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Ritonavir
Selected AbstractsIndinavir/ritonavir-based therapy in HIV-1-infected antiretroviral therapy-naive patients: comparison of 800/100 mg and 400/100 mg twice dailyHIV MEDICINE, Issue 1 2005D Konopnicki Objectives To compare the efficacy and tolerability of indinavir (IDV)/ritonavir (RTV) at 800/100 and 400/100 mg twice daily (bid) in antiretroviral therapy (ART)-naive patients. Methods An open comparison of two groups of ART-naive patients treated with IDV/RTV 800/100 or 400/100 mg bid plus two nucleoside analogues was carried out. Viral load, CD4 cell count and tolerability were measured at baseline and at weeks 4, 12, 24 and 48. IDV plasma concentrations were measured retrospectively. Results A total of 107 patients were included in the study. Of these, 57 were treated with 800/100 and 50 with 400/100 mg IDV/RTV bid. At week 48, a viral load of <50 HIV-1 RNA copies/mL was achieved by 77 and 64% of the patients, respectively, and the median CD4 cell count increases were +171 and +164 cells/,L (intent-to-treat; P not significant), respectively. Side effects leading to protease inhibitor discontinuation occurred in 61% of subjects in the 800/100 mg group vs. 20% in the 400/100 mg group (P<0.0001). Switching from 800/100 to 400/100 mg dosage improved adverse events in 16 of 20 patients. IDV concentrations were above 0.15 mg/L in 89% of the 28 patients tested in the 400/100 mg group. Conclusions Indinavir/ritonavir 400/100 mg bid provided the same efficacy as 800/100 mg bid at 48 weeks in an ART-naive population, but safety and tolerance were significantly better for 400/100 mg, while convenience was also improved and cost was reduced. [source] Lopinavir protein binding in HIV-1-infected pregnant womenHIV MEDICINE, Issue 4 2010FT Aweeka Background Pregnancy may alter protein binding (PB) of highly bound protease inhibitors due to changes in plasma concentrations of albumin and ,-1 acid glycoprotein (AAG). Small changes in PB can greatly impact the fraction of drug unbound (FU) exerting pharmacological effect. We report lopinavir (LPV) PB during third trimester (antepartum, AP) compared to ,1.7 weeks postpartum (PP) to determine if FU changes compensate for reduced total concentrations reported previously. Methods P1026s enrolled women receiving LPV/ritonavir, soft gel capsules 400/100 mg or 533/133 mg twice daily. LPV FU, albumin and AAG were determined AP and PP. Results AP/PP samples were available from 29/25 women respectively with all but one woman receiving the same dose AP/PP. LPV FU was increased 18% AP vs. PP (mean 0.96±0.16% AP vs. 0.82±0.21% PP, P=0.001). Mean protein concentrations were reduced AP (AAG=477 mg/L; albumin=3.28 mg/dL) vs. PP (AAG=1007 mg/L; albumin=3.85 mg/dL) (P<0.0001 for each comparison). AAG concentration correlated with LPV binding. Total LPV concentration did not correlate with LPV FU AP or PP. However, higher LPV concentration PP was associated with reduced PB and higher FU after adjustment for AAG. Conclusions LPV FU was higher and AAG lower AP vs. PP. The 18% increase in LPV FU AP is smaller than the reduction in total LPV concentration reported previously and is not of sufficient magnitude to eliminate the need for an increased dose during pregnancy. [source] HIV protease inhibitors attenuate adherence of Candida albicans to epithelial cells in vitroFEMS IMMUNOLOGY & MEDICAL MICROBIOLOGY, Issue 1 2001Jasmin Bekti Abstract Oropharyngeal candidiasis is one of the first and most commonly reported opportunistic infections of untreated AIDS patients. With the introduction of the new antiviral HAART therapy, including HIV protease inhibitors, this mucocutaneous infection is nowadays only rarely observed in treated patients. It was recently shown that HIV protease inhibitors have a direct attenuating effect on Candida albicans secreted aspartic proteinases (Saps), an investigation prompted by the fact that both Sap and HIV protease belong to the superfamily of aspartic proteinases and by the observation that mucocutaneous infections sometimes resolve even in the absence of an immunological improvement of the host. As these Saps are important fungal virulence factors and play a key role in adhesion to human epithelial cells we tried to assess the effect of the HIV protease inhibitors Ritonavir, Indinavir and Saquinavir on fungal adhesion to these cells. The effect on phagocytosis by polymorphonuclear leukocytes was also assessed. Ritonavir was found to be the most potent inhibitor of fungal adhesion. A dose-dependent inhibition of adhesion to epithelial cells was found already at 0.8 ,M and was significant at 4 ,M or higher, at 500 ,M the inhibition was about 55%. Indinavir and Saquinavir inhibited significantly at 4 ,M or 20 ,M, respectively; at 500 ,M the inhibition was 30% or 50%. In contrast, no protease inhibitor was able to modulate phagocytosis of Candida by polymorphonuclear leukocytes. In conclusion, inhibition of Saps by HIV protease inhibitors may directly help to ease the resolution of mucosal candidiasis. In future, derivatives of HIV protease inhibitors, being more specific for the fungal Saps, may form an alternative in the treatment of mucosal candidiasis insensitive to currently available antimycotics. [source] Scutellaria baicalensis and a constituent flavonoid, baicalein, attenuate ritonavir-induced gastrointestinal side-effectsJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 11 2007Sangeeta Mehendale Ritonavir, a protease inhibitor drug, is commonly used in AIDS therapy. As with other chemotherapeutic drugs that cause gastrointestinal adverse effects, ritonavir treatment is associated with significant nausea and vomiting. This study investigated whether Scutellaria baicalensis, and its active flavonoid constituent, baicalein, attenuate the gastrointestinal effects of ritonavir. The effects of herb administration were evaluated in ritonavir-treated rats using a rat pica model, which simulates nausea and vomiting in humans. The effects of herb administration on gastric emptying in rats were also measured. Ritonavir treatment resulted in increased kaolin intake or severe pica, the intensity of which was reduced significantly with S. baicalensis administration (1 mg kg,1; P < 0.05). High-performance liquid chromatography analysis of S. baicalensis showed the presence of an extremely potent flavonoid constituent, baicalein. The study aimed to determine if baicalein contributed to the anti-pica effect of the extract. It was observed that baicalein dose-dependently decreased pica in ritonavir-treated rats (P < 0.001). In addition to inducing pica, ritonavir also significantly delayed gastric emptying, which could contribute to ritonavir-induced gastrointestinal dysfunction. When S. baicalensis extract was administered to ritonavir-treated rats the delayed gastric emptying was significantly attenuated (P < 0.05). The results suggest that S. baicalensis and the constituent baicalein reduce the gastrointestinal dysfunction caused by ritonavir. It is concluded that S. baicalensis may potentially have a role to play in reducing drug-induced adverse effects. [source] Absent reduction by HIV protease inhibitors of Candida albicans adhesion to endothelial cellsMYCOSES, Issue 3 2007Barbara Falkensammer Summary Highly active antiretroviral therapy including HIV protease inhibitors has led to a marked reduction of clinically relevant mucosal candidiasis. We have previously shown that HIV protease inhibitors directly inhibit adhesion of Candida albicans to epithelial cells at concentrations that are reached in vivo during antiretroviral therapy. The aim of this study was to establish whether HIV protease inhibitors also inhibit adhesion of Candida to endothelial cells, which play a major role in systemic fungal disease. Three C. albicans strains were incubated with human umbilical vein endothelial cells or an endothelial cell line in the presence of either Ritonavir, Saquinavir or Indinavir. Subsequently, adherence was determined by counting colony-forming units. The results were comparable and revealed that Ritonavir and Saquinavir significantly inhibited adherence to endothelial cells at only very high concentrations which are likely not reached in vivo, and Indinavir did not even inhibit then. Inhibition of adhesion of C. albicans to human cells by HIV protease inhibitors is not a general feature, but strongly cell type-dependent, and clearly not observed for endothelial cells in vitro, which are a main target of systemic candidiasis in vivo. [source] Orofacial effects of antiretroviral therapiesORAL DISEASES, Issue 4 2001C Scully This paper summarises some of the oral adverse effects of antiretroviral agents. Some are related to bone marrow suppression which may also predispose to mouth ulcers. Erythema multiforme and toxic epidermal necrolysis are especially well recognized in HIV disease, particularly as reactions to sulphonamides and to antiretroviral agents. Oral lichenoid reactions have been described in HIV disease often relating to zidovudine use. Didanosine has also produced erythema multiforme and not unusually induces xerostomia, again by an unknown mechanism. Xerostomia may be seen in up to one-third of patients taking didanosine. Taste abnormalities are common with the protease inhibitors and oral and perioral paraesthesia can be a disturbing adverse effect. Ritonavir in particular can give rise to circumoral paraesthesia in over 25% of patients. Indinavir can also produce cheilitis. [source] Population pharmacokinetics of intravenously and orally administered docetaxel with or without co-administration of ritonavir in patients with advanced cancerBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 5 2010Stijn L. W. Koolen WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT , Docetaxel is an approved drug for the treatment of cancer of various primary origins. , An oral docetaxel regimen is warranted because of patient convenience and the opportunity to investigate more schedule intensive treatment regimens. , Co-administration of ritonavir significantly enhanced the apparent oral bioavailability of docetaxel. WHAT THIS STUDY ADDS , This study demonstrates that ritonavir increased the absorption of docetaxel after oral administration. , Furthermore, we showed that the clearance of docetaxel was inhibited in a concentration dependent manner. , The developed model will be used for further development of an oral docetaxel regimen. AIM Docetaxel has a low oral bioavailability due to affinity for P-glycoprotein and cytochrome P450 (CYP) 3A4 enzymes. Inhibition of the CYP3A4 enzymes by ritonavir resulted in increased oral bioavailability. The aim of this study was to develop a population pharmacokinetic (PK) model and to evaluate and quantify the influence of ritonavir on the PK of docetaxel. METHODS Data from two clinical trials were included in the data analysis, in which docetaxel (75 mg m,2 or 100 mg) had been administered intravenously or orally (10 mg or 100 mg) with or without co-administration of oral ritonavir (100 mg). Population modelling was performed using non-linear mixed effects modelling. A three-compartment model was used to describe the i.v. data. PK data after oral administration, with or without co-administration of ritonavir, were incorporated into the model. RESULTS Gut bioavailability of docetaxel increased approximately two-fold from 19 to 39% (CV 13%) with ritonavir co-administration. The hepatic extraction ratio and the elimination rate of docetaxel were best described by estimating the intrinsic clearance. Ritonavir was found to inhibit in a concentration dependent manner the intrinsic clearance of docetaxel, which was described by an inhibition constant of 0.028 µg ml,1 (CV 36%). A maximum inhibition of docetaxel clearance of more then 90% was reached. CONCLUSIONS A PK model describing both the PK of orally and intravenously administered docetaxel in combination with ritonavir, was successfully developed. Co-administration of ritonavir lead to increased oral absorption and reduced elimination rate of docetaxel. [source] The HIV protease inhibitor ritonavir synergizes with butyrate for induction of apoptotic cell death and mediates expression of heme oxygenase-1 in DLD-1 colon carcinoma cellsBRITISH JOURNAL OF PHARMACOLOGY, Issue 7 2004Heiko Mühl The protease inhibitor ritonavir is an integral part of current antiretroviral therapy targeting human immunodeficiency virus. Recent studies demonstrate that ritonavir induces apoptotic cell death with high efficiency in lymphoblastoid cell lines. Moreover, ritonavir can suppress activation of the transcription factor nuclear factor- ,B and is an inhibitor of interleukin-1, and tumor necrosis factor- , production in peripheral blood mononuclear cells. Thus, ritonavir appears to have anti-inflammatory properties. In the present study, we investigated in DLD-1 colon carcinoma cell effects of ritonavir on apoptotic cell death and expression of heme oxygenase-1 (HO-1), an anti-inflammatory enzyme that may be critically involved in the modulation of colonic inflammation. Compared to unstimulated control, ritonavir resulted in a moderate increase in the rate of apoptotic cell death as observed after 20 h of incubation. Notably, ritonavir potently synergized with the short-chain fatty acid butyrate for induction of caspase-3-dependent apoptosis in DLD-1 cells. Ritonavir enhanced mRNA and protein expression of HO-1 in DLD-1 cells. Ritonavir-induced HO-1 protein was suppressed by SB203580 or SB202190 and preceded by immediate upregulation of cellular c-Fos and c-Jun protein levels. This process was associated with induction of activator protein-1 as detected by electrophoretic mobility shift analysis. The present data suggest that ritonavir has the potential to curb colon carcinogenesis by reducing cell growth via mechanisms that include apoptosis and by simultaneously modulating colonic inflammation via induction of anti-inflammatory HO-1. British Journal of Pharmacology (2004) 143, 890,898. doi:10.1038/sj.bjp.0706023 [source] Novel Heterocyclic Analogues of the HIV-1 Protease Inhibitor, Ritonavir.CHEMINFORM, Issue 50 2004Perry T. Kaye Abstract For Abstract see ChemInform Abstract in Full Text. [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] 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] 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] Lopinavir/ritonavir monotherapy as maintenance treatment in HIV-infected individuals with virological suppression: results from a pilot study in BrazilHIV MEDICINE, Issue 5 2008E Sprinz Objective The aim of the study was to evaluate the possibility of using lopinavir/ritonavir (LPV/RTV) alone as maintenance therapy in HIV-infected individuals with virological suppression. Design This was a single-armed single-centre pilot trial. Methods Asymptomatic HIV-infected patients on highly active antiretroviral therapy (HAART) including LPV/RTV, and with plasma HIV RNA <40 copies/mL for at least 6 months, were enrolled in the study, during which they continued with LPV/RTV alone. The intention was to recruit 25 patients to be followed for 2 years. Viral failure was defined as two consecutive HIV RNA measurements >40 copies/mL. Nadir and baseline CD4 cell counts, highest ever HIV RNA load, time with undetectable viraemia before monotherapy, number of previous antiretroviral (ARV) regimens, and gene polymorphism at CYP3A4 and CYP3A5 were evaluated. Results All patients (27) completed the study. Their median age was 43 years, and 66% were men. Ten patients (37%) failed to maintain virological suppression (the median time to HIV rebound was 10.5 months, with a range of 4,23 months). One patient developed full resistance to LPV and another developed neurocognitive impairment while on LPV/RTV which improved after HAART reintroduction. There were no differences between failures and nonfailures according to the analysed parameters. Patients with viral failure were successfully resuppressed. Conclusions LPV/RTV maintenance therapy was associated with 37% failure, a higher than expected failure rate. In order to ensure that unnecessary risks are not being taken in patients on LPV/RTV, this finding should be further evaluated in large randomized trials for longer periods of follow-up. [source] Atazanavir and lopinavir with ritonavir alone or in combination: analysis of pharmacokinetic interaction and predictors of drug exposureHIV MEDICINE, Issue 4 2008S Di Giambenedetto Objectives Studies on the pharmacokinetic interaction between atazanavir and lopinavir with ritonavir (lopinavir/ritonavir) report contradictory results. We aimed to establish the in vivo interaction between these two protease inhibitors as well as the variables influencing drug exposure. Methods Pharmacokinetic parameters were investigated in HIV-infected patients treated with atazanavir 300 mg with ritonavir 100 mg q24h (group A) or lopinavir/ritonavir 400/100 mg q12h (group B) or atazanavir 300 mg q24h with lopinavir/ritonavir 400/100 mg q12h (group C). Patients receiving other concomitant protease inhibitors or non-nucleoside reverse transcriptase inhibitors were excluded. Results In group A (n=10), mean ± standard deviation atazanavir Cmin was 390 ± 460 ng/mL, Cmax 3051 ± 1996 ng/mL and AUC24 29 913 ± 17 686 ng/mL/h. In group B (n=9), lopinavir Cmin was 7562 ± 4292 ng/mL, Cmax 12 944 ± 4838 ng/mL and AUC0,12 122 313 ± 38 225 ng/mL/h. In group C (n=7), atazanavir Cmin was 876 ± 460 ng/mL (P=0.039 vs. group A), Cmax 3421 ± 3399 ng/mL and AUC0,24 65 055 ± 49 843 ng/mL/h (two-sided P>0.05 for each comparison with group A), lopinavir Cmin was 7471 ± 3745 ng/mL, Cmax 10 143 ± 5217 ng/mL and AUC0,12 104 501 ± 43 565 ng/mL/h (P>0.05 for each comparison with group B). When analysing all the groups, including controls from routine clinical practice, higher body mass index was associated with lower atazanavir Cmin and with lower lopinavir Cmax. Atazanavir Cmin showed a correlation with total bilirubin levels. Conclusions Combination with lopinavir/ritonavir provides higher atazanavir Cmin than combination with ritonavir alone, possibly because of an effect of the additional ritonavir dose. Low BMI may be associated with higher drug exposure. [source] Treatment outcomes amongst previously antiretroviral-naïve HIV-infected patients starting lopinavir/ritonavir-containing antiretroviral regimens at the Royal Free Hospital,HIV MEDICINE, Issue 1 2007CJ Smith Objective To describe outcomes in patients starting first-line antiretroviral regimens including lopinavir/ritonavir (LPV/r) in a routine clinic setting. Methods Previously naïve patients starting LPV/r-containing antiretroviral therapy were included in the study. Virological failure was defined as the first of two viral loads >500 HIV-1 RNA copies/mL more than 6 months after starting LPV/r. Cumulative percentages experiencing virological failure were calculated using Kaplan,Meier methods. Results A total of 195 individuals had a median follow-up time of 1.7 years. At 48 weeks, 87.9, 77.4 and 71.6% of patients with pretreatment CD4 counts of <50, 50,200 and >200 cells/,L, respectively, remained on LPV/r. By 48, 72 and 96 weeks, 2.2, 3.0 and 5.0% of patients, respectively, had experienced virological failure, ignoring treatment changes but censoring follow-up at discontinuation of all antiretrovirals; these percentages became 24.0, 33.7 and 42.3% when LPV/r discontinuation was considered as virological failure. Censoring those who stopped LPV/r with a viral load <50 copies/mL and considering as virological failures those who stopped LPV/r with a viral load >50 copies/mL gave 12.1, 14.6 and 17.0% virological failure at 48, 72 and 96 weeks, respectively. Median CD4 count increases at 24, 48 and 72 weeks were 167, 230 and 253 cells/,L, respectively. Conclusions Few patients experienced virological failure whilst on a LPV/r-based regimen, although it was not uncommon for patients in our clinic with higher baseline CD4 counts to discontinue LPV/r. [source] Factors associated with virological response in HIV-infected patients failing antiretroviral therapy: a prospective cohort studyHIV MEDICINE, Issue 2 2005S Fournier Objectives To assess the antiviral response to optimized therapy following genotypic resistance testing and to identify factors associated with virological response in HIV-1-infected patients failing antiretroviral therapy. Methods A prospective cohort study was conducted in 344 HIV-1-infected patients who underwent genotypic resistance testing because of virological failure. Virological response was defined as a plasma HIV RNA level below 200 HIV-1 RNA copies/mL or a drop of plasma viral load from baseline of more than 1 log10. A multivariate logistic regression analysis was performed to identify factors associated with virological response. Results The median age of the patients was 40 years, with a male to female ratio of 4:1. Fifty-one per cent of patients had received the three major classes of antiretrovirals and the median duration of previous antiretroviral therapy was 4.6 years. At baseline, the median plasma HIV RNA level was 4.4 log10 copies/mL and the median CD4 cell count was 274 cells/,L. At 3 months, 55% of patients (188 of 344) had a virological response, which was sustained at 6 months (53%). Predictors of virological response were exposure to two or fewer protease inhibitors [odds ratio (OR) 1.8; P=0.046], and use in optimized therapy of a new class of antiretrovirals (OR 2.9; P=0.006), of more than two new drugs (OR 3.0; P<0.0001), of abacavir (OR 1.9; P=0.03), or of lopinavir/ritonavir (OR 3.7; P=0.0002). Conclusions A high proportion of patients achieved a short-term virological response in this cohort study. Patients with the least experience of protease inhibitor treatment and in whom a new class of antiretroviral, more than two new drugs, abacavir or lopinavir/ritonavir was used in optimized therapy had the best virological outcome. [source] Haemodynamic crisis and reversible multiorgan failure caused by HIV post-exposure prophylaxis after needle-stick injury in a health care workerHIV MEDICINE, Issue 2 2004T Feldt We report the case of a 59-year-old nurse from our HIV ward who developed a severe haemodynamic crisis with concomitant acute multiorgan failure after initiation of a post-exposure prophylaxis (PEP) with zidovudine/lamivudine (CombivirTM) and lopinavir/ritonavir (KaletraTM) after a needle-stick injury with an HIV-contaminated needle. Although serious and life-threatening adverse effects of post-exposure prophylaxis have been documented in several cases, this is the first report of a severe acute cardiovascular incident following PEP initiation. [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] Bioavailability of generic ritonavir and lopinavir/ritonavir tablet products in a dog modelJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 2 2010Kevin W. Garren Abstract In this study, we explored the bioavailability in dogs and chemical potency of generic ritonavir and lopinavir/ritonavir tablet products manufactured by various pharmaceutical companies. Chemical potency of the products was examined by HPLC quantitation of ritonavir and lopinavir. Using a dog model, we determined point estimates for Cmax and AUC of ritonavir and lopinavir/ritonavir for eight generic products compared to Abbott's Norvir® capsule and Kaletra® tablet. Chemical potencies ranged from 79.0% to 104.6%. Point estimates for AUC in the generic tablet products ranged from 0.01 to 1.11, indicating that the relative bioavailability of these formulations was in the range of 1,111% compared to the branded products. This study showed significant variability in bioavailability in a dog model amongst generic tablet products containing the protease inhibitors ritonavir or lopinavir/ritonavir. The chemical potency of the generic products was not indicative of the plasma levels of ritonavir or lopinavir that were achieved. These results reinforce the need for human bioequivalence testing of generic products containing ritonavir or lopinavir/ritonavir to assure that efficacy in patients is not compromised prior to these products being made available to patients. Procurement policies of funding agencies should require such quality assurance processes. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:626,631, 2010 [source] Enfuvirtide: A safe and effective antiretroviral agent for human immunodeficiency virus,infected patients shortly after liver transplantationLIVER TRANSPLANTATION, Issue 10 2009Elina Teicher The aim of this study was to evaluate the impact of an enfuvirtide-based antiretroviral (ARV) regimen on the management of immunosuppression and follow-up in hepatitis C virus (HCV)/hepatitis B virus (HBV)/human immunodeficiency virus (HIV),coinfected liver transplant patients in comparison with a lopinavir/ritonavir-based ARV regimen. Tacrolimus and cyclosporine trough concentrations were determined at a steady state during 3 periods: after liver transplantation without ARV treatment (period 1), at the time of ARV reintroduction (period 2), and 2 to 3 months after liver transplantation (period 3). The findings for 22 HIV-coinfected patients were compared (18 with HCV and 4 with HBV); 11 patients were treated with enfuvirtide and were matched with 11 lopinavir/ritonavir,exposed patients. During period 1, tacrolimus and cyclosporine A doses were 8 and 600 mg/day, respectively, and the trough concentrations were within the therapeutic range in both groups. In period 2, the addition of lopinavir/ritonavir to the immunosuppressant regimen enabled a reduction in the dose of immunosuppressants required to maintain trough concentrations within the therapeutic range (to 0.3 mg/day for tacrolimus and 75 mg/day for cyclosporine). Immunosuppressant doses were not modified by the reintroduction of enfuvirtide, there being no change in the mean trough concentrations over the 3 periods. CD4 cell counts remained at about 200 cells/mm. The HIV RNA viral load remained undetectable. Both groups displayed signs of mild cytolysis and cholestasis due to the recurrence of HCV, whereas no renal insufficiency was observed. Enfuvirtide is an attractive alternative to standard ARV therapy, facilitating the management of drug-drug interactions shortly after liver transplantation. Moreover, the lack of liver toxicity renders this drug valuable in the event of a severe HCV recurrence. Liver Transpl 15:1330,1335, 2009. © 2009 AASLD. [source] Management of drug-to-drug interactions between cyclosporine A and the protease-inhibitor lopinavir/ritonavir in liver-transplanted HIV-infected patientsLIVER TRANSPLANTATION, Issue 7 2004Martin Vogel Highly active antiretroviral therapy (HAART) has improved the life expectancy of HIV-infected patients, allowing orthotopic liver transplantation as a reasonable treatment option for selected patients with terminal liver disease. Both non-nucleoside reverse transcriptase inhibitors and protease inhibitors, key elements of HAART, give rise to substantial drug-to-drug interactions with immunosuppressive drugs such as tacrolimus and cyclosporine A. After studying 12-hour pharmacokinetic profiles in 3 HIV-positive patients after liver transplantation, we describe how dosing of cyclosporine A can be adjusted to maintain effective immunosuppressive drug levels on a daily dosing schedule when ritonavir-boosted indinavir or lopinavir-based antiretroviral therapy is given. To avoid toxic drug levels, we used an orally available cyclosporine A formulation prepared from the commercial available intravenous solution, which enabled dose adjustments in 1-mg increments. Under ritonavir-boosted HAART, cyclosporine A levels showed markedly altered absorption/elimination characteristics with more or less constant blood-levels throughout the dosing interval and prolonged elimination half-lives up to 38 hours. To obtain equivalent areas under the curve of cyclosporine A, daily doses were reduced to 5,20% of the individual standard doses given before initiation of ritonavir-boosted HAART. Because of the flat absorption/elimination profiles under ritonavir-boosted HAART cyclosporine A, dosing could be reliably monitored long term by measuring cyclosporine A trough-levels. (Liver Transpl 2004;10:939,944.) [source] The In Vivo Response of Novel Buprenorphine Metabolites, M1 and M3, to Antiretroviral Inducers and Inhibitors of Buprenorphine MetabolismBASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 3 2009David E. Moody The identification of two, M1 and M3, in urine suggests that they may be quantitatively significant metabolites. To further understand the in vivo regulation of this mode of metabolism, we evaluated 24-hr urine from subjects (10 per treatment group) on buprenorphine alone or with the antiretroviral agents: efavirenz, delavirdine, nelfinavir, ritonavir, and lopinavir/ritonavir. Quantitative analysis for buprenorphine and traditional metabolites and semi-quantitative analysis of M1 and M3 in urine were performed by liquid chromatography-electrospray ionization-tandem mass spectrometry. The renal clearance of buprenorphine and traditional metabolites were similar for all treatments except for lopinavir/ritonavir, suggesting that urine amounts of M1 and M3 would adequately reflect systemic changes (except lopinavir/ritonavir). Efavirenz decreased M1 and increased M3 consistent with its ability to induce cytochrome P450 (CYP) 3A. Delavirdine increased M1 and decreased M3 consistent with its ability to inhibit CYP3A. Both nelfinavir and ritonavir decreased both M1 and M3, consistent with their ability to inhibit CYP3A and 2C8. These results provide further information on the in vivo response of novel secondary metabolites of buprenorphine to metabolic inhibitors and inducers. [source] The effects of ritonavir and lopinavir/ritonavir on the pharmacokinetics of a novel CCR5 antagonist, aplaviroc, in healthy subjectsBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 3 2006Kimberly K. Adkison Aims This study assessed the effects of the CYP3A inhibitors lopinavir/ritonavir (LPV/r) on the steady-state pharmacokinetics (PK) of aplaviroc (APL), a CYP3A4 substrate, in healthy subjects. Methods In Part 1, APL PK was determined in eight subjects who received a single oral 50-mg APL test dose with/without a single dose of 100 mg ritonavir (RTV). Part 2 was conducted as an open-label, single-sequence, three-period repeat dose study in a cohort of 24 subjects. Subjects received APL 400 mg every 12 h (b.i.d.) for 7 days (Period 1), LPV/r 400/100 mg b.i.d. for 14 days (Period 2) and APL 400 mg +,LPV/r 400/100 mg b.i.d. for 7 days (Period 3). All doses were administered with a moderate fat meal. PK sampling occurred on day 7 of Periods 1 and 3 and day 14 of Period 2. Results In Part 1, a single RTV dose increased the APL AUC0,, by 2.1-fold [90% confidence interval (CI) 1.9, 2.4]. Repeat dose coadministration of APL with LPV/r increased APL exposures to a greater extent with the geometric least squares mean ratios (90% CI) being 7.7 (6.4, 9.3), 6.2 (4.8, 8.1) and 7.1 (5.6, 9.0) for the APL AUC, Cmax, and Cmin, respectively. No change in LPV AUC or Cmax and a small increase in RTV AUC and Cmax (28% and 32%) were observed. The combination of APL and LPV/r was well tolerated and adverse events were mild in severity with self-limiting gastrointestinal complaints most commonly reported. Conclusions Coadministration of APL and LPV/r was well tolerated and resulted in significantly increased APL plasma concentrations. [source] CLINICAL STUDY: Effect of saquinavir/ritonavir (1000/100 mg bid) on the pharmacokinetics of methadone in opiate-dependent HIV-negative patients on stable methadone maintenance therapyADDICTION BIOLOGY, Issue 3 2009Candice Jamois ABSTRACT This study was performed to determine the effect of two protease inhibitors, saquinavir (SQV, oral 1000 mg bid) boosted by ritonavir (RTV, oral 100 mg bid), on pharmacokinetics (PK) of methadone in opiate-dependent HIV-negative patients on stable methadone maintenance therapy. This was a two-center, open-label, one-sequence cross-over, multiple-dose study in 13 HIV-negative patients who were on stable methadone therapy (oral, 60,120 mg qd). All patients continued methadone treatment on days 2,15. All patients received SQV/RTV in combination with methadone from days 2,15. PK of methadone was assessed on day 1 (alone) and on day 15 when methadone treatment was combined with SQV/RTV at steady state. Twelve patients completed the study. Median age, body weight and height were 50 years (range: 24,54 years), 80 kg (range: 57,97 kg) and 174 cm (range: 163,189 cm), respectively. All patients were Caucasian, and 11 were smokers. Median methadone dose was 85 mg qd. Geometric mean area under curve of the plasma concentration-time curve over 24 hour dosing interval (AUC0,24 hour) ratio of methadone with and without SQV/RTV was 0.81% (90% confidence interval: 71,91%). There was no significant plasma protein-binding displacement of methadone by SQV/RTV. The combination of SQV/RTV and methadone was well tolerated. There were no clinically significant adverse events or significant changes in laboratory parameters, electrocardiograms or vital signs. The 19% decrease in R-methadone AUC0,24 hour in the presence of SQV/RTV was not clinically relevant. There appears to be no need for methadone dose adjustment when methadone (60,120 mg qd) and SQV/RTV (1000/100 mg bid) are coadministered. [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] Effect of simplification from protease inhibitors to boosted atazanavir-based regimens in real-life conditionsHIV MEDICINE, Issue 9 2010R Rubio Background Atazanavir (ATV) boosted with ritonavir (ATV/r) is a potent, well-tolerated, once-daily protease inhibitor (PI). Few data are available on this agent as a treatment simplification option for patients taking other PIs. Objective The aim of the study was to determine the effectiveness and safety of ATV-containing regimens in patients who have simplified their antiretroviral treatment. Methods SIMPATAZ was a multicentre, prospective, noninterventional study in patients who had undetectable HIV RNA on their current PI-containing therapy and who were switched to an ATV/r-based regimen. Patients underwent a routine physical examination, and data were collected on HIV RNA levels, CD4 cell counts, liver function, lipid parameters, adverse reactions, adherence to treatment and patient satisfaction. Results A total of 183 patients were enrolled in the study and included in the analysis (80% were male, 29% had AIDS, and 52% were coinfected with HIV and hepatitis B virus or hepatitis C virus). The median baseline CD4 count was 514 cells/,L. Median exposure to previous HIV therapy was 8 years, and 32% of patients had a history of PI failures. Lopinavir boosted with ritonavir was the most frequent PI replaced (62%) and tenofovir+lamivudine /emtricitabine the backbone most used during the study (29%). The study drug was discontinued early by 25 patients (14%), two of whom discontinued as a result of adverse events (Hodgkin lymphoma and vomiting). Two patients died (lung cancer and myocardial infarction). At month 12, 93% of the study population had an undetectable HIV RNA viral load. Hyperbilirubinaemia >3 mg/dL and increased alanine aminotransferase levels>200 IU/L were observed in 38.5% and 4.4% of patients, respectively. Median changes from baseline to month 12 in total cholesterol, triglycerides and low-density lipoprotein cholesterol were ,13 mg/dL (,7%; P<0.0001), ,19 mg/dL (,13%; P<0.0001) and ,7 mg/dL (,6%; P=0.021), respectively. Conclusions In a real-world setting, switching from other PIs to ATV/r is a well-tolerated and safe option for improving the lipid profile and for retaining virological response in controlled pretreated patients. [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] Atazanavir and lopinavir with ritonavir alone or in combination: analysis of pharmacokinetic interaction and predictors of drug exposureHIV MEDICINE, Issue 4 2008S Di Giambenedetto Objectives Studies on the pharmacokinetic interaction between atazanavir and lopinavir with ritonavir (lopinavir/ritonavir) report contradictory results. We aimed to establish the in vivo interaction between these two protease inhibitors as well as the variables influencing drug exposure. Methods Pharmacokinetic parameters were investigated in HIV-infected patients treated with atazanavir 300 mg with ritonavir 100 mg q24h (group A) or lopinavir/ritonavir 400/100 mg q12h (group B) or atazanavir 300 mg q24h with lopinavir/ritonavir 400/100 mg q12h (group C). Patients receiving other concomitant protease inhibitors or non-nucleoside reverse transcriptase inhibitors were excluded. Results In group A (n=10), mean ± standard deviation atazanavir Cmin was 390 ± 460 ng/mL, Cmax 3051 ± 1996 ng/mL and AUC24 29 913 ± 17 686 ng/mL/h. In group B (n=9), lopinavir Cmin was 7562 ± 4292 ng/mL, Cmax 12 944 ± 4838 ng/mL and AUC0,12 122 313 ± 38 225 ng/mL/h. In group C (n=7), atazanavir Cmin was 876 ± 460 ng/mL (P=0.039 vs. group A), Cmax 3421 ± 3399 ng/mL and AUC0,24 65 055 ± 49 843 ng/mL/h (two-sided P>0.05 for each comparison with group A), lopinavir Cmin was 7471 ± 3745 ng/mL, Cmax 10 143 ± 5217 ng/mL and AUC0,12 104 501 ± 43 565 ng/mL/h (P>0.05 for each comparison with group B). When analysing all the groups, including controls from routine clinical practice, higher body mass index was associated with lower atazanavir Cmin and with lower lopinavir Cmax. Atazanavir Cmin showed a correlation with total bilirubin levels. Conclusions Combination with lopinavir/ritonavir provides higher atazanavir Cmin than combination with ritonavir alone, possibly because of an effect of the additional ritonavir dose. Low BMI may be associated with higher drug exposure. [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] | ||||||||||||||||||||||||||||