250 words). Background. Smoking prevalence is higher amongst individuals with schizophrenia and depression compared to the general population. Mendelian randomisation (MR) can examine whether this association is causal using genetic variants identified in genome-wide association studies (GWAS).Methods. We conducted a GWAS of lifetime smoking behaviour (capturing smoking duration, heaviness and cessation) in a sample of 462,690 individuals from the UK Biobank, and validated the findings via two-sample MR analyses of positive control outcomes (e.g., lung cancer). Having established the validity of our instrument, we used bi-directional twosample Mendelian randomisation to explore its effects on schizophrenia and depression.Outcomes. There was strong evidence to suggest smoking is a causal risk factor for both schizophrenia (OR = 2.27, 95% CI = 1.67 -3.08, P < 0.001) and depression (OR = 1.99, 95% CI = 1.71 -2.32, P < 0.001). We also found some evidence that genetic risk for both schizophrenia and depression cause increased lifetime smoking (β = 0.022, 95% CI = 0.005 -0.038, P = 0.009; β = 0.091, 95% CI = 0.027 -0.155, P = 0.005).Interpretation. These findings suggest that the association between smoking, schizophrenia and depression is due, at least in part, to a causal effect of smoking, providing further evidence for the detrimental consequences of smoking for mental health.Evidence before this study: The association between smoking and mental health (especially schizophrenia and depression) is often assumed to be the result of selfmedication (for example, to alleviate symptoms). However, more recent evidence has suggested that smoking might also be a risk factor for schizophrenia and depression. This alternative direction of effect is supported by meta-analyses and previous prospective observational evidence using related individuals to control for genetic and environmental confounding. However, observational evidence cannot completely account for confounding or the possibility of reverse causation. One way to get around these problems is Mendelian randomisation (MR). Previous MR studies of smoking and mental health have not shown an effect of smoking on depression and are inconclusive for the effects of smoking on schizophrenia. However, these studies have only looked at individual aspects of smoking behaviour and some studies required stratifying participants into smokers and non-smokers, reducing power. Added value of this study:We have developed a novel genetic instrument for lifetime smoking exposure which can be used within a two-sample MR framework, using publiclyavailable GWAS summary statistics. We were therefore able to test the bi-directional association between smoking with schizophrenia and depression to see if the effects are causal. We found strong evidence to suggest that smoking is a causal risk factor for both schizophrenia and depression. There was some evidence to suggest that risk of schizophrenia and depression increases lifetime smoking (consistent with the selfmedication hypothesis) but t...

ObjectiveTo determine the pharmacokinetics of cessation of nevirapine (NVP) in order to design clinical protocols which will reduce the risk of resistance to nonnucleoside reverse transcriptase inhibitors (NNRTIs). MethodsIn a case study, NNRTI genotypic resistance was demonstrated in a patient discontinuing therapy for toxicity. Subsequently, nine patients receiving NVP-containing antiretroviral regimens and stopping treatment were recruited. Patients were advised to continue the nucleoside analogue reverse transcriptase inhibitor (NRTI) backbone for 5 days following cessation of NVP. Plasma NVP concentrations were determined over 7-10 days after the last dose. HIV-1 reverse transcriptase genotyping was performed at viral load rebound (approximately day 21 following cessation) to detect mutations associated with reduced NNRTI sensitivity. ResultsThe median predicted time for plasma NVP concentration to fall below the inhibitory concentration (IC) 50 of wild-type virus was 168 h (range 108-264 h). De novo genotypic mutations conferring resistance to NRTIs or NNRTIs were not demonstrated following cessation of therapy. ConclusionsThe prolonged elimination half-life of NVP compared with NRTIs, which persists even after 20 weeks of therapy, raises concern over the development of NNRTI resistance if all three drugs are stopped together. Continuation of the NRTI backbone for a further 5 days, allowing the elimination of NVP, may avoid the development of drug resistance.Keywords: drug resistance, nevirapine, pharmacokinetics, stopping therapy IntroductionHighly active antiretroviral therapy (HAART) can durably suppress viral replication to below the current limits of detection (o50 HIV-1 RNA copies/mL plasma) with significant clinical benefit. Persistent HIV replication in the presence of HAART selects mutations within HIV pol that are associated with reduced susceptibility to therapy. These mutations can also reduce the efficacy of subsequent regimens as a result of cross-resistance, with obvious clinical implications. After stopping therapy, drug-resistant strains may become undetectable by current techniques as wild-type virus re-emerges as the dominant strain.Nonnucleoside reverse transcriptase inhibitors (NNRTIs) are frequently part of the currently recommended combinations for the treatment of HIV-1 infection. Two NNRTIs are licensed in the UK: nevirapine (NVP) and efavirenz (EFV). NNRTIs are characterized by similar pharmacokinetic parameters, including excellent oral absorption and a long half-life, and are extensively metabolized in the liver through cytochrome P450. NVP is also an inducer of the cytochrome P450 enzyme CYP3A (and CYP2B6), with maximal induction occurring within 2-4 weeks of initiating The current NNRTIs have a low genetic barrier to the selection of resistance, and a single key mutation in the NNRTIspecific pocket site or in the surrounding domain poses a major therapeutic problem for this class. Resistant virus emerges rapidly and uniformly when NVP is administered as monotherapy, and so NV...

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Nevirapine has been widely used in pregnancy for its efficacy, low pill burden, bioavailability and rapid transplacental transfer. Concern about nevirapine toxicity during pregnancy has emerged over recent years. ObjectivesThe aims of the study were to document the frequency of cutaneous and hepatic toxicity secondary to nevirapine use during pregnancy and to compare rates in women starting nevirapine during the current pregnancy with those in women who had commenced nevirapine prior to the current pregnancy. DesignThis was a retrospective, comparative, five-centre study carried out in London, UK, in 1997UK, in -2003. MethodsAll HIV-1-infected women who received nevirapine as part of combination antiretroviral therapy (ART) during pregnancy were included in the study. Data on demographics, HIV infection risk, Centers for Disease Control and Prevention (CDC) status, surrogate markers at initiation of therapy, other medications hepatitis B and C virus coinfection and clinical data relating to potential toxicity were collated and analysed. ResultsFifteen of 235 eligible women (6.4%) developed rash and eight (3.4%) developed hepatotoxicity, including four with coexistent rash, giving a combined incidence of 19 potential cases of nevirapine toxicity during pregnancy (8.1%). Alternative causes of rash/hepatotoxicity were suspected in seven cases and only 10 mothers (5.8%) discontinued nevirapine. Of the 170 women who commenced nevirapine during this pregnancy, 13 (7.6%) developed rash and eight (4.7%) hepatotoxicity, a combined incidence of 10%. Only two of 65 women with nevirapine exposure prior to this pregnancy developed rash (3.1%). ConclusionsNevirapine-containing ART was well tolerated in this cohort of pregnant women. Although pregnancy did not appear to increase the risk of nevirapine-associated toxicity compared to published adult data, CD 4 count may be less predictive of toxicity in pregnancy.Keywords: cutaneous side effects, hepatic side effects, nevirapine, pregnancy IntroductionThe use of antiretroviral therapy (ART) during pregnancy to minimize mother-to-child transmission of HIV-1 infection is well established [1,2]. Ideally, ART should be safe for mother and baby, effective and simple. Nevirapine has been widely used in pregnancy both as single-dose therapy during labour in resource-restricted settings and as part of short-and long-term highly active antiretroviral therapy (HAART). Physiological changes in pregnancy can significantly alter pharmacokinetics but nevirapine concentrations during pregnancy have been found to be comparable to those in nonpregnant adults [3,4]. Recent safety data on the use of nevirapine in pregnancy has given rise to concern. In the Paediatric AIDS Clinical Trials Group 1022 study, five of 17 subjects (29.4%) were reported to have an adverse event related to nevirapine, including one fatality from fulminant hepatitis [5]. Furthermore, a number of deaths in pregnancy among women taking nevirapine-containing ART have been reported to the Food and Drug Administration [6]. S...

Aims of the guidelines These guidelines, drawn up by a multidisciplinary group of clinicians and lay workers active in the management of pregnant women infected with HIV, aim to give up‐to‐date information on interventions to reduce the risk of mother to child transmission of the virus. The evidence on the use of interventions to prevent mother to child transmission of HIV has been graded according to the strength of the data as per the definitions of the US Agency for Health Care Policy and Research [1]. Weighted evidence on the use of combination antiretroviral therapy (ART) for the treatment of HIV infection per se is presented in the BHIVA guidelines for adults [2,3]. The highest level evidence (i.e. randomised controlled trials (RCTs) or large, well conducted meta‐analyses) is only available for formula feeding, prelabour caesarean section and zidovudine monotherapy. The need to treat mothers for HIV infection has led to the widespread use of ART in pregnancy which in turn results in new questions such as how to deliver when the mother, on therapy, has no detectable plasma viraemia with the most sensitive assays. In addressing many common and/or difficult clinical scenarios in the absence of ‘best evidence’ the guidelines rely heavily on ‘expert opinion’. Recommendations for management are given in the section on clinical scenarios, and summarized in Table 3. An expanded version of these guidelines with an appendix on safety and toxicity data is available on the BHIVA website http://www.bhiva.org. The authors are available to discuss individual cases.