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Transcriptase Inhibitors (transcriptase + inhibitor)
Kinds of Transcriptase Inhibitors Selected AbstractsSynthesis of Novel Uracil Non-Nucleoside Derivatives as Potential Reverse Transcriptase Inhibitors of HIV-1ARCHIV DER PHARMAZIE, Issue 11 2009Nasser R. El-Brollosy Abstract Novel emivirine and TNK-651 analogues 5a,d were synthesized by reaction of chloromethyl ethyl ether and / or benzyl chloromethyl ether, respectively, with uracils having 5-ethyl and 6-(4-methylbenzyl) or 6-(3,4-dimethoxybenzyl) substituents. A series of new uracil non-nucleosides substituted at N-1 with cyclopropylmethyloxymethyl 9a,d, 2-phenylethyloxymethyl 9e,h, and 3-phenylprop-1-yloxymethyl 9i,l were prepared on treatment of the corresponding uracils with the appropriate acetals 8a,c. Some of the tested compounds showed good activity against HIV-1 wild type. Among them, 1-cyclopropylmethyloxymethyl-5-ethyl-6-(3,5-dimethylbenzyl)uracil 9c and 5-ethyl-6-(3,5-dimethylbenzyl)-1-(2-phenylethyloxymethyl)uracil 9g showed inhibitory potency equally to emivirine against HIV-1 wild type. Furthermore, compounds 9c and 9g showed marginal better activity against NNRTI resistant mutants than emivirine. [source] ChemInform Abstract: Synthesis of Novel Uracil Non-Nucleoside Derivatives as Potential Reverse Transcriptase Inhibitors of HIV-1.CHEMINFORM, Issue 11 2010Nasser R. El-Brollosy Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a "Full Text" option. The original article is trackable via the "References" option. [source] Design, Synthesis, and Biological Evaluations of Novel Oxindoles as HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors.CHEMINFORM, Issue 30 2006Part 2. Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF. [source] Design, Synthesis and Biological Evaluations of Novel Oxindoles as HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors.CHEMINFORM, Issue 29 2006Part 1. Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF. [source] Newer Aminopyrimidinimino Isatin Analogues as Non-Nucleoside HIV-1 Reverse Transcriptase Inhibitors for HIV and Other Opportunistic Infections of AIDS: Design, Synthesis and Biological Evaluation.CHEMINFORM, Issue 39 2005D. Sriram Abstract For Abstract see ChemInform Abstract in Full Text. [source] ChemInform Abstract: 3,3a-Diyhdropyrano[4,3,2-de]quinazolin-2(1H)-ones Are Potent Non-Nucleoside Reverse Transcriptase Inhibitors.CHEMINFORM, Issue 16 2001Jeffrey W. Corbett Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a "Full Text" option. The original article is trackable via the "References" option. [source] Centrosome amplification induced by the antiretroviral nucleoside reverse transcriptase inhibitors lamivudine, stavudine, and didanosineENVIRONMENTAL AND MOLECULAR MUTAGENESIS, Issue 8 2009Mia Yu Abstract In cultured cells, exposure to the nucleoside reverse transcriptase inhibitor (NRTI) zidovudine (AZT) induces genomic instability, cell cycle arrest, micronuclei, sister chromatid exchanges, and shortened telomeres. In previous studies, we demonstrated AZT-induced centrosome amplification (>2 centrosomes/cell). Here, we investigate centrosome amplification in cells exposed to other commonly used NRTIs. Experiments were performed using Chinese Hamster ovary (CHO) cells, and two normal human mammary epithelial cell (NHMEC) strains: M99005 and M98040, which are high and low incorporators of AZT into DNA, respectively. Cells were exposed for 24 hr to lamivudine (3TC), stavudine (d4T), didanosine (ddI), and thymidine, and stained with anti-pericentrin antibody. Dose response curves were performed to determine cytotoxicity and a lower concentration at near plasma levels and a 10 fold higher concentration were chosen for the experiments. In CHO cells, there was a concentration-dependent, significant (P < 0.05) increase in centrosome amplification for each of the NRTIs. In NHMEC strain M99005, an NRTI-induced increase (P < 0.05) in centrosome amplification was observed for the high concentrations of each NRTI and the low doses of 3TC and ddI. In NHMEC strain M98040, the high doses of ddI and d4T showed significant increases in centrosome amplification. Functional viability of amplified centrosomes was assessed by arresting microtubule nucleation with nocodazole. In cells with more than two centrosomes, the ability to recover microtubule nucleation was similar to that of unexposed cells. We conclude that centrosome amplification is a consequence of exposure to NRTIs and that cells with centrosome amplification are able to accomplish cell division. Environ. Mol. Mutagen., 2009. © 2009 Wiley-Liss, Inc. [source] HIV-1 proviral resistance mutations: usefulness in clinical practiceHIV MEDICINE, Issue 8 2010B Kabamba-Mukadi Objectives Transmitted HIV strains may harbour drug resistance mutations. HIV-1 drug resistance mutations are currently detected in plasma viral RNA. HIV-1 proviral DNA could be an alternative marker, as it persists in infected cells. Methods This was a prospective study assessing the prevalence and persistence of HIV-1 drug resistance mutations in DNA from CD4 cells before and after protease inhibitor (PI)- or nonnucleoside reverse transcriptase inhibitor (NNRTI)-based therapy initiation in 69 drug-naïve patients. Results Before therapy, 90 and 66% of detected mutations were present in CD4 cells and plasma, respectively. We detected seven key mutations, and four of these (M184M/V, M184M/I, K103K/N and M46M/I) were only found in the cells. When treatment was started, 40 patients were followed; the mutations detected at the naïve stage remained present for at least 1 year. Under successful treatment, new key mutations emerged in CD4 cells (M184I, M184M/I and Y188Y/H). Conclusions The proportion of mutations detected in the DNA was statistically significantly higher than that detected in standard RNA genotyping, and these mutations persisted for at least 1 year irrespective of therapy. The pre-existence of resistance mutations did not jeopardise treatment outcome when the drug concerned was not included in the regimen. Analysis of HIV-1 DNA could be useful in chronic infections or when switching therapy in patients with undetectable viraemia. [source] No significant effect of uridine or pravastatin treatment for HIV lipoatrophy in men who have ceased thymidine analogue nucleoside reverse transcriptase inhibitor therapy: a randomized trial,HIV MEDICINE, Issue 8 2010A Calmy Background Lipoatrophy can complicate thymidine analogue nucleoside reverse transcriptase inhibitor (tNRTI)-based antiretroviral therapy (ART). Lipoatrophy may be less likely with ART including ritonavir-boosted lopinavir (LPV/r). Small, placebo-controlled studies found that uridine (in tNRTI recipients) and pravastatin improved HIV lipoatrophy over 12 weeks. Today, most patients with lipoatrophy receive non-tNRTI-based ART; the effect of uridine in such patients is unknown. Methods We performed a prospective, randomized trial in lipoatrophic adults with plasma HIV RNA<50 HIV-1 RNA copies/mL on tNRTI-sparing ART including LPV/r. Patients received uridine [36 g three times a day (tid) on 10 consecutive days per month; n=10], pravastatin [40 mg every night (nocte); n=12], uridine plus pravastatin (n=11) or neither (n=12) for 24 weeks. The primary endpoint was mean change in limb fat mass as assessed by dual-energy X-ray absorptiometry (DEXA). With 20 patients per intervention, the study had 80% power to detect a mean difference between a treatment and the control of 0.5 kg, assuming a standard deviation of 0.9 and an alpha threshold equal to 5% (two-sided). Results Of 45 participants (all men, with median age 49.5 years and median limb fat 2.6 kg), two discontinued pravastatin and one participant stopped both pravastatin and uridine. The difference between the mean changes in limb fat mass for uridine vs. no uridine was 0.03 kg [95% confidence interval (CI) ,0.35, +0.28; P=0.79]. The respective difference for pravastatin was ,0.03 kg (95% CI ,0.29, +0.34; P=0.84). Pravastatin slightly decreased total cholesterol (0.44 mmol/L; P=0.099). Visceral adipose tissue measured by computed tomography did not change significantly. Conclusion In this population and at the doses used, neither uridine nor pravastatin for 24 weeks significantly increased limb fat mass. [source] PENTA 2009 guidelines for the use of antiretroviral therapy in paediatric HIV-1 infectionHIV MEDICINE, Issue 10 2009PENTA Steering Committee PENTA Guidelines aim to provide practical recommendations for treating children with HIV infection in Europe. Changes to guidance since 2004 have been informed by new evidence and by expectations of better outcomes following the ongoing success of antiretroviral therapy (ART). Participation in PENTA trials of simplifying treatment is encouraged. The main changes are in the following sections: ,When to start ART': Treatment is recommended for all infants, and at higher CD4 cell counts and percentages in older children, in line with changes to adult guidelines. The number of age bands has been reduced to simplify and harmonize with other paediatric guidelines. Greater emphasis is placed on CD4 cell count in children over 5 years, and guidance is provided where CD4% and CD4 criteria differ. ,What to start with': A three-drug regimen of two nucleoside reverse transcriptase inhibitors (NRTIs) with either a nonnucleoside reverse transcriptase inhibitor (NNRTI) or a boosted protease inhibitor (PI) remains the first choice combination. Lamivudine and abacavir are the NRTI backbone of choice for most children, based on long-term follow-up in the PENTA 5 trial. Stavudine is no longer recommended. Whether to start with an NNRTI or PI remains unclear, but PENPACT 1 trial results in 2009 may help to inform this. All PIs should be ritonavir boosted. Recommendations on use of resistance testing, therapeutic drug monitoring and HLA testing draw from data in adults and from European paediatric cohort studies. Recently updated US and WHO paediatric guidelines provide more detailed review of the evidence base. Differences between guidelines are highlighted and explained. [source] Effects of nucleoside reverse transcriptase inhibitor backbone on the efficacy of first-line boosted highly active antiretroviral therapy based on protease inhibitors: meta-regression analysis of 12 clinical trials in 5168 patientsHIV MEDICINE, Issue 9 2009A Hill Objectives Tenofovir/emtricitabine (TDF/FTC) and abacavir/lamivudine (ABC/3TC) are widely used with ritonavir (RTV)-boosted protease inhibitors (PIs) as first-line highly active antiretroviral therapy (HAART), but there is conflicting evidence on their relative efficacy. The ACTG 5202 and BICOMBO trials suggested higher efficacy for TDF/FTC, whereas the HEAT trial showed no efficacy difference between the nucleoside reverse transcriptase inhibitor (NRTI) backbones. Methods A systematic MEDLINE search identified 21 treatment arms in 12 clinical trials of 5168 antiretroviral-naïve patients, where TDF/FTC (n=3399) or ABC/3TC (n=1769) was used with RTV-boosted PI. For each NRTI backbone and RTV-boosted PI, the percentage of patients with viral load <50 HIV-1 RNA copies/mL at week 48 by standardized Intent to Treat, Time to Loss of Virological Failure (ITT TLOVR) analysis were combined using inverse-variance weighting. The effect of baseline HIV RNA, CD4 cell count and choice of NRTI backbone were examined using a weighted analysis of covariance. Results Across all the trials, HIV RNA suppression rates were significantly higher for those with baseline viral load below 100 000 copies/mL (77.2%) vs. above 100 000 copies/mL (70.9%) (P=0.0005). For the trials of lopinavir/ritonavir (LPV/r), atazanavir/ritonavir (ATV/r) and fosamprenavir/ritonavir (FAPV/r) using either TDF/FTC or ABC/3TC, the HIV RNA responses were significantly lower when ABC/3TC was used, relative to TDF/FTC, for all patients (P=0.0015) and for patients with baseline viral load <100 000 copies/mL (70.1%vs. 80.6%, P=0.0161), and was borderline for those with viral load >100 000 copies/mL (67.5%vs. 71.5%, P=0.0523). Conclusions This systematic meta-regression analysis suggests higher efficacy for first-line use of a TDF/FTC NRTI backbone with boosted PIs, relative to use of ABC/3TC. However, this effect may be confounded by differences between the trials in terms of baseline characteristics, patient management or adherence. [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] Increased rate of prematurity associated with antenatal antiretroviral therapy in a German/Austrian cohort of HIV-1-infected womenHIV MEDICINE, Issue 1 2008I Grosch-Woerner Objective The aim of the study was to assess the risk of adverse pregnancy outcomes after antenatal antiretroviral therapy in a well-defined prospective cohort of nontransmitting HIV-infected women. Methods Prospective monitoring of 183 mother,child pairs from 13 centres in Germany and Austria, delivering between 1995 and 2001, was carried out. Following German,Austrian guidelines recommending an elective Caesarean section (CS) at 36 weeks, prematurity was defined as <36 weeks' gestation for these analyses. Results Of 183 mother,child pairs, 42% were exposed to antenatal monotherapy and 17% to dual therapy. Of the 75 women exposed to highly active antiretroviral therapy (HAART), 21 (28%) received protease inhibitor (PI)-based HAART and the remaining 54 received nonnucleoside reverse transcriptase inhibitor-based HAART. In multivariable analysis (176 pregnancies), PI-based HAART exposure during pregnancy was associated with an increased risk of premature delivery [adjusted odds ratio 3.40; 95% confidence interval (CI) 1.13,10.2; P=0.029, compared with monotherapy]. Congenital abnormalities affected 3.3% infants. Perinatally, 18.9% of children (34 of 179) had respiratory problems requiring interventions, which were associated with prematurity but not with type of treatment exposure. From adjusted regression analysis, the mean birth weight z -score for children exposed to HAART with PI (+0.46; 95% CI 0.01,0.92; P=0.047) or dual therapy (+0.43; 95% CI 0.03,0.82; P=0.034) was slightly but significantly higher than that for those exposed to monotherapy; head circumference was appropriate for gestational age and there were no significant differences between treatment groups. Conclusions Use of antenatal PI-based HAART initiated before or during pregnancy was associated with a significantly increased risk of premature delivery at <36 weeks' gestation. The overall crude prematurity rate was 34% (63 of 183; 95% CI 28,42). [source] Antiviral activity of low-dose alovudine in antiretroviral-experienced patients: results from a 4-week randomized, double-blind, placebo-controlled dose-ranging trial,HIV MEDICINE, Issue 3 2007J Ghosn Background Alovudine inhibits replication of highly nucleoside reverse transcriptase inhibitor (NRTI)-resistant HIV strains in vitro. However, dose-dependent safety concerns resulted in its initial development being halted. Recently, a 4-week course of alovudine 7.5 mg/day added to a stavudine-free failing regimen yielded a significant decrease in viral load by ,1.88 log10 HIV-1 RNA copies/mL. The magnitude of the reduction in viral load suggested that lower doses might still be effective while offering adequate safety during long-term use. Objective To determine whether lower dosages of alovudine still provide significant antiviral activity in patients with broad NRTI resistance. Methods A randomized, double-blind, placebo-controlled trial investigating three doses of alovudine (0.5, 1 and 2 mg) or placebo added for 4 weeks to a failing regimen in patients with evidence of NRTI-resistant HIV strains [,2 thymidine-associated mutations (TAMs)]. The primary endpoint was the mean viral load reduction between baseline and week 4. Results Seventy-two patients were enrolled in the study: 21, 13, 18 and 20 in the placebo and 0.5, 1 and 2 mg arms, respectively. Baseline median CD4 count and viral load were 298 cells/,L (range 44,692 cells/,L) and 3.9 log10 copies/mL (range 2.5,5.2 log10 copies/mL), respectively. Baseline viral isolates harboured a median of four TAMs. Alovudine was added to a median four-drug failing regimen. At week 4, compared with placebo, mean viral load changes were ,0.42 log10 [95% confidence interval (CI) ,0.67 to ,0.18] and ,0.30 log10 (,0.55 to ,0.06) in the 2 and 1 mg arms, respectively. There was no significant change in CD4 cell count. Alovudine was well tolerated. Conclusion: A 4-week course of alovudine 2 mg/day provided a modest but significant viral load reduction in patients harbouring viruses with a median of four TAMs. [source] Effect of concurrent zidovudine use on the resistance pathway selected by abacavir-containing regimensHIV MEDICINE, Issue 6 2004ER Lanier Objectives Abacavir (ABC) selects for four mutations (K65R, L74V, Y115F and M184V) in HIV-1 reverse transcriptase (RT), both in vitro and during monotherapy in vivo. The aim of this analysis was to compare the selection of these and other nucleoside reverse transcriptase inhibitor (NRTI)-associated mutations by ABC-containing therapies in the presence and absence of concurrent lamivudine (3TC) and/or zidovudine (ZDV) and to assess the effect of these mutations on phenotypic susceptibility to the NRTIs. Design This study was a retrospective analysis of the patterns of NRTI-associated mutations selected following virological failure in six multicentre trials conducted during the development of ABC. Methods Virological failure was defined as confirmed vRNA above 400 HIV-1 RNA copies/mL. RT genotype and phenotype were determined using standard methods. Results K65R was selected infrequently by ABC-containing regimens in the absence of ZDV (13 of 127 patients), while L74V/I was selected more frequently (51 of 127 patients). Selection of both K65R and L74V/I was significantly reduced by co-administration of ZDV with ABC (one of 86 and two of 86 patients, respectively). Y115F was uncommon in the absence (seven of 127 patients) or presence (four of 86 patients) of ZDV. M184V was the most frequently selected mutation by ABC alone (24 of 70 patients) and by ABC plus 3TC (48 of 70 patients). Thymidine analogue mutations were associated with ZDV use. The K65R mutation conferred the broadest phenotypic cross-resistance of the mutations studied. Conclusions The resistance pathway selected upon virological failure of ABC-containing regimens is significantly altered by concurrent ZDV use, but not by concurrent 3TC use. These data may have important implications for the efficacy of subsequent lines of NRTI therapies. [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] TRIZAL study: switching from successful HAART to TrizivirTM (abacavir-lamivudine-zidovudine combination tablet): 48 weeks efficacy, safety and adherence resultsHIV MEDICINE, Issue 2 2003C Katlama Objective To assess the antiviral efficacy, safety, and adherence in subjects who switched to TrizivirÔ following long-term HIV-1 RNA suppression. Study design A randomized, open-label, multicentre, 48-week comparative study in subjects who have received two nucleoside reverse transcriptase inhibitors plus a protease inhibitor or an nonnucleoside reverse transcriptase inhibitor or three nucleoside reverse transcriptase inhibitors for at least 6 months, with a history of undetectable plasma HIV-1 RNA since initiation of therapy and plasma viral load of < 50 HIV-1 RNA copies/mL at screening. Methods Subjects were randomized 1:1 to continue their current treatment or to switch to a simplified treatment with TrizivirÔ administered twice daily. Assessments included plasma HIV-1 RNA, lymphocyte counts, clinical laboratory evaluations, adverse events, and adherence to treatment (obtained via subject self-report). Treatment failure was defined as a plasma viral load of , 400 HIV-1 RNA copies/mL on two consecutive occasions or premature discontinuation of randomized treatment. Results At week 48, the proportion of treatment failures in TrizivirÔ arm (23/106, 22%) was noninferior to that observed in continued arm (23/103, 22%) with a treatment difference stratified by prior ART of 1.2%[-10.1; 12.5]. Incidence of adverse events was similar in both treatment groups. The incidence of possible hypersensitivity reaction in the TrizivirÔ arm was 10%. Significant reductions in cholesterol and triglyceride plasma levels were observed in the TrizivirÔ arm (P < 0.001 and P = 0.006, respectively). Conclusion Switching to TrizivirÔ offers a potent and simplified regimen with equivalent efficacy and significant improvement in lipid abnormalities compared to continued triple therapy. [source] Determinants of adherence to highly active antiretroviral therapy (HAART) in Chinese HIV/AIDS patientsHIV MEDICINE, Issue 2 2003OW Fong Objective Drug adherence is crucial to the success of highly active antiretroviral therapy (HAART) in the treatment of HIV disease. Adherence to HAART and its determinants may, however, differ across HIV/AIDS populations. Methods We retrospectively studied drug adherence by self-report in HIV-1 infected Chinese patients who have been on HAART for at least 1 year as at the end of year 2000. HAART is defined as three or more antiretrovirals with at least one protease inhibitor or non-nucleoside analogue reverse transcriptase inhibitor. Results The last drug adherence level assessed by self-report in 161 Chinese patients were: grade A (100%) , 130, 80.7%; grade B (95,99%) , 25, 15.5%; grade C (90,94%) , three, 1.9% and grade D (< 90%) , three, 1.9%. Patients with full adherence were more likely to have undetectable (< 500 copies/mL) plasma virus level (adjusted OR, 4.22; 95% CI, 1.75,12.33). Patients' demographics, HIV disease status and antiretroviral regimen did not affect adherence. Partial drug adherence was, however, independently associated with the psychosocial factors of missing clinic appointments (adjusted OR, 3.13; 95% CI, 1.23,8.33), forgetfulness (adjusted OR, 4.55; 95% CI, 1.64,12.5) and a busy work life (adjusted OR, 6.67; 95% CI, 1.75,25). Conclusion There were similarities and differences in determinants affecting HAART adherence in Chinese compared with other patients. Psychosocial factors rather than HIV disease or treatment were more important factors in our Chinese patients. The relevance of patient populations and care setting for adherence to HAART shall be further studied. [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] The prevalence of lipodystrophy in an ambulant HIV-infected population: it all depends on the definitionHIV MEDICINE, Issue 3 2001VM Carter Objectives This study's objective was to determine the prevalence of body shape changes and metabolic abnormalities in an ambulant population with HIV infection. Three different definitions of lipodystrophy were used to assess these changes. Patients' anthropometric measures and dual-energy X-ray absorptiometry (DEXA) scans were compared in order to estimate fat distribution in this population. We sought to evaluate potential predictors for lipodystrophy according to each of the three definitions. Methods We performed a cross-sectional study in the outpatient clinic of a tertiary referral hospital in Melbourne, Australia. We enrolled a total of 167 HIV-infected ambulatory patients over 3 months in mid-1998. Data on 159 males, 149 of whom were receiving triple combination antiretroviral therapy, were evaluated. Anthropometric measures, clinical examination, self-report of body shape changes, biochemical measures and DEXA scan were used to assess lipodystrophy and risk factors for cardiovascular disease. Patients described body shape changes in the face, trunk, arms and legs. Laboratory parameters measured included fasting triglyceride (TG), cholesterol, high-density lipoproteins (HDL), glucose, insulin, CD4 cell count and plasma HIV RNA. Current and past antiretroviral therapies were ascertained. Results According to one proposed Australian national definition of lipodystrophy (LDNC), the prevalence of lipodystrophy in this population was 65%. This definition included an objective assessment with major and minor criteria. Patient-defined lipodystrophy (LDP), which involved a subjective assessment of thinning arms and legs and central adiposity, occurred in 19%. Patient-defined lipoatrophy (LAP), which involved a subjective assessment of thinning arms and legs without central adiposity, occurred in 21.3%. No change in body habitus was noted by 37% of the cohort. Hypercholesterolaemia was recorded in 44%, hypertriglyceridaemia in 52% and elevated insulin levels in 23%. Anthropometry was predictive of the per cent total body fat recorded by DEXA scan, but produced consistently lower values. In multivariate analysis, LDP and LAP were significantly associated with stavudine (d4T) use, while LAP was also associated with zidovudine (ZDV) treatment. There were no treatment associations with LDNC. Protease inhibitor (PI) exposure was associated with metabolic changes but not patient perceived body shape changes, while d4T and ZDV exposure was associated with increased triglycerides and reduced peripheral fat stores. Conclusions The prevalence of body shape changes in a single population varied depending on the definition applied. The LDNC definition overestimated body shape abnormalities in comparison with patient perception. LAP was associated with significantly lower fat stores measured by anthropometry and DEXA scan than those identified under the LDNC definition. In contrast to LDNC, LAP was associated with d4T exposure, nucleoside reverse transcriptase inhibitor (NRTI) and ZDV duration of use, but not PI use. Until a consensus definition for lipodystrophy is developed, including agreement on objective measurement and thresholds for abnormality, careful description of the individual components of the syndrome is required to enable cohort comparisons so that predictors of the syndrome can be assessed more accurately and outcome studies made feasible. [source] Evidence for prolonged clinical benefit from initial combination antiretroviral therapy: Delta extended follow-upHIV MEDICINE, Issue 3 2001Delta Coordinating Committee Background The findings from therapeutic trials in HIV infection with surrogate endpoints based on laboratory markers are only partially relevant for clinical decisions on treatment. Although the collection of clinical follow-up data from such a trial would be relatively straightforward, this rarely occurs. An important reason for this may be the perception that such data have little value because the number of participants remaining on their original allocated therapy has usually fallen substantially. Methods Delta was an international, multicentre trial in which 3207 HIV infected individuals were randomly allocated to treatment with zidovudine (ZDV) alone, ZDV combined with didanosine (ddI) or ZDV combined with zalcitabine (ddC). Although the trial closed in September 1995, information on vital status, AIDS events, treatment changes and CD4 counts was still collected every 12 months until at least March 1997. This has allowed analyses of the longer term clinical effect of treatment. Results The median follow-up to date of death or last known vital status was 43 months (10th percentile 18 months; 90th percentile 55 months). The proportion of participants remaining on their allocated treatment fell steadily over time; by 4 years after trial entry, 3% remained on ZDV, 20% on ZDV + ddI and 21% on ZDV + ddC. Changes mainly involved the stopping, addition or switching of a nucleoside reverse transcriptase inhibitor (NRTIs). There was little use of protease inhibitors (PIs) or non-nucleoside reverse transcriptase inhibitors (NNRTIs) before the third year of the trial. Between the third and fourth years, regimens included a drug from one of these classes for approximately 17% of person-time in all treatment groups. Relative to ZDV monotherapy, the beneficial effects of combination therapy on mortality and disease progression rates increased significantly with time since randomization. The maximum effects on mortality were observed between 2 and 3 years, with a 48% reduction for ZDV + ddI and a 26% reduction for ZDV + ddC. These rates were observed when the original allocated treatment was received 42% and 47% of the time in the ZDV + ddI and ZDV + ddC groups, respectively. The mean CD4 count remained significantly higher (approximately 50 cells/,L) in the combination therapy groups 4 years after randomization, suggesting a projection of a clinical benefit beyond this time point. Conclusions The sustained clinical effect of the initial allocation to combination therapy, particularly ZDV + ddI, was remarkable in light of the convergence of drug regimens actually received across the three treatment groups. Interpretation of this finding is not straightforward. One of the possible explanations is that the effectiveness of ddI and ddC is diminished if first used later in infection or with greater prior exposure to ZDV, although the data do not clearly support either hypothesis. This analysis highlights the value of long-term clinical follow-up of therapeutic trials in HIV infection, which should be considered in the planning of all new studies. [source] A convenient synthesis of 5- and 8-nitroquinazoline-2,4-dione derivativesJOURNAL OF HETEROCYCLIC CHEMISTRY, Issue 2 2002D. Aziane 3-Nitrophthalic acid 1 was converted selectively to the two regioisomeric monoesters 2 and 3, which were subsequently transformed via Curtius rearrangement to the corresponding 5- and 8-nitroquinazoline-2,4-diones 4 and 5, respectively. The reduction of the nitro group produced 5- and 8-aminoquinazoline-2,4-diones 6 and 7, respectively, in good yields. The condensation of compounds 7b and 7c with carbon disulfide in pyridine afforded tricyclic derivatives 9, which are analogues of the HIV-1 reverse transcriptase inhibitor 4,5,6,7-tetrahydro-5-methylimidazo[4,5,1- jk][1,4]benzodiazepin-2(1H)-one(TIBO). [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] Therapeutic immunization with Modified Vaccinia Virus Ankara (MVA) vaccines in SIV-infected rhesus monkeys undergoing antiretroviral therapyJOURNAL OF MEDICAL PRIMATOLOGY, Issue 1 2007Klaus Überla Abstract Background, The long-term benefits of highly active antiretroviral therapy in HIV-infected patients are limited by emergence of drug-resistant variants and side effects. Therefore, we studied the concept of therapeutic immunization in 18 rhesus monkeys infected with a highly pathogenic simian immunodeficiency virus (SIV) swarm. Methods, Monkeys were treated with the reverse transcriptase inhibitor (R)-9-(2-phosphonylmethoxypropyl)adenine (PMPA) for 19 weeks starting 10 days after infection. After suppression of viremia, one group of monkeys was immunized with recombinant modified vaccinia virus Ankara (MVA) vectors expressing gag-pol and env. A second group received MVA vectors expressing the regulatory genes tat, rev and nef, while a third group was not immunized. Results, Immunization with gag-pol and env expressing MVA enhanced SIV antibody titers. Following discontinuation of PMPA treatment, a rebound in viral load was observed. However, in three of six monkeys immunized with MVA gag-pol and MVA env, and two of six monkeys immunized MVA expressing regulatory genes set point RNA levels were below or close to a threshold level of 104 RNA copies/ml, while only one of six unvaccinated monkeys maintained such low RNA levels. Conclusions, Although a subset of animals seem to benefit from therapeutic immunization with MVA vectors, the difference in set point RNA levels between the groups did not reach statistical significance. [source] Prediction of the virological response to etravirine in clinical practice: Comparison of three genotype algorithms,,JOURNAL OF MEDICAL VIROLOGY, Issue 4 2009Laurent Cotte Abstract The current Agence Nationale de Recherche sur le SIDA (ANRS)/International AIDS Society (IAS) algorithm predicts resistance to etravirine for viruses harboring ,3 mutations from a list of 13 reverse transcriptase (RT) mutations. Two weighted algorithms, best correlated with fold changes to etravirine, have been described recently. A retrospective virological analysis of a major French city HIV sequences database was undertaken to assess the proportion of etravirine resistant viruses according to these three algorithms and the correlations between them. Two thousand six hundred eighty RT sequences were analyzed, including 749 from naive patients and 926 from patients previously treated with non-nucleoside reverse transcriptase inhibitor (NNRTI). Combinations of mutations associated with etravirine resistance according to the three algorithms were found in 0%, 2.3%, and 3.6% of naive patients, and in 2.4%, 20.4%, and 19.3% of patients previously treated with NNRTIs. Concordance between the algorithms was weak (2,×,2 Kendall's tau: 0.787, 0.395, and 0.584). Most of the discordance was due to the differential weights attributed to Y181C/V, L100I, and K101P in the two weighted algorithms. It is concluded that the current ANRS/ IAS algorithm probably underestimates the proportion of viruses partially resistant to etravirine in NNRTI-experienced patients. Improvements in algorithms are needed to take into account the partial resistance associated with some mutation patterns, and should include either additional mutations to the current list and/or differential weights for specific mutations. Surveys of naive patients should be conducted to estimate the risk of primary resistance to etravirine in a minority of cases. J. Med. Virol. 81:672,677, 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 levels of MDR1, MRP1, MRP4, and MRP5 in peripheral blood mononuclear cells from HIV infected patients failing antiretroviral therapyJOURNAL OF MEDICAL VIROLOGY, Issue 5 2008Ombretta Turriziani Abstract The aim of the study was to evaluate the mRNA expression of four relevant ABC-transporter genes [MDR1 (P-glycoprotein; Pgp), MRP1, MRP4, and MRP5] in HIV-positive individuals failing treatment and analyze the association between the levels of their expression and viral load, CD4 cell count, and therapeutic history. Ninety-eight HIV-positive samples and 20 samples from healthy donors were analyzed, retrospectively. Peripheral blood mononuclear cells (PBMCs) from HIV1-positive individuals were collected at the time of virological failure. Expression of mRNA of Pgp, MRP1, MRP4, and MRP5 in PBMCs was evaluated by real-time PCR. A high inter-individual variability was observed in both HIV-positive individuals and healthy donors but the expression levels of all mRNA analyzed were significantly higher in the HIV-infected group (P,<,0.05). A weak but significant inverse correlation was observed between CD4 cell counts and expression levels of MRP4 and MRP5. Comparison of mRNA expression between individuals with different therapeutic histories showed that expression of MRP4 and MRP5 genes in patients who were both protease inhibitor (PI) and non-nucleoside reverse transcriptase inhibitor (NNRTI)-experienced was significantly higher than in patients who were PI experienced but NNRTI-naïve. In conclusion, the mRNA expression of Pgp, MRP1, MRP4, and MRP5 varies among HIV-infected patients and healthy donors but is significantly higher in HIV-positive patients than in donors. The expression of MRP4 and MRP5 seems to correlate with CD4 cell counts. The same protein seems to be overexpressed in patients receiving NNRTIs. J. Med. Virol. 80:766,771, 2008. © 2008 Wiley-Liss, Inc. [source] Prevalence and risk factors associated with antiretroviral resistance in HIV-1-infected childrenJOURNAL OF MEDICAL VIROLOGY, Issue 9 2007Constance Delaugerre Abstract In the USA and West Europe, nearly 80% of HIV-1-infected adults, experiencing virologic failure, harbored virus strain resistant to at least one antiretroviral drug. Limited data are available on antiretroviral drug resistance in pediatric HIV infection. The aims of this study were to analyze prevalence of HIV-1 drug resistance and to identify risk factors associated with resistance in this population. Prevalence of genotypic resistance was estimated retrospectively in treated children who experienced virologic failure (with HIV-1-RNA,>,500 copies/ml) followed in Necker hospital between 2001 and 2003. Among 119 children with resistance testing, prevalence of resistance to any drug was 82.4%. Resistance ranged from 76.5% to nucleoside reverse transcriptase inhibitor (NRTI), to 48.7% to non-nucleoside reverse transcriptase inhibitor (NNRTI) and 42.9% to protease inhibitor (PI). Resistance to at least one drug of two classes and three classes (triple resistance) was 31.9 and 26.9%, respectively. Resistance was not associated with geographic origin, HIV-1 subtype, and CDC status. In multivariate analysis, resistance to any drug remained associated independently with current low viral load and high lifetime number of past PI. Triple resistance was independently associated with the high lifetime number of past PI and with gender, particularly among children aged 11 years old or more with a prevalence seven times higher in boys than in girls. In conclusion, antiretroviral resistance is common among treated HIV-1-infected children and prevalence was similar with those observed in adult population in the same year period. However, adolescent boys seem to be at greater risk. J. Med. Virol. 79:1261,1269, 2007. © Wiley-Liss, Inc. [source] | ||||||||||||||||||||||||||||||||||