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Nevirapine
Selected AbstractsOnce-daily nevirapine dosing: a pharmacokinetics, efficacy and safety reviewHIV MEDICINE, Issue 1 2007CL Cooper In the context of attempts to simplify treatment regimens and enhance adherence, there is great interest in once-daily dosing regimens for the treatment of HIV-1 infection. Nevirapine has a long half-life and achieves high steady-state plasma concentrations relative to the concentration required to inhibit 50% viral replication in vitro (IC50) in patients. For this reason, it has been considered as a once-daily antiretroviral. Pharmacokinetic and efficacy data support the use of this dosing approach, but excess rash and lingering concerns over liver toxicity preclude use of once-daily dosed nevirapine at this time. Tolerance to high nevirapine concentrations may develop when dose escalation is used during initiation of therapy. It is theoretically possible that the benefits of once-daily dosing may be achieved without excess toxicity by switching to once-daily nevirapine following several months of twice-daily administration. This dosing strategy is currently under evaluation. [source] Safety of nevirapine in pregnancyHIV MEDICINE, Issue 1 2007U Natarajan Background 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. Objectives The 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. Design This was a retrospective, comparative, five-centre study carried out in London, UK, in 1997,2003. Methods All 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. Results Fifteen 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%). Conclusions Nevirapine-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, CD4 count may be less predictive of toxicity in pregnancy. [source] Synthesis of five nevirapine metabolitesJOURNAL OF HETEROCYCLIC CHEMISTRY, Issue 2 2000Karl G. Grozinger Nevirapine (1) is a non-nucleoside reverse transcriptase inhibitor marketed for HIV treatment by Boehringer Ingelheim as Viramune® since 1996. In vitro studies of nevirapine biotransformation using human liver microsomes demonstrated the formation of five major metabolites. This paper describes the syntheses of these metabolites. [source] Effective program against mother-to-child transmission of HIV at Saint Camille Medical Centre in Burkina FasoJOURNAL OF MEDICAL VIROLOGY, Issue 7 2007J. Simpore Abstract The present research was aimed to prevent mother-to-child transmission of HIV; to use RT-PCR in order to detect, 6 months after birth, infected children; and to test the antiretroviral resistance of both children and mothers in order to offer them a suitable therapy. At the Saint Camille Medical Centre, 3,127 pregnant women (aged 15,44 years) accepted to be enrolled in the mother-to-child transmission prevention protocol that envisages: (i) Voluntary Counselling and Testing for all the pregnant women; (ii) Antiretroviral therapy for HIV positive pregnant women and for their newborns; (iii) either powdered milk feeding or short breast-feeding and RT-PCR test for their children; (iv) finally, pol gene sequencing and antiretroviral resistance identifications among HIV positive mothers and children. Among the patients, 227/3,127 HIV seropositive women were found: 221/227 HIV-1, 4/227 HIV-2, and 2/227 mixed HIV infections. The RT-PCR test allowed the detection of 3/213 (1.4%) HIV infected children: 0/109 (0%) from mothers under ARV therapy and 3/104 (2.8%) from mothers treated with Nevirapine. All children had recombinant HIV-1 strain (CRF06_CPX) with: minor PR mutations (M36I, K20I) and RT mutations (R211K). Among them, two twins had Non-Nucleoside Reverse Transcriptase Inhibitor mutation (Y18CY). Both mothers acquired a major PR mutation (V8IV), investigated 6 months after a single-dose of Nevirapine. Prevention by single-dose of Nevirapine reduced significantly mother-to-child transmission of HIV, but caused many mutations and resistance to antiretroviral drugs. Based on present study the antiretroviral therapy protocol, together with the artificial-feeding, might represent the ideal strategy to avoid transmission of HIV from mother-to-child. J. Med. Virol. 79:873,879, 2007. © 2007 Wiley-Liss, Inc. [source] Reduction of mother-to-child transmission of HIV at Saint Camille Medical Centre in Burkina FasoJOURNAL OF MEDICAL VIROLOGY, Issue 2 2006J. Simpore Abstract One thousand three hundred and twenty-eight pregnant women with less than 32 weeks of amenorrhea received voluntary counseling and testing at Saint Camille Medical Center from May 1, 2002 to December 30, 2004. Following informed consent and pre-test counseling, HIV screening was performed in 1,202 women. According to the prevention protocol, HIV-positive women received a single dose of Nevirapine (200 mg) during their labor, while their newborn received a single dose of Nevirapine (2 mg/kg) within 72 hr from birth. HIV seroprevalence (11.2%) was higher than in the overall population. One hundred and ninty-three children were born at the end of December 2004; 53 children (27.5%) followed a short breastfeeding protocol for 4 months, while 140 (72.5%) were fed artificially. All the children underwent RT-PCR test for HIV 5,6 months after their birth: 173 (89.6%) were HIV negative whilst 20 children (10.4%) were HIV positive. Out of the 20 positive children 5/53 (9.4%) had received breast milk for 4 months, while the remaining 15/140 (10.7%) had been fed artificially (P,=,0.814). Artificially fed babies (3/140 (2.1%)) and 1/53 (1.9%) of those breast fed for 4 months deceased according to mortality rate of HIV-positive children. This shows that there is no statistically significant difference (P,=,0.648) between the mortality of artificially fed (3/140 or 2.1%) and breast-fed (1/53 or 1.9%) children. Artificially fed children (20/140 (14.3%)) and 5/53 (9.4%) of breast-fed children died within 6,10 months. This figure indicates that there is no significant difference between the mortality rate of artificially and that of breast-fed children (P,=,0.427). Although the HIV prevention program reduced significantly the vertical transmission of HIV at Saint Camille Medical Center, the mortality of artificially fed children was still high due to gastrointestinal diseases. The HIV diagnosis by RT-PCR technique was of great help in the early identification of HIV-infected children. J. Med. Virol. 78:148,152, 2006. © 2005 Wiley-Liss, Inc. [source] Erratum: Nevirapine restores androgen signaling in hormone-refractory human prostate carcinoma cells both in vitro and in vivo,THE PROSTATE, Issue 12 2009Matteo Landriscina No abstract is available for this article. [source] Allosteric modulation of anti-HIV drug and ferric heme binding to human serum albuminFEBS JOURNAL, Issue 24 2005Alessio Bocedi Human serum albumin (HSA), the most prominent protein in plasma, is best known for its exceptional capacity to bind ligands (e.g. heme and drugs). Here, binding of the anti-HIV drugs abacavir, atazanavir, didanosine, efavirenz, emtricitabine, lamivudine, nelfinavir, nevirapine, ritonavir, saquinavir, stavudine, and zidovudine to HSA and ferric heme,HSA is reported. Ferric heme binding to HSA in the absence and presence of anti-HIV drugs was also investigated. The association equilibrium constant and second-order rate constant for the binding of anti-HIV drugs to Sudlow's site I of ferric heme,HSA are lower by one order of magnitude than those for the binding of anti-HIV drugs to HSA. Accordingly, the association equilibrium constant and the second-order rate constant for heme binding to HSA are decreased by one order of magnitude in the presence of anti-HIV drugs. In contrast, the first-order rate constant for ligand dissociation from HSA is insensitive to anti-HIV drugs and ferric heme. These findings represent clear-cut evidence for the allosteric inhibition of anti-HIV drug binding to HSA by the heme. In turn, anti-HIV drugs allosterically impair heme binding to HSA. Therefore, Sudlow's site I and the heme cleft must be functionally linked. [source] Impact of nevirapine or efavirenz co-administration on ritonavir-boosted amprenavir pharmacokinetics in HIV-infected patientsFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 1 2008Eric Dailly Abstract The influence of nevirapine or efavirenz co-administration on ritonavir-boosted amprenavir pharmacokinetics was investigated in HIV-infected patients with a population pharmacokinetic approach. The analysis was performed with a population of 61 patients treated with fosamprenavir/ritonavir (700 mg/100 mg twice daily) combined with nucleoside/nucleotide reverse transcriptase inhibitors ± enfuvirtide and no other antiretroviral drugs (group A, n = 46) or nevirapine (group B, n = 10) or efavirenz (group C, n = 5). No significant increase in amprenavir clearance [mean ± standard deviation: 22.49 ± 10.32 (group A) vs. 21.57 ± 9.62 (group B) vs. 20.15 ± 5.18 (group C) L/h] and no significant decrease in trough amprenavir plasma concentrations [1.75 ± 0.95 (group A) vs. 1.82 ± 0.72 (group B) vs. 1.55 ± 0.66 (group C) mg/L] were found in groups B and C in comparison with group A, although nevirapine and efavirenz are inductors of protease inhibitors metabolism. These results suggest that fosamprenavir/ritonavir should be used at standard doses of 700 mg/100 mg twice daily when combined with efavirenz or nevirapine. [source] Long-term follow-up of nevirapine-treated patients in a single-centre cohortHIV MEDICINE, Issue 8 2009M Colafigli Objectives We reviewed the safety and efficacy of nevirapine (NVP)-based therapy in all patients initiating NVP-containing combined antiretroviral therapy [cART (,3 drugs)] in our clinic since 1994. Methods Patient characteristics and laboratory values from the start of the NVP-based cART regimen to the last available follow-up or to NVP discontinuation were retrieved from an observational database. Results Five hundred and seventy-three patients were treated with NVP-based cART for a median of 18.4 (range 0.1,128.8) months. The 1-year cumulative estimated probability of discontinuing NVP-containing regimens for toxicity was 0.203. Only 1.9% developed a grade 3 alanine aminotransferase (ALT) elevation. Significant increases in high-density lipoprotein cholesterol were observed up to month 12 except in treatment-naïve patients, where the increase was limited to 3 months. Discontinuation because of cutaneous reaction was predicted independently by female gender [Hazard Ratio (HR) 3.21, P<0.001] and Centers for Disease Control class C (HR 0.50, P=0.012). Discontinuation because of liver toxicity was predicted independently by anti-hepatitis C virus positivity (HR 3.84, P<0.001). In patients starting NVP-containing cART with undetectable viral loads, the 5-year estimated probability of viral load >400 HIV-1 RNA copies/mL was 0.34. Conclusions Long-term follow-up with an NVP-containing cART showed a low rate of discontinuation caused by liver toxicity and the maintenance of virological suppression in patients switched with undetectable viral loads. [source] Tenofovir disoproxil fumarate in pregnancy and prevention of mother-to-child transmission of HIV-1: is it time to move on from zidovudine?HIV MEDICINE, Issue 7 2009C Foster Objectives Zidovudine (ZDV) has been the cornerstone of antiretroviral (ARV) therapy for pregnant women infected with HIV-1 in the prevention of mother-to-child transmission (MTCT) and remains the only licensed ARV for use in pregnancy. We explored the current and future roles of tenofovir disoproxil fumarate (TDF) in the prevention of MTCT of HIV-1. Methods We reviewed the published literature by conducting database searches of in vitro, animal and clinical studies, reported in journals and at conferences, using the search terms Tenofovir/gs4331/viread, pregnant/pregnancy, lactate, lactation, natal, reproduce/reproduction, placenta/placental, malformation, and teratogenicity/teratogenic. Results In a macaque model, perinatal exposure to very high dose tenofovir resulted in bone toxicity in some offspring. However, perinatal use of TDF, both single dose and as part of highly active antiretroviral therapy in women, has been well tolerated in the short term by mothers and their infants. Further, the addition of single-dose TDF to single-dose nevirapine (SD-NVP) during delivery following maternal ZDV use during pregnancy significantly reduces the frequency of nonnucleoside reverse transcriptase inhibitor (NNRTI) resistance. Conclusions The addition of TDF to SD-NVP reduces NNRTI resistance. The role of TDF in this setting and during pregnancy for reducing rates of MTCT requires investigation. While short-term toxicity data are encouraging, long-term follow-up of exposed mothers and infants is required. [source] Low prevalence of insulin resistance among HIV-infected children receiving nonnucleoside reverse transcriptase inhibitor-based highly active antiretroviral therapy in ThailandHIV MEDICINE, Issue 2 2009B Lee Background Highly active antiretroviral therapy (HAART) is reported to cause insulin resistance among adults, but effects on children are less clear. We attempted to describe the prevalence of insulin resistance among HIV-infected children receiving HAART. Methods Insulin resistance was assessed at 96 weeks of treatment with nonnucleoside reverse transcriptase inhibitor (NNRTI)-based HAART (nevirapine or efavirenz with stavudine and lamivudine) among children in Chiang Mai, Thailand. Insulin resistance was defined as homeostasis model assessment for insulin resistance (HOMA-IR) ,3.16, fasting c-peptide ,4.40 ng/mL or fasting insulin ,25.0 ,U/mL. Impaired fasting glucose (IFG) was defined as glucose ,110 mg/dL. Measurements were analysed for associations with age, lipodystrophy, treatment regimen and clinical data. Results The prevalence of insulin resistance was 6.5%; no child had IFG. Those with insulin resistance were older with higher body mass index. Children ,10 years had higher HOMA-IR, c-peptide and insulin, but no difference was seen in the frequency of insulin resistance. No associations between insulin resistance and lipodystrophy or treatment regimen were detected. Conclusions Insulin resistance is uncommon among children receiving NNRTI-based HAART and is unrelated to lipodystrophy. [source] Lipodystrophy and weight changes: data from the Swiss HIV Cohort Study, 2000,2006HIV MEDICINE, Issue 3 2008A Nguyen Background and Objectives Combination antiretroviral therapy (cART) is changing, and this may affect the type and occurrence of side effects. We examined the frequency of lipodystrophy (LD) and weight changes in relation to the use of specific drugs in the Swiss HIV Cohort Study (SHCS). Methods In the SHCS, patients are followed twice a year and scored by the treating physician as having ,fat accumulation', ,fat loss', or neither. Treatments, and reasons for change thereof, are recorded. Our study sample included all patients treated with cART between 2003 and 2006 and, in addition, all patients who started cART between 2000 and 2003. Results From 2003 to 2006, the percentage of patients taking stavudine, didanosine and nelfinavir decreased, the percentage taking lopinavir, nevirapine and efavirenz remained stable, and the percentage taking atazanavir and tenofovir increased by 18.7 and 22.2%, respectively. In life-table Kaplan,Meier analysis, patients starting cART in 2003,2006 were less likely to develop LD than those starting cART from 2000 to 2002 (P<0.02). LD was quoted as the reason for treatment change or discontinuation for 4% of patients on cART in 2003, and for 1% of patients treated in 2006 (P for trend <0.001). In univariate and multivariate regression analysis, patients with a weight gain of ,5 kg were more likely to take lopinavir or atazanavir than patients without such a weight gain [odds ratio (OR) 2, 95% confidence interval (CI) 1.3,2.9, and OR 1.7, 95% CI 1.3,2.1, respectively]. Conclusions LD has become less frequent in the SHCS from 2000 to 2006. A weight gain of more than 5 kg was associated with the use of atazanavir and lopinavir. [source] Once-daily nevirapine dosing: a pharmacokinetics, efficacy and safety reviewHIV MEDICINE, Issue 1 2007CL Cooper In the context of attempts to simplify treatment regimens and enhance adherence, there is great interest in once-daily dosing regimens for the treatment of HIV-1 infection. Nevirapine has a long half-life and achieves high steady-state plasma concentrations relative to the concentration required to inhibit 50% viral replication in vitro (IC50) in patients. For this reason, it has been considered as a once-daily antiretroviral. Pharmacokinetic and efficacy data support the use of this dosing approach, but excess rash and lingering concerns over liver toxicity preclude use of once-daily dosed nevirapine at this time. Tolerance to high nevirapine concentrations may develop when dose escalation is used during initiation of therapy. It is theoretically possible that the benefits of once-daily dosing may be achieved without excess toxicity by switching to once-daily nevirapine following several months of twice-daily administration. This dosing strategy is currently under evaluation. [source] Safety of nevirapine in pregnancyHIV MEDICINE, Issue 1 2007U Natarajan Background 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. Objectives The 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. Design This was a retrospective, comparative, five-centre study carried out in London, UK, in 1997,2003. Methods All 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. Results Fifteen 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%). Conclusions Nevirapine-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, CD4 count may be less predictive of toxicity in pregnancy. [source] Long-term assessment of nevirapine-containing highly active antiretroviral therapy in antiretroviral-naive HIV-infected patients: 3-year follow-up of the VIRGO studyHIV MEDICINE, Issue 7 2006V Reliquet Objectives Data on the durability of antiretroviral regimens over a 3-year period have only rarely been reported. The aim of this study was to evaluate the long-term efficacy and safety of one or two daily doses of nevirapine (NVP), in combination with stavudine (d4T) and didanosine (ddI), in HIV-infected patients. Methods This study was a follow-up of the VIR (amune) Grand Ouest (VIRGO) study, a 12-month open-label trial to assess the safety and immunovirological activity of NVP-d4T-ddI combination therapy in antiretroviral-naive HIV-1-infected adults with baseline CD4 counts ,200 cells/,L and plasma viral loads ,5000 HIV-1 RNA copies/mL. Of the 100 patients included in the study, the 67 patients remaining on the initial triple therapy at the end of the study (1 year) were offered an extra 24 months of follow-up. Results Of the 60 patients who extended follow-up, 46 were still being treated with d4T-ddI-NVP at month 36; 91% (39/43) had a plasma viral load <500 copies/mL (data were missing for three patients). CD4 cell counts increased over 36 months. Safety and tolerance were good with no unexpected long-term toxicity. Conclusion After 3 years of treatment with NVP-d4T-ddI, nearly half of the patients were still receiving the initial antiretroviral therapy with a sustained and durable immunovirological benefit. Long-term toxicity was mainly related to the nucleoside reverse transcriptase inhibitor components of the regimen. [source] Plasma lipid concentrations after 1.5 years of exposure to nevirapine or efavirenz together with stavudine and lamivudineHIV MEDICINE, Issue 6 2006F Van Leth Objectives To assess long-term changes in lipids and lipoproteins concentrations associated with exposure to non-nucleoside reverse transcriptase inhibitors. Methods Long-term analysis of plasma lipid concentrations was performed in patients starting first-line antiretroviral therapy with stavudine (d4T) and lamivudine, and either nevirapine or efavirenz. Results Concentrations of total cholesterol, low-density lipoprotein cholesterol and triglycerides continued to increase, while high-density lipoprotein cholesterol showed a slight decrease compared with earlier reported increases after 48 weeks. Conclusions Changes in body fat distribution expected to occur with continued exposure to d4T could offer a potential explanation for these findings. [source] The value of serum albumin in pretreatment assessment and monitoring of therapy in HIV/AIDS patientsHIV MEDICINE, Issue 6 2006HO Olawumi Objectives We sought to examine the utility of serum albumin measurement in staging AIDS and monitoring patients' response to therapy. Methods The possible importance of serum albumin measurement in assessing AIDS stage and in monitoring the response to highly active antiretroviral therapy using CD4 cell count and body weight as parameters was examined in 185 consecutive HIV-infected, therapy-naïve individuals who were recruited for antiretroviral therapy at the university of Ilorin Teaching Hospital. The regimen included lamivudine, stavudine and nevirapine. The diagnosis of AIDS was established through a combination of clinical features and HIV seropositivity using two different enzyme-linked immunosorbent assay techniques. Serum albumin level was determined by the Bromocresol green method, while the CD4 lymphocyte count was obtained using the Dynal T4 count method. Body weight was measured in kilograms with light clothes on. Results There were significant positive correlations between pretreatment albumin and both pretreatment CD4 cell count and pretreatment weight, and between post-treatment albumin and both post-treatment weight and post-treatment CD4 cell count up to a count of 700 cells/,L. There were also significant positive correlations between increase in serum albumin and both increase in body weight and duration of treatment. Conclusions We conclude that, in developing countries where many patients may not be able to afford to pay for CD4 cell counts and viral load tests, which are the traditional markers for HIV disease, serum albumin would be a very useful surrogate test for predicting severity of HIV infection and for clinical monitoring of response to antiretroviral therapy. [source] Clinical implications of stopping nevirapine-based antiretroviral therapy: relative pharmacokinetics and avoidance of drug resistanceHIV MEDICINE, Issue 3 2004NE Mackie Objective To 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). Methods In 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. Results The 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. Conclusions The 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. [source] Risk factors and occurrence of rash in HIV-positive patients not receiving nonnucleoside reverse transcriptase inhibitor: data from a randomized study evaluating use of protease inhibitors in nucleoside-experienced patients with very low CD4 levels (<50 cells/m,L)HIV MEDICINE, Issue 1 2004M Floridia Background Most of the studies evaluating rash in HIV-positive patients have focused on nonnucleoside reverse transcriptase inhibitors (NNRTI), particularly nevirapine, and little is known about the occurrence of rash and the risk factors for its development in patients receiving regimens not based on NNRTI. Methods We evaluated all cases of rash observed during a 48-week randomized multicentre trial in 1251 nucleoside-experienced patients who started treatment with protease inhibitors (ritonavir or indinavir) at CD4 counts below 50 cells/,L. Incidence rates for rash were calculated according to gender, clinical status, age, use of highly active antiretroviral therapy (HAART), Pneumocystis carinii pneumonia (PCP) prophylaxis and use of individual antiretroviral drugs at enrolment. Differences between groups defined according to the above characteristics were tested for statistical significance using the log-rank test in a Kaplan-Meier survival analysis. All factors that gave results in the univariate analyses below the significance level of 0.05 were included in a multivariate analysis using a Cox regression model. Results During a follow-up period of 9690 person-months, 66 patients (5.3%) developed rash (0.68 events/100 person-months). In the univariate analyses, risk of rash did not differ with trial treatment (indinavir or ritonavir), clinical status, PCP prophylaxis, or age. During follow-up, rash was observed in 7.5% of enrolled women and in 4.5% of enrolled men (P=0.03). Serious rash occurred in 4.5% of enrolled women and in 1.6% of enrolled men (P=0.003). Use of HAART (P<0.001) and inclusion of zidovudine and of zalcitabine in the prescribed regimen (P=0.02) appeared to be associated with a lower risk of rash. In the multivariate analysis, the variables that remained significantly predictive of rash were gender (risk for women compared to men: 1.65, 95% confidence interval (CI): 1.00,2.72, P=0.048) and use of a non-HAART regimen (risk for non-HAART patients compared to HAART: 2.73, 95% CI: 1.49,5.02, P=0.001). Conclusions In our study, about 5% of HIV-positive patients who started treatment with protease inhibitors at very low CD4 counts developed rash, generally in the first few weeks after treatment. Risk was significantly higher in women and in patients who did not receive a HAART regimen. Our data indicate that women have a higher risk of rash than men, also with regimens that do not include NNRTI. [source] Switch studies: a reviewHIV MEDICINE, Issue 2 2002RL Murphy Many physicians and patients wish to switch from successful protease inhibitor (PI)-based regimens to alternative regimens, usually composed of a nonnucleoside reverse transcriptase inhibitor (NNRTI) or abacavir plus two nucleoside reverse transcriptase inhibitors (NRTIs). This reflects a desire to avoid or reverse the metabolic changes observed during long-term PI-based antiretroviral therapy; to alleviate PI-associated adverse effects; and to improve adherence by simplifying the regimen. Data from a number of randomized and cohort PI switch studies are reviewed. Overall, the results of these studies are mixed, perhaps because of limitations in study design, patient number and duration of follow-up. In most studies, the frequency of virological failure is reduced by switching to a NNRTI regimen. Switching to an abacavir-based regimen is associated with two-fold higher risk of virological failure if mutations in the reverse transcriptase gene pre-exist. Improvements in metabolic and lipid abnormalities have not been uniform but favourable lipid changes have been reported, particularly after switching to nevirapine. Resolution of lipodystrophy symptoms has not been demonstrated objectively, perhaps because of insufficient follow-up and/or the role of NRTIs in this syndrome. [source] P9 Extended follow-up of ARV-naive patients treated with nevirapineHIV MEDICINE, Issue 3 2000C Sabin [source] Human immunodeficiency virus,hepatitis C coinfection: swapping new problems for newer onesINTERNAL MEDICINE JOURNAL, Issue 7 2001J. Sasadeusz Abstract Recent successes in HIV therapy have uncovered other health problems for HIV-infected individuals. Hepatitis C has become an especially significant problem, partly due to its faster progression in an immunocompromised setting. In addition, the higher viral loads in coinfected patients likely result in more efficient perinatal and perhaps even sexual transmission. Therapy has largely been neglected, despite data suggesting its efficacy in HIV,HCV coinfected patients. Studies of combination interferon and ribavirin studies are lacking, although underway. A major concern is the potential inactivation of certain thymidine analogues by ribavirin. Some antiretroviral therapies, such as ritonavir, indinavir and nevirapine, may enhance liver toxicity in coinfected patients and should be avoided if possible. The role of chronic low-grade liver function abnormalities remains uncertain and requires further investigation. (Intern Med J 2001; 31: 418,421) [source] Non-nucleoside reverse transcriptase inhibitors: a reviewINTERNATIONAL JOURNAL OF CLINICAL PRACTICE, Issue 1 2007L. Waters Summary Non-nucleoside reverse transcriptase inhibitors form the backbone of antiretroviral treatment for many HIV-infected individuals. The tolerability, pill burden and efficacy associated with this class of agents make them a frequent choice for first-line therapy. Here we review nevirapine and efavirenz in terms of efficacy, resistance and toxicity, focusing particularly on the use of nevirapine to prevent mother-to-child transmission in developing countries. [source] Systematic review of the efficacy of antiretroviral therapies for reducing the risk of mother-to-child transmission of HIV infectionJOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Issue 3 2007N. Suksomboon PhD Summary Objective:, To evaluate the efficacy of antiretroviral therapies in reducing the risk of mother-to-child transmission of HIV infection. Methods:, Systematic review and meta-analysis of randomized controlled trials. Clinical trials of antiretrovirals were identified through electronic searches (MEDLINE, EMBASE, BIOSIS, EBM review and the Cochrane Library) up until November 2006. Historical searches of reference lists of relevant randomized controlled trials, and systematic and narrative reviews were also undertaken. Studies were included if they were (i) randomized controlled trials of any antiretroviral therapy aimed at decreasing the risk of mother-to-child transmission of HIV infection, (ii) reporting outcomes in terms of HIV infection in infant, infant death, stillbirth, premature delivery, or low birth weight. The data were extracted by a single investigator and checked by a second investigator. Disagreements were resolved through discussion or a third investigator. The efficacy was estimated using relative risk (RR), risk difference (RD) and number needed to treat (NNT) together with 95% confidence intervals. Results:, Fifteen trials were included in the systematic review. Based on five placebo-controlled trials, a zidovudine regimen reduced the risk of mother-to-child transmission by 43% (95% CI: 29,55%). The incidence of low birth weight seems to be decreased with zidovudine (pooled RR 0·75, 95% CI: 0·57,0·99). The efficacy of short-short course of zidovudine was comparable with that of the long-short course. Nevirapine monotherapy given to mothers and babies as a single dose reduced the risk of vertical transmission compared with an intrapartum and post-partum regimen of zidovudine (RR 0·60, 95% CI: 0·41,0·87). Zidovudine plus lamivudine was effective in reducing the risk of maternal-child transmission of HIV (RR 0·63, 95% CI: 0·45,0·90). Adding zidovudine to single-dose nevirapine in babies was no more effective than nevirapine alone (pooled RR 0·88, 95% CI: 0·47,1·63), nor was there any significant difference between zidovudine plus lamivudine and nevirapine. In mothers who were treated with standard antiretroviral therapy, no additional benefit was observed with the addition of a single dose of nevirapine in mothers and newborns. In addition, for mothers who received zidovudine prophylaxis, a two-dose intrapartum/newborn nevirapine reduced the risk of HIV infection and death of babies by 68% (95% CI: 39,83%) and 80% (95% CI: 10,95%), respectively, when compared with placebo. Conclusions:, The available evidence suggests that zidovudine alone or in combination with lamivudine and nevirapine monotherapy is effective for the prevention of mother-to-child transmission of HIV. They may also be beneficial in reducing the risk of infant death. Different antiretroviral regimens appear to be comparably effective in reducing HIV transmission from mothers to babies. In mothers already receiving zidovudine prophylaxis, adding a single dose of nevirapine to mothers during labour and giving the same drug to infants may further decrease the risk of vertical transmission and infant death. [source] A comparison of HIV-1 drug susceptibility as provided by conventional phenotyping and by a phenotype prediction tool based on viral genotypeJOURNAL OF MEDICAL VIROLOGY, Issue 10 2009Margriet Van Houtte Abstract Concordance between the conventional HIV-1 phenotypic drug resistance assay, PhenoSenseÔ (PS), and virco®TYPE HIV-1 (vT), a drug resistance assay based on prediction of the phenotype, was investigated in a data set from the Stanford HIV Resistance database (hivdb). Depending on the drug, between 287 and 902 genotype,phenotype data pairs were available for comparisons. Test results (fold-change values) in the two assays were highly correlated, with an overall mean correlation coefficient of 0.90 using single PS measurements. This coefficient rose to 0.94 when the vT results were compared to the mean of repeat PS measurements. These results are comparable with the corresponding correlation coefficients of 0.87 and 0.95, calculated using single measurements, and the mean of repeat measurements, respectively, as obtained in the Antivirogram® assay, the conventional HIV-1 phenotypic drug resistance test on which vT is based. The proportion of resistance calls resulting in a "major" discordance (fully susceptible or maximal response by one assay but fully resistant or minimal response by the other) ranged from 0% to 8.1% for drugs for which two clinical test cut-offs were available in both assays (didanosine, abacavir, tenofovir, saquinavir/r, fosamprenavir/r, and lopinavir/r), from 2.4% to 8.1% for the drugs for which two clinical test cut-offs were available in the vT assay and one clinical test cut-off in the PS assay (lamivudine, stavudine, indinavir/r, and atazanavir/r) and from 3.1% to 10.3% for drugs for which biological test cut-offs were used (zidovudine, nevirapine, delavirdine, efavirenz, indinavir, ritonavir, nelfinavir, saquinavir, and fosamprenavir). Our analyses suggest that these assays provide comparable resistance information, which will be of value to physicians who may be presented with either or both types of test report in their practice. J. Med. Virol. 81:1702,1709, 2009. © 2009 Wiley-Liss, Inc. [source] Ultrasensitive assessment of residual HIV viraemia in HAART-treated patients with persistently undetectable plasma HIV-RNA: A cross-sectional evaluationJOURNAL OF MEDICAL VIROLOGY, Issue 3 2009Stefano Bonora Abstract Improvements in HIV-RNA assays have made accurate detection of as few as 2 copies/ml possible. This study objective was the evaluation of ultrasensitive HIV-RNA quantitation (beneath current threshold: 50 copies/ml) in patients receiving different antiretroviral regimens. A cross-sectional, ultrasensitive measurement of HIV-RNA levels (detection limit: 2.5 HIV-RNA copies/ml) was performed in 154 HIV-1-infected patients receiving ARV therapy, all classed as full responders according to the 50 copies/ml cut-off. Patients were undergoing treatment with two nucleoside/nucleotide reverse transcriptase inhibitors (N/NtRTIs) plus nevirapine (NVP, n,=,48), efavirenz (EFV, n,=,57) or lopinavir/ritonavir (LPV/r, n,=,49). Undetectable HIV-RNA (<2.5 copies/ml) occurred in 29/48 (60.4%), 24/57 (42.1%) and 14/49 (28.6%) NVP, EFV and LPV/r recipients, respectively. Mean virological-suppression (<50 copies/ml) duration was 28.6 months (median,=,22, SD,=,17.8), and only in LPV/r recipients length of suppression was associated with significantly lower HIV-RNA levels (P,=,0.015). Mean nadir CD4+ cell count of 270 cells/mm3 (median,=,240, SD,=,194.5) was significantly lower in the LPV/r arm (P,<,0.001). Nadir CD4+ level correlated with virological suppression but had opposite trends between NVP (positive) and LPV/r (negative; two tailed P,=,0.01). Logistic regression analysis showed NVP was the only independent factor associated with virologic suppression. NVP has demonstrated a distinct virological advantage at sub-clinical viral loads, possibly due to its greater penetration in extra-vascular compartments, warranting further investigation in the context of persistent low-level viraemia in long-term HAART. J. Med. Virol. 81:400,405, 2009. © 2009 Wiley-Liss, Inc. [source] Zidovudine with nevirapine for the prevention of HIV mother-to-child transmission reduces nevirapine resistance in mothers from the Western Cape, South AfricaJOURNAL OF MEDICAL VIROLOGY, Issue 6 2008G.U. van Zyl Abstract In the Western Cape province of South Africa, an intensified regimen for the prevention-of-mother-to-child-transmission-of-HIV consisting of zidovudine (AZT) from 34 weeks of pregnancy plus single dose (sd) nevirapine (NVP) during labor was instituted in 2004. The newborn baby receives a single dose of NVP and AZT for 7 days. Similar strategies in Thailand and Africa have been shown to be more effective in reducing transmission than NVP alone. The use of sd NVP only for the prevention-of-mother-to-child-transmission-of-HIV has a high risk of inducing resistance (25,69%) with an average of 35.7% by a recent meta-analysis and has been shown to adversely affect non-nucleoside reverse transcriptase inhibitor (NNRTI)-based antiretroviral therapy when initiated within 6 months. In this study the prevalence of resistance to NVP and AZT in mothers who had received the intensified regimen was measured. Specimens collected from mothers were genotyped by in-house PCR and sequencing. In specimens obtained within 60 days of delivery, acquired NVP resistance mutations were detected in 13 of 76 patients (17.1%, 95% confidence interval: 8.7,25.6%), which appears to be lower than in studies with sd NVP alone (37.5%, 95% confidence interval: 23.0,50.6%). J. Med. Virol. 80:942,946, 2008. © 2008 Wiley-Liss, Inc. [source] Expression of LINE-1 retroposons is essential for murine preimplantation developmentMOLECULAR REPRODUCTION & DEVELOPMENT, Issue 3 2006Rosanna Beraldi Abstract In higher eukaryotes, reverse transcriptase (RT) activities are encoded by a variety of endogenous retroviruses and retrotransposable elements. We previously found that mouse preimplantation embryos are endowed with an endogenous RT activity. Inhibition of that activity by the non nucleosidic inhibitor nevirapine or by microinjection of anti-RT antibody caused early embryonic developmental arrest. Those experiments indicated that RT is required for early development, but did not identify the responsible coding elements. We now show that microinjection of morpholino-modified antisense oligonucleotides targeting the 5, end region of active LINE-1 retrotransposons in murine zygotes irreversibly arrests preimplantation development at the two- and four-cell stages; the overall level of functional RT is concomitantly downregulated in arrested embryos. Furthermore, we show that the induction of embryo developmental arrest is associated with a substantial reprogramming of gene expression. Together, these results support the conclusion that expression of LINE-1 retrotransposons is required for early embryo preimplantation development. Mol. Reprod. Dev. © 2005 Wiley-Liss, Inc. [source] Probing nonnucleoside inhibitor-induced active-site distortion in HIV-1 reverse transcriptase by transient kinetic analysesPROTEIN SCIENCE, Issue 8 2007Qing Xia Abstract Nonnucleoside reverse transcriptase inhibitors (NNRTI) are a group of structurally diverse compounds that bind to a single site in HIV-1 reverse transcriptase (RT), termed the NNRTI-binding pocket (NNRTI-BP). NNRTI binding to RT induces conformational changes in the enzyme that affect key elements of the polymerase active site and also the association between the two protein subunits. To determine which conformational changes contribute to the mechanism of inhibition of HIV-1 reverse transcription, we used transient kinetic analyses to probe the catalytic events that occur directly at the enzyme's polymerase active site when the NNRTI-BP was occupied by nevirapine, efavirenz, or delavirdine. Our results demonstrate that all NNRTI,RT,template/primer (NNRTI,RT,T/P) complexes displayed a metal-dependent increase in dNTP binding affinity (Kd) and a metal-independent decrease in the maximum rate of dNTP incorporation (kpol). The magnitude of the decrease in kpol was dependent on the NNRTI used in the assay: Efavirenz caused the largest decrease followed by delavirdine and then nevirapine. Analyses that were designed to probe direct effects on phosphodiester bond formation suggested that the NNRTI mediate their effects on the chemistry step of the DNA polymerization reaction via an indirect manner. Because each of the NNRTI analyzed in this study exerted largely similar phenotypic effects on single nucleotide addition reactions, whereas each of them are known to exert differential effects on RT dimerization, we conclude that the NNRTI effects on subunit association do not directly contribute to the kinetic mechanism of inhibition of DNA polymerization. [source] Nevirapine-Induced Stevens Johnson,Syndrome and Fulminant Hepatic Failure Requiring Liver TransplantationAMERICAN JOURNAL OF TRANSPLANTATION, Issue 7 2010J. Jao We describe a case of nevirapine-induced Stevens,Johnson Syndrome (SJS) and fulminant hepatic failure (FHF) requiring liver transplantation. Five weeks prior to admission, a 57-year-old female with HIV infection had been switched to a nevirapine-based regimen of highly active antiretroviral therapy (HAART) with a CD4 cell count of 695/mm3. Examination of the explanted native liver at initial transplantation revealed massive hepatic necrosis consistent with drug-induced liver injury. Primary graft nonfunction complicated the early postoperative course and liver retransplantation was required. On follow-up 2 years later, she remains in good health with an undetectable viral load on an efavirenz-based regimen of HAART. To our knowledge, this is the first report of successful liver transplantation following SJS and FHF. 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