Amina Carlebach

Virological response to protease inhibitor therapy in an HIV clinic cohort.

OBJECTIVE New antiretroviral strategies aim to reduce plasma HIV RNA (viral load) to below the limits of detectability of assays with the objective of reducing viral replication in order to stop or reverse the pathogenic process and prevent development of drug resistance. First use of a protease inhibitor might offer the most realistic chance of achieving this aim. Our objective was to study the virological response to protease inhibitors in patients taking them for the first time. METHODS A total of 901 patients from a large outpatient clinic were followed a mean of 15 months from the time of starting a protease inhibitor until 1 May 1998. Viral load and CD4 cell count measurements were made on average every 34 days. RESULTS Overall there was a 79% [95% confidence interval (CI), 76-82] probability of the patients achieving a viral load < 500 copies/ml by 24 weeks after starting the protease inhibitor. In a multiple Cox regression model, those with lower initial viral load [relative hazard (RH), 0.72; P < 0.0001], higher CD4 cell count (RH, 1.07; P = 0.002), those starting other new drugs at same time as the protease inhibitor (RH, 1.46 for two versus none; P = 0.003), those who were antiretroviral-naive, and those using indinavir or nelfinavir were more likely to achieve such levels. In those 651 patients achieving viral load < 500 copies/ml within 24 weeks, there was an estimated 53% (95% CI, 51-55) probability of rebound of viral load to > 500 copies/ml by 52 weeks from the first undetectable value. Again, those who had started other new drugs at the same time as the protease inhibitor (RH, 0.57; P = 0.003 for starting two versus none) tended to experience a lower probability of viral load rebound, as did those with higher initial CD4 cell count (RH, 0.87 per 100 x 10(6)/l higher; P = 0.0007). Those who took saquinavir achieved less durable virological responses than those who took other protease inhibitors. CONCLUSIONS Starting protease inhibitor therapy with two other new antiretroviral drugs simultaneously with protease inhibitor therapy offers a better best chance of achieving sustained viral load < 500 copies/ml than starting fewer new drugs.

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 × 107 copies/ml compared to 1.37 × 108copies/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.

CD4 Lymphocyte Count as a Predictor of the Duration of Highly Active Antiretroviral Therapy—Induced Suppression of Human Immunodeficiency Virus Load

The association between CD4 cell count and duration of virus load suppression was investigated in 558 patients in the Frankfurt HIV Clinic Cohort who had begun highly active antiretroviral therapy and who had virus load declines to </=500 copies/mL. The Kaplan-Meier method estimated viral rebound in 42.5% of patients by 24 weeks and in 64.3% by 84 weeks. Risk of viral rebound was independently associated with baseline and changes from baseline CD4 cell count. The achieved CD4 cell count was the most important factor for prediction of viral rebound (relative hazard, 5.4 for an updated CD4 cell count of <20 vs. >500 copies/mL; P=.0001). Baseline virus load was not associated with virus load rebound. Lower baseline CD4 cell counts were associated with increased risk of viral rebound; however, this risk was significantly reduced in persons with low baseline CD4 cell counts who experienced substantial increases in CD4 cell counts during follow-up.

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.

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.

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

BackgroundLiver 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]).MethodsIn 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.ResultsSignificant 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).ConclusionsChronic 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 Protease Inhibitor Transfer Study (PROTRA 1): abacavir and efavirenz in combination as a substitute for a protease inhibitor in heavily pretreated HIV-1-infected patients with undetectable plasma viral load.

The aim of the study was to evaluate the safety and efficacy of abacavir (ABC) and efavirenz (EFV) instead of a protease inhibitor (PI) in HIV‐1‐infected subjects treated with two nucleoside reverse transcriptase inhibitors (NRTIs) and one PI with undetectable viral loads (<50 HIV‐1 RNA copies/mL). To be eligible for inclusion, patients had to have a history of viral load <400 copies/mL for at least 3 months and had to be naïve to treatment with nonnucleoside reverse transcriptase inhibitors (NNRTIs) and ABC, but multiple pretreatment and treatment failure were allowed.

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.