Treating hepatitis C in HIV-HCV coinfected patients

As the natural history of HIV infection has changed following the introduction of highly active antiretroviral therapy (HAART), morbidity and mortality in the afflicted patients could be significantly reduced. The decreasing risk of suffering from opportunistic infections and tumors, however, is at the cost of antiretroviral drug-related toxicities. Today, mortality by liver disease is the major cause of death in HIV-infected patients from industrial countries. In the US and Europe about 30% of HIV-positive individuals are also infected with hepatitis C virus (HCV), and approximately 50-90% of persons who acquired HIV from injecting drugs are coinfected with HCV. In these dually infected individuals the presence of each viral infection impacts the natural history of the other one, and worsening of associated liver disease and complications within this population are increasing. The management of chronic hepatitis C (cHC) in HCV-HIV coinfection has become a major challenge, since possible interactions with antiretroviral therapies, increased risk of special side effects and compromises in adherence in patients already taking several drugs have to be taken into account. On the other hand, treatment strategies to fight HCV have been essentially ameliorated during the past 2 years by using pegylated interferon-alpha2b (Peg-IFN-alpha2b) combined with ribavirin, and there is hope that the successful therapeutic outcome in HCV-monoinfected individuals may beat least partly translated into benefits for the difficult-to-treat population of HCV-HIV dually infected persons. During the 15th International AIDS Conference in July 2002 in Barcelona, a satellite symposium, as well as a session in the main program and a number of poster presentations focussed on HCV-HIV coinfection and addressed the urgent problems and therapeutic challenges in managing cHC in the situation of underlying HIV disease.     

Occult hepatitis B in HIV-HCV coinfected patients

The prevalence of occult hepatitis B infection in HIV infected patients is controversial, varying from less than 1% to 62% in different studies. Blood samples of 111 HIV-infected patients, HCV-positive, HBs antigen negative, followed in the APROCO-ANRS EP11 cohort, were used to detect HBV DNA by using 2 different validated assays (Cobas Amplicor HBV Monitor Test and INSERM U271 qualitative ultra-sensitive PCR), completed when positive by HBV real-time PCR. HBV DNA was found in 6 (5.4%, 95% CI 1.2%-9.6%) patients by at least 1 of these assays, but none tested positive in all 3 assays. All 6 patients had anti-HBc without anti-HBs antibodies; 5 were not on lamivudine. Their median CD4 and CD8 counts were significantly lower and their HIV viral load higher than in the other 105 patients. In conclusion, the prevalence of occult hepatitis B may vary significantly according to the molecular assay used, even though these assays are validated with high specificity and quite high sensitivity. Occult hepatitis B may be encountered in HIV-HCV coinfected patients without anti-HBV treatment, with anti-HBc but without anti-HBs antibodies, and relatively low immunity, suggesting a potential risk of further reactivation, as already sporadically reported.     

Detection of HCV-RNA in saliva of HIV-HCV coinfected patients

The presence of HCV-RNA in saliva of patients with chronic hepatitis C provides a biological basis for the potential transmission of this virus. HCV viremia is particularly high in HCV-HIV-coinfected patients, which could favor the presence of HCV in their saliva. This study was designed to evaluate the prevalence of HCV in saliva of HCV-HIV-coinfected patients. Stimulated whole saliva was collected from 75 HCV-HIV-coinfected patients and 75 HCV controls. The presence of HCV-RNA in saliva was tested by a highly sensitive noncommercialized nested PCR, and analyzed in relation to demographic, clinical, and analytical variables. HCVRNA was detected in the saliva of 49 (65%) HCV-HIV-coinfected patients and 39 (52%) HCV controls. The presence of HCV in saliva was not related to any of the analyzed variables in HCV-HIV-coinfected patients. In the HCV control group a statistically significant relationship was demonstrated only between the detection of HCV-RNA in saliva and the viral load in peripheral blood (p < 0.001). Our results indicate that there is a trend toward a higher HCV-RNA prevalence in the saliva of HCV-HIV-coinfected patients.     

Contributions to hepatic fibrosis in HIV-HCV coinfected and HCV monoinfected patients

OBJECTIVES: The aim of this study was to further explore the severity of liver disease and its predictors in a cohort of hepatitis C virus (HCV) infected patients, some of whom were coinfected with the human immunodeficiency virus (HIV). METHODS: This is a retrospective, cross-sectional study of patients undergoing liver biopsy to stage HCV disease prior to consideration of anti-HCV therapy. RESULTS: A total of 92 HIV-HCV coinfected and 372 HCV monoinfected patients were included. As might be expected, coinfected patients differed from monoinfected patients in a number of ways, including having lower body mass index (BMI), and lower alcohol intake. Liver disease was very similar between the two groups, with mean fibrosis score of 1.45 u for coinfected and 1.53 u for monoinfected (p = NS). Histological inflammation score dominated multivariate models of fibrosis when it was included in them. When only clinical predictors were used in multivariate models, BMI and type 2 diabetes had independent associations in monoinfected patients, whereas low CD4 count, current or nadir, was the only variable with an independent association in coinfected patients. CONCLUSIONS: Coinfected patients do not have uniformly worse liver disease than monoinfected patients. Immune compromise plays an important role in liver disease in coinfected patients, and the role of other clinical factors in liver disease may differ between these two groups, as well.     

Nelfinavir in HIV-HCV coinfected patients: a 24-month follow-up in a cohort of 82 patients

This retrospective and longitudinal study evaluated the long-term hepatic tolerance of a nelfinavir (NFV)-antiretroviral combined regimen in 82 patients of the HCV-HIV Cohort of CISIH-Sud of Marseilles. Follow-up data (liver enzyme levels, CD4 cell count, HIV viral load, and metabolic parameters) of patients treated with NFV on inclusion or during the follow-up of the cohort were analyzed under treatment over 24 months. Comparisons were performed with X2 or Kruskal-Wallis tests. At baseline (n = 82), the median exposure to NFV was 4.1 months; 58 patients received NFV combined with NRTI and 24 with NNRTI. The median CD4 cell count was 337/mm3 [interquartile range (IR): 216-480) and 39.7% had an undetectable HIV RNA level. Qualitative HCV PCR was positive in 91% of the patients and 19/51 patients with liver biopsy were F3-F4. Median alanine and aspartate aminotransferase (ALAT, ASAT), gamma-glutamyltransferase (GT), and alkaline phosphatase (ALP) were 46 UI/liter (IR: 36-76), 55 UI/liter (IR: 32-97), 97 UI/liter (IR: 50-194), and 88 UI/liter (IR: 72-104), respectively, with 76% of the patients with ALAT/ASAT grade <2. Median follow-up was 23 months (IR: 13.8-37). No significant difference was observed in the distribution of ALAT, ASAT, GT, and ALP as well as of ALAT/ASAT grades over the 24-month study period. Patients treated with NFV + NNRTI had significantly higher GT and ALP levels at baseline with no significant increase during follow-up. Cholesterol, triglyceride, and glycemia distributions remained stable over time. In conclusion, this study showed a good hepatic and metabolic tolerance of a long-term NFV-combined regimen in HIV-HCV coinfected patients.     

Hepatic steatosis in hepatitis B virus infected patients: meta-analysis of risk factors and comparison with hepatitis C infected patients

Background and Aims: Although hepatic steatosis (HS) has an association with hepatitis C virus (HCV) infection, an association with hepatitis B virus (HBV) is controversial. We performed a meta‐analysis to evaluate HS prevalence and risk factors, in HBV infection. Methods: Standard guidelines for performance of meta‐analyses were followed. Studies with HS assessed by histology were included. Pooled odd ratios (OR) and standardized mean differences (SMD) were obtained with the random‐effects model and DerSimonian‐Laid method. Results: Seventeen out of 21 studies were included, comprising 4100 HBV infected patients. Overall HS prevalence was 29.6%. Eight studies also included 945 HCV infected patients, showing decreased risk of HS in HBV versus HCV patients (OR 0.55, 95%CI [0.45–0.67], P < 0.001). In HBV, HS positively associated with male gender (OR 1.74, 95%CI [1.28–2.38], P < 0.001), body mass index (SMD 2.17, 95%CI [1.23, 3.11], P < 0.001), obesity (OR 6.59, 95%CI [3.51–12.257], P = 0.003), diabetes (OR 2.62, 95%CI [1.37–4.00], P = 0.004), glycemia (SMD 0.84, 95%CI [0.00, 1.67], P = 0.049), triglycerides (SMD 1.18, 95%CI [0.48, 1.89], P = 0.001), cholesterol (SMD 0.88, 95%CI [0.31, 1.45], P = 0.003), moderate alcohol consumption (OR 1.54, 95%CI [1.10–2.15], P = 0.011) and negatively with HBV DNA (SMD ?74.12, 95%CI [?82.93, ?65.31], P < 0.001). HS had no association with aminotransferases, HBeAg, genotype or hepatic histology, necroinflammation or fibrosis. Conclusion: HS in HBV seems to be as frequent as in the general population, and lower than in HCV infected patients, relating to metabolic factors but not with hepatic histology severity. A puzzling strong negative association between viral load and HS, may even suggest a protective effect of the virus on HS.     

HIV-HCV RNA loads and liver failure in coinfected patients with coagulopathy.

BACKGROUND AND OBJECTIVE: The aim of this study was to measure contemporaneously HCV-RNA load, HIV-RNA load and CD4+ lymphocyte count in HCV/HIV coinfected patients with coagulopathy and to examine the relationship between these parameters and the liver failure. DESIGN AND METHODS: A cross-sectional study was performed on 54 patients with severe coagulopathy: 39 HCV/HIV coinfected and 15 HCV+/HIV- comparable for age and HCV exposure time. HCV-RNA and HIV-RNA load, CD4+ lymphocyte count, biochemical and ultrasonographic parameters were evaluated at the time of entry to the study. RESULTS: Mean HCV-RNA load was significantly higher in coinfected patients (643,872 717,687 copies/mL) than in HCV+/HIV- (mean 161,573 276,896 copies/mL) (p = 0.01). The 39 HCV/HIV coinfected patients had a mean HIV-RNA load of 205,913 456,311 copies/mL (range 4,000-2,500,000) and a mean CD4+ lymphocyte count of 206.5171/microL (range 5-693). Five of the 39 (12.8%) coinfected patients had liver failure. In these five patients the mean HCV-RNA load (770,200 996,426 copies/mL) was high but not significantly different from that in the 34 HCV+/HIV+ patients (623,496 682,239 copies/mL) without liver failure (p = 1.0). Coinfected patients with liver failure had a significantly higher HIV-RNA load (mean 764, 599 978,542 copies/mL) and lower CD4+ lymphocyte count (mean 52.655. 6/microL) than those observed in coinfected patients without liver failure (p = 0.007 and p = 0.03, respectively). A significant inverse correlation was found between CD4+ lymphocyte count and HIV-RNA load (r = -0.37, p = 0.01). INTERPRETATION AND CONCLUSIONS: HCV-RNA load is significantly higher in HIV+ than in HIV- patients with coagulopathy. Liver failure was found only in the HCV/HIV coinfected patients with severe immunodepression, expressed either by low CD4+ lymphocyte count or by high HIV-RNA load.     

Biochemical non-invasive assessment of liver fibrosis cannot replace biopsy in HIV-HCV coinfected patients

Background and rationale. The liver biopsy has been considered the gold standard for the diagnosis and quantification of fibrosis. However, this method presents limitations. In addition, the non-invasive evaluation of liver fibrosis is a challenge. The aim of this study was to validate the fibrosis cirrhosis index (FCI) index in a cohort of human immunodeficiency virus (HIV)/hepatitis C virus (HCV) coinfected patients, and compare to AST/ALT ratio (AAR), AST to platelet ratio index (APRI) and FIB-4 scores, as a tool for the assessment of liver fibrosis in coinfected patients.Material and methods. Retrospective cross sectional study including 92 HIV-HCV coinfected patients evaluated in two reference centers for HIV treatment in the Public Health System in Southern Brazil. Patients who underwent liver biopsy for any indication and had concomitant laboratory data in the 3 months prior to liver biopsy, to allow the calculation of studied noninvasive markers (AAR, APRI, FIB-4 and FCI) were included.Results. APRI < 0.5 presents the higher specificity to detect no or minimal fibrosis, whereas APRI > 1.5 presents the best negative predictive value and FCI > 1.25 the best specificity to detect significant fibrosis. The values of noninvasive markers for each Metavir fibrosis stage showed statistically significant differences only for APRI. In conclusion, until better noninvasive markers for liver fibrosis are developed and validated for HIV-HCV coinfected patients, noninvasive serum markers should be used carefully in this population.     

Hepatic steatosis and metabolic risk factors among patients with chronic hepatitis B: The multicentre,prospective CAP-Asia study

We aimed to compare the severity of liver disease, metabolic profile and cardiovascular disease (CVD) risk of chronic hepatitis B (CHB) patients with and without hepatic steatosis and patients with non-alcoholic fatty liver disease (NAFLD). Patients with NAFLD and CHB were prospectively enrolled from 10 Asian centres. Fibroscan was performed for all patients and hepatic steatosis was defined based on controlled attenuation parameter >248 dB/m. CVD risk was assessed using the Framingham risk score. The data for 1080 patients were analysed (67% NAFLD, 33% CHB). A high proportion (59%) of CHB patients had hepatic steatosis. There was a significant stepwise increase in alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transpeptidase, controlled attenuation parameter and liver stiffness measurement, from CHB patients without hepatic steatosis to CHB patients with hepatic steatosis to NAFLD patients (p < 0.001 for all comparisons). There was a significant stepwise increase in the proportion of patients with metabolic syndrome and in CVD risk, with very high or extreme CVD risk seen in 20%, 48% and 61%, across the groups (p < 0.001 between CHB patients with and without hepatic steatosis and p < 0.05 between CHB patients with hepatic steatosis and NAFLD patients). In conclusion, there was a high proportion of CHB patients with hepatic steatosis, which should be diagnosed, as they may have more severe liver disease, so that this and their metabolic risk factors can be assessed and managed accordingly for a better long-term outcome     

Didanosine (ddI) associates with increased liver fibrosis in adult HIV-HCV coinfected patients

Summary. The role of exposure to antiretrovirals (ARV) and serum matrix metalloproteases (MMPs) on liver fibrosis (LF) progression in human immunodeficiency virus (HIV) mono or HIV– hepatitis C virus (HCV) coinfection is unclear. Thus, 213 Caucasian adult HIV‐infected patients were studied, 111 of whom had HCV‐coinfection and 68 were HCV‐monoinfected. Patients with ethanol consumption >50 g/day, hepatitis B coinfection, non‐infective liver diseases or HAART adherence <75% were excluded. LF was assessed by transient elastometry (TE, Fibroscan). Serum levels of MMPs (MMP ‐1,‐2,‐3,‐8,‐9,‐10 and ‐13) and their tissue inhibitors (TIMP‐1,‐2 and ‐4) were measured by ELISA microarrays. Associations with LF were statistically analysed. Protease inhibitors, usually administered to patients with advanced LF were excluded from the analysis. Increased LF was significantly associated with d4T (P = 0.006) and didanosine (ddI) use (P = 0.007), months on d4T (P = 0.001) and on ARV (P = 0.025), duration of HIV (P < 0.0001) and HCV infections (P < 0.0001), higher HIV (P = 0.03) and HCV loads (P < 0.0001), presence of lipodystrophy (P = 0.02), male gender (P = 0.02), older age (P = 0.04), low nadir (P = 0.02) and current CD4⁺ T‐cells (P < 0.0001), low gain of CD4⁺ T‐cells after HAART (P = 0.01) and higher MMP‐2 (P = 0.02) and TIMP‐2 serum levels (P = 0.02). By logistic regression the only variables significantly associated with increased LF were: use of ddI (OR 8.77, 95% CI: 2.36–32.26; P = 0.005), male gender (OR 7.75, 95% CI: 2.33–25.64, P = 0.0008), HCV viral load (in log) (OR 3.53, 95% CI: 2.16–5.77; P < 0.0001) and age (in years) (OR 1.21, 95% CI: 1.09–1.34, P = 0.0003). We conclude that only higher HCV viral load, older age, male gender, and use of ddI associated independently with increased LF in our study.     

Liver fibrosis stage and HCV genotype distribution in HIV-HCV coinfected patients with persistently normal transaminases

Hepatitis C virus (HCV)-infected patients with normal transaminases may show significant liver damage. The proportion of subjects with alanine aminotransferase (ALT) levels within normal limits was examined in HIV-infected patients never exposed to interferon and with detectable plasma HCV-RNA on regular follow-up at one single institution. Liver fibrosis was evaluated using transient elastography (FibroScan). Out of 281 coinfected patients, 25 (8.9%) had persistently normal ALT levels. Patients with HCV genotypes 2 (1/5; 20%) and 4 (10/50; 20%), more often had significantly normal ALT than patients with HCV-1 (13/158; 8%) (p = 0.01) and HCV-3 (1/49; 2%) (p = 0.01). Liver fibrosis stages in these patients were as follows: F0-F1 in 13 (59.1%), F2 in 4 (18.2%), F3 in 2 (9.1%), and F4 in 3 (13.6%). Advanced liver fibrosis (F3-F4) tended to be more frequent in patients infected with HCV-4 than HCV-1 (33.3% versus 9.1%; p = 0.2). Of HIV-infected patients with chronic hepatitis C 8.9% show persistently normal ALT levels. Nearly 25% of HIV-HCV-coinfected patients with persistently normal ALT show advanced liver fibrosis. Therefore, HCV-HIV-coinfected patients with normal ALT levels should be closely monitored.