Real-world persistence with antiretroviral therapy for HIV in the United Kingdom: A multicentre retrospective cohort study.

OBJECTIVES: Persistence with an antiretroviral therapy (ART) regimen for HIV can be defined as the length of time a patient remains on therapy before stopping or switching. We aimed to describe ART persistence in treatment naïve patients starting therapy in the United Kingdom, and to describe differential persistence by treatment regimen. METHODS: We performed a retrospective cohort study at eight UK centres of ART-naïve adults commencing ART between 2012 and 2015. Aggregate data were extracted from local treatment databases. Time to discontinuation was compared for different third agents and NRTI backbones using incidence rates. RESULTS: 1949 patients contributed data to the analysis. Rate of third agent change was 28 per 100 person-years of follow up [95% CI 26-31] and NRTI backbone change of 15 per 100 person-years of follow up [95% CI 14-17]). Rilpivirine, as co-formulated rilpivirine/tenofovir/emtricitabine had a significantly lower discontinuation rate than all other third agents and, excluding single tablet regimens, co-formulated tenofovir/emtricitabine had a significantly lower discontinuation rate than co-formulated abacavir/lamivudine. The reasons for discontinuation were not well recorded. CONCLUSIONS: Treatment discontinuation is not an uncommon event. Rilpivirine had a significantly lower discontinuation rate than other third agents and tenofovir/emtricitabine a lower rate than co-formulated abacavir/lamivudine.

Antenatal atazanavir: a retrospective analysis of pregnancies exposed to atazanavir.

INTRODUCTION: There are few data regarding the tolerability, safety, or efficacy of antenatal atazanavir. We report our clinical experience of atazanavir use in pregnancy. METHODS: A retrospective medical records review of atazanavir-exposed pregnancies in 12 London centres between 2004 and 2010. RESULTS: There were 145 pregnancies in 135 women: 89 conceived whilst taking atazanavir-based combination antiretroviral therapy (cART), "preconception" atazanavir exposure; 27 started atazanavir-based cART as "first-line" during the pregnancy; and 29 "switched" to an atazanavir-based regimen from another cART regimen during pregnancy. Gastrointestinal intolerance requiring atazanavir cessation occurred in five pregnancies. Self-limiting, new-onset transaminitis was most common in first-line use, occurring in 11.0%. Atazanavir was commenced in five switch pregnancies in the presence of transaminitis, two of which discontinued atazanavir with persistent transaminitis. HIV-VL < 50 copies/mL was achieved in 89.3% preconception, 56.5% first-line, and 72.0% switch exposures. Singleton preterm delivery (<37 weeks) occurred in 11.7% preconception, 9.1% first-line, and 7.7% switch exposures. Four infants required phototherapy. There was one mother-to-child transmission in a poorly adherent woman. CONCLUSIONS: These data suggest that atazanavir is well tolerated and can be safely prescribed as a component of combination antiretroviral therapy in pregnancy.

A randomised controlled trial of computer-assisted interviewing in sexual health clinics.

OBJECTIVES: To assess the impact of computer-assisted interview compared with pen and paper on disclosure of sexual behaviour, diagnostic testing by clinicians, infections diagnosed and referral for counselling. METHODS: Two-centre parallel three-arm randomised controlled open trial. Computer-generated randomisation with allocation concealment using sealed envelopes. SETTING: Two London teaching hospital sexual health clinics. PARTICIPANTS: 2351 clinic attenders over the age of 16 years. INTERVENTIONS: Computer-assisted self-interview (CASI). Computer-assisted personal interview (CAPI). Pen and paper interview (PAPI). MAIN OUTCOME MEASURES: Diagnostic tests ordered, sexually transmitted infections (STI). SECONDARY OUTCOMES: Disclosure of sexual risk, referral for counselling. RESULTS: 801, 763 and 787 patients randomly allocated to receive CASI, CAPI and PAPI. 795, 744 and 779 were available for intention-to-treat analysis. Significantly more diagnostic testing for hepatitis B and C and rectal samples in the CAPI arm (odds for more testing relative to PAPI 1.32; 95% CI 1.09 to 1.59). This pattern was not seen among CASI patients. HIV testing was significantly lower among CASI patients (odds for less testing relative to PAPI 0.73; 95% CI 0.59 to 0.90). STI diagnoses were not significantly different by trial arm. A summary measure of seven prespecified sensitive behaviours found greater reporting with CASI (OR 1.4; 95% CI 1.2 to 1.6) and CAPI (OR 1.4; 95% CI 1.2 to 1.7) compared with PAPI. CONCLUSION: CASI and CAPI can generate greater recording of risky behaviour than traditional PAPI. Increased disclosure did not increase STI diagnoses. Safeguards may be needed to ensure that clinicians are prompted to act upon disclosures made during self-interview.

A randomized comparative trial of tenofovir DF or abacavir as replacement for a thymidine analogue in persons with lipoatrophy.

BACKGROUND: Long-term antiretroviral therapy, while dramatically reducing HIV-related morbidity and mortality, is associated with metabolic and morphological changes. Peripheral fat loss, lipoatrophy, appears most associated with prolonged therapy with thymidine nucleoside analogues. METHODS: A randomized, open-label, comparative study of switching from a thymidine nucleoside analogue to either tenofovir disoproxil fumarate (DF) or abacavir in 105 individuals on successful antiretroviral therapy with clinically evident moderate to severe lipoatrophy. RESULTS: Individuals were randomized to tenofovir DF (52) or abacavir (53). The switch was well tolerated and the majority of patients completed 48 weeks of study. One individual in the tenofovir DF group and three in the abacavir group discontinued due to drug-related adverse events. Both groups similarly maintained virological control. Limb fat mass increased similarly in both groups: mean increases by week 48 of 329 and 483 g in tenofovir DF and abacavir groups, respectively [mean 95% confidence interval for difference, -154.3 (range -492.8 to 184.3)]. This change from baseline was statistically significant in both groups (tenofovir DF, P = 0.01; abacavir, P = 0.0001). Mean total cholesterol, low density lipoprotein cholesterol and triglycerides improved modestly with switching to tenofovir DF but were unchanged with abacavir. The changes in these parameters were significantly greater in the tenofovir DF arm relative to abacavir. CONCLUSIONS: Switching from a thymidine nucleoside analogue to either tenofovir DF or abacavir leads to significant improvement in limb fat mass over 48 weeks. Tenofovir DF may have modest advantages over abacavir for changes in lipids. Peripheral lipoatrophy, when clinically apparent, resolves slowly following treatment switching.

Indole-3-acetic acid antagonists of the prostaglandin D2 receptor CRTH2.

Prostaglandin D2 (PGD2) acting at the CRTH2 receptor (chemoattractant receptor-homologous molecule expressed on Th2 cells) has been linked with a variety of allergic and other inflammatory diseases. We describe a family of indole-1-sulfonyl-3-acetic acids that are potent and selective CRTH2 antagonists that possess good oral bioavailability. The compounds may serve as novel starting points for the development of treatments of inflammatory disease such as asthma, allergic rhinitis, and atopic dermatitis.

Furanyl-1,3-thiazol-2-yl and benzoxazol-5-yl acetic acid derivatives: novel classes of heparanase inhibitor.

Using a furanylthiazole acetic acid as a starting point, a novel series of benzoxazol-5-yl acetic acid derivatives have been identified as heparanase inhibitors. Several compounds possess an IC50 of approximately 200 nM against heparanase, for example, trans 2-[4-[3-(3,4-dichlorophenylamino)-3-oxo-1-propenyl]-2-fluorophenyl]benzoxazol-5-yl acetic acid (16e). Several of the compounds show anti-angiogenic properties. Improvement to the DMPK profile of compounds has provided compounds of potential use in in vivo models.

Glyco- and peptidomimetics from three-component Joullié-Ugi coupling show selective antiviral activity.

Chlorination-elimination chemistry coupled with three-component Joullié-Ugi reaction and facile deprotection allowed efficient access to an array of polyhydroxylated pyrrolidines through parallel synthesis that may be considered to be a library of imino (aza) sugars (glycomimetics) and/or dihydroxyprolyl peptides (peptidomimetics). The utility of generating such a library was illustrated by screening against 15 different targets that revealed potent and selective inhibition of the Gaucher's disease glycosyltransferase enzyme glucosylceramide synthase and of primary pathogen model for human hepatitis C virus (HCV) and bovine diarrhoeal virus (BVDV). An observed selectivity for this HCV model over hepatitis B virus and remarkably low toxicity suggest a novel mode of action.

2,3-Dihydro-1,3-dioxo-1H-isoindole-5-carboxylic acid derivatives: a novel class of small molecule heparanase inhibitors.

A novel class of 2,3-dihydro-1,3-dioxo-1H-isoindole-5-carboxylic acids are described as inhibitors of the endo-beta-glucuronidase heparanase. Several of the compounds, for example, 2-[4-propylamino-5-[5-(4-chloro)phenyl-benzoxazol-2-yl]phenyl]-2,3-dihydro-1,3-dioxo-1H-isoindole-5-carboxylic acid (9c), display potent heparanase inhibitory activity (IC(50) 200-500 nM) and have high selectivity (>100-fold) over human beta-glucuronidase. They also show anti-angiogenic effects. Such compounds should serve as useful biological tools and may provide a basis for the design of novel therapeutic agents.

Bacterial vaginosis and preterm birth: a prospective community-based cohort study.

BACKGROUND: Preterm birth before 37 weeks' gestation is associated with 70% of perinatal morbidity and nearly half of long-term neurological morbidity. Hospital-based studies have shown that bacterial vaginosis is associated with preterm birth. AIM: To estimate the relative risk of preterm birth in women with and without bacterial vaginosis, detected by self-administered vaginal swab at < 10 weeks' gestation. DESIGN: Prospective cohort study. SETTING: Thirty-two general practices and five family planning clinics in South London. PARTICIPANTS: A total of 1216 women with bacterial vaginosis status established before 10 weeks' gestation, by analysis of Gram stained vaginal smears by two independent observers. METHOD: All women who did not miscarry or have a termination of pregnancy before 16 weeks' gestation were sent a brief confidential questionnaire at 16 weeks and at term asking about pregnancy outcome. Data on non-responders were obtained by searches of hospital and general practice records and by telephone calls to patients. RESULTS: Ascertainment was 87% (937/1072). The mean age of the women was 31 years. Thirteen per cent (122/925) had bacterial vaginosis and 5% (44/897) had a spontaneous preterm birth. The relative risk (RR) of preterm birth in women with bacterial vaginosis was 0.9 (95% confidence interval [CI] = 0.4 to 2.2). However, bacterial vaginosis was associated with late miscarriage at 13-23 weeks (R = 4.0, 95%CI = 1.3 to 12.1). Preterm birth was not associated with previous preterm birth, black ethnicity, age < 20 years, low social class, single marital status, or chlamydial infection. However, it was more common in women who reported smoking in pregnancy (RR = 2.9, 95% CI = 1.5 to 5.5). Of 867 responders, 552 (64%) said that providing a vaginal swab was at least as easy as providing a urine specimen. CONCLUSIONS: In this low-risk community-based cohort, bacterial vaginosis was not a strong risk factor for preterm birth.

The efficacy of vaginal clindamycin for the treatment of abnormal genital tract flora in pregnancy.

OBJECTIVE: To assess the efficacy of 2% clindamycin vaginal cream (CVC) to treat bacterial vaginosis (BV) in pregnancy. METHODS: A prospective, randomized, double-blind, placebo-controlled, tricenter study. Four hundred and four women with BV on Gram stain at their first antenatal clinic visit were randomized to receive a 3-day course of 2% CVC or placebo. The outcome was assessed using an intention to treat analysis at 3 weeks and 6 weeks post-treatment according to three different diagnostic methods based on five criteria (Gram stain and all four elements of clinical composite criteria: vaginal discharge, abnormal vaginal pH, clue cells, amine odor), three criteria (vaginal pH, clue cells, amine odor) or two criteria (clue cells and amine odor) to reflect stringency of diagnosis, historical precedence and government agency recommendations respectively. RESULTS: Using five diagnostic criteria, 18% of CVC patients were cured and 70.8% either cured and/or improved compared to 1.6% and 12% of placebo patients respectively (p < 0.0001). Using three diagnostic criteria, 44.8% of CVC patients were cured and 77.3% were either cured and/or improved compared to 9.3% and 28.8% of placebo patients respectively (p < 0.000 1). Using two diagnostic criteria, 75.0% of CVC patients were cured compared to 18.0% of placebo patients (p < 0.0001 ). Recurrence rates in those CVC patients successfully treated were approximately 6% at 6 weeks post baseline and 10% at 28 to 34 weeks gestation. CONCLUSIONS: A 3-day course of CVC appears to be well tolerated by the mother and statistically significantly more efficacious than placebo in the treatment of BV during the second trimester of pregnancy.