Assessment of liver fibrosis and associated risk factors in HIV-infected individuals using transient elastography and serum biomarkers.

BACKGROUND: Liver fibrosis in human immunodeficiency virus (HIV)-infected individuals is mostly attributable to co-infection with hepatitis B or C. The impact of other risk factors, including prolonged exposure to combined antiretroviral therapy (cART) is poorly understood. Our aim was to determine the prevalence of liver fibrosis and associated risk factors in HIV-infected individuals based on non-invasive fibrosis assessment using transient elastography (TE) and serum biomarkers (Fibrotest [FT]). METHODS: In 202 consecutive HIV-infected individuals (159 men; mean age 47 ± 9 years; 35 with hepatitis-C-virus [HCV] co-infection), TE and FT were performed. Repeat TE examinations were conducted 1 and 2 years after study inclusion. RESULTS: Significant liver fibrosis was present in 16% and 29% of patients, respectively, when assessed by TE (≥ 7.1 kPa) and FT (> 0.48). A combination of TE and FT predicted significant fibrosis in 8% of all patients (31% in HIV/HCV co-infected and 3% in HIV mono-infected individuals). Chronic ALT, AST and γ-GT elevation was present in 29%, 20% and 51% of all cART-exposed patients and in 19%, 8% and 45.5% of HIV mono-infected individuals. Overall, factors independently associated with significant fibrosis as assessed by TE (OR, 95% CI) were co-infection with HCV (7.29, 1.95-27.34), chronic AST (6.58, 1.30-33.25) and γ-GT (5.17, 1.56-17.08) elevation and time on dideoxynucleoside therapy (1.01, 1.00-1.02). In 68 HIV mono-infected individuals who had repeat TE examinations, TE values did not differ significantly during a median follow-up time of 24 months (median intra-patient changes at last TE examination relative to baseline: -0.2 kPa, p = 0.20). CONCLUSIONS: Chronic elevation of liver enzymes was observed in up to 45.5% of HIV mono-infected patients on cART. However, only a small subset had significant fibrosis as predicted by TE and FT. There was no evidence for fibrosis progression during follow-up TE examinations.

The steady-state pharmacokinetics of atazanavir/ritonavir in HIV-1-infected adult outpatients is not affected by gender-related co-factors.

OBJECTIVES: Pharmacokinetic differences, contributing to drug-related side effects, between men and women have been reported for HIV protease inhibitors. As only limited and inconclusive data on ritonavir-boosted atazanavir are available, we evaluated the respective steady-state pharmacokinetics in 48 male and 26 female HIV-1-infected adults receiving atazanavir/ritonavir 300/100 mg once-daily as part of their antiretroviral therapy. METHODS: Pharmacokinetic profiles (24 h) of atazanavir/ritonavir were assessed and measured by HPLC/tandem mass spectrometry. Geometric mean (GM; ANOVA) of minimum and maximum plasma drug concentrations (C(min) and C(max)), area under the concentration-time curve (AUC) and total clearance (CL(total)) were compared between the sexes and correlated to demographic (age, gender and ethnicity), physiological (weight and body mass index) and clinical (CD4+ cell count, HIV-RNA, co-medication and hepatitis serology) co-factors. RESULTS: The GM of the atazanavir AUC, C(max) and C(min) of men versus women were 32 643 versus 36 232 ng.h/mL [GM ratio (GMR) = 1.11, P = 0.435], 2802 versus 3211 ng/mL (GMR = 1.15, P = 0.305) and 398 versus 470 ng/mL (GMR = 1.18, P = 0.406), respectively. Although weight (80.6 versus 63.9 kg, P = 0.001) and body weight-adjusted atazanavir dose (3.84 versus 4.60 mg/kg, P = 0.013) were different between the sexes, no significant correlation to atazanavir pharmacokinetics was observed. A linear regression analysis detected significant correlations of atazanavir C(min) with ritonavir AUC (P < 0.001) and the co-administration of methadone oral solution (P = 0.032), and inverse correlations with the time since the first HIV infection diagnosis (P = 0.003) and the number of previous antiretroviral treatments (P = 0.022). CONCLUSIONS: Atazanavir/ritonavir steady-state pharmacokinetics was comparable in men and women, despite gender-related significant differences in atazanavir dose/body weight. The administration of atazanavir/ritonavir is pharmacokinetically safe; 95% of all trough samples were above the recommended plasma concentration of 150 ng/mL.

Combination of tenofovir and lamivudine versus tenofovir after lamivudine failure for therapy of hepatitis B in HIV-coinfection.

OBJECTIVE: At present sequential monotherapy for chronic hepatitis B with hepatitis B virus (HBV)-polymerase inhibitors is clinical practice. It is unknown to date whether combination therapy with lamivudine plus tenofovir could be superior to sequential therapy with tenofovir after the occurrence of lamivudine resistance. METHODS: We conducted a multicenter, 1: 2 matched pair analysis comparing patients with HBV/HIV-coinfection starting an antiretroviral regimen including tenofovir plus lamivudine with patients who had highly replicative, lamivudine resistant HBe-antigen positive chronic hepatitis B and started with tenofovir as the only active HBV polymerase inhibitor subsequent to lamivudine. RESULTS: At baseline patients on tenofovir plus lamivudine (n = 25) had a median HBV DNA of 5.9 x 10(7) copies/ml compared to 1.37 x 10(8) copies/ml in the tenofovir arm (n = 50; P = 0.32). A sustained undetectable HBV DNA < 1000 copies/ml was achieved in 19/25 (76%) patients on tenofovir plus lamivudine and in 42/50 (84%) on tenofovir (P = 0.53). A loss of HBe-antigen was observed in 9/25 (36%) patients on tenofovir plus lamivudine and in 12/50 (24%) patients on tenofovir (P = 0.29). HBs-antigen loss was found in 1/25 (4%) and 3/50 (6%) patients. CONCLUSIONS: In this cohort of HBV/HIV-coinfected individuals, full HBV DNA suppression was achieved in the majority of patients independent of treatment allocation. Loss of HBe- and HBs-antigen was not different between the two study arms. Over a median treatment period of 116 weeks tenofovir was as effective as tenofovir plus lamivudine. Longer treatment periods may be needed to evaluate potential benefits of first-line combination therapy for chronic hepatitis B.

Short communication: Different mutation patterns in subtype CRF06_cpx after mother-to-child transmission.

Abstract Development of drug resistance mutation patterns (DRMP) in HIV after treatment failure depends on the drugs used in the failing regimen. However, selected patterns may not be unique; there is evidence that selection of DRMP for nelfinavir is dependent on subtype and/or background polymorphisms. Here we describe the selection of DRMP in a mother and son infected with subtype CRF06_cpx by mother-to-child transmission. Four years after delivery the mother received stavudine/lamivudine/nelfinavir as first-line therapy. Genotypic resistance tests (GRT) during follow-up showed selection of M184V/L283I in reverse transcriptase (RT) and H63Q/A71V/L90M in protease (PR). The child started treatment 8 months after birth with stavudine/didanosine/nelfinavir followed by an intensification period with efavirenz. Due to toxicity, efavirenz was removed from the regimen again. GRT during follow-up showed selection of L74V/K103N/M184V/M230L in RT and M46I/H63Q/N88S in PR. The viral load (VL) of the mother was initially undetectable followed by intermediate replication (1000-21,000 copies/ml), whereas the child had both periods of undetectable VL and low-level replication. Although both patients were infected with the same virus and treated with the same protease inhibitor, different DRMPs were selected. Whether the nucleoside backbone, course of antiretroviral therapy, or different host environment is responsible for this variability must be determined in larger studies.

The LOPSAQ study: 48 week analysis of a boosted double protease inhibitor regimen containing lopinavir/ritonavir plus saquinavir without additional antiretroviral therapy.

OBJECTIVES: To evaluate the virological, immunological and clinical responses to the boosted double protease inhibitor (PI) regimen combination of lopinavir/ritonavir and saquinavir ('LOPSAQ') without reverse transcriptase inhibitors (RTI) in HIV-positive patients who have few viable RTI treatment options. METHODS: Cohort study of 128 heavily pre-treated patients who were experiencing therapy failure on their current regimen due to RTI resistance and/or systemic toxicities. Patients with PI-resistance mutations or RTI toxicity underwent a structured treatment interruption (STI) (n=76) until virus reverted to wild-type or until resolution of toxicity symptoms. Baseline was defined as the time point when lopinavir/ritonavir plus saquinavir therapy was initiated. Virological response was defined as viral load<400 copies/mL at week 48. RESULTS: A total of 78 (61%) patients experienced a virological response to therapy (ITT). Median viral load at baseline was 5.06 log10 copies/mL; at week 48 median was 2.16 log10 copies. Median CD4 at week 48 was 280 cells/mm3 compared with 172 cells at baseline. At week 48, 78/128 patients were still on therapy. In univariable analyses, significant predictors of virological response included higher CD4 count (P<0.001), lower viral load (P=0.002), less PI-experience (P=0.006) at baseline and fewer PI-resistance mutations (P=0.043) at end of prior failing regimen; in the multivariable analysis only higher CD4 count at baseline (P=0.009) and fewer number of drugs previously taken (P=0.003) could be specified as independent predictors for response. CONCLUSIONS: The combination of lopinavir/ritonavir and saquinavir without RTIs is a potential option as salvage therapy for patients experiencing therapy failure due to RTI resistance or toxicity. This regimen may not be suitable for patients with very low baseline CD4 cell counts, very broad antiretroviral therapy experience or extensive PI-resistance mutations.

A comparison of the steady-state pharmacokinetics of nevirapine in men, nonpregnant women and women in late pregnancy.

AIMS: To evaluate the pharmacokinetics of nevirapine and any possible influencing factors in pregnant women (n = 16), nonpregnant women (n = 13) and men (n = 14), who received nevirapine 200 mg twice daily together with nucleoside reverse transcriptase inhibitors. METHODS: Blood samples were taken for 12 h at steady state. Nevirapine concentrations were measured by liquid chromatography-tandem mass spectrometry. The influence of gender, age, body weight and comedication on minimum and maximum concentrations (C(min), C(max)), area under the concentration-time curve (AUC), total clearance (CL(tot)), half-life (t(1/2)) and volume of distribution (V(d)) was analysed by multivariate techniques. RESULTS: Mean [95% confidence interval (CI)]C(max), AUC(ss) and clearance were 5221 ng ml(-1) (4267, 6175), 50 789 ng (-1)h ml(-1) (43 453, 58 125) and 69.9 ml min(-1) for men, 5871 ng ml(-1) (4848, 6895), 57 045 ng h(-1) ml(-1) (45 997, 68 093) and 65.6 ml min(-1) for nonpregnant women and 4505 ng ml(-1) (3644, 5366), 44 579 ng h(-1) ml(-1) (36 564, 52 594) and 82.1 ml min(-1) for pregnant women. The differences between pregnant and nonpregnant women (% difference, 95% CI) in C(max) (-30.3; -28.5, -33.0), AUC(ss) (-28.0; - 25.8, - 29.5) and clearance (20.2; 26.6, 15.6) reached statistical significance (P = 0.010, P = 0.028 and P = 0.028, respectively). The multivariate analysis underscored the influence of bodyweight on the plasma exposure to nevirapine. CONCLUSIONS: Pregnant women exhibited an increased nevirapine clearance and comparably low plasma concentrations, whereas women with a low bodyweight achieved high plasma nevirapine concentrations. The large variability in nevirapine concentrations in women may lead to loss of efficacy and viral resistance, or drug toxicity, and therefore these patients should be monitored frequently.

Severe CNS side-effect and persistent high efavirenz plasma levels in a patient with HIV/HCV coinfection and liver cirrhosis.

We describe an HIV/HCV coinfected patient with liver cirrhosis, who experienced severe CNS side-effects during efavirenz-based HIV therapy. Plasma levels of efavirenz were 10 times the upper limit and remained elevated (at twice the upper limit) 4 weeks after cessation of therapy. Efavirenz resistance (K103N) developed and was probably due to 'functional' monotherapy.

Impact of tenofovir-containing antiretroviral therapy on chronic hepatitis B in a cohort co-infected with human immunodeficiency virus.

OBJECTIVES: We studied the impact of tenofovir disoproxil fumarate, given as an antiretroviral medication, on patients with chronic hepatitis B virus (HBV) co-infection. METHODS: The polymerase gene-sequence evolution and quantitative HBV loads (HBVL) were observed for 48 weeks in patients taking tenofovir-containing antiretroviral therapy. The patients were grouped according to baseline strata: high-replicative virus (>6 log copies/mL), low-replicative virus at detectable virus loads (<6 log) and HBs-antigen-positive, HBV-DNA-negative individuals. RESULTS: Thirty-one patients were evaluated. The median decline in 20 patients with high-replicative HBV infection was -5.37 log (range: 3.57-7); 11 out of 20 decreased to undetectable levels (lower limit of detection = < 200 copies/mL) and another three were below 400 copies/mL. Out of six patients with detectable HBV-DNA at week 48 (HBVL result: range 3.36-4.32 log(10)), we were able to carry out a re-sequence in four patients. We did not observe relevant emerging resistance mutations, or a relevant virus load re-increase from nadir (>+0.5 log). The patients with low-replicative virus (n = 9) and the baseline DNA-negative patients (n = 2) had an undetectable HBV-DNA at week 48. Two patients became HBeAg-negative; one DNA-negative patient became HBsAg-negative. CONCLUSIONS: Tenofovir is effective in treating HBV infection in HIV patients. Patients with high-replicative virus may benefit from this treatment strategy by a reduction in replicative status, a precondition for improved hepatic function. A few patients showed low-level HBV replication. Indicators for clinical HBV-resistance to tenofovir were not observed.