Showing papers in "Hiv Medicine in 2014"

The CD4:CD8 ratio is associated with markers of age‐associated disease in virally suppressed HIV‐infected patients with immunological recovery

Abstract: Objectives Inversion of the CD4:CD8 ratio (< 1) has been identified as a hallmark of inmmunosenescence and an independent predictor of mortality in the general population. We aimed to assess the association between the CD4:CD8 ratio and markers of age-associated disease in treated HIV-infected patients with good immunovirological response. Methods A cross-sectional analysis was conducted in 132 HIV-infected adults on antiretroviral therapy (ART), with plasma HIV RNA 350 cells/μL and age < 65 years. We analysed the associations between the CD4:CD8 ratio and subclinical atherosclerosis [assessed using carotid intima-media thickness (IMT)], arterial stiffness [assessed using the augmentation index (AIx)], the estimated glomerular filtration rate (eGFR), muscle wasting and sarcopenia [assessed using appendicular lean mass/height2 (ALM) measured by dual-energy X-ray absorptiometry (DEXA)]. Results CD4:CD8 ratio inversion was associated with higher IMT, lower eGFR and lower ALM (all values P 200 cells/μL and those with CD4 counts > 500 cells/μL. Conclusions The CD4:CD8 ratio in treated HIV-infected subjects with good immunovirological response is independently associated with markers of age-associated disease. Hence, it might be a clinically useful predictor of non-AIDS-defining conditions.

British HIV Association guidelines for the management of HIV infection in pregnant women 2012 (2014 interim review).

Abstract: (Updated May 2014. All changed text is cast in yellow highlight.) NHS Evidence has accredited the process used by the British HIV Association (BHIVA) to produce guidelines. Accreditation is valid for five years from July 2012 and is applicable to guidance produced using the processes described in the British HIV Association (BHIVA) Guideline Development Manual. More information on accreditation can be viewed at

Mortality in perinatally HIV‐infected young people in England following transition to adult care: an HIV Young Persons Network (HYPNet) audit

Abstract: Objectives: Mortality in young people with perinatally acquired HIV infection (PHIV) following transfer to adult care has not been characterized in the UK. We conducted a multicentre audit to establish the number of deaths and associated factors. Methods: Fourteen adult clinics caring for infected young people reported deaths to 30 September 2011 on a proforma. Deaths were matched to the Collaborative HIV Paediatric Study, a clinical database of HIV-infected children in the UK/Ireland, to describe clinical characteristics in paediatric care of those who died post-transition. Results: Eleven deaths were reported from 14 clinics which cared for 248 adults with PHIV. For the 11 deaths, the median age at transfer to adult care was 17 years (range 15–21 years), and at death was 21 years (range 17–24 years). Causes of death were suicide (two patients), advanced HIV disease (seven patients) and bronchiectasis (one patient), with one cause missing. At death, the median CD4 count was 27 cells/μL (range 0–630 cells/μL); five patients were on antiretroviral therapy (ART) but only two had a viral load < 50 HIV-1 RNA copies/mL. Nine had poor adherence when in paediatric care, continuing into adult care despite multidisciplinary support. Eight had ART resistance, although all had potentially suppressive regimens available. Nine had mental health diagnoses. Conclusions: Our findings highlight the complex medical and psychosocial issues faced by some adults with PHIV, with nine of the 11 deaths in our study being associated with poor adherence and advanced HIV disease. Novel adherence interventions and mental health support are required for this vulnerable cohort.

Prevalence of and risk factors for pulmonary abnormalities in HIV-infected patients treated with antiretroviral therapy.

Abstract: Background Pulmonary abnormalities are often present in patients infected with the human immunodeficiency virus (HIV). Objectives The aim of the study was to determine the prevalence and characteristics of, and risk factors for, pulmonary abnormalities in HIV-positive patients. Methods A total of 275 HIV-positive patients [mean (± standard deviation) age 48.5 ± 6.6 years] were included in the study, of whom 95.6% had been receiving highly active antiretroviral therapy (HAART) for a mean (± standard deviation) duration of 11.9 ± 5.4 years. The median (interquartile range) CD4 lymphocyte count was 541 (392–813) cells/μL, and 92% of the patients had an undetectable viral load. We determined: (1) spirometry, static lung volumes, lung diffusing capacity, pulmonary gas exchange and exercise tolerance, and (2) the amount of emphysema via a computed tomography (CT) scan. Results Chronic cough and expectoration (47%) and breathlessness during exercise (33.9%) were commonly reported. Airflow limitation (AL) was present in 17.2%, low pulmonary diffusing capacity in 52.2% and emphysema in 10.5−37.7% of patients, depending on the method used for quantification. Most of these abnormalities had not been diagnosed or treated previously. Smoking exposure and previous tuberculosis were the main risk factors for AL, whereas smoking exposure and several variables related to HIV infection appeared to contribute to the risk of emphysema and low diffusing capacity. Conclusions Despite HAART, pulmonary structural and functional abnormalities are frequent in HIV-positive patients. They are probably attributable to both environmental (smoking and tuberculosis) and HIV-related factors. Most of these abnormalities remain unnoticed and untreated. Given the relatively young age of these patients, these results anticipate a significant health problem in the next few years as, thanks to the efficacy of HAART, patients survive longer and experience the effects of aging.

Linkage to care following community-based mobile HIV testing compared with clinic-based testing in Umlazi Township Durban South Africa.

Abstract: Objectives The aim of the study was to assess HIV prevalence, disease stage and linkage to HIV care following diagnosis at a mobile HIV testing unit, compared with results for clinic-based testing, in a Durban township. Methods This was a prospective cohort study. We enrolled adults presenting for HIV testing at a community-based mobile testing unit (mobile testers) and at an HIV clinic (clinic testers) serving the same area. Testers diagnosed with HIV infection, regardless of testing site, were offered immediate CD4 testing and instructed to retrieve results at the clinic. We assessed rates of linkage to care, defined as CD4 result retrieval within 90 days of HIV diagnosis and/or completion of antiretroviral therapy (ART) literacy training, for mobile vs. clinic testers. Results From July to November 2011, 6957 subjects were HIV tested (4703 mobile and 2254 clinic); 55% were female. Mobile testers had a lower HIV prevalence than clinic testers (10% vs. 36%, respectively), were younger (median 23 vs. 27 years, respectively) and were more likely to live >5 km or >30 min from the clinic (64% vs. 40%, respectively; all P < 0.001). Mobile testers were less likely to undergo CD4 testing (33% vs. 83%, respectively) but more likely to have higher CD4 counts [median (interquartile range) 416 (287–587) cells/μL vs. 285 (136–482) cells/μL, respectively] than clinic testers (both P < 0.001). Of those who tested HIV positive, 10% of mobile testers linked to care, vs. 72% of clinic testers (P < 0.001). Conclusions Mobile HIV testing reaches people who are younger, who are more geographically remote, and who have earlier disease compared with clinic-based testing. Fewer mobile testers underwent CD4 testing and linked to HIV care. Enhancing linkage efforts may improve the impact of mobile testing for those with early HIV disease.

Comparison of transient elastography (FibroScan), FibroTest, APRI and two algorithms combining these non‐invasive tests for liver fibrosis staging in HIV/HCV coinfected patients: ANRS CO13 HEPAVIH and FIBROSTIC collaboration

Abstract: Objectives Combining noninvasive tests increases diagnostic accuracy for staging liver fibrosis in hepatitis C virus (HCV)-infected patients, but this strategy remains to be validated in HIV/HCV coinfection. We compared the performances of transient elastography (TE), Fibrotest (FT), the aspartate aminotransferase-to-platelet ratio index (APRI) and two algorithms combining TE and FT (Castera) or APRI and FT (SAFE) in HIV/HCV coinfection. Methods One hundred and sixteen HIV/HCV-coinfected patients (64% male; median age 44 years) enrolled in two French multicentre studies (the HEPAVIH cohort and FIBROSTIC) for whom TE, FT and APRI data were available were included in the study. Diagnostic accuracies for significant fibrosis (METAVIR F ≥ 2) and cirrhosis (F4) were evaluated by measuring the area under the receiver-operating characteristic curve (AUROC) and calculating percentages of correctly classified (CC) patients, taking liver biopsy as a reference. Results For F ≥ 2, both TE and FT (AUROC = 0.87 and 0.85, respectively) had a better diagnostic performance than APRI (AUROC = 0.71; P < 0.005). Although the percentage of CC patients was significantly higher with Castera's algorithm than with SAFE (61.2% vs. 31.9%, respectively; P < 0.0001), this percentage was lower than that for TE (80.2%; P < 0.0001) or FT (73.3%; P < 0.0001) taken separately. For F4, TE (AUROC = 0.92) had a better performance than FT (AUROC = 0.78; P = 0.005) or APRI (AUROC = 0.73; P = 0.025). Although the percentage of CC patients was significantly higher with the SAFE algorithm than with Castera's (76.7% vs. 68.1%, respectively; P < 0.050), it was still lower than that for TE (85.3%; P < 0.033). Conclusions In HIV/HCV-coinfected patients, TE and FT have a similar diagnostic accuracy for significant fibrosis, whereas for cirrhosis TE has the best accuracy. The use of the SAFE and Castera algorithms does not seem to improve diagnostic performance.

Switch from tenofovir to raltegravir increases low bone mineral density and decreases markers of bone turnover over 48 weeks

Abstract: Background Tenofovir, particularly when given with a ritonavir-boosted protease inhibitor (rPI), reduces bone mineral density (BMD) and increases bone turnover markers (BTMs), both of which are associated with increased fracture risk. Raltegravir has not been associated with bone loss. Methods In an open-label, nonrandomized, pilot study, tenofovir was switched to raltegravir in adults also receiving a rPI for at least 6 months with a spine or hip T-score ≤ −1.0 and plasma HIV RNA < 50 HIV-1 RNA copies/mL for at least 3 months. The primary endpoint was BMD change by dual-energy X-ray absorptiometry. Student's paired t-test was used to compare continuous variables. Factors associated with BMD increase were assessed using linear regression. Results Thirty-seven patients were enrolled in the study: 97% were male, the mean age was 49 years, the mean T-scores were −1.4 (spine) and −1.3 (total left hip), and the mean tenofovir treatment duration was 3.1 years. BMD increases were significant at weeks 24 and 48. At week 48, spine BMD increased by 3.0% [95% confidence interval (CI) 1.9, 4.0%; P < 0.0001] and left total hip BMD increased by 2.5% (95% CI 1.6, 3.3%; P < 0.0001). BTMs (N-telopeptide, osteocalcin and bone alkaline phosphatase) all decreased significantly at week 24 (P ≤ 0.0017). There were no raltegravir-related serious or grade 3−4 adverse events. HIV viral load remained <50 copies/mL plasma on raltegravir/rPI therapy. Conclusions Switching virologically suppressed HIV-infected adults with low BMD taking an rPI from tenofovir to raltegravir was safe and significantly improved hip and spine BMD and reduced markers of bone turnover over 48 weeks.

Helping our patients take HIV pre‐exposure prophylaxis (PrEP): a systematic review of adherence interventions

Abstract: Objectives Adherence is critical for maximizing the effectiveness of pre-exposure prophylaxis (PrEP) in preventing HIV infection. Strategies for promoting adherence to HIV treatment, and their potential application to PrEP adherence, have received considerable attention. However, adherence promotion strategies for prevention medications have not been well characterized and may be more applicable to PrEP. We aimed to identify adherence support interventions that have been effective in other prevention fields and could be applied in the HIV prevention context to support pill taking among PrEP users. Methods To identify adherence support interventions that could be evaluated and applied in the PrEP context, we conducted a systematic review across the following prevention fields: hypertension, latent tuberculosis infection, hyperlipidaemia, oral contraceptives, osteoporosis, malaria prophylaxis, and post-exposure prophylaxis for HIV infection. We included randomized controlled trials that evaluated the efficacy of interventions to improve adherence to daily oral medications prescribed for primary prevention in healthy individuals or for secondary prevention in asymptomatic individuals. Results Our searches identified 585 studies, of which 48 studies met the eligibility criteria and were included in the review; nine evaluated multiple strategies, yielding 64 separately tested interventions. Interventions with the strongest evidence for improving adherence included complex, resource-intensive interventions, which combined multiple adherence support approaches, and low-cost, low-intensity interventions that provided education or telephone calls for adherence support. Conclusions Our review identified adherence interventions with strong evidence of efficacy across prevention fields and provides recommendations for evaluating these interventions in upcoming PrEP studies.

Raltegravir-emtricitabine-tenofovir as HIV nonoccupational post-exposure prophylaxis in men who have sex with men: safety, tolerability and adherence

Abstract: Objectives Three-drug nonoccupational post-exposure prophylaxis (NPEP) typically includes co-formulated emtricitabine-tenofovir (FTC-TDF) and a protease inhibitor. However, protease inhibitors can cause significant toxicities, can interact with prescribed and illicit drugs, and work late in the viral cycle. Agents that act before viral integration into host DNA may have efficacy advantages. Raltegravir (RAL) is a good candidate for NPEP as it has few side effects or drug interactions and acts prior to HIV integration. The objective of this study was to investigate the use of RAL in 3-drug NPEP in terms of safety, adherence and tolerability. Methods We evaluated 28 days of RAL-FTC-TDF treatment in 86 men and FTC-TDF treatment in 34 men eligible for three- and two-drug NPEP, respectively. We assessed adherence (compared between groups and with nonstudy controls) and clinical and adverse events at weeks 1, 2 and 4, and efficacy at week 12. Analyses were by intention to treat, excluding from the adherence analysis subjects who ceased NPEP because their source was HIV-uninfected. Results No participant became infected with HIV. For RAL-FTC-TDF and FTC-TDF, regimen completion rates were 92% and 91% and medication adherence rates were 89% and 90%, respectively. Eight (9%) RAL recipients developed mild myalgias, with four developing transient grade 4 elevations in creatine kinase (two developed both), all of which improved to grade 2 or less by week 4 without RAL discontinuation. Eight prescribed and 37 potential illicit drug interactions with a protease inhibitor were avoided by use of RAL. Conclusions RAL-FTC-TDF is well tolerated as NPEP, results in high levels of adherence and avoids potential drug−drug interactions. Patients and clinicians should be aware of the potential for acute muscle toxicity when RAL is used as NPEP.

Preterm delivery risk in women initiating antiretroviral therapy to prevent HIV mother-to-child transmission.

Abstract: Objectives The aim of the study was to describe the relationship between preterm delivery (PTD; < 37 weeks of gestation) and antiretroviral therapy in a single-centre cohort of pregnant women with HIV infection. Methods A retrospective analysis of data for 331 women who received care in a dedicated HIV antenatal clinic between 1996 and 2010 was carried out. Data on first CD4 cell count and viral load (HIV-1 RNA copies/mL) recorded in pregnancy, class and timing of antiretroviral therapy, gestational age at delivery, and risk factors for and causes of PTD were available from a clinical database. Results Overall, 13.0% of deliveries were preterm, of which 53% were severe preterm (< 34 weeks of gestation). The lowest rate of PTD was observed in women treated with zidovudine monotherapy (6.2%). Higher rates of PTD were observed in women starting combination antiretroviral therapy (cART) in pregnancy compared with women conceiving while on cART [odds ratio (OR) 2.52; 95% confidence interval (CI) 1.22–5.20; P = 0.011]. Of the women who were eligible for zidovudine monotherapy on the basis of CD4 counts and HIV viral load but who were treated with short-term cART to prevent HIV mother-to-child transmission, 28.6% delivered preterm. Women on short-term cART remained at the highest risk of PTD compared with zidovudine monotherapy in multivariate analysis (OR 5.00; 95% CI 1.49–16.79; P = 0.015). Conclusions The causes of PTD are multiple and poorly understood. The timing of initiation and type of antiretroviral therapy administered during pregnancy appear to contribute to PTD risk. Understanding this association should improve the safety of antiretroviral therapy in pregnancy without increasing the risk of transmission.

Increased risk of cardiovascular disease (CVD) with age in HIV-positive men: a comparison of the D:A:D CVD risk equation and general population CVD risk equations.

Abstract: Objectives: The aim of the study was to statistically model the relative increased risk of cardiovascular disease (CVD) per year older in Data collection on Adverse events of anti-HIV Drugs (D:A:D) and to compare this with the relative increased risk of CVD per year older in general population risk equations. Methods: We analysed three endpoints: myocardial infarction (MI), coronary heart disease (CHD: MI or invasive coronary procedure) and CVD (CHD or stroke). We fitted a number of parametric age effects, adjusting for known risk factors and antiretroviral therapy (ART) use. The best-fitting age effect was determined using the Akaike information criterion. We compared the ageing effect from D:A:D with that from the general population risk equations: the Framingham Heart Study, CUORE and ASSIGN risk scores. Results: A total of 24323 men were included in analyses. Crude MI, CHD and CVD event rates per 1000 person-years increased from 2.29, 3.11 and 3.65 in those aged 40-45 years to 6.53, 11.91 and 15.89 in those aged 60-65 years, respectively. The best-fitting models included inverse age for MI and age + age(2) for CHD and CVD. In D:A:D there was a slowly accelerating increased risk of CHD and CVD per year older, which appeared to be only modest yet was consistently raised compared with the risk in the general population. The relative risk of MI with age was not different between D:A:D and the general population. Conclusions: We found only limited evidence of accelerating increased risk of CVD with age in D:A:D compared with the general population. The absolute risk of CVD associated with HIV infection remains uncertain.

Total and unbound darunavir pharmacokinetics in pregnant women infected with HIV-1: results of a study of darunavir/ritonavir 600/100 mg administered twice daily.

Abstract: Objectives Antiretroviral therapy during pregnancy is recommended to reduce the risk of mother-to-child transmission of HIV and for maternal care management. Physiological changes during pregnancy can affect pharmacokinetics, potentially altering pharmacological activity. We therefore evaluated the pharmacokinetics of twice-daily (bid) darunavir in HIV-1-infected pregnant women. Methods HIV-1-infected pregnant women receiving an antiretroviral regimen containing darunavir/ritonavir 600/100 mg bid were enrolled in this study. Total and unbound darunavir and total ritonavir plasma concentrations were obtained over 12 h during the second and third trimesters and postpartum. Total darunavir and ritonavir plasma concentrations were determined using a validated high-performance liquid chromatography tandem mass spectrometry assay and unbound darunavir was determined using 14C-darunavir-fortified plasma. Pharmacokinetic parameters were derived using noncompartmental analysis. Results Data were available for 14 women. The area under the plasma concentration–time curve from 0 to 12 h (AUC12h) for total darunavir was 17–24% lower during pregnancy than postpartum. The AUC12h for unbound darunavir was minimally reduced during pregnancy vs. postpartum. The minimum plasma concentration (Cmin) of total and unbound darunavir was on average 43–86% and 10–14% higher, respectively, during pregnancy vs. postpartum. The antiviral response (< 50 HIV-1 RNA copies/mL) was 33% at baseline and increased to 73–90% during treatment; the percentage CD4 count increased over time. One serious adverse event was reported (increased transaminase). All 12 infants born to women remaining in the study at delivery were HIV-1-negative; four of these infants were premature. Conclusions Total darunavir exposure decreased during pregnancy. No clinically relevant change in unbound (active) darunavir occurred during pregnancy, suggesting that no dose adjustment is required for darunavir/ritonavir 600/100 mg bid in pregnant women.

Patterns of adherence to antiretroviral therapy and HIV drug resistance over time in the Stratall ANRS 12110/ESTHER trial in Cameroon

Abstract: Objectives The emergence of HIV drug resistance is a crucial issue in Africa, where second-line antiretroviral therapy (ART) is limited, expensive and complex. We assessed the association between adherence patterns and resistance emergence over time, using an adherence measure that distinguishes low adherence from treatment interruptions, in rural Cameroon. Methods We performed a cohort study among patients receiving nonnucleoside reverse transcriptase inhibitor (NNRTI)-based ART in nine district hospitals, using data from the Stratall trial (2006−2010). Genotypic mutations associated with antiretroviral drug resistance were assessed when 6-monthly HIV viral loads were > 5000 HIV-1 RNA copies/mL. ART adherence data were collected using face-to-face questionnaires. Combined indicators of early (1−3 months) and late (6 months to t − 1; t is the time point when the resistance had been detected) adherence were constructed. Multivariate logistic regression and Cox models were used to assess the association between adherence patterns and early (at 6 months) and late (after 6 months) resistance emergence, respectively. Results Among 456 participants (71% women; median age 37 years), 45 developed HIV drug resistance (18 early and 27 late). Early low adherence ( 2 days) were associated with early resistance [adjusted odds ratio (95% confidence interval) 8.51 (1.30–55.61) and 5.25 (1.45–18.95), respectively]. Early treatment interruptions were also associated with late resistance [adjusted hazard ratio (95% confidence interval) 3.72 (1.27–10.92)]. Conclusions The emergence of HIV drug resistance on first-line NNRTI-based regimens was associated with different patterns of adherence over time. Ensuring optimal early adherence through specific interventions, adequate management of drug stocks, and viral load monitoring is a clinical and public health priority in Africa.

Urinary biomarkers of kidney injury are associated with all-cause mortality in the Women's Interagency HIV Study (WIHS).

Abstract: Objectives Chronic kidney disease (CKD) is common in HIV-infected individuals, and is associated with mortality in both the HIV-infected and general populations. Urinary markers of tubular injury have been associated with future kidney disease risk, but associations with mortality are unknown. Methods We evaluated the associations of urinary interleukin-18 (IL-18), liver fatty acid binding protein (L-FABP), kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL) and the albumin-to-creatinine ratio (ACR) with 10-year, all-cause death in 908 HIV-infected women. Serum cystatin C was used to estimate the glomerular filtration rate (eGFRcys). Results There were 201 deaths during 9269 person-years of follow-up. After demographic adjustment, compared with the lowest tertile, the highest tertiles of IL-18 [hazard ratio (HR) 2.54; 95% confidence interval (CI) 1.75–3.68], KIM-1 (HR 2.04; 95% CI 1.44–2.89), NGAL (HR 1.50; 95% CI 1.05–2.14) and ACR (HR 1.63; 95% CI 1.13–2.36) were associated with higher mortality. After multivariable adjustment including adjustment for eGFRcys, only the highest tertiles of IL-18 (HR 1.88; 95% CI 1.29–2.74) and ACR (HR 1.46; 95% CI 1.01–2.12) remained independently associated with mortality. Findings for KIM-1 were borderline (HR 1.41; 95% CI 0.99–2.02). We found a J-shaped association between L-FABP and mortality. Compared with persons in the lowest tertile, the HR for the middle tertile of L-FABP was 0.67 (95% CI 0.46–0.98) after adjustment. Associations were stronger when IL-18, ACR and L-FABP were simultaneously included in models. Conclusions Among HIV-infected women, some urinary markers of tubular injury are associated with mortality risk, independently of eGFRcys and ACR. These markers represent potential tools with which to identify early kidney injury in persons with HIV infection.

Multiple hepatitis C virus (HCV) reinfections in HIV-positive men who have sex with men: no influence of HCV genotype switch or interleukin-28B genotype on spontaneous clearance.

Abstract: Objectives The incidence of sexually transmitted hepatitis C virus (HCV) reinfection is on the rise in HIV-infected men who have sex with men (MSM) Data on natural history of acute hepatitis C and possible factors associated with spontaneous clearance are limited The aim of this study was to analyse the outcome of HCV reinfections in HIV-positive MSM Methods A retrospective analysis was carried out on patients with more than one sexually acquired HCV infection who were diagnosed at four major German HIV and hepatitis care centres Reinfection was defined by genotype or phylogenetic clade switch, detectable HCV RNA after a sustained virological response (SVR) or after spontaneous clearance (SC) Results In total, 48 HIV-positive MSM were identified with HCV reinfection, among them 11 with a third episode and one patient with four episodes At the first episode, 43 and five patients had an SVR and SC, respectively The second episode was accompanied by a genotype switch in 29 patients (60%) Whereas 30 and nine patients showed an SVR and SC, respectively, eight patients developed chronic hepatitis Neither HCV genotype switch nor interleukin-28B genotype was associated with SC However, SC rates at the second episode were higher for patients with SC at the first episode compared with patients without SC (60 vs 14%, respectively; P = 003) Two patients with SC at the first episode were reinfected with the same genotype Conclusions Multiple reinfections in HIV-infected MSM do occur, with or without genotype switch, and with prior SC of previous episodes In this large case series, except for SC at the first episode, no factor was of value in clinical decision-making for early therapeutic intervention in acute HCV reinfection

Pregnancy complications in HIV-positive women: 11-year data from the Frankfurt HIV Cohort.

Abstract: Objectives The aim of the study was to assess pregnancy complications in HIV-positive women and changes in the rates of such complications over 11 years in the Frankfurt HIV Cohort. Methods There were 330 pregnancies in HIV-positive women between 1 January 2002 and 31 December 2012. The rate of pregnancy-related complications, such as gestational diabetes mellitus (GDM), pre-eclampsia and preterm delivery, the mode of delivery and obstetric history were analysed. Maternal and neonatal morbidity/mortality as well as HIV mother-to-child transmission (MTCT) were evaluated. Results In our cohort, GDM was diagnosed in 38 of 330 women (11.4%). Five women (1.5%) developed pre-eclamspia or hypertension. In 16 women (4.8%), premature rupture of membranes (PROM) occurred and 46 women (13.7%) were admitted with preterm contractions. The preterm delivery rate was 36.5% (n = 122), and 26.9% of deliveries (n = 90) were between 34+0 and 36+6 weeks of gestation. Over the observation period, the percentage of women with undetectable HIV viral load (VL) increased significantly (P < 0.001), from 26.1% to 75%, leading to obstetric changes, including an increase in the rate of vaginal deliveries (P < 0.001), from no vaginal births to 50%. The preterm delivery rate decreased significantly (P < 0.001), from 79.2% to 8.3%. There were no significant changes in the rate of GDM, pre-eclampsia, PROM or preterm contractions. Conclusions In the 11 years of our analysis, there was a significant reduction in the rate of preterm deliveries and an increase in the vaginal delivery rate, possibly reflecting changes in treatment policies in the same period and the availability of more effective antiretroviral therapy options. The rates of complications such as GDM, pre-eclampsia, preterm contractions, PROM and postnatal complications were stable over the 11 years, but were still increased compared with the general population.

Patients who present late to HIV care and associated risk factors in Nigeria.

Abstract: Objectives Our objectives were to assess trends in late presentation and advanced HIV disease (AHD) and determine associated risk factors. Methods We conducted a retrospective cohort analysis of patients who had received care and treatment at the AIDS Prevention Initiative Nigeria Plus (APIN)/Harvard School of Public Health−President's Emergency Plan for AIDS Relief (PEPFAR) programme at the Jos University Teaching Hospital, Jos, Nigeria from 2005 to 2010. We used the European Consensus Definition to assess trends in late presentation (CD4 count < 350 cells/μL or AIDS-defining illness) and AHD (CD4 count < 200 cells/μL or AIDS-defining illness) and evaluated associated risk factors using logistic regression methods. Results Among 14 487 eligible patients, 12 401 (85.6%) were late presenters and 9127 (63.0%) presented with AHD. Late presentation decreased from 88.9% in 2005 to 80.1% in 2010 (P < 0.001). Similarly, AHD decreased from 67.8% in 2005 to 53.6% in 2010 (P < 0.001). In logistic regression models adjusting for sociodemographic and biological variables, male sex [adjusted odds ratio (aOR) = 1.80; 95% confidence interval (CI) 1.60–2.04], older age (aOR = 1.37; 95% CI 1.22–1.54), civil service employment (aOR = 1.48; 95% CI 1.00–2.21), referral from out-patient (aOR = 2.18; 95% CI 1.53–3.08) and in-patient (aOR = 1.55; 95% CI 1.11–2.17) services, and hepatitis B virus (aOR = 1.43; 95% CI 1.26–1.63) and hepatitis C virus (aOR = 1.18; 95% CI 1.02–1.37) coinfections were associated with late presentation. Predictors of AHD were male sex (aOR = 1.67; 95% CI 1.54–1.82), older age (aOR = 1.26; 95% CI 1.16–1.36), unemployment (aOR = 1.34; 95% CI 1.00–1.79), referral from out-patient (aOR = 2.40; 95% CI 1.84–3.14) and in-patient (aOR = 1.97; 95% CI 1.51–2.57) services and hepatitis B virus coinfection (aOR = 1.30; 95% CI 1.19–1.42). Conclusions Efforts to reduce the proportion of patients who first seek care at late stages of disease are needed. The identified risk factors should be utilized in formulating targeted public health interventions to improve early diagnosis and presentation for HIV care.

HIV-associated neurocognitive disorder in HIV-infected Koreans: The Korean NeuroAIDS Project

Abstract: Author(s): Ku, NS; Lee, Y; Ahn, JY; Song, JE; Kim, MH; Kim, SB; Jeong, SJ; Hong, KW; Kim, E; Han, SH; Song, JY; Cheong, HJ; Song, YG; Kim, WJ; Kim, JM; Smith, DM; Choi, JY | Abstract: Objectives: HIV-associated neurocognitive disorder (HAND) is an independent predictor of early mortality and is associated with many difficulties in activities of daily living. We sought to determine the prevalence of and risk factors for HAND in HIV-infected Koreans. In addition, we investigated the performance of screening tools and components of neuropsychological (NP) tests for diagnosing HAND. Methods: HIV-infected patients were enrolled consecutively from two different urban teaching hospitals in Seoul, South Korea between March 2012 and September 2012. Participants completed a detailed NP assessment of six cognitive domains commonly affected by HIV. The Frascati criteria were used for diagnosing HAND. Four key questions, the International HIV Dementia Scale (IHDS) and Montreal Cognitive Assessment (MoCA)-K were also assessed as potential tools for screening for HAND. Results: Among the 194 participants, the prevalence of HAND was 26.3%. Asymptomatic neurocognitive impairment and minor neurocognitive disorder accounted for 52.9 and 47.1% of the patients with HAND, respectively. In multivariate analysis, haemoglobin (Hb) level ≤13g/dL (P=0.046) and current use of a protease inhibitor-based regimen (P=0.031) were independent risk factors for HAND. The sensitivity and specificity of the IHDS were 72.6 and 60.8%, and those of MoCA-K were 52.9 and 73.4%, respectively. The IHDS (Pl0.001) and MoCA-K (Pl0.001) were both useful for screening for HAND. Among NP tests, the sensitivity and specificity of the Grooved Pegboard Test were 90.2 and 72.0%, and those of the Wisconsin Card Sorting Test were 61.2 and 84.4%, respectively. Conclusions: HAND is a prevalent comorbidity in HIV-infected Koreans. Active screening and diagnosis with effective tools, such as the IHDS, MoCA-K and Grooved Pegboard Test, could be used to identify this important complication. © 2014 British HIV Association.

Switch to Raltegravir Decreases Soluble CD14 in Virologically Suppressed Overweight Women: The Women, Integrase, and Fat Accumulation Trial

Abstract: Objectives Soluble CD14 (sCD14) is a monocyte activation marker associated with increased mortality in HIV infection. We assessed 48-week changes in sCD14 and other inflammatory biomarkers in virologically suppressed, HIV-infected women switching to raltegravir (RAL) from a protease inhibitor (PI) or nonnucleoside reverse transcriptase inhibitor (NNRTI). Methods HIV-infected women with central adiposity and HIV-1 RNA < 50 HIV-1 RNA copies/mL continued their thymidine-sparing nucleoside reverse transcriptase inhibitor (NRTI) backbone and were randomized to switch to open-label RAL at week 0 (immediate) or 24 (delayed). In an exploratory analysis, inflammatory biomarkers were measured on stored fasting plasma. Results Of the 37 evaluable subjects, 78% were non-White; the median age was 43 years, the median body mass index (BMI) was 32 kg/m2 and the median CD4 count was 558 cells/μL. At baseline, biomarker values were similar between groups. After 24 weeks, median sCD14 significantly declined in subjects switching to RAL [−21% (P < 0.001) vs. PI/NNRTI −5% (P = 0.49); between-group P < 0.01]. After 48 weeks, immediate-switch subjects maintained this decline and delayed-switch subjects experienced a similar decline following the switch to RAL (−10%; within-group P < 0.01). Immediate-switch subjects also experienced an initial increase in tumour necrosis factor (TNF)-α that was neither maintained after 48 weeks nor seen in delayed-switch subjects. After adjustment for multiple testing, only declines in sCD14 remained significant. Conclusions In this randomized trial of women with central adiposity, a switch to RAL from a PI or NNRTI was associated with a statistically significant decline in sCD14. Further studies are needed to determine whether integrase inhibitors have improved monocyte activation profiles compared with PIs and/or NNRTIs, and whether measured differences between antiretroviral agents translate to demonstrable clinical benefit.

HIV Tat protein affects circadian rhythmicity by interfering with the circadian system

Abstract: Objectives Sleep disorders are common in patients with HIV/AIDS, and can lead to poor quality of life. Although many studies have investigated the aetiology of these disorders, it is still unclear whether impaired sleep quality is associated with HIV itself, social problems, or side effects of antiretroviral therapy (ART). Moreover, despite its known neurological associations, little is known about the role of the trans-activator of transcription (Tat) protein in sleep disorders in patients with HIV/AIDS. The purpose of this study was to test the hypothesis that the sleep quality of patients with HIV/AIDS affected by an altered circadian rhythm correlates with cerebrospinal HIV Tat protein concentration. Methods Ninety-six patients with HIV/AIDS between 20 and 69 years old completed the Pittsburgh Sleep Quality Index. Their circadian rhythm parameters of blood pressure, Tat concentration in cerebrospinal fluid, melatonin concentration, CD4 cell count and HIV RNA viral load in serum were measured. Results The circadian amplitude of systolic blood pressure and the score for sleep quality (Pittsburgh Sleep Quality Index) were negatively correlated with HIV Tat protein concentration, while the melatonin value was positively correlated with Tat protein concentration. Conclusions The HIV Tat protein affects circadian rhythmicity by interfering with the circadian system in patients with HIV/AIDS and further increases the melatonin excretion value. A Tat protein-related high melatonin value may counteract HIV-related poor sleep quality during the progression of HIV infection. This study provides the first clinical evidence offering an explanation for why sleep quality did not show an association with progression of HIV infection in previous studies.

Early lipid changes with atazanavir/ritonavir or darunavir/ritonavir.

Abstract: Objectives Ritonavir-boosted atazanavir and darunavir are protease inhibitors that are recommended for initial treatment of HIV infection because each has shown better lipid effects and overall tolerability than ritonavir-boosted lopinavir. The extent to which lipid effects and overall tolerability differ between treatments with atazanavir and darunavir and whether atazanavir-induced hyperbilirubinaemia may result in more favourable metabolic effects are issues that remain to be resolved. Methods A 96-week randomized clinical trial was carried out. The primary endpoint was change in total cholesterol at 24 weeks. Secondary endpoints were changes in lipids other than total cholesterol, insulin sensitivity, total bilirubin, estimated glomerular filtration rate, and CD4 and CD8 cell counts, and the proportion of patients with plasma HIV RNA < 50 HIV-1 RNA copies/mL and study drug discontinuation because of adverse effects at 24 weeks. Analyses were intent-to-treat. Results One hundred and seventy-eight patients received once-daily treatment with either atazanavir/ritonavir (n = 90) or darunavir/ritonavir (n = 88) plus tenofovir/emtricitabine. At 24 weeks, mean total cholesterol had increased by 7.26 and 11.47 mg/dL in the atazanavir/ritonavir and darunavir/ritonavir arms, respectively [estimated difference −4.21 mg/dL; 95% confidence interval (CI) −12.11 to +3.69 mg/dL; P = 0.75]. However, the ratio of total to high-density lipoprotein (HDL) cholesterol tended to show a greater decrease with atazanavir/ritonavir compared with darunavir/ritonavir (estimated difference −1.02; 95% CI −2.35 to +0.13; P = 0.07). Total bilirubin significantly increased with atazanavir/ritonavir (estimated difference +1.87 mg/dL; 95% CI +1.58 to +2.16 mg/dL; P < 0.01), but bilirubin changes were not associated with lipid changes. Secondary endpoints other than total bilirubin were not significantly different between arms. Conclusions Atazanavir/ritonavir and darunavir/ritonavir plus tenofovir/emtricitabine did not show significant differences in total cholesterol change or overall tolerability at 24 weeks. However, there was a trend towards a lower total to HDL cholesterol ratio with atazanavir/ritonavir and this effect was unrelated to bilirubin.

The natural history of HIV-associated lipodystrophy in the changing scenario of HIV infection.

Abstract: Objectives In long-term HIV-infected patients, peripheral lipoatrophy (LA) and central lipohypertrophy (LH) appear to be related to the same insults (virus and antiretroviral drugs), but are likely to be associated with different fat depot physiologies. The objective of this study was to describe the natural history of lipodystrophy assessed using dual energy X-ray absorptiometry (DEXA) and computed tomography (CT) in a large HIV out-patients metabolic clinic. Methods An observational retrospective study was carried out including HIV-infected patients recruited at the Metabolic Clinic of Modena, Modena, Italy, who were assessed for lipodystrophy and had at least two anthropometric evaluations using DEXA for leg fat per cent mass and abdominal CT for visceral adipose tissue (VAT). Factors associated with leg fat per cent and VAT changes were analysed using multivariable generalized estimating equation (GEE) regression models. Results A total of 6789 DEXAs and 7566 CT scans were evaluated in the observation period. A total of 1840 patients were included; the mean age was 45.2 ± 7.2 (standard deviation) years, 621 (34%) were women, and the median HIV infection duration was 176 (interquartile range 121–232) years. According to the GEE multivariable regression analysis, leg fat per cent evaluated with DEXA appeared to increase over calendar years (s = 0.92; P < 0.001); moreover, a progressive increase in VAT was observed in the cohort (s = 5.69; P < 0.001). No association with antiretroviral drugs was found. Conclusions In our study, neither LA nor LH appeared to be associated with antiretroviral drug exposure. We observed a progressive increase in LH in HIV-infected patients over calendar years. This anthropometric change, together with loss of appendicular lean mass, could describe a physiological aging process in HIV-infected patients.

Virological response rates for telaprevir-based hepatitis C triple therapy in patients with and without HIV coinfection.

Abstract: Objectives Pegylated-interferon/ribavirin dual therapy for hepatitis C virus (HCV) infection has a lower sustained virological response (SVR) rate in HIV/HCV-coinfected patients than in HCV monoinfected patients, but little is known about the relative effectiveness of teleprevir-based triple therapy in the two groups Methods Data on 33 coinfected and 116 monoinfected patients were analysed on an intention-to-treat basis SVR12 was defined as undetectable HCV RNA at week 12 post-end-of-treatment, severe anaemia as haemoglobin ≤ 89 g/L or a drop of ≥ 45 g/L, and advanced fibrosis/cirrhosis as Fib-4 ≥ 325 All coinfected patients had well controlled HIV infection Results The groups were similar in age, gender, percentage with Fib-4 ≥ 325 and HCV viral load, but differed in previous treatment response, with more coinfected patients being nonresponders or treatment-intolerant (758% vs 500% for monoinfected patients; P < 001) During treatment, the percentages of patients with undetectable HCV RNA were similar, but, surprisingly, this percentage tended to be higher in coinfected patients SVR12 rates were 606% in coinfected patients vs 422% in monoinfected patients (P = 006) In multivariable analysis, SVR12 was associated with HIV infection [odds ratio (OR) 355; P < 001], African American race (OR 037; P = 003) and previous treatment response (OR 046; P = 003) Rates of severe anaemia (455 vs 586% in coinfected and monoinfected patients, respectively; P = 018) were similar in the two groups, but rash (152 vs 345%, respectively; P = 003) and rectal symptoms (121 vs 431%, respectively; P < 001) were less common in coinfected patients Conclusions Virological responses of coinfected and monoinfected patients did not differ significantly, but tended to be higher in coinfected patients, who had a 606% SVR12 rate Telaprevir-based triple therapy is a promising option for coinfected patients with well-controlled HIV infection

Risk of clinically significant depression in HIV-infected patients: effect of antiretroviral drugs.

Abstract: Objectives We aimed to characterize depression in newly diagnosed HIV-infected patients, to determine the effect of antiretroviral therapy (ART) on its incidence, and to investigate whether efavirenz use was associated with a higher risk, compared with non-efavirenz-containing regimens, in the Spanish CoRIS cohort. Methods CoRIS is a contemporary, multicentre cohort of HIV-infected patients, antiretroviral-naive at entry, launched in 2004. Poisson regression models were used to investigate demographic, clinical and treatment-related factors associated with a higher incidence of clinically significant depression to October 2010. Results In total, 5185 patients (13 089 person-years) participated in the study, of whom 3379 (65.2%) started ART during follow-up. The incidence rates of depression before and after starting ART were 11.68 [95% confidence interval (CI) 9.01–15.15] and 7.06 (95% CI 5.45–9.13) cases per 1000 person-years, respectively. After adjustment, there was an inverse association between the occurrence of depression and the initiation of ART [incidence rate ratio (IRR) 0.53; 95% CI 0.28–0.99], while the likelihood of depression increased in patients of age > 50 years (IRR 1.94; 95% CI 1.21–3.12). Longer exposure to ART was associated with a decreased IRR of depression in unadjusted and adjusted analyses. The IRR for patients receiving 4 years of ART was 0.72 (95% CI 0.36–1.44), 0.10 (95% CI 0.04–0.25) and 0.05 (95% CI 0.01–0.17), respectively, compared with ART-naive patients. This protective effect was also observed when durations of exposure to nonnucleoside reverse transcriptase inhibitor-based regimens and efavirenz-containing regimens were analysed separately. Conclusions The incidence of clinically significant depression was lower among HIV-infected patients on ART. The protective effect of ART was also observed with efavirenz-containing regimens.

Week 96 analysis of rilpivirine or efavirenz in HIV-1-infected patients with baseline viral load ≤ 100 000 copies/mL in the pooled ECHO and THRIVE phase 3, randomized, double-blind trials.

Abstract: Objectives These 96-week, ECHO/THRIVE pooled analyses evaluated data for antiretroviral treatment-naive, HIV-1-infected adults with viral load (VL) ≤ 100 000 HIV-1 RNA copies/mL receiving rilpivirine or efavirenz. Methods ECHO and THRIVE were phase 3, randomized, double-blind trials. Patients received rilpivirine 25 mg once daily (qd) or efavirenz 600 mg qd, with a fixed (ECHO) or investigator-chosen (THRIVE) nucleoside/tide reverse transcriptase inhibitor (N[t]RTI) background regimen. Response rate (the percentage of patients with VL < 50 copies/mL, using an intent-to-treat-population, time-to-loss-of-virological-response algorithm), virological failure (VF), resistance development, safety and tolerability were evaluated. Results Baseline characteristics were comparable between the rilpivirine (n = 368) and efavirenz (n = 329) groups. At week 96, response rates [84% for rilpivirine vs. 80% for efavirenz; difference 4.0%; 95% confidence interval (CI) –1.7% to 9.7%] and incidences of VF for the resistance analysis (VFres) (8% for rilpivirine vs. 6% for efavirenz; P = 0.46) were similar in the two groups. Among patients with VFres, a comparable proportion in each group developed nonnucleoside reverse transcriptase inhibitor (NNRTI) resistance-associated mutations (RAMs). Among those with VFres, more patients in the rilpivirine group than in the efavirenz group developed N[t]RTI RAMs, mostly M184I/V. The mean (95% CI) CD4 cell count increased from baseline to week 96 by 224 (208–240) cells/μL in the rilpivirine group and by 206 (188–225) cells/μL in the efavirenz group. Treatment-related grade 2–4 overall adverse events, any rash and dizziness were less frequent for rilpivirine than for efavirenz (P < 0.0001). Conclusions Rilpivirine demonstrated antiviral efficacy similar to that of efavirenz in antiretroviral treatment-naive adults with baseline VL ≤ 100 000 copies/mL over 96 weeks. Frequencies of VFres and emergent NNRTI RAMs in each group were similar. More patients with VFres in the rilpivirine group than in the efavirenz group developed N[t]RTI RAMs (mostly M184I/V). Rilpivirine had a more favourable safety/tolerability profile than efavirenz.

Etravirine in treatment-experienced, HIV-1-infected children and adolescents: 48-week safety, efficacy and resistance analysis of the phase II PIANO study

Abstract: Objectives PIANO (Paediatric study of Intelence As an NNRTI Option; TMC125-C213; NCT00665847) assessed the safety/tolerability, antiviral activity and pharmacokinetics of etravirine plus an optimized background regimen (OBR) in treatment-experienced, HIV-1-infected children (≥ 6 to < 12 years) and adolescents (≥ 12 to < 18 years) over 48 weeks. Methods In a phase II, open-label, single-arm study, 101 treatment-experienced patients (41 children; 60 adolescents) with screening viral load (VL) ≥ 500 HIV-1 RNA copies/mL received etravirine 5.2 mg/kg (maximum dose 200 mg) twice a day (bid) plus OBR. Results Sixty-seven per cent of patients had previously used efavirenz or nevirapine. At week 48, the most common treatment-related grade ≥ 2 adverse event (AE) was rash (13%); 12% experienced grade 3 AEs. Only two grade 4 AEs occurred (both thrombocytopaenia, not etravirine related). At week 48, 56% of patients (68% children; 48% adolescents) achieved a virological response (VL 95%, male sex, low baseline etravirine weighted genotypic score and high etravirine trough concentration (C0h). Seventy-six patients (75%) completed the trial; most discontinuations occurred because of protocol noncompliance or AEs (8% each). Sixty-five per cent of patients were > 95% adherent by questionnaire and 39% by pill count. Forty-one patients experienced virological failure (VF; time-to-loss-of-virological-response non-VF-censored algorithm) (29 nonresponders; 12 rebounders). Of 30 patients with VF with paired baseline/endpoint genotypes, 18 (60%) developed nonnucleoside reverse transcriptase inhibitor (NNRTI) mutations, most commonly Y181C. Mean etravirine area under the plasma concentration–time curve over 12 h (AUC0–12h; 5216 ng h/mL) and C0h (346 ng/mL) were comparable to adult target values. Conclusions Results with etravirine 5.2 mg/kg bid (with OBR) in this treatment-experienced paediatric population and etravirine 200 mg bid in treatment-experienced adults were comparable. Etravirine is an NNRTI option for treatment-experienced paediatric patients.

Anal intraepithelial neoplasia and squamous cell carcinoma in HIV-infected adults.

Abstract: Anal cancer is one of the most common non-AIDS-defining malignancies in the era of combination antiretroviral therapy. Its precursor lesion, anal intraepithelial neoplasia (AIN), is highly prevalent in HIV-infected populations. More than 90% of anal squamous cell cancers are attributable to human papillomavirus (HPV). While the biology of HPV-related intraepithelial neoplasia is consistent across lower anogenital sites, the natural history of AIN is not well established and cannot be assumed to be identical to that of cervical intraepithelial neoplasia. Screening strategies to prevent anal cancer should be developed based on robust natural history data in HIV-infected and uninfected populations. Likewise, treatments need to be tested in randomized clinical trials, and reserved for those at significant risk of progression to cancer. This review covers the epidemiology, pathogenesis and immunology of HPV infection, AIN and anal cancer, and summarizes the current diagnosis, screening and treatment strategies in HIV-infected adults.

Glomerular filtration rate estimated using creatinine, cystatin C or both markers and the risk of clinical events in HIV-infected individuals

Abstract: Objectives: The accuracy and precision of glomerular filtration rate (GFR) estimating equations based on plasma creatinine (GFR), cystatin C (GFR) and the combination of these markers (GFR) have recently been assessed in HIV-infected individuals. We assessed the associations of GFR, estimated by these three equations, with clinical events in HIV-infected individuals. Methods: We compared the associations of baseline GFR, GFR and GFR [using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations] with mortality, cardiovascular events (CVEs) and opportunistic diseases (ODs) in the Strategies for the Management of Antiretroviral Therapy (SMART) study. We used Cox proportional hazards models to estimate unadjusted and adjusted hazard ratios per standard deviation (SD) change in GFR. Results: A total of 4614 subjects from the SMART trial with available baseline creatinine and cystatin C data were included in this analysis. Of these, 99 died, 111 had a CVE and 121 had an OD. GFR was weakly to moderately correlated with HIV RNA, CD4 cell count, high-sensitivity C-reactive protein, interleukin-6, and D-dimer, while GFR had little or no correlation with these factors. GFR had the strongest associations with the three clinical outcomes, followed closely by GFR, with GFR having the weakest associations with clinical outcomes. In a model adjusting for demographics, cardiovascular risk factors, HIV-related factors and inflammation markers, a 1-SD lower GFR was associated with a 55% [95% confidence interval (CI) 27-90%] increased risk of mortality, a 21% (95% CI 0-47%) increased risk of CVE, and a 22% (95% CI 0-48%) increased risk of OD. Conclusions: Of the three CKD-EPI GFR equations, GFR had the strongest associations with mortality, CVE and OD.