Lionel Piroth

Does hepatitis C virus co-infection accelerate clinical and immunological evolution of Hiv-infected patients?

Objective:To study the influence of hepatitis C virus (HCV) co-infection on clinical and immunological evolution of HIV-infected patients. Design:A longitudinal study of HIV-infected individuals with or without HCV infection, identified at the Infectious Diseases Department of Dijon University Hospital and enrolled in a historical cohort, was performed. Methods:One hundred and nineteen HIV-infected people co-infected with HCV and 119 matched individuals infected with HIV alone were included in the cohort (median participation time 3 years; range, 2 months to 11.5 years). Clinical progression was defined as one or more of the following: a 30% decrease in the Karnofsky index; a 20% loss of body weight; an AIDS-defining illness (for non-AIDS patients); death (except by accident, suicide or overdose). Immunological progression was defined as a 50% decrease in the initial CD4 T-cell count (for patients with an initial count > 100 × 106 cells/l). Effects of HCV co-infection were evaluated using Kaplan-Meier survival analysis and significance was tested using univariate (log-rank and Petos tests) and multivariate methods (Coxs model). Results:In univariate analysis, immunological progression was not statistically different between the HCV-positive group and the HCV-negative group, whereas clinical progression was significantly faster in HCV-positive patients (P < 0.005, log–rank test). In a multivariate Cox model, clinical progression remained significantly associated with infection by HCV [hazard ratio (HR), 1.64; 95% confidence interval (CI), 1.06–2.55; P < 0.05]. Stratified multivariable analysis retained HCV as a significant prognostic factor of clinical progression (HR, 10.9; 95% CI, 1.09–109.3; P < 0.05) and immunological progression (HR, 2.31; 95% CI, 1.16–4.62; P < 0.02) for patients with an initial CD4 count above 600 × 106 cells/l. Conclusions:Clinical progression is more rapid in HIV–HCV co-infected patients than in HIV-seropositive patients are not infected by HCV. The prognostic value of HCV infection for both clinical and immunological progression is significant at early stages of HIV infection. These findings may argue for active management of hepatitis C infection in co-infected individuals, especially for asymptomatic patients whose CD4 count is above 600 × 106 cells/l, to predict and prevent accelerated progression of HCV and HIV diseases.

Predictors of virological rebound in HIV-1-infected patients initiating a protease inhibitor-containing regimen.

Objective To study the predictors of virological rebound in patients having early virological response to protease inhibitor (PI)-containing regimen. Design and methods APROCO cohort study prospectively enrolled 1283 HIV-infected patients starting a PI-containing regimen in 1997–1999. Adherence to therapy was measured with self-administered questionnaires after 4 months of therapy (M4). Virological rebound was defined as a viral load (VL) > 500 copies/ml in patients having early virological response, defined as a VL < 500 copies/ml at M4. Predictors of time to virological rebound were studied with multivariate proportional hazards model. Results During a median follow-up of 20 months, virological rebound was observed in 32% of the 830 patients with early virological response. Virological rebound was more frequent when patients had received previous antiretroviral treatment [adjusted hazards ratio (HR) = 2.4;P < 0.0001], were younger (HR = 1.4 per each 10 years younger;P < 0.0001), had baseline CD4 cell count < 500 × 106/l (HR = 2.3;P < 0.001), had higher baseline VL (HR = 1.4 per each log10 copies/ml higher;P < 0.001), reported low adherence to therapy at M4 (HR = 2.1;P < 0.001) or had stopped PI at M4 (HR = 1.7;P = 0.04). Conclusion Initiation of treatment at a stage of preserved immunity is associated with a more durable virological response under protease inhibitor. Every effort should be made to monitor and strengthen adherence to therapy, even in patients having early virological response.

Association between Insulin resistance and hepatitis C virus chronic infection in HIV-hepatitis C virus-coinfected patients undergoing antiretroviral therapy

Summary: Insulin resistance (IR) in the context of highly active antiretroviral therapy (HAART) is becoming more common in HIV‐infected patients. Patients with chronic hepatitis C virus (HCV) infection have an increased risk of IR and type 2 diabetes mellitus. A cross‐sectional study was performed to investigate whether chronic HCV infection constitutes a risk factor for IR in HIV‐HCV‐coinfected patients undergoing HAART. Inclusion criteria were positive HCV viremia and a sustained increase of alanine aminotransferase of at least twice the normal value. A total of 29 HIV‐HCV patients, 76 HIV patients, and 121 HCV controls were tested for IR and body mass index (BMI). IR was measured using the homeostasis model assessment. In HIV‐HCV and HIV patients, fat redistribution and lipid profile were assessed. There was no significant difference in age, CD4 cell count, HIV viral load, or duration of HAART between the HIV‐HCV and HIV groups. HIV‐HCV patients and HCV controls had a significant increase in IR when compared with HIV patients (0.25 ± 0.28 and 0.21 ± 0.34 versus 0.04 ± 0.37; p = .01 and p = .003, respectively). Lipoatrophy was observed more frequently in HIV‐HCV patients in comparison with HIV patients (41% versus 14%; p = .003). In HIV‐HCV patients, total cholesterol and triglyceride levels were significantly lower than in HIV patients. In multivariate analysis, IR, BMI, triglyceride levels, and peripheral fat wasting were the independent variables associated with HCV infection. Our findings suggest that chronic HCV infection is a significant factor associated with the development of metabolic abnormalities and with modifications in body composition in HIV patients receiving antiretroviral treatment.

Safety and Immunogenicity of 4 Intramuscular Double Doses and 4 Intradermal Low Doses vs Standard Hepatitis B Vaccine Regimen in Adults With HIV-1 A Randomized Controlled Trial

CONTEXT Alternative schedules more immunogenic than the standard hepatitis B vaccine regimen are needed in patients with human immunodeficiency virus 1 (HIV-1) infection. OBJECTIVE To compare the safety and immunogenicity of 4 intramuscular double-dose and 4 intradermal low-dose regimens vs the standard hepatitis B vaccine regimen. DESIGN, SETTING, AND PARTICIPANTS An open-label, multicenter, 1:1:1 parallel-group, randomized trial conducted between June 28, 2007, and October 23, 2008 (date of last patient visit, July 3, 2009) at 33 centers in France with patients enrolled in French National Agency for Research on AIDS and Viral Hepatitis trials in adults with HIV-1 infection who were hepatitis B virus (HBV) seronegative and having CD4 cell counts of more than 200 cells/μL. INTERVENTION Patients were randomly assigned to receive 3 intramuscular injections of the standard dose (20 μg) of recombinant HBV vaccine at weeks 0, 4, and 24 (IM20 × 3 group, n = 145); 4 intramuscular double doses (40 μg [2 injections of 20 μg]) of recombinant HBV vaccine at weeks 0, 4, 8, and 24 (IM40 × 4 group, n = 148); or 4 intradermal injections of low doses (4 μg [1/5 of 20 μg]) of recombinant HBV vaccine at weeks 0, 4, 8, and 24 (ID4 × 4 group, n = 144). MAIN OUTCOME MEASURES Percentage of responders at week 28, defined as patients with hepatitis B surface antibody (anti-HBs) of at least 10 mIU/mL in patients who received at least 1 dose of vaccine. Patients with missing anti-HBs titer measurement at the final follow-up visit at week 28 were considered as nonresponders in the primary (efficacy) analysis. RESULTS A total of 437 patients were randomized to the 3 study groups, of whom 11 did not receive any vaccine. Of these, 396 had available anti-HBs titers at week 28. The percentage of responders at week 28 was 65% (95% confidence interval [CI], 56%-72%) in the IM20 × 3 group (n = 91), 82% (95% CI, 77%-88%) in the IM40 × 4 group (n = 119) (P < .001 vs IM20 × 3 group), and 77% (95% CI, 69%-84%) in the ID4 × 4 group (n = 108) (P = .02 vs IM20 × 3 group). No safety signal and no effect on CD4 cell count or viral load were observed. CONCLUSION In adults with HIV-1, both the 4 intramuscular double-dose regimen and the 4 intradermal low-dose regimen improved serological response compared with the standard HBV vaccine regimen. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00480792.

The evolution of hepatitis B virus serological patterns and the clinical relevance of isolated antibodies to hepatitis B core antigen in HIV infected patients

BACKGROUND/AIMS The evolution of hepatitis B virus (HBV) serological patterns and the clinical relevance of isolated anti-HBc pattern are not well established in HIV infected patients. METHODS A cohort of 240 patients was followed for 6.9+/-3.4 years, with iterative HBV serologic assays performed (mean interval of 2.2 years). RESULTS Five patients without HBV markers at baseline subsequently developed positive anti-HBs (incidence 0.66/100 patient-year), as did two patients with chronic HBs antigenemia (incidence 1.66/100 patient-year). Only one patient with isolated anti-HBc pattern developed HBs chronic antigenemia. Persistent isolated anti-HBc pattern was observed in 37 patients (13 with detectable blood HBV DNA) and was strongly associated with positive hepatitis C virus (HCV) viremia (hazard ratio=9.5, confidence interval 95%: 4.5-20.0, P<0.0001). Hepatic lesions were more severe in HCV infected patients with persistent isolated anti-HBc pattern than in those without (Knodell score 9.2+/-4.6 versus 6.7+/-5.0, P=0.04). In time updated analysis, this pattern was not associated with an increased risk of hepatotoxicity, by contrast with HCV infection or positive HBs antigenemia. CONCLUSIONS In HIV infected patients, HBV serological status must be systematically and regularly assessed, and systematic HBV vaccination must be proposed in those without HBV marker. Isolated anti-HBc pattern must be considered in the management of hepatitis C, but not for antiretroviral therapy.

Spread of Extended-Spectrum β-Lactamase—Producing Klebsiella pneumoniae: Are β-Lactamase Inhibitors of Therapeutic Value?

Because of recurrent colonization by Klebsiella pneumoniae strains producing type SHV-4 extended-spectrum β-lactamases (ESBLs), a case-control study was conducted in an intensive care unit to investigate the risk of acquisition, with special reference to antibiotic therapy and resuscitation procedures. Fifty-one patients colonized or infected by ESBL-producing K. pneumoniae (cases) were matched with 51 noncolonized patients (controls). Duration of intubation was significantly longer for cases than for controls, while duration of β-lactamase inhibitor therapy was significantly shorter. By means of multivariate analysis, intubation was the only risk factor identified (odds ratio [OR] = 1.19), while β-lactamase inhibitor therapy was shown to be a protective factor (OR = 0.849). During outbreaks of SHV-4 type ESBL-producing K. pneumoniae in intensive care units, preferential use of β-lactamase inhibitors may help control the emergence and spread of these pathogens even if essential hand washing and isolation procedures are adhered to.

Risk factors for symptomatic mitochondrial toxicity in HIV/hepatitis C virus-coinfected patients during interferon plus ribavirin-based therapy.

Objective:To evaluate the incidence, clinical features, and risk factors for symptomatic mitochondrial toxicity in HIV/hepatitis C virus (HCV)-coinfected patients receiving anti-HCV therapy. Methods:All cases of symptomatic mitochondrial toxicity reported in 416 patients participating in an open, randomized trial of peg-interferon α-2b plus ribavirin vs. interferon α-2b plus ribavirin for 48 weeks were reviewed. Associations with antiretroviral treatments and with clinical and laboratory findings were sought by univariate and multivariate analysis. Results:Eleven of the 383 patients who received at least 1 dose of anti-HCV treatment developed symptomatic mitochondrial toxicity (symptomatic hyperlactatemia and pancreatitis in 6 and 5 patients, respectively). All cases occurred in patients being treated for HIV infection, and the incidence of symptomatic mitochondrial toxicity was 47.5 per 1000 patient-years. In multivariate analysis, symptomatic mitochondrial toxicity was significantly associated with didanosine-containing antiretroviral regimens (odds ratio 46; 95% CI, 7.4 to infinity; P < 0.001), but not with stavudine or with nucleoside reverse transcriptase inhibitor regimens not containing didanosine. The incidence of symptomatic mitochondrial toxicity was 200.2 per 1000 patient-years in patients receiving didanosine. Demographic characteristics were not associated with symptomatic mitochondrial toxicity. Conclusions:Coadministration of ribavirin with didanosine should be avoided. If unavoidable, patients should be monitored closely for mitochondrial toxicity. Didanosine should be suspended if clinical signs or symptoms of mitochondrial toxicity occur.

Hepatic steatosis in HIV-HCV coinfected patients: analysis of risk factors.

Objective:To evaluate the prevalence and severity of steatosis and possible interactions between steatosis, host factors, viral factors, and treatment for HIV infection in HIV–hepatitis C virus (HCV) coinfected patients. Methods:Steatosis was assessed among 395 HIV–HCV coinfected patients who were enrolled in the ANRS trial HC02 Ribavic and for whom histological data were available. Steatosis was graded as follows: 0 (none); 1 (< 30% hepatocytes containing fat); 2 (30–70%); 3 (> 70%). Results:Steatosis was present in 241 patients (61%), of whom 149 (38%) had grade 1, 64 (16%) grade 2 and 28 (7%) grade 3. In multivariate analysis, the following five independent risk factors were associated with steatosis: HCV genotype 3 [odds ratio (OR), 3.02; 95% confidence interval (CI), 1.91–4.79; P < 0.0001], the mean METAVIR fibrosis score (OR, 1.43; 95% CI, 1.11–1.84; P = 0.0053), the body mass index (BMI; OR, 1.13; 95% CI, 1.05–1.21; P = 0.0013), HCV viral load (OR. 1.65; 95% CI, 1.22–2.23; P = 0.0012) and ferritin (OR, 1.13; 95% CI, 1.06–1.21; P < 0.0003). As HCV genotype 3 was a risk factor for steatosis, further exploratory analyses were stratified according to the HCV genotype (1 and 3). Factors independently associated with steatosis were BMI and HCV viral load in patients with HCV genotype 3 infection and the mean METAVIR fibrosis score, the BMI and ferritin in patients with HCV genotype 1 infection. Conclusion:Steatosis is particularly frequent in HIV–HCV coinfected patients, who appear to have the same risk factors for steatosis as HCV monoinfected patients. None of the characteristics of HIV infection, including antiretroviral therapy, was independently associated with steatosis.

Ten-year incidence and risk factors of bone fractures in a cohort of treated HIV1-infected adults.

In the ANRS CO8 APROCO-COPILOTE cohort of patients treated with combination antiretroviral therapy since 1997–1999, the incidence density of bone fractures was 3.3 for 1000 patient-years [95% confidence interval (CI) = 2.0–4.6]. The rate was 2.9-fold (95% CI = 1.3–6.5) higher among patients with excessive alcohol consumption and 3.6-fold (95% CI = 1.6–8.1) higher in those with hepatitis C virus (HCV) coinfection. Specific monitoring of HCV/HIV-coinfected patients and active promotion of alcohol cessation should be recommended for the prevention of bone fractures.

Value of Patient Self-Report and Plasma Human Immunodeficiency Virus Protease Inhibitor Level as Markers of Adherence to Antiretroviral Therapy: Relationship to Virologic Response

Three methods of adherence to antiretroviral therapy were evaluated for 149 patients infected with human immunodeficiency virus (HIV): plasma level of protease inhibitors (PIs), patient self-report, and routine biological parameters associated with the use of some antiretroviral drugs. Adherence to therapy was estimated from a score calculated from answers to a self-administered questionnaire and on the basis of measurement of relevant plasma and blood levels. Of the 149 patients, 112 had a virologic response, and 122 had adequate trough PI levels. Plasma PI levels and virologic outcome were significantly correlated (P<.0001). The adherence score was significantly correlated with virologic response (P<.001). Macrocytosis was significantly associated with virologic response in the patients treated with zidovudine or stavudine (P=.006). PI level was the higher significant predictor of virologic response (P=.0003). Self-reported adherence (P=.01) and macrocytosis (P=.05) were also independently associated with antiretroviral efficacy.