Christian Perronne

Liver‐related mortality in human‐immunodeficiency‐virus‐infected patients between 1995 and 2003 in the French GERMIVIC Joint Study Group Network (MORTAVIC 2003 Study)*

Summary.  The objective of the present study was to determine mortality because of end‐stage liver disease (ESLD) in a nationwide population of HIV‐infected patients, 7 years following the introduction of highly active antiretroviral therapy (HAART). All departments of internal medicine and infectious diseases from the GERMIVIC Study Group prospectively recorded all deaths in HIV‐infected patients during 2003. Fifty‐nine departments, following a total of 20 940 HIV‐infected patients, participated in the study. Results were compared with those of previous surveys conducted using similar methodology in 1995, 1997 and 2001. Among 215 deaths observed during 2003, 101 (46.9%) were related to AIDS, 27 (12.6%) to ESLD and 87 (40.5%) to other causes. Mortality because of ESLD represented 23.7% of non‐AIDS‐related deaths. Patients dying from ESLD had chronic hepatitis because of hepatitis C virus (HCV) in 92.6% of cases and moderate (30–60 g) or high (>60 g) alcohol consumption (43.5% and 26.0%, respectively). In this population, deaths because of ESLD were 1.5% in 1995, 6.6% in 1997, 14.3% in 2001 and 12.6% in 2003. The prevalence of hepatocellular carcinoma as a cause of death remained high in 2003 but stable when compared with 2001 (25%vs 14.8%). Treatment of hepatitis C in patients who died from ESLD was more frequent in 2003 (44.4%) than in 2001 (26.3%). Seven years after the introduction of HAART, ESLD associated with HCV infections is a leading cause of mortality in HIV‐infected patients, which did not increase between the years 2001 and 2003.

Comparison of non-invasive liver fibrosis biomarkers in HIV/HCV co-infected patients: The fibrovic study – ANRS HC02

BACKGROUND/AIMS To compare non-invasive biological liver fibrosis scores, as alternatives to liver biopsy, in HIV/HCV co-infected patients. METHODS Two hundred and seventy-two HIV/HCV patients, nai ve for HCV treatment, underwent liver biopsy [197 (72%) men, 39.9 years, fibrosis stage (Metavir) F1 (25%), F2 (40%), F3 (25%), F4 (10%), median CD4 486/mm(3) and median HIV viral load 3.5log. Fibrotest (FT), Hepascore (HS), Fibrometer (FM), SHASTA, APRI, Forns index, and Fib-4 were tested in order to differentiate patients with mild to moderate fibrosis (F2) and those with advanced fibrosis (F3). The AUROC and the rate of well-classified patients were compared to liver biopsy. RESULTS FT, HS, and FM were able to stage liver fibrosis in all patients with AUROCs of 0.78, 0.84 and 0.89 for the diagnosis of F2, respectively. The correlation coefficient indexes were 0.37, 0.46 and 0.48, respectively. The rates of well-classified patients were 62%, 68% and 71%, respectively. Fib-4, APRI and the Forns index were only able to stage 37-61% of patients and showed lower accuracies. Using a combination of FT, HS and FM did not significantly increase the performance of each test. CONCLUSIONS In HIV/HCV co-infected patients, Fibrometer, Hepascore and Fibrotest outperformed other non-invasive liver fibrosis biomarkers for the prediction of significant liver fibrosis.

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.

Pentamidine-Induced Derangements of Glucose Homeostasis: Determinant roles of renal failure and drug accumulation: A study of 128 patients

OBJECTIVE To assess the prevalence, presentation, and risk factors of pentami-dine-induced dysglycernia. RESEARCH DESIGN AND METHODS Blood glucose values were screened in 244 consecutive immunocompromised patients with Pneumocystis carinii pneumonia: 116 being treated with cotrimoxazole and 128 others with pentamidine. RESULTS Two cotrimoxazole patients developed diabetes as a result of necrotiz-ing pancreatitis (1.7%); the others remained euglycemic. Forty-eight pentamidine-treated patients (38.5%) developed severe glucose homeostasis disorders: hypoglyce-mia in 7, hypoglycemia and then diabetes in 18, and diabetes alone in 23 (P < 0.001 vs. the cotrimoxazole group). Hypoglycemia was early, sudden, often recurrent, and life-threatening, associated with inappropriately high insulin levels in plasma; the B-cell response to stimuli was poor. Of the 41 diabetic patients, 26 required insulin therapy; their plasma C-peptide levels were lower than normal, and the B-cell secretory responses to stimuli were poor. Islet cell antibodies, insulin antibodies, and insulitis were not detected. The pentamidine-treated dysglycemic patients differed from their euglycemic counterparts by higher pentamidine doses (P < 0.001), higher plasma creatinine levels (P < 0.001), and more severe anoxia (P < 0.05) and shock (P < 0.001). Most of them had received pentamidine mesylate parenterally (n = 36; 75%); six others received the isethionate salt and six exclusively pentamidine aerosols. CONCLUSIONS Pentamidine-induced dysglycemic accidents are primarily due to inappropriate insulin release and toxicity to the islet B-cells. Drug accumulation due to excessive doses, iterative courses, and/or renal impairment is the determining risk factor.

Progression of Fibrosis in HIV and Hepatitis C Virus-Coinfected Patients Treated with Interferon plus Ribavirin-Based Therapy: Analysis of Risk Factors

BACKGROUND We determined the prevalence and determinants of worsening fibrosis in patients coinfected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) who were receiving anti-HCV therapy. METHODS Among 383 HIV-HCV-coinfected patients who received at least 1 dose of anti-HCV treatment (weekly subcutaneous injections of 1.5 mug/kg pegylated interferon-alpha-2b plus daily ribavirin or thrice-weekly subcutaneous injections of 3 MU of interferon-alpha-2b plus daily ribavirin for 48 weeks), paired pretreatment and posttreatment liver biopsy specimens were available and interpretable for 198 cases. Hepatic necroinflammation and fibrosis were graded with Ishaks classification. Histological worsening of fibrosis was defined as a score increase of > or =2 points in patients with fibrosis stage of <4 and as a score increase of 1 point in patients with stage-5 fibrosis. RESULTS The mean interval +/- standard deviation between the 2 biopsies was 109 +/- 34 weeks. Fibrosis worsened in 34 patients (17.1%). In univariate analysis, ongoing antiretroviral therapy, failure to achieve a sustained viral response, nucleoside reverse-transcriptase inhibitor therapy, didanosine therapy, and stavudine therapy were significantly associated with worsening of fibrosis. Didanosine (odds ratio, 3.34; 95% confidence interval, 1.39-7.96; P = .007) and failure to have a sustained viral response (odds ratio, 9.05; 95% confidence interval, 2.06-39.66; P = .003) remained significantly associated with worsening of fibrosis. CONCLUSION The mitochondrial toxicity of antiretrovirals, such as didanosine, seems to play a major role in worsening of fibrosis during HCV therapy. Therefore, anti-HCV therapy should ideally be administered before antiretroviral treatment initiation. If anti-HCV and anti-HIV treatments have to be administered concomitantly, then nucleoside reverse-transcriptase inhibitors with the lowest mitochondrial toxicity should be preferred.

Spontaneous Hepatic Decompensation in Patients Coinfected with HIV and Hepatitis C Virus during Interferon-Ribavirin Combination Treatment

Spontaneous hepatic decompensation was observed in 7 of 383 patients coinfected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) who were receiving treatment with interferon and ribavirin. Multivariate analysis identified the following risk factors: didanosine use (odds ratio [OR], 8.8; 95% confidence interval [CI], 1.2-102.3; P < .02), cirrhosis, (OR, 8.8; 95% CI, 1.2-104.2; P<.02), and elevated total bilirubin level (OR, 7.9; 95% CI, 1.08-93.3; P<.03). Didanosine should thus not be given to patients with cirrhosis, particularly when treatments for HCV and HIV infections have to be administered concomitantly.

Treatment of hepatitis C virus and human immunodeficiency virus coinfection: from large trials to real life

Summary.  To analyse the barriers for anti‐hepatitis C virus (anti‐HCV) treatment in human immunodeficiency virus (HIV)–HCV coinfected patients, we surveyed 71 physicians specializing in infectious disease (39%), internal medicine (27%), HIV/AIDS information and care (17%), haematology (10%) and hepatology (6%). A standard data collection form was used to identify patients observed in 7 days in November 2004. Three hundred and eighty patients with the following characteristics were included: male gender 71%; mean age 41.5 years; HIV diagnosed 12 years ago; routes of transmission via injection drug use (78%); undetectable HIV viral load (235/373, 63%) or <10 000 copies/mL (86/373, 23%). HCV RNA was positive in 325 of 369 (88%) patients; HCV genotype was 1 or 4 in 65% and liver biopsy had been carried out in 56%. There were several explanations for the nontreatment of HCV in 205 of the 380 (54%) patients, with 2.4 reasons per patient: anti‐HCV treatment was deemed questionable (n = 109) because of minor hepatic lesions, alcohol consumption, or active drug use; no liver biopsy had been performed (n = 68); treatment was contraindicated (n = 62), mainly for psychiatric reasons; there was physician conviction of poor patient compliance (n = 62) and patient refusal (n = 33). Patients having received anti‐HCV treatment (n = 91) compared with those who had never received any (n = 205) were more commonly of European origin, had better control of their HIV infection, were followed by a hepatologist more often, had a liver biopsy more often and had more commonly a high HCV viral load (P < 0.001). In ‘real life’ in France in 2004, more than half of the HIV–HCV coinfected patients have never received anti‐HCV treatment. The main reasons are a treatment that may be deemed questionable (minimal hepatic lesions, alcohol, active drug use), a lack of available liver biopsy, a psychiatric contraindication and physician conviction of poor patient compliance.

Risk factors for anaemia in human immunodeficiency virus/hepatitis C virus-coinfected patients treated with interferon plus ribavirin

Summary.  The most frequent and the most troublesome adverse effect of interferon plus ribavirin‐based therapy is anaemia. The aim of this analysis was to determine the incidence and risk factors of anaemia (Hb < 10 g/dL) in human immunodeficiency virus/hepatitis C virus (HCV)‐coinfected patients receiving anti‐HCV therapy. We reviewed all cases of anaemia occurring among 416 patients participating in a randomized, controlled 48‐week trial comparing peginterferon (peg‐IFN) alpha 2b plus ribavirin with interferon alpha‐2b plus ribavirin. Univariate and multivariate analyses were used to identify links with antiretroviral treatments, HCV therapy and clinical and laboratory findings. Sixty‐one (15.9%) of the 383 patients who received at least one dose of anti‐HCV treatment developed anaemia. In multivariate analysis the risk of anaemia was significantly associated with zidovudine (OR, 3.27 95% CI, 1.64–6.54, P = 0.0008) and peg‐IFN (OR, 2.35; 95% CI, 1.16–4.57, P = 0.0179). The risk of anaemia was lower in patients with higher baseline haemoglobin levels (OR, 0.35 95% CI, 0.26–0.49, P < 0.0001) and in patients receiving protease inhibitor‐based antiretroviral therapy (OR, 0.51 95% CI, 0.30–0.86, P = 0.0114). Zidovudine discontinuation could help to avoid anaemia associated with anti‐HCV therapy.

Severe weight loss in HIV / HCV-coinfected patients treated with interferon plus ribavirin: incidence and risk factors

Summary.  Weight loss is reported by more than 20% of hepatitis C virus (HCV)‐monoinfected patients treated with the peg‐interferon (peg‐IFN) and ribavirin combination. The aim of this study was to determine the incidence and risk factors of severe weight loss (≥10%) in human immunodeficiency virus (HIV) / HCV‐coinfected patients participating in a randomized, controlled 48‐week trial comparing peg‐IFN alpha 2b plus ribavirin with IFN alpha‐2b plus ribavirin. Univariate and multivariate analyses were used to identify links with antiretroviral treatments, anti‐HCV therapy and clinical and laboratory findings. One hundred eleven (28.9%) of 383 patients who received at least one dose of anti‐HCV treatment subsequently had severe weight loss. Among patients who took at least 80% of the planned total dose, severe weight loss occurred in 74 patients (32.7%). In multivariate analysis, age >40 years [hazard ratio (HR), 1.59; 95% CI 1.09 to 2.31; P = 0.016], body mass index (BMI) >22 (HR, 1.72; 95% CI, 1.16 to 2.55; P = 0.0069), peg‐IFN alpha‐2b (HR, 1.82; 95% CI, 1.24 to 2.69; P = 0.0022) and female sex (HR, 1.60; 95% CI, 1.05 to 2.43; P = 0.027) were associated with severe weight loss. In contrast, patients taking non‐nucleoside reverse transcriptase inhibitors (NNRTI)‐containing antiretroviral regimens were less likely to lose weight (HR, 0.62; 95% CI, 0.39 to 0.96; P = 0.034). Lipodystrophy tended to occur more frequently in patients who had severe weight loss than in the other patients (26.1%vs 17.6%; P = 0.0682) and patients whose weight loss >5% persisted 24 weeks after the completion of anti‐HCV therapy (n = 58 / 111) were more likely to be receiving stavudine‐based antiretroviral therapy, suggesting that mitochondrial toxicity plays some role in weight loss. These findings show that severe weight loss is a frequent side effect of anti‐HCV therapy in HIV / HCV‐coinfected patients. The underlying mechanisms remain to be identified.