Miriam Romero

Incidence and Predictors of Severe Liver Fibrosis in Human Immunodeficiency Virus—Infected Patients with Chronic Hepatitis C: A European Collaborative Study

A study was performed in 10 European health care centers in which 914 patients coinfected with hepatitis C virus (HCV) and human immunodeficiency virus (HIV) who had elevated serum alanine aminotransferase (ALT) levels underwent liver biopsy during the period of 1992 through 2002. Overall, the METAVIR liver fibrosis stage was F0 in 10% of patients, F1 in 33%, F2 in 22%, F3 in 22%, and F4 in 13%. Predictors of severe liver fibrosis (METAVIR stage, F3 or F4) in multivariate analysis were age of >35 years (odds ratio [OR], 2.95; 95% confidence interval [CI], 2.08-4.18), alcohol consumption of >50 g/day (OR, 1.61; 95% CI, 1.1-2.35), and CD4+ T cell count of <500 cells/mm3 (OR, 1.43; 95% CI, 1.03-1.98). Forty-six percent of patients aged >40 years had severe liver fibrosis, compared with 15% of subjects aged <30 years. The use of antiretroviral therapy was not associated with the severity of liver fibrosis. In summary, severe liver fibrosis is frequently found in HCV-HIV-coinfected patients with elevated serum ALT levels, and its severity increases significantly with age. The rate of complications due to end-stage liver disease will inevitably increase in this population, for whom anti-HCV therapy should be considered a priority.

Association of pretreatment serum interferon γ inducible protein 10 levels with sustained virological response to peginterferon plus ribavirin therapy in genotype 1 infected patients with chronic hepatitis C

Background: Increased serum and intrahepatic interferon γ inducible protein 10 (IP-10) levels in patients with chronic hepatitis C (CHC) have been described. Aim: To analyse the possible association of serum IP-10 levels with different outcomes to antiviral therapy. Patients: A total of 137 CHC patients treated with peginterferon plus ribavirin. Methods: Serum IP-10 levels were determined by enzyme linked immunosorbent assay before therapy, after 12 weeks of treatment, and 24 weeks after cessation of therapy. Variables significantly associated with a sustained virological response (SVR) on univariate analysis were included in a multivariate logistic regression model. Results: Pretreatment serum IP-10 levels in patients with SVR were significantly lower than in non-responders (NR) (332.4 (222.1) v 476.8 (305.3) pg/ml, respectively; p = 0.004). Serum IP-10 concentrations significantly decreased in patients with SVR (pretreatment: 332.4 (222.1) pg/ml; post-treatment: 170.2 (140.1) pg/ml; p<0.001) but not in NR (pretreatment: 476.8 (305.3) pg/ml; post treatment: 387.3 (268.1) pg/ml; p = 0.06). By multivariate analysis, non-1 genotype (odds ratio (OR) 3.5 (95% confidence interval (CI) 1.1–10.4); p = 0.003) and low viral load at baseline (OR 0.34 (95% CI 0.14–0.79); p = 0.01) were independent predictors of SVR in all patients. When multivariate analysis was restricted to patients with genotype 1, only baseline viral load (OR 0.38 (95% CI 0.155–0.96); p = 0.04) and pretreatment serum IP-10 levels (OR 0.99 (95% CI 0.996–0.999); p = 0.03) were identified as predictive factors of SVR. Conclusion: Pretreatment serum IP-10 behaves as a predictive factor of SVR to peginterferon plus ribavirin therapy in genotype 1 infected patients.

Consensus conference on chronic viral hepatitis and HIV infection: updated Spanish recommendations

Summary.  Chronic hepatitis B and C represent a leading cause of morbidity and mortality among human immunodeficiency virus (HIV)‐infected patients worldwide. New treatment options against both hepatitis B (HBV) and C (HCV) viruses have prompted us to update previous recommendations for the management of coinfected individuals. Fifteen topics (nine related to HCV, five to HBV and one to both viruses) were selected for this purpose. A panel of Spanish experts in the field was invited to review these areas and propose specific recommendations, which were scored according to the Infectious Disease Society of America (IDSA) grading system. These guidelines represent a comprehensive and updated overview on the management of hepatitis B and C in HIV‐infected patients.

Early monitoring of ribavirin plasma concentrations may predict anemia and early virologic response in HIV/hepatitis C virus-coinfected patients.

Ribavirin (RBV) in combination with pegylated interferon α (pegIFN) is currently the standard treatment of hepatitis C virus (HCV) infection. The development of anemia requires a reduction in RBV doses in a substantial proportion of patients, limiting their chances of treatment response. The primary goal of this study was to assess if early monitoring of RBV plasma levels could help to predict anemia as well as early HCV RNA response in HIV/HCV-coinfected individuals. The secondary goal was to evaluate if antiretroviral drugs might influence RBV plasma levels. Plasma RBV concentrations were measured at weeks 4 and 12 in 98 HIV/HCV-coinfected individuals who initiated therapy with pegIFN-2a (180 μg/wk) plus RBV (800-1200 mg/d). RBV plasma levels correlated with RBV dose per kilogram of body weight (P = 0.02). Larger drops in hemoglobin levels were independently associated with higher RBV plasma levels and zidovudine (ZDV) use (P < 0.001). Likewise, higher RBV levels (P = 0.007) and HCV genotype 3 (P < 0.001) were found to be independent predictors of virologic response at week 4. Similar findings were obtained at week 12. Patients receiving ZDV concomitantly showed significantly higher RBV plasma concentrations compared with those who did not (3.28 μg/mL vs. 2.51 μg/mL; P = 0.002). RBV levels were not significantly altered by the coadministration of other nucleoside/nucleotide analogues. In summary, RBV plasma levels correlate with the development of anemia and with the achievement of an early virologic response. Therefore, early therapeutic drug monitoring might help to tailor RBV dosages, improving the efficacy and safety of anti-HCV treatment.

Hepatitis b virus genotypes and lamivudine resistance mutations in HIV/hepatitis B virus-coinfected patients

Background:Differences in subtypes, hepatitis B early antigen (HBeAg)-negative variants, and drug resistance mutations all seem to influence the clinical and therapeutic outcome in patients with chronic hepatitis B virus (HBV) infection. Information available on the prevalence and distribution of distinct HBV variants in HIV-positive patients is scarce. Methods:All HIV-infected patients with persistent serum hepatitis B surface antigen and detectable HBV viremia were identified in a reference HIV clinic located in Madrid, Spain. HBV load, subtypes, precore (PC) and basal core promoter (BCP) variants, and lamivudine (LAM) resistance mutations were analyzed. Results:A total of 81 HBV/HIV-coinfected patients (4.1%) were identified in a population of 1968 HIV-positive patients. Plasma specimens with detectable HBV viremia could be obtained from 62 subjects, and this was the study population that underwent further virologic characterization. HBV genotype distribution was as follows: A (n = 27), D (n = 27), E (n = 1), F (n = 2), and G (n = 3). Two patients had mixed HBV genotypes (A/E and A/F). HBV subtype A was predominant (74%) among patients infected through sexual contact, whereas HBV-D was most frequent (74%) among intravenous drug users (P < 0.001). PC/BCP mutants were more frequent in patients with HBV-D than in those with HBV-A (63% vs. 18%; P < 0.01). Median time on LAM was 40 months; patients with HBV-A tended to show LAM resistance mutations more often (53% vs. 44%) and to develop them earlier (35 vs. 45 months) than patients with HBV-D. The dual L180M + M204V/I mutant was the predominant resistance pattern, although a triple rt173V + 180M + 204V, which acts as a vaccine escape mutant, was found in 1 individual. In the multivariate analysis, patients with LAM resistance mutations were significantly more frequently HBeAg-positive and older than individuals with wild-type HBV. Hepatitis-delta was recognized in 13 (21%) of these 62 HBV viremic patients, with no association with specific HBV variants. Conclusion:Risk transmission group, age, and positive serum HBeAg are the main determinants of distinct HBV virologic variants, including HBV genotypes and LAM-resistant mutants, in HBV/HIV-coinfected patients.

Level, phenotype and activation status of CD4+FoxP3+ regulatory T cells in patients chronically infected with human immunodeficiency virus and/or hepatitis C virus

CD4+ regulatory T (Treg) cells have been involved in impaired immunity and persistence of viral infections. Herein, we report the level, phenotype and activation status of Treg cells in patients chronically infected with human immunodeficiency virus (HIV) and/or hepatitis C virus (HCV). Expression of CD25, CD45RA, CD27, CD127 and CD38 was assessed on these cells using polychromatic flow cytometry in 20 healthy controls, 20 HIV‐monoinfected, 20 HCV‐monoinfected and 31 HIV/HCV‐co‐infected patients. Treg cells were defined as CD4+forkhead box P3 (FoxP3)+. The percentage of Treg cells was increased significantly in HIV patients compared with controls. Moreover, there was a significant inverse correlation between CD4 counts and Treg cell levels. Fewer than 50% of Treg cells expressed CD25, with differences in terms of CD127 expression between CD25+ and CD25(–) Treg cells. CD4+Foxp3+ Treg cells displayed predominantly a central memory phenotype (CD45RA–CD27+), without differences between patients and healthy controls. Activated Treg cells were increased in HIV patients, particularly considering the central memory subset. In summary, HIV infection, but not HCV, induces an up‐regulation of highly activated Treg cells, which increases in parallel with CD4 depletion. Hypothetically, this might contribute to the accelerated course of HCV‐related liver disease in HIV‐immunosuppressed patients.

Liver fibrosis in patients with chronic hepatitis C and persistently normal liver enzymes: influence of HIV infection.

Summary.  Liver fibrosis progress slowly in patients with chronic hepatitis C and persistently normal alanine aminotransferase (PNALT) compared to subjects with elevated aminotransferases. Differences in liver fibrosis according to human immunodeficiency virus (HIV) status in this population have not been examined. All patients with serum hepatitis C virus (HCV)‐RNA and PNALT who underwent liver fibrosis assessment using elastometry since 2004 at three different European hospitals were evaluated. Patients previously treated with interferon were excluded. PNALT was defined as ALT below the upper limit of normality in at least three consecutive determinations within the last 12 months. Fibrosis stage was defined as mild (Metavir F0–F1) if stiffness ≤7.1 kPa; moderate (F2) if 7.2–9.4 kPa; severe (F3) if 9.5–14 kPa, and cirrhosis (F4) if >14 kPa. A total of 449 HIV‐negative and 133 HIV‐positive patients were evaluated. HIV‐negative patients were older (mean age 51.8 vs 43.5 years) and more frequently females (63%vs 37%) than the HIV counterparts. Mean serum HCV‐RNA was similar in both the groups (5.9 vs 5.8 log IU/mL). Overall, 78.8% of the HIV patients were on HAART and their mean CD4 count was 525 (±278) cells/μL. In HIV‐negatives, liver fibrosis was mild in 84.6%; moderate in 8.7%, severe in 3.3% and cirrhosis was found in 3.3%. In HIV patients, these figures were 70.7%, 18.8%, 6%, and 4.5%, respectively. In the multivariate logistic regression analysis, older age (odds ratio or OR: 1.04; 95% confidence interval or CI: 1.02–1.07; P < 0.001) and being HIV+ (OR: 2.6; 95% CI: 1.21–5.85; P < 0.01) were associated with severe liver fibrosis or cirrhosis (F3–F4). Thus, severe liver fibrosis and cirrhosis are seen in 6.6% of the HCV‐monoinfected and in 10.5% of HCV‐HIV co‐infected patients with PNALT. Some degree of liver fibrosis that justifies treatment is seen in 15% of the HCV‐monoinfected but doubles to nearly 30% in HIV‐HCV co‐infected patients with PNALT.

Treatment of Chronic Hepatitis C in HIV-Infected Patients with Interferon α-2b Plus Ribavirin

One hundred six HIV-infected patients with chronic hepatitis C virus (HCV) infection were randomized to receive ribavirin (RBV) 400 mg bid plus interferon α-2b (IFN-α) at two different doses, 3 mU tiw (control arm) or 5 mU daily for the first 6 weeks, followed by 3 mU tiw until completing 6 months of therapy (induction arm). All patients had CD4 counts above 350 cells/μl and 89% were taking antiretroviral therapy. Adverse effects leading to treatment discontinuation occurred in 12.3% of patients, a rate quite similar to that seen in HCV-monoinfected patients. Negative serum HCV-RNA values (<60 IU/ml) were recorded in 24.7% and 35.5% of patients at 3 and 6 months of therapy. However, in the intent-to-treat analysis, sustained response was reached by only 16% of patients (22.4% in the on-treatment analysis). No differences between treatment arms were noticed. Patients with HCV genotypes 2 or 3 had a 7-fold higher response rate than those with HCV genotypes 1 or 4. Therefore, early, end-of-treatment, and sus...

Virological characteristics of hepatitis C virus infection in HIV-infected individuals with chronic hepatitis C: implications for treatment.

The treatment of chronic hepatitis C virus (HCV) infection is vital in patients co-infected with HIV, because end-stage liver disease is a leading cause of mortality in this population. The response to HCV therapy depends on the viral load and genotype. Patients with HCV genotypes 2/3 and low HCV-RNA titres show greater response rates, and may be treated for just 6 months, which is useful in HIV-co-infected patients, in whom anti-HCV drugs are toxic and may interact with antiretroviral agents.

Evaluation of initial virological response to adefovir and development of adefovir-resistant mutations in patients with chronic hepatitis B

Summary.  The aims of the present study were to assess initial virological response (IVR) to adefovir (ADV) treatment for chronic hepatitis B, to identify patients with suboptimal response and to determine the incidence of ADV‐resistant mutants. All patients treated with ADV for at least 12 months were evaluated for virological response and ADV resistance. IVR was defined as a reduction ≥4 log10 IU/mL in hepatitis B virus (HBV)‐DNA at month 6. Forty‐two patients were analysed. Mean treatment duration was 23 ± 7 months; 50% had prior lamivudine (LAM) therapy (LAM resistance 62%); 88% were hepatitis B e antigen (HBeAg)‐negative; and 76% carried genotype D. IVR was seen in 40.5% of patients. Higher baseline ALT level was the only factor associated with IVR (P = 0.043). Patients with IVR achieved undetectable HBV‐DNA at month 12 in 77% of cases compared with only 5% of those without IVR (P < 0.001). Five (12%) patients developed ADV‐resistant mutations: rtN236T in four cases and one case with an rtV207L change, which has not been previously reported. This mutation was accompanied by viral rebound and alanine aminotransferase (ALT) flare. The cumulative probability of ADV‐resistant mutations at 12 and 24 months was 5% and 17% respectively. IVR defined as a reduction ≥4 log10 IU/mL in HBV‐DNA at month 6 is a useful tool to predict virological response at month 12 and to identify patients with suboptimal response to ADV. Cumulative probability of ADV resistance is higher than previously reported for nucleos(t)ide‐naïve patients.