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Plasma concentration of atazanavir (ATV) may be reduced when coadministered with tenofovir (TDF) or proton pump inhibitors. Boosting ATV exposure with ritonavir (r) may make it possible to overcome these drug interactions. However, jaundice and loss of the metabolic advantages of ATV are more frequent using ATV/r than ATV alone. Herein, we assessed whether therapeutic drug monitoring (TDM) could make it possible to identify the subset of patients in whom removal of ritonavir could be attempted without risk of suboptimal plasma ATV exposure and subsequent virological failure. A total of 56 patients with undetectable plasma HIV-RNA under a stable triple regimen containing ATV 300/100 mg qd were switched to ATV 400 mg qd. Plasma ATV concentrations were measured using a reliable high-performance liquid chromatography method. Median plasma ATV C(min) fell from 880 to 283 ng/ml (p = 0.03) after removal of ritonavir. While all patients on ATV/r showed ATV plasma concentrations within therapeutic values (IC(min) above 150 ng/ml) before switching, four patients (7%) fell below this threshold after switching to ATV 400 mg qd. However, only one of this group experienced virological failure at week 24 of follow-up. TDF was part of the antiretroviral regimen in all four cases. From a total of 29 (52%) patients on ATV/r showing grade 3-4 hyperbilirubinemia, only 7 (12%) remained on it upon switching to ATV 400 mg qd (p0.001). Patients with complete viral suppression under ATV/r 300/100 mg qd may benefit from switching to ATV 400 mg qd guided by TDM, which may make it possible to minimize adverse events without compromising antiviral efficacy in most cases.

BACKGROUND Tipranavir (TPV) and darunavir (DRV) are potent against protease inhibitor (PI)-resistant viruses. Efficacy of these compounds when confronting distinct HIV subtypes is not known. METHODS All clinical specimens from HIV-positive patients sent to our institution for drug resistance testing between 1999 and 2006 were analysed. The prevalence of TPV and DRV resistance mutations was assessed based on the latest International AIDS Society-USA panel list. Phenotypic susceptibility to DRV and TPV was examined in a subset of these samples using the PhenoSense assay. RESULTS A total of 1364 genotypes were analysed, including 1178 from individuals infected with clade B (285 drug naive) and 186 with non-B subtypes (137 drug naive). The mean number (+/-SD) of DRV resistance-associated mutations was higher in clade B than non-B (0.4 +/- 0.9 versus 0.06 +/- 0.3; P < 0.001), and more frequent among PI-experienced than drug-naive patients (0.6 +/- 1.02 versus 0.02 +/- 0.21; P < 0.001). In contrast, the mean number of TPV resistance-associated mutations was higher in non-B than B subtypes (2.7 +/- 1 versus 1.2 +/- 1.6; P < 0.001), regardless of PI experience. Susceptibility to TPV and DRV was examined in 29 drug-naive patients infected with non-B subtypes (1A, 3C, 2CRF01_AE, 9CRF02_AG, 1CRF12_BF, 3CRF14_BG, 3F and 7G). All showed susceptibility to DRV and 93% to TPV. Interestingly, two subtype F specimens showed reduced TPV susceptibility, with fold-changes of 2.7 and 2.1, respectively. CONCLUSIONS Non-B subtypes show a greater number of TPV resistance-associated mutations than B viruses, regardless of PI exposure. While HIV clade has no influence on DRV susceptibility, some F subtypes may show reduced TPV susceptibility.

The risk of liver toxicity during antiretroviral drug use in human immunodeficiency virus (HIV)-positive patients increases in the presence of chronic hepatitis C virus (HCV) infection. It is unknown whether sustained HCV clearance after interferon (IFN)-based therapy might reduce this complication. The incidence of severe elevations in liver enzyme levels during antiretroviral therapy was retrospectively analyzed in a group of HIV/HCV-coinfected patients after completion of a full course of IFN-based therapy. Hepatic events were recorded according to the achievement of a sustained virological response (SVR) and the presence of advanced liver fibrosis was assessed by transient elastometry. A total of 132 HIV/HCV-coinfected patients were analyzed (66% men; mean age 38 years). Overall 33% achieved an SVR and 40% had advanced liver fibrosis after IFN therapy. A total of 49 episodes of liver toxicity occurred during a mean of 35 months of follow-up (9.7% per year) after IFN therapy. The yearly incidence of hepatic events was greater in patients who did not achieve an SVR than in those who did (12.9% vs. 3.1%; P < .001) and in patients with advanced liver fibrosis than in those without it (14.4% vs. 7.6%; P = .003). Drugs involved in hepatic events were dydeoxynucleoside analogues (namely didanosine and stavudine; 40%) nevirapine (30%) efavirenz (11%) and protease inhibitors (PIs; 8%). In logistic regression analysis lack of an SVR (odds ratio [OR] 6.13 [95% confidence interval {CI} 1.83-37.45]; P = .003) and the use of dydeoxynucleosides (OR 3.59 [95% CI 1.23-10.42]; P = .02) were independent predictors of hepatotoxicity after IFN therapy. Conversely regimens containing PIs (OR 0.07 [95% CI 0.02-0.30]; P < .01) or efavirenz (OR 0.13 [95% CI 0.04-0.44]; P = .001) were associated with a diminished risk of hepatic events. Sustained HCV clearance after IFN-based therapy reduces the risk of liver toxicity during antiretroviral therapy which should further encourage the treatment of chronic hepatitis C in HIV-coinfected patients. In this population prescription of PIs or efavirenz decreases and use of dydeoxynucleoside analogues increases the risk of hepatotoxicity. (authors)

The use of abacavir (ABC) may be associated with a hypersensitivity reaction (HSR) that requires discontinuation of the drug. The HLA-B*5701 allele has been linked to this HSR. Information on the strength of this association across distinct geographic regions and ethnicities is scarce. We tested HLA-B*5701 in 53 Spaniards infected with HIV who received ABC treatment. The presence of HLA-B5701 had strong positive and negative predictive values for ABC HSR, 92% and 63%, respectively.

Darunabir, formerly TMC114, is a new protease inhibitor (PI) under clinical development designed to be active against HIV strains resistant to currently available PI. The virological and immunological response to ritonavir-boosted darunabir was assessed in four heavily antiretroviral-experienced patients who had failed enfuvirtide and two or more previous ritonavir-boosted PI regimens, including tipranavir in one instance. All four patients reached undetectable plasma HIV-RNA levels within 8 weeks of therapy and experienced significant CD4 cell count gains.

Summary CD4+ regulatory T (Treg) cells have been involved in impaired immunity and persistence of viral infections. Herein, we report the level, phenotype and activation status of Treg cells in patients chronically infected with human immunodeficiency virus (HIV) and/or hepatitis C virus (HCV). Expression of CD25, CD45RA, CD27, CD127 and CD38 was assessed on these cells using polychromatic flow cytometry in 20 healthy controls, 20 HIV-monoinfected, 20 HCV-monoinfected and 31 HIV/HCV-co-infected patients. Treg cells were defined as CD4+forkhead box P3 (FoxP3)+. The percentage of Treg cells was increased significantly in HIV patients compared with controls. Moreover, there was a significant inverse correlation between CD4 counts and Treg cell levels. Fewer than 50% of Treg cells expressed CD25, with differences in terms of CD127 expression between CD25+ and CD25(–) Treg cells. CD4+Foxp3+ Treg cells displayed predominantly a central memory phenotype (CD45RA–CD27+), without differences between patients and healthy controls. Activated Treg cells were increased in HIV patients, particularly considering the central memory subset. In summary, HIV infection, but not HCV, induces an up-regulation of highly activated Treg cells, which increases in parallel with CD4 depletion. Hypothetically, this might contribute to the accelerated course of HCV-related liver disease in HIV-immunosuppressed patients.

Objective Multiple factors may lead to hepatic steatosis (HS) in HIV-positive patients. HS may result in severe liver damage on its own and/or by accelerating the progression of chronic viral hepatitis B or C. Methods The sensitivity/specificity of liver ultrasound (US) to recognize severe HS is above 85%. A cross-sectional case–control study of all HIV out-patients who underwent liver US since 2004 was conducted at our institution. Results Eight hundred and thirty (36.1%) out of 2300 HIV-positive patients on regular follow-up underwent liver US during the study period. Severe HS was diagnosed in 108 (13%) patients. A total of 117 matched HIV controls lacking HS were selected randomly. In patients with severe HS, we found significantly higher values of body mass index (BMI), plasma viral load, serum glucose, alkaline phosphatase, triglycerides and low-density lipoprotein cholesterol, as well as significantly higher prevalence of diabetes, elevated alcohol consumption, lipohypertrophy and advanced liver fibrosis. Furthermore, a trend towards longer exposure to nucleoside analogues was noticed. In the multivariate analysis, only elevated alcohol consumption [odds ratio (OR) 7, P=0.013], lipohypertrophy (OR 5.3, P=0.008), plasma viral load (OR 2.1, P=0.02), BMI (OR 1.2, P=0.013) and serum glucose (OR 1.03, P=0.027) were significantly associated with severe HS. Conclusions Severe HS in HIV-positive patients is associated with predisposing factors that are similar to those of HIV-negative individuals. However, its characteristic association with elevated plasma viral load might suggest a direct involvement of HIV in liver fat deposition. Therefore, the benefit of controlling HIV replication with antiretroviral therapy should be balanced against its effect of occasionally inducing metabolic abnormalities and lipodystrophy.

Pegylated interferon (PEG-IFN) alpha2a and alpha2b differ in their pharmacokinetic properties, which might have an effect on their antiviral effects against hepatitis C virus (HCV). Differences between PEG-IFN-alpha molecules could be more pronounced in HIV-coinfected individuals, in whom response to HCV treatment is impaired.All HCV-HIV-coinfected patients included in PRESCO and EXTENT trials recruited at one referral centre were retrospectively analysed. In both trials, ribavirin (RBV) 1,000-1,200 mg/day was prescribed together with standard doses of PEG-IFN-alpha2a or -alpha2b. The attainment of serum HCV RNA10 IU/ml at weeks 4, 12 and 24 was assessed. On-treatment analyses were made to estimate the intrinsic potency of PEG-IFN-alpha2a versus -alpha2b.A total of 218 patients were examined, 138 on PEG-IFN-alpha2a and 80 on PEG-IFN-alpha2b. Baseline characteristics were comparable in both groups. Undetectable serum HCV RNA at weeks 4, 12 and 24 was more frequently attained using PEG-IFN-alpha2a than -alpha2b (45% versus 27% [P=0.02]; 65% versus 45%/ [P=0.01]; and 75% versus 55%/ [P=0.01], respectively), regardless of HCV genotype. Plasma RBV levels did not differ between groups. In multivariate analysis, HCV genotypes 2/3 (odds ratio [OR] 12.5; 95% confidence interval [95% CI] 3.45-33.33; P0.001), use of zidovudine (OR 0.30; 95% CI 0.11-0.85; P=0.02) and treatment with PEG-IFN-alpha2a (OR 2.12; 95% CI 1.02-4.54; P=0.04) were independent predictors of undetectable HCV RNA at week 24. Conversely, the incidence of serious adverse events was more common with PEG-IFN-alpha2a than -alpha2b (13.2% versus 3.6%; P=0.018).The antiviral effect against HCV seems to be greater for PEG-IFN-alpha2a than -alpha2b in the HIV setting. A shorter half-life of PEG-IFN-alpha2b could explain this finding.

The recent availability of non-invasive tools to measure liver fibrosis has allowed examination of its extent and determination of predictors in all patients with chronic hepatitis C virus (HCV) infection. On the other hand, most information on hepatic fibrosis in HCV/human immunodeficiency virus (HIV)-coinfected patients has been derived from liver biopsies taken before highly active antiretroviral therapy (HAART) was widely available. All consecutive HCV patients with elevated aminotransferases seen during the last 3 years were evaluated and liver fibrosis measured using transient elastography (FibroScan) and biochemical indexes. Patients were split according to their HIV serostatus. A total of 656 (69.6%) HCV-monoinfected and 287 (30.4%) HIV/HCV-coinfected patients were assessed. Mean CD4 count of coinfected patients was 493 cells/muL and 88% were under HAART (mean time, 4.2 +/- 2.4 years). Advanced liver fibrosis or cirrhosis was recognized in 39% of the coinfected and 18% of the monoinfected patients (P0.005). A good correlation was found between FibroScan) and biochemical indexes [AST to platelet ratio index (r = 0.405, P0.0001), FIB-4 (r = 0.393, P0.0001) and Forns (r = 0.407, P0.0001)], regardless of the HIV status. In the multivariate analysis, age45 years, body mass index (BMI)25 kg/m(2), and HIV infection were independently associated with advanced liver fibrosis or cirrhosis. HIV/HCV-coinfected patients have more advanced liver fibrosis than HCV-monoinfected patients despite the immunologic benefit of HAART.

The rate, predictors and outcome following episodes of low-level viral rebound (LLVR) in HIV patients on highly active antiretroviral therapy (HAART) are unknown.Retrospective assessment of all HIV patients who experienced LLVR episodes on HAART at one institution from January 1999 to December 2006. LLVR was defined as plasma HIV-RNA between 51 and 500 copies/mL after at least two consecutive undetectable plasma viral load measurements made during the last 6 months. Virological failure was defined as plasma HIV-RNA500 copies/mL.Out of 2720 HIV patients on successful HAART during the 8 year study period, 779 (28.6%) developed at least one LLVR episode. Only 655 patients who kept unchanged their HAART regimen following LLVR episodes were further examined. After 12 weeks, undetectable viraemia was regained in 458 (71%), which were considered as blips. In contrast, 66 (9%) LLVR episodes were followed by virological failure, and drug resistance mutations developed in most cases, mainly rtM184V (66%) and rtK103N (29.5%). Plasma HIV-RNA remained between 51 and 500 copies/mL at 12 weeks in the remaining 131 (20%) patients with LLVR episodes. In the multivariate analysis, only plasma HIV-RNA levels at the time of LLVR predicted subsequent virological failure.Episodes of LLVR in HIV patients on successful HAART are relatively common and represent transient events (blips) in most cases (71%). Keeping the same treatment regimen, virological failure follows in10% of the cases. Plasma HIV-RNA level at the time of LLVR is the best predictor of subsequent failure.

BACKGROUND Atazanavir seems to be a protease inhibitor (PI) with a more favourable metabolic profile. Information regarding the potential benefit of replacing lopinavir/ritonavir by atazanavir in HIV-infected patients with prolonged viral suppression is scarce. If proved, this strategy could be particularly attractive for the subset of patients with greater cardiovascular risk. METHODS SLOAT was a prospective, open, comparative trial in which patients receiving lopinavir/ritonavir-based regimens and having undetectable plasma HIV-RNA for longer than 24 weeks were randomized to continue on the same therapy or switch to atazanavir. Outcomes in viral rebound, CD4 counts, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides and glucose were compared in both groups of patients at 48 weeks of follow-up. RESULTS A total of 189 patients were recruited and took at least the first dose of the assigned treatment arm. Overall, 102 switched to atazanavir (49 on 400 mg once daily, and 53 on 300 mg plus 100 mg of ritonavir once daily due to concomitant tenofovir use) and 87 continued on lopinavir/ritonavir. All patients received the PI along with two nucleoside analogues. Virological failure occurred in 12 patients switched to atazanavir and 9 continuing on lopinavir/ritonavir. A reduction (P < 0.001) in median total cholesterol (-19 mg/dL) and triglycerides (-80 mg/dL) was observed after 48 weeks of atazanavir switching, whereas no significant changes occurred in the lopinavir/ritonavir arm. Greater reductions in total cholesterol and triglycerides were seen in patients switched to atazanavir without ritonavir boosting. CONCLUSIONS The replacement of lopinavir/ritonavir by atazanavir provides an overall significant reduction in total cholesterol and triglycerides, without increased risk of virological failure.

Tipranavir (TPV) is a novel non-peptidic protease inhibitor (PI). It binds strongly and selectively to the HIV-1 protease, is orally administered twice daily, boosted with low doses of ritonavir, and shows a favourable resistance profile. In the two registrational trials, named RESIST 1 and 2, TPV/ritonavir 500/200 mg b.i.d., along with an optimised antiretroviral backbone, provided better virologic responses than controls receiving standard of care ritonavir-boosted PI-based regimens. A total of 21 mutations at 16 protease codons have been shown to impact on TPV susceptibility and response rates. The TPV mutation score includes L10V, I13V, K20M/R/V, L33F, E35G, M36I, K43T, M46L, I47V, I54A/M/V, Q58E, H69K, T74P, V82L/T, N83D and I84V. Viruses containing eight or more of these mutations are generally resistant to the drug. TPV use is associated with an excess of grade 3/4 liver enzyme elevations compared with other ritonavir-boosted PIs, and the potential for drug-drug interactions is relevant and must be considered when prescribing TPV.

Objectives To describe the clinical presentation of HIV disease in older patients. Methods In the period 1989–1996 we reviewed the medical records of 100 patients with human immunodeficiency virus (HIV) infection aged 50 years or older and, 197 controls among HIV-infected patients aged 15–40 years, who attended six institutions in the autonomous community of Valencia (Spain). Results Older patients were mostly males (86%), men who have sex with men (42%) or unknown (20%) as exposure categories. Older patients had lower CD4 cell counts/mm 3 (163 ± 136 vs. 450 ± 373, P = 0.008), and had AIDS at first evaluation (49% vs. 29%, P = 0.0006) compared with younger patients. For patients presenting with AIDS at HIV infection diagnosis, type and frequency of AIDS indicator diseases did not differ between older and young patients. Conclusion Studies on clues for early detection of HIV infection in patients aged 50 years or older are urgently needed to improve the health care in this population.

suggest to lead to suppression of tumor-associated antigen reactive lymphocytes. Aim of the study: To evaluate whether CD4+CD25+ Treg cells in chronic liver disease and Hepatocellular carcinoma patients exhibit an expanded Treg pool correlate it with liver tumor marker and grading. Patients and Methods: 20 pts suffering from chronic liver disease (CLD) mean age 50±9.9 yrs and 15 pts with HCC, mean age 60±8.3 yrs. And ten control subjects mean age 37±7.4 yrs were recruited. Alpha feto-protein (AFP), HBV and HCV antibodies were detected by EIA. HCV confirmed by immunoblotting and RT-PCR. To evaluate HCC grading US guided liver biopsy were done. Patients’ group were categorized into moderately differentiated (grade II); and poorly differentiated (grade III). All studied groups were subjected to LFTs, AFP by EIA. Cytometric analysis of Tregs CD4+CD25+ T cells in PBMCs was performed using anti-CD3; CD4, CD25, CD45RA and IgG-isotype control (FITC and PE). Results: Both CLD and HCC patients groups were 80% +ve for HCV while, were 20% and 11% respectively for HBV. Mean percentage of CD4+CD25+T cells populations demonstrated highly significant increase in comparing HCV to HCC patients 2.47±0.66 vs. 8.96±1.38 (P = 0.00) and when comparing both group to controls 1.15±0.5 (P 0.05). Correlation were found between mean CD4+CD25+ T cells percentage and serum AFP in HCC (r = 0.615) and with tumor grades (II and III) patients groups (r = 0.474, 0.582) respectively. CLD patients group showed significant negative correlation with AFP level (r = −0.48). Conclusion: Tumor specific T reg cells may limit the efficacy of anti tumor response. They correlate properly with the unique marker AFP and with tumor grades. Better understanding of the underlying mechanism of T-reg regulation or strategy for controlling T-regs may enhance tumor immunity and effective cancer immunotherapy.

Liver disease is frequently seen in HIV+ patients as a result of coinfection with hepatitis B (HBV) or C (HCV) viruses, alcohol abuse and/or exposure to hepatotoxic drugs. The aim of this study was to assess the prevalence of liver cirrhosis, its main causes and clinical presentation in HIV+ patients. Observational, cross-sectional, retrospective study of all HIV+ individuals followed at one reference HIV outpatient clinic in Madrid. Liver fibrosis was measured in all cases using transient elastometry (FibroScan). All 2168 HIV+ patients on regular follow-up (76% males, 46% injecting drug users) were successfully examined by FibroScan) between October 2004 and August 2006. Liver cirrhosis was recognized in 181 (overall prevalence, 8.3%), and the main aetiologies were HCV, 82.3%; HBV, 1.6%; dual HBV/HCV, 2.8%; and triple HBV/HCV/ hepatitis delta virus (HDV) infection, 6.6%. The prevalence of cirrhosis differed among patients with distinct chronic viral hepatitis: HCV, 19.2%; HBV, 6.1%; HBV/HCV, 41.7%; and HBV/HCV/HDV, 66.7%. In 12 patients with cirrhosis (6.7%), no definite aetiology was recognized. Overall, cirrhotics had lower mean CD4 counts than noncirrhotics (408 vs 528 cells/microL respectively; P = 0.02), despite similar proportion of subjects with undetectable viraemia on highly active antiretroviral therapy. Clinical manifestations of liver cirrhosis were: splenomegaly, 61.5%; oesophageal varices, 59.8%; ascites, 22.6%; encephalopathy, 12.1%; and variceal bleeding, 6.1%. Liver cirrhosis and hepatic decompensation events are relatively frequent in HIV+ individuals. Chronic HCV and alcohol abuse, but not chronic HBV, play a major role. Transient elastometry may allow the identification of a significant number of HIV+ individuals with asymptomatic liver cirrhosis.

Background Pegylated interferon (PEG-IFN) α2a and α2b differ in their pharmacokinetic properties, which might have an effect on their antiviral effects against hepatitis C virus (HCV). Differences between PEG-IFN-α molecules could be more pronounced in HIV-coinfected individuals, in whom response to HCV treatment is impaired. Methods All HCV–HIV-coinfected patients included in PRESCO and EXTENT trials recruited at one referral centre were retrospectively analysed. In both trials, ribavirin (RBV) 1,000–1,200 mg/day was prescribed together with standard doses of PEG-IFN-α2a or -α2b. The attainment of serum HCV RNA Results A total of 218 patients were examined, 138 on PEG-IFN-α2a and 80 on PEG-IFN-α2b. Baseline characteristics were comparable in both groups. Undetectable serum HCV RNA at weeks 4, 12 and 24 was more frequently attained using PEG-IFN-α2a than -α2b (45% versus 27% [ P=0.02]; 65% versus 45% [ P=0.01]; and 75% versus 55% [ P=0.01], respectively), regardless of HCV genotype. Plasma RBV levels did not differ between groups. In multivariate analysis, HCV genotypes 2/3 (odds ratio [OR] 12.5; 95% confidence interval [95% CI] 3.45–33.33; PConclusions The antiviral effect against HCV seems to be greater for PEG-IFN-α2a than -α2b in the HIV setting. A shorter half-life of PEG-IFN-α2b could explain this finding.