Alicia Gutierrez-Valencia

The Use of Transient Elastometry for Assessing Liver Fibrosis in Patients with HIV and Hepatitis C Virus Coinfection

BACKGROUND Transient elastometry (TE) is accurate for detecting significant liver fibrosis and cirrhosis in hepatitis C virus (HCV)-monoinfected patients. However, this procedure has been insufficiently validated in patients with human immunodeficiency virus (HIV) and HCV coinfection. The purpose of this study was to validate reported cutoff values of TE that discriminate significant liver fibrosis and cirrhosis in HIV-HCV-coinfected subjects. METHODS Liver stiffness measurements were obtained for 169 HIV-HCV-coinfected adult patients who had undergone a liver biopsy or who had received a nonhistologic diagnosis of cirrhosis within 12 months before or after a liver stiffness measurement. Patients had received no prior therapy for HCV infection. RESULTS TE measurements ranged from 3.6 kPa to 75 kPa. The area under the receiver operating characteristic curve was 0.87 (95% confidence interval, 0.84-0.93) for significant liver fibrosis and 0.95 (95% confidence interval, 0.92-0.99) for cirrhosis. To diagnose significant liver fibrosis, a cutoff value of 7.2 kPa was associated with a positive predictive value of 88% and a negative predictive value of 75%. Thirty-four patients (20%) were misclassified when this cutoff value was used. Thirteen (24%) of 54 patients with liver stiffness values <7.2 kPa had significant liver fibrosis detected by liver biopsy. To diagnose cirrhosis, a cutoff value of 14.6 kPa was associated with a positive predictive value of 86% and a negative predictive value of 94%. Thus, 13 patients (10%) had disease that was misclassified using this cutoff value. CONCLUSIONS We found that the diagnostic accuracy of TE was high for detecting cirrhosis and good for diagnosis of significant liver fibrosis. However, the performance of TE was low for discriminating mild fibrosis from significant liver fibrosis, which might limit the applicability of this technique in clinical practice.

Cellular HIV reservoir replenishment is not affected by blip or intermittent viremia episodes during darunavir/ritonavir monotherapy.

Objective:To assess the impact of blips and persistent viremia episodes on cell-associated HIV-DNA reservoir in extensively pretreated patients receiving ritonavir-boosted darunavir monotherapy (MtDRV/rtv) for 24 months. Design and methods:Patients from the MonDAR prospective study (NCT01606722) who received at least 6 months of MtDRV/rtv and had at least two available peripheral blood mononuclear cells (PBMCs) samples were selected and classified according to the viral outcome as continuous undetectable viremia (cUV; n = 40), blips (n = 31), intermittent viremia (IV; n = 23), and virological failure (VF, two consecutive viral loads >200 copies/ml; n = 20). Proviral HIV-DNA was quantified by real-time PCR in PBMCs samples at baseline, and months 6, 12, 18 and 24. Additionally, HIV-DNA levels were exhaustively analyzed at virological failure and blip episodes. Results:The HIV-DNA levels remained constant during the 24 months in every group. Neither blips nor intermittent viremia influenced the HIV-DNA levels at short-term or at middle term. By contrast, virological failure episodes gave rise to a significant increase in proviral DNA (2.15 vs. 2.32 log10 HIV-DNA copies/106 PBMCs; P = 0.042). Basal proviral DNA levels more than 2 log10 copies/106 PBMCs predicted the time to viral rebound at any given cut-off point (>20, >50, and >200 copies/ml. HR: 3.02, 2.61, and 3.02, respectively; P ⩽ 0.03. Besides, an adherence less than 95% was also strongly associated with virological failure (HR, 3.17; P = 0.021). Conclusion:Blip episodes and intermittent viremia did not affect the cellular HIV reservoir dynamic during MtDRV/rtv. Higher adherence and an HIV-DNA levels less than 2 log10 copies/106 PBMCs at baseline were associated with a lower risk of virological failure.

Role of Pegylated Interferon‐α‐2a and Ribavirin Concentrations in Sustained Viral Response in HCV/HIV‐Coinfected Patients

The effect of simultaneous plasma concentrations of pegylated interferon‐α‐2a (pegIFN‐α‐2a) and ribavirin (Rbv) on viral response has not been addressed to date. Hepatitis C virus (HCV)/human immunodeficiency virus (HIV)–coinfected patients received pegIFN‐α‐2a and Rbv under routine clinical care conditions. Plasma concentrations of the two drugs were measured using enzyme‐linked immunosorbent assay and high‐performance liquid chromatography after 2, 4, 8, and 12 weeks and at the end of the treatment period (24–48 weeks, according to HCV genotype and treatment duration). Large interindividual variability was observed in the plasma levels of both drugs. After multivariate analysis, only HCV genotype 3, low HCV‐RNA levels, and pegIFN‐α‐2a exposure remained as independent factors associated with sustained viral response (SVR). The probability of attaining an SVR in HCV genotypes 1 and 4 was more than three to four times higher in patients with pegIFN‐α‐2a levels above the selected cutoff point. Early therapeutic drug monitoring of pegIFN‐α‐2a levels could be beneficial in improving current treatment outcomes.

Intracellular and plasma pharmacokinetics of 400 mg of etravirine once daily versus 200 mg of etravirine twice daily in HIV-infected patients

OBJECTIVES To compare intracellular and plasma etravirine concentrations when etravirine was given at 200 mg/12 h versus 400 mg/24 h and to evaluate whether the results would support once-daily dosing. METHODS This was an open-label sequential study in which eight patients on protease inhibitor (PI)-sparing regimens containing etravirine were included. Full pharmacokinetic profiles were performed while on 200 mg of etravirine/12 h and after switching to 400 mg of etravirine/24 h. Intracellular and plasma levels were determined by liquid chromatography coupled with mass spectrometry. Pharmacokinetic parameters were calculated by non-compartmental analysis and compared by geometric mean ratios (GMRs) using 200 mg of etravirine/12 h as the reference group. TRIAL REGISTRATION ClinicalTrials.gov NCT01121809. RESULTS The geometric mean (GM) for etravirine AUC(0-τ) (5602 versus 5076 ng · h/mL, GMR 0.91), C(max) (403 versus 495 ng/mL, GMR 1.23) and C(min) (139 versus 102 ng/mL, GMR 0.74) were similar with both dosing schedules at the intracellular level. In plasma, the GMRs for AUC(0-τ), C(max) and C(min) were 1.31, 1.76 and 0.99, respectively. The mean intracellular penetration, evaluated as intracellular and plasma AUC(0-τ) ratios, was 81% when etravirine was dosed twice daily and 56% with once-daily dosing. CONCLUSIONS Our results show that intracellular etravirine levels were similar with both dosing regimens in patients with PI-sparing regimens, while etravirine plasma AUC(0-τ) and C(max) were 30% and 76% higher with the once-daily regimen, respectively. Thus, a once-daily dosing regimen is supported not only by plasma etravirine pharmacokinetic profiles but also by intracellular levels.

Differential Effects of Viremia and Microbial Translocation on Immune Activation in HIV-Infected Patients Throughout Ritonavir-Boosted Darunavir Monotherapy

AbstractThe purpose of this article is to evaluate the evolution of microbial translocation (MT) and its role in CD4+ and CD8+ T cells immune activation (IA) in HIV-1-infected patients on ritonavir-boosted darunavir monotherapy (mtDRV/rtv).Prospective study of consecutive HIV-1-infected patients switched to mtDRV/rtv as a simplification regimen. Subjects were classified according to the virological behavior during a 24-month follow-up as continuous undetectable viral load, blips, intermittent viremia, and virological failure (VF). MT was evaluated by plasma LPS and 16S genomic rDNA (16S rDNA) levels, whereas IA was assessed by the coexpression of HLA-DR and CD38 in CD4+ and CD8+ T cells, and plasma sCD14 levels.Seventy-one patients were included in this substudy of the MonDar cohort (ClinicalTrials.gov: NCT01505722). At baseline, CD4+ (&rgr; = −0.352, P = 0.01) and CD8+ T-cell activation (&rgr; = −0.468, P < 0.001) were correlated with time with viral suppression, but not with MT markers. A significant decrease in plasma LPS levels was found only in patients without VF (baseline, 77.8 vs month 24, 60.4 pg/mL; P < 0.001]. Both plasma 16S rDNA and sCD14 levels were unchanged irrespective of the viral behavior. The only variable independently associated with a decrease in CD4+ and CD8+ T cells activation was an undetectable HIV-1 viremia (&bgr; = 4.78, P < 0.001 and &bgr; = 2.93, P = 0.005, respectively).MT does not have a pivotal role in T-cell activation, at least in patients with long-term viral suppression. The viremic episodes and VF are the main factors related to CD4+ and CD8+ T-cells IA, even during mtDRV/rtv.

Role of Ritonavir in the Drug Interactions Between Telaprevir and Ritonavir-Boosted Atazanavir

BACKGROUND Detrimental bidirectional pharmacokinetic interactions have been observed when telaprevir (TVR) and ritonavir (RTV)-boosted human immunodeficiency virus (HIV) protease inhibitors are coadministered in healthy volunteers. Our aim was to evaluate the role of RTV in the bidirectional TVR and atazanavir (ATV) interactions. METHOD An open-label, sequential study was carried out in hepatitis C virus (HCV)/HIV-coinfected patients on a RTV-boosted ATV-based (ATVr) antiretroviral regimen (300/100 mg every 24 hours) and triple therapy for chronic C hepatitis genotype 1 (TVR, 1125 mg every 12 hours, pegylated interferon-alpha and ribavirin). Pharmacokinetic profiles were acquired before and after switching from ATVr to unboosted ATV (200 mg every 12 hours). The plasma levels of both drugs were determined by liquid chromatography coupled with mass spectrometry. Pharmacokinetic parameters were calculated by noncompartmental analysis and compared by geometric mean ratios and their 90% confidence intervals. RESULTS Fourteen white HCV/HIV-coinfected males were enrolled in this study. After RTV was withdrawn, the TVR AUC(0-12) (area under the concentration-time curve), maximum concentration (C(max)), and minimum concentration (C(min)) values increased by 19% (7%-30%), 12% (0.9%-29%), and 18% (2%-34%), respectively, without any changes in the TVR terminal half-life. The ATV AUC(0-12), C(max), and C(min) values were 39% (13%-66%), 19% (8%-59%), and 48% (1%-96%) higher, respectively, with a significantly shorter terminal half-life (22.6 hours vs 10.4 hours). CONCLUSIONS RTV is responsible for the adverse interactions that occur when TVR and ATVr are administered together, possibly by influencing either the absorption phase or first-pass metabolism of TVR. The boost effect of TVR on ATV exposure is higher than on RTV, despite its shorter terminal half-life. The coadministration of TVR and unboosted ATV results in increased exposure of both drugs compared with their coadministration with RTV. CLINICAL TRIALS REGISTRATION ClinicalTrials.gov: NCT01818856. European Medicines Agency EudraCT no. 2012-002515-25.

Darunavir minimum plasma concentration and ritonavir-boosted darunavir monotherapy outcome in HIV-infected patients.

BACKGROUND This study aimed to evaluate whether low darunavir (DRV) minimum plasma concentration (Cmin) values contribute to virological outcomes during DRV/ritonavir monotherapy (mtDRV/rtv). METHODS This was a prospective observational single-arm 96-week efficacy study in virologically suppressed subjects on triple therapy switched to mtDRV/rtv (800/100 mg every 24 h). Previous virological failures (VF) on protease-inhibitor-based regimens were allowed if the historical resistance tests showed no major resistance mutation to DRV/rtv. VF was defined as two consecutive HIV RNA measurements of >200 copies/ml. Efficacy was analysed by per-protocol and by intention-to-treat analyses. Plasma DRV Cmin values were measured by LC-MS/MS. RESULTS A total of 150 subjects were included. At week 96, the efficacy rate on treatment was 83.6% (95% CI 77.2%, 90.0%) by per-protocol analysis and 67.6% (95% CI 60.0%, 75.2%) by intention-to-treat. In the whole cohort the median (IQR) DRV Cmin was significantly higher during the periods of undetectable than of detectable viraemia (1.82 µg/ml [1.47-2.46] versus 1.56 µg/ml [0.93-2.32]; P=0.006) as well as in the subjects with blips and VF. However, a cutoff point sufficiently sensitive and specific could not be found. CONCLUSIONS The DRV Cmin values are related to viral control during mtDRV/rtv, but therapeutic drug monitoring cannot be recommended routinely as a precise cutoff point is unknown. Adherence is a key success factor on this regimen.

The IL28B effect on hepatitis C virus kinetics among HIV patients after the first weeks of pegylated-interferon/ribavirin treatment varies according to hepatitis C virus-1 subtype.

Objective:To evaluate the IL28B effect on hepatitis C virus (HCV) decline during first weeks of treatment according to HCV-1 subtypes. Methods:Patients coinfected with HIV/HCV genotype 1 and naive to peginterferon-alpha-2a and ribavirin (Peg-IFN-alpha-2a/RBV) were included. Plasma HCV-RNA was measured at baseline, and then at weeks 1, 2, and 4. HCV-1 subtype (1a or 1b) was determined. HCV viral decline was analyzed according to HCV-1 subtype between baseline and week 1, week 2 and week 4 of treatment. Additionally, we analyzed the effect of the IL28B (rs12979860) genotype on HCV viral decline with HCV-1a and HCV-1b genotype patients (CC versus non-CC). Results:Two hundred and six patients were included in the study, of whom 113 (54.8%) and 93 (45.2%) were infected by HCV-1a and 1b genotypes, respectively. No differences were found between HCV-1 subtypes in terms of HCV viral decline or rapid virological response rate. The effect of the IL28B-CC genotype on HCV viral decline was observed only among patients infected with HCV-1b at all time points analyzed (week 1: CC 1.53 ± 0.33, non-CC 0.27 ± 0.24, P <0.001; week 2: CC 1.81 ± 0.39, non-CC 0.74 ± 0.39, P = 0.002; week 4: CC 2.97 ± 0.53, non-CC 1.2 ± 0.61, P < 0.001). Conclusion:Our study suggests that the effect associated with the impact of the IL28B-CC genotype on HCV decline during the first weeks of treatment with Peg-IFN-alpha-2a/RBV differs according to HCV-1 subtype and may be limited to HCV-1b patients.

Protease inhibitor monotherapy is effective in controlling human immunodeficiency virus 1 shedding in the male genital tract

Cross-sectional study comparing seminal human immunodeficiency virus type 1 (HIV-1) shedding in patients receiving boosted protease inhibitor monotherapy (mtPI/rtv) (n = 66) versus triple therapy (TT) (n = 61). Seminal HIV-1 shedding rates in patients with undetectable plasma HIV-RNA were 16.0% on mtPI/rtv compared with 28.6% on TT (p 0.173). Aviraemic status and time on viral suppression were independently associated with lack of seminal HIV-1 shedding. During TT, non PI/rtv-based regimens were associated with a better control of HIV infection in semen despite similar time on viral suppression. The use of mtPI/rtv in well-controlled patients is not associated with increased seminal HIV excretion compared with TT.

Impact of the peginterferon-α 2a and ribavirin plasma levels on viral kinetics and sustained virological response in genotype 1 HCV/HIV-co-infected patients with the unfavourable non-CC IL28B genotypes.

Studies on the association between the peginterferon‐α and ribavirin levels and sustained virological response (SVR) have shown yielded conflicting results, but most of them were performed before the influence of IL28B polymorphisms was known. Our aim was to assess the effects of peginterferon‐α 2a and ribavirin plasma levels on viral kinetics and SVR in hepatitis C virus genotype 1 HCV‐1/HIV‐co‐infected patients according to IL28B genotype. This was a cohort study of HCV‐1/HIV‐co‐infected patients who were HCV‐treatment naïve and for whom the efficacy of peginterferon‐α 2a plus ribavirin was evaluated by per‐protocol analysis. The peginterferon‐α 2a and ribavirin levels were measured by ELISA and HPLC‐UV, respectively. The relationships among host and viral factors, the trough drugs levels and virological responses were analysed by multivariate regression analyses. A total of 131 Caucasian patients were included (cirrhosis:38.9%). Overall, SVR rate was 39.6%. In patients with CC IL28B genotype, SVR was related neither to peginterferon‐α 2a nor to ribavirin plasma levels, while higher levels of both drugs were the only variables independently associated with SVR in individuals with CT/TT IL28B genotypes (OR, 5.02; CI95, 1.45–17.1; P = 0.001 and 4.0; CI95, 1.08–14.7; P = 0.038, respectively). Moreover, faster viral declines were observed in CT/TT patients when pegIFN‐α 2a and ribavirin plasma levels were greater than 3400 pg/mL and 1.6 μg/mL, respectively. In contrast to the results for CC patients, the results in patients carrying the unfavourable CT/TT IL28B genotypes showed that plasma levels of both drugs have significant effects on viral kinetics and SVR.