmful (AUDIT=16-19) consumption and likely dependence (AUDIT>20). We explored the association between risky alcohol intakes (AUDIT>8) and clinical/demographical variables, conducting logistic regressions when significant association was found (p

Platelet dysfunction was detected in six children with purpura and eosinophilia. We conducted clinical evaluations, hematologic and platelet function tests, clotting studies (bleeding time, prothrombin time, partial thromboplastin time, thrombin time, factor XIII, factor VIII, and von Willebrand factor), assays for IgG and IgM antibodies to platelets, and a search for stool parasites. Mild bleeding phenomena (ecchymoses, petechiae, epistaxis, and gingival) were transient. All children showed intestinal parasites and marked eosinophilia (mean count = 2,615.2 cells/muL, 95% confidence interval = 1,259.6-5,429.8). Main abnormalities included prolonged bleeding times (50%) and defective aggregation with collagen (100%) adrenaline (66%), or ADP (66%). Antibodies to platelets were not detected. Anti-parasite therapy reversed the hemorrhagic manifestations and normalized eosinophil counts and platelet alterations. No relationship could be established between excess eosinophils, intensity of bleeding, or type and degree of platelet abnormalities. Thrombocytopathic features mimicked the intrinsic defect of storage pool disease. The possible pathogenic roles of eosinophilia and parasitism are reviewed. This is the first report of this pathologic combination in Latin American children.

A cross sectional survey was conducted to determine the association between enteric parasites and diarrhoea in HIV-infected adults in Caracas. Three hundred and four patients were evaluated: 104 had acute diarrhoea, 113 chronic diarrhoea and 87 were controls. Isopora belli infection was associated with acute ( P = 0.022) and chronic diarrhoea ( P = 0.003), Entamoeba histolytica/dispar infection was also associated with both acute ( P = 0.015) and chronic diarrhoea ( P = 0.017). Strongyloides stercoralis ( P = 0.003), and Cryptosporidium parvum ( P = 0.017) infections were associated mainly with chronic episodes. Weight loss ( P < 0.001), a non-infectious factor investigated, was significantly associated with diarrhoea. Eosinophilia, a laboratory parameter studied, was found to be associated with strongyloidiasis ( P = 0.001), giardiasis ( P = 0.001) and isoporiasis ( P = 0.003). In summary, the presence of enteric parasites in HIV-infected patients from tropical urban areas with diarrhoea, with or without significant weight loss, must be considered. Similarly, eosinophilia might suggest parasitic infection in these patients.

OBJECTIVE\ud \ud To describe factors associated with neurocognitive (NC) function in HIV-positive patients on stable combination antiretroviral therapy.\ud \ud DESIGN\ud \ud We undertook a cross-sectional analysis assessing NC data obtained at baseline in patients entering the Protease-Inhibitor-Monotherapy-Versus-Ongoing-Triple therapy (PIVOT) trial.\ud \ud MAIN OUTCOME MEASURE\ud \ud NC testing comprised of 5 domains. Raw results were z-transformed using standard and demographically adjusted normative datasets (ND). Global z-scores (NPZ-5) were derived from averaging the 5 domains and percentage of subjects with test scores >1 standard deviation (SD) below population means in at least two domains (abnormal Frascati score) calculated. Patient characteristics associated with NC results were assessed using multivariable linear regression.\ud \ud RESULTS\ud \ud Of the 587 patients in PIVOT, 557 had full NC results and were included. 77% were male, 68% Caucasian and 28% of Black ethnicity. Mean (SD) baseline and nadir CD4+ lymphocyte counts were 553(217) and 177(117) cells/µL, respectively, and HIV RNA was

Didanosine (ddl) has been used to treat HIV infection, in combination with other anti-retroviral drugs, for over 15 years. However, the use of the original formulation of ddI was limited by serious gastro-intestinal adverse effects, which were mainly attributable to the buffer used to protect ddI from the effect of gastric pH. Didanosine enteric-coated capsule (ddI-EC), a more recently introduced formulation, is less likely to cause gastrointestinal intolerance and its absorption might not be compromised by food intake. In this review we discuss efficacy of ddI-EC-containing anti-retroviral combinations (cART) both in naïve and previously treated patients. Because of its favorable resistance profile, ddI-EC has been shown to be potentially efficacious in rescuing patients in virological failure, even if they have nucleoside reverse transcriptase inhibitors (NRTI)-associated resistance mutations. However, ddI has been shown as a potent inducer of mitochondrial dysfunction. Peripheral neuropathy, severe hyperlactatemia and pancreatitis have all been described in patients exposed to ddI. Close monitoring of patients on ddI-EC-containing cART and low threshold for treatment modifications are required to prevent major complications. In the context of once daily cART, ddI-EC is a valid option, particularly when other agents are not available, or when other medical conditions preclude the use of drugs such as tenofovir or abacavir. The role of ddI-EC in second line cART may be even more important in resource-limited settings where additional options are lacking.