Maurizio Bonacini

Survival in patients with HIV infection and viral hepatitis B or C: a cohort study

Aim: To assess survival in patients with HIV and viral hepatitis co-infection. Methods: A prospective university clinic cohort of 472 patients with HIV infection who were followed for 8343 patient-months. The outcome measures were the survival from HIV or liver disease assessed by the Kaplan–Meier method. Multivariable analysis using a Cox regression model identified variables associated with mortality. Results: Patients were divided into four subgroups: HIV/hepatitis B virus (HBV) (n = 72), HIV/hepatitis C virus (HCV) (n = 256), multiple hepatitides (n = 18) and HIV alone (n = 126). One hundred and thirty-four patients (28.4%) died during follow-up. Liver mortality was noted in 55 patients, representing 12% of the cohort and 41% of the total mortality. Survival curves were similar in patients with HIV alone and those with any viral hepatitis co-infection. Liver deaths were more common in patients with multiple hepatitides (28%) HIV/HBV (15%), HIV/HCV co-infection (13%) versus HIV alone (6%). Liver mortality was comparable in HIV/HBV as in HIV/HCV co-infected patients and was not associated with gender, ethnicity, age, or mode of infection. HIV deaths were similar in patients co-infected with viral hepatitis compared with those with HIV alone. In patients with viral hepatitis co-infection, initial CD4 cell count > 200 × 106 cells/l and use of highly active antiretroviral therapy (HAART) were associated with significantly reduced liver mortality. Conclusions: Patients with HIV and viral hepatitis had greater liver mortality than patients with HIV alone, but had comparable HIV mortality. Co-infection with hepatitis B is associated with hepatic outcomes similar to hepatitis C. Control of immunosuppression with HAART and CD4 counts > 200 × 106 cells/l are associated with better hepatic outcomes and should be the first priority in patients with HIV and viral hepatitis.

Causality assessment in drug-induced liver injury using a structured expert opinion process: Comparison to the Roussel-Uclaf causality assessment method

Drug‐induced liver injury (DILI) is largely a diagnosis of exclusion and is therefore challenging. The US Drug‐Induced Liver Injury Network (DILIN) prospective study used two methods to assess DILI causality: a structured expert opinion process and the Roussel‐Uclaf Causality Assessment Method (RUCAM). Causality assessment focused on detailed clinical and laboratory data from patients with suspected DILI. The adjudication process used standardized numerical and descriptive definitions and scored cases as definite, highly likely, probable, possible, or unlikely. Results of the structured expert opinion procedure were compared with those derived by the RUCAM approach. Among 250 patients with suspected DILI, the expert opinion adjudication process scored 78 patients (31%) as definite, 102 (41%) as highly likely, 37 (15%) as probable, 25 (10%) as possible, and 8 (3%) as unlikely. Among 187 enrollees who had received a single implicated drug, initial complete agreement was reached for 50 (27%) with the expert opinion process and for 34 (19%) with a five‐category RUCAM scale (P = 0.08), and the two methods demonstrated a modest correlation with each other (Spearmans r = 0.42, P = 0.0001). Importantly, the RUCAM approach substantially shifted the causality likelihood toward lower probabilities in comparison with the DILIN expert opinion process. Conclusion: The structured DILIN expert opinion process produced higher agreement rates and likelihood scores than RUCAM in assessing causality, but there was still considerable interobserver variability in both. Accordingly, a more objective, reliable, and reproducible means of assessing DILI causality is still needed. HEPATOLOGY 2010

Liver fibrosis progression is related to CD4 cell depletion in patients coinfected with hepatitis C virus and human immunodeficiency virus.

A total of 204 patients with liver biopsy-proven hepatitis C virus (HCV) infection, 84 with and 120 without human immunodeficiency virus (HIV) coinfection, were studied, to evaluate variables possibly associated with the stage of liver fibrosis. All patients were injection drugs users, with a mean age of 32 years and an estimated duration of HCV infection of 12 years. Twenty-four patients (11%) had many fibrous septa with (5%) or without (6%) cirrhosis, 56 (27%) had few fibrous septa, and 124 (60%) had no fibrous septa. In all patients, an association was found between CD4 cell counts <500 cells/mm(3)and the presence of many fibrous septa (odds ratio, 3.2; P=.037), independent of HIV infection and other factors. These results suggest that HIV infection-induced CD4 depletion is independently associated with the severity of liver fibrosis in chronic HCV infection.

Potency, safety, and pharmacokinetics of the NS3/4A protease inhibitor BI201335 in patients with chronic HCV genotype-1 infection

BACKGROUND & AIMS BI201335 is a highly specific and potent HCV protease inhibitor. This multiple rising dose trial evaluated antiviral activity and safety in chronic HCV genotype-1 patients. METHODS Thirty-four treatment-naïve patients were randomized to monotherapy with placebo or BI201335 at 20-240 mg once-daily for 14 days, followed by combination with pegylated interferon alfa/ribavirin (PegIFN/RBV) through Day 28. Nineteen treatment-experienced patients received 48-240 mg BI201335 once-daily with PegIFN/RBV for 28 days. HCV-RNA was measured with Roche COBAS TaqMan. RESULTS In treatment-naïve patients, median maximal viral load (VL) reductions during 14-day monotherapy were -3.0, -3.6, -3.7, and -4.2 log(10) for the 20, 48, 120, and 240 mg groups. VL breakthroughs (≥1 log(10) from nadir) were seen in most patients on monotherapy and were caused by NS3/4A variants (R155K, D168V) conferring in vitro resistance to BI201335. Adding PegIFN/RBV at Days 15-28 led to continuous viral load reductions in most patients. In treatment-experienced patients, treatment with BI201335 and PegIFN/RBV achieved VL<25 IU/ml at Day 28 in 3/6, 4/7, and 5/6 patients in the 48, 120, and 240 mg dose groups. VL breakthroughs were observed during triple combination in only 3/19 patients. BI201335 was generally well tolerated. Mild rash or photosensitivity was detected in four patients. Mild unconjugated hyperbilirubinemia was the only dose-dependent laboratory abnormality of BI201335. BI201335 elimination half-life supports once-daily dosing. CONCLUSIONS BI201335 combined with PegIFN/RBV was well tolerated and induced strong antiviral responses. These results support further development of BI201335 in HCV genotype-1 patients.

Methotrexate (MTX) plus ursodeoxycholic acid (UDCA) in the treatment of primary biliary cirrhosis.

This placebo‐controlled, randomized, multicenter trial compared the effects of MTX plus UDCA to UDCA alone on the course of primary biliary cirrhosis (PBC). Two hundred and sixty five AMA positive patients without ascites, variceal bleeding, or encephalopathy; a serum bilirubin less than 3 mg/dL; serum albumin 3 g/dL or greater, who had taken UDCA 15 mg/kg daily for at least 6 months, were stratified by Ludwigs histological staging and then randomized to MTX 15 mg/m2 body surface area (maximum dose 20 mg) once a week while continuing on UDCA. The median time from randomization to closure of the study was 7.6 years (range: 4.6‐8.8 years). Treatment failure was defined as death without liver transplantation; transplantation; variceal bleeding; development of ascites, encephalopathy, or varices; a doubling of serum bilirubin to 2.5 mg/dL or greater; a fall in serum albumin to 2.5 g/dL or less; histological progression by at least two stages or to cirrhosis. Patients were continued on treatment despite failure of treatment, unless transplantation ensued, drug toxicity necessitated withdrawal, or the patient developed a cancer. There were no significant differences in these parameters nor to the time of development of treatment failures observed for patients taking UDCA plus MTX, or UDCA plus placebo. The trial was conducted with a stopping rule, and was stopped early by the National Institutes of Health at the advice of our Data Safety Monitoring Board for reasons of futility. In conclusion, methotrexate when added to UDCA for a median period of 7.6 years had no effect on the course of PBC treated with UDCA alone. Supplementary material for this article can be found on the HEPATOLOGY website (http://www.interscience.wiley.com/jpages/0270‐9139/suppmat/index.html). (HEPATOLOGY 2005;42:1184–1193.)

Effect of coexisting HIV-1 infection on the diagnosis and evaluation of hepatitis C virus.

Objectives: To evaluate the diagnostic accuracy of the test for antibodies to hepatitis C virus by enzyme‐linked immunosorbent assay (anti‐HCV ELISA‐2) in patients with and without HIV‐1 infection. Design: Cohort study. Methods: In all, 369 patients were tested and grouped by available serologic tests. HCV RNA was quantified in these 369 patients using an Amplicor HCV (and/or HIV‐1) Monitor, v1.0 test. Among 110 patients who were anti‐HCV negative by ELISA‐2, 39 were HIV/HBV coinfected and 71 had HIV alone. One hundred twelve patients were HIV/HCV coinfected and 147 patients had HCV infection alone. Results: Six of 110 (5.5%) ELISA‐2 anti‐HCV‐negative, HIV‐infected patients had circulating serum HCV RNA. Their median CD4 count was 36 cells/mm3, which was significantly lower than that observed in the HIV/HBV group (median CD4 = 109, p < .001) or the HIV/HCV cohort (CD4 = 235; p < .0001). The positive predictive value of the ELISA‐2 test for diagnosing ongoing HCV infection in HIV‐infected patients was 91%, which is significantly better than that determined for the HCV group, 76% (p = .002) presumably because HCV is less likely to resolve in the HIV patients. Mean alanine aminotransferase (ALT) levels were similar in the HIV/HCV (133 IU/L) and HCV (130 IU/L) cohorts. Median HCV RNA levels were higher in the HIV/HCV group (6.53 log10 copies/ml) compared with the patients with HCV infection (5.62 log10 copies/ml; p < .00001). There was no significant correlation between HCV RNA levels and ALT values, CD4 counts, or HIV RNA concentrations. Conclusions: The predictive value of the anti‐HCV ELISA‐2 test is better in HIVcoinfected patients than in patients infected only with HCV. False negative results, usually associated with acute infection or with low CD4 counts, are uncommon. These patients may be diagnosed with the ELISA‐3 assay or by reverse transcriptase polymerase chain reaction (RT‐PCR). Compared with patients with only HCV infection, HIV/HCV patients display similar ALT profiles, but a higher proportion of detectable serum HCV RNA.

Liver Injury From Tumor Necrosis Factor-α Antagonists: Analysis of Thirty-four Cases

BACKGROUND & AIMS Tumor necrosis factor (TNF)-α antagonists have been associated with drug-induced liver injury (DILI). We reviewed cases of DILI in the United States to identify those associated with use of TNF-α antagonists. METHODS We searched the U.S. DILI Network (DILIN) database, from 2003 to 2011, for cases associated with TNF-α antagonists. Mean Roussel-Uclaf Causality Assessment Method scores were calculated. A DILIN severity score was assigned according to a previously published scale, and we identified 6 subjects likely to have DILI associated with use of TNF-α antagonists. We also searched PubMed for articles that reported hepatotoxicity from TNF-α antagonists, identifying 28 additional cases suitable for analysis. RESULTS The drugs presumed to have caused DILI were infliximab (n = 26), etanercept (n = 4), and adalimumab (n = 4). The anti-TNF-α agent was the probable cause of 12 cases of DILI (35%), a very likely cause for 21 (62%), and a definite cause for 1 (3%). Median latency was 13 weeks (range, 2-104); however, 7 cases (20%) had latency periods longer than 24 weeks. Twenty-two of 33 subjects who underwent serologic analysis (67%) tested positive for anti-nuclear and/or smooth muscle antibodies. Of these 22, 17 underwent liver biopsy; 15 subjects had clear features of autoimmunity. The 22 subjects with autoimmune features had longer median latency (16 vs 10 weeks) and higher peak levels of alanine aminotransferase (784 vs 528 U/L) than the 12 without such features. There was 1 case of severe cholestasis. All but one subject improved after discontinuation of the implicated drug; 12 subjects received corticosteroid therapy. No deaths were attributed to liver injury, although one patient with preexistent cirrhosis required liver transplantation. CONCLUSIONS Acute liver injury caused by TNF-α antagonists may be a class effect because multiple agents in this category have been implicated. The most common presentation is an autoimmune phenotype with marked hepatocellular injury, but a mixed non-autoimmune pattern or predominant cholestasis also occurs. The prognosis is usually good after drug discontinuation, although some patients may benefit from a course of corticosteroids. ClinicalTrials.gov: Number, NCT00345930.

Do Type and Duration of Antiretroviral Therapy Attenuate Liver Fibrosis in HIV—Hepatitis C Virus—Coinfected Patients?

BACKGROUND This study aimed to determine whether type and duration of therapy for human immunodeficiency virus (HIV) infection attenuates liver fibrosis in patients with HIV and hepatitis C virus (HCV) coinfection. METHODS Patients with HCV monoinfection (group 1) and HIV-HCV coinfection were retrospectively selected; the latter patients were classified into the following 3 groups: group 2, patients who received no therapy or only nucleoside reverse-transcriptase inhibitors (NRTIs); group 3, those who received highly active antiretroviral therapy (HAART); and group 4, those who initially received NRTIs followed by HAART. Fibrosis stage (scale, 0-6) and necroinflammatory score (scale, 0-18) were assessed according to the Ishak system. Data are presented as mean +/- standard deviation. RESULTS Three hundred eighty-one patients (296 HCV-monoinfected patients and 85 HIV-HCV-coinfected patients) were recruited. The durations of HIV therapy before liver biopsy was performed for groups 2, 3, and 4 were 3.8 +/- 2.8, 3.3 +/- 1.8, and 6.6 +/- 2.2 years. The time from HIV diagnosis to HAART initiation was shorter for group 3 than for group 4 (9.1 +/- 7.3 vs. 34.1 +/- 13.1 months; P < .0001). Groups 1 and 3 had similar fibrosis stages (3.1 +/- 2 vs. 3.4 +/- 2.4), rates of fibrosis progression (0.13 +/- 0.09 vs. 0.16 +/- 0.11 per year), and necroinflammatory scores (6.1 +/- 1.8 vs. 6.1 +/- 2.0). Groups 2 and 4 had significantly more-advanced liver disease, as determined by fibrosis stage (4.6 +/- 1.8 vs. 4.3 +/- 2.0; P < .0009), rate of fibrosis progression (0.24 +/- 0.11 vs. 0.20 +/- 0.10 per year; P < .0001), and prevalence of cirrhosis (68% vs. 55%; P < .006), compared with group 1. CONCLUSIONS HIC-HCV-coinfected subjects who receive HAART as their sole form of therapy have liver histology findings comparable to those for HCV-monoinfected patients. A similar degree of benefit is not observed for HIV-HCV-coinfected patients who receive no therapy, NRTIs, or HAART after NRTIs, despite having a longer duration of therapy.

Treatment of chronic hepatitis C in HIV/HCV‐coinfection with interferon α‐2b+ full‐course vs. 16‐week delayed ribavirin

Human immunodeficiency virus (HIV)‐infected patients increasingly experience the consequences of chronic hepatitis C virus (HCV) coinfection. This trial randomized 107 patients coinfected with HIV and HCV to receive 48 weeks of interferon alfa‐2b (IFN) 3 million units three times weekly plus either a full course of ribavirin (RBV) at 800 mg/day (group A; n = 53) or 16 weeks of placebo, followed by RBV (group B; n = 54). The primary endpoint of sustained viral response (SVR) rate (undetectable HCV RNA at posttreatment week 24) was not different between groups A (11.3%) and B (5.6%; P = .32). Within group A, the SVR rate was lower in genotype 1 (2.5%) than in genotypes 2 through 4 (41.7%; P = .002). Fifty‐five patients discontinued therapy prematurely, mostly because of adverse events or patient decisions. At treatment week 12, the percentage of CD4+ cells rose in group A (+4.1%; P < .001), but not in group B (−0.3%). A significant proportion (22%) of patients who were HIV viremic at baseline had undetectable HIV RNA at week 12. By week 16, the hemoglobin level decreased more in group A (−2,52 g/dL) than in group B (−1.02 g/dL; P < .001). In group A, the hemoglobin decline was steeper in patients receiving zidovudine (azidothymidine [AZT], −3.64 g/dL vs. no AZT, −2.08 g/dL), and patients receiving zidovudine had more anemia‐related RBV dose reductions (AZT, 60% vs. no AZT, 16%). In conclusion, HCV therapy with IFN plus RBV is relatively safe in patients coinfected with HIV and HCV, but frequent treatment discontinuations and anemia‐related RBV dose reductions contribute to a poor SVR rate. Control of HIV infection improves rather than worsens during therapy. (HEPATOLOGY 2004;39:989–998.)

Chronic hepatitis C in ethnic minority patients evaluated in Los Angeles County.

OBJECTIVE:The aim of this study was to compare demographic, clinical, and histological features of hepatitis C in four ethnic groups seen at the Los Angeles County/University of Southern California Hepatitis Clinic.METHODS:We evaluated 256 patients with chronic hepatitis C, with 132 (52%) receiving a liver biopsy as part of their evaluation. We estimated fibrosis progression in 103 patients with known duration of disease.RESULTS:Asians (6%) were underrepresented in the hepatitis C cohort, whereas Latinos (51%) were overrepresented, as compared with the entire county population. A history of injection drug use was more frequent in whites (65%) than in African Americans (45%, p = 0.05), Latinos (47%, p = 0.01), or Asians (0%) and more frequent in Latinos (59%) than in Latinas (26%, p = 0.003). Such a gender difference was not found in African Americans or whites. Baseline laboratory values were comparable. The amount of alcohol consumed daily was higher in African Americans than in Asians (p = 0.0001) and whites (p = 0.10). African Americans (0.077 fibrosis stages/yr) and whites (0.084/yr) had significantly lower mean estimated progression of liver fibrosis than Latinos (0.215/yr) with hepatitis C virus infection (ps = 0.03 and 0.02, respectively); this was likely related to their longer estimated duration of disease.CONCLUSION:Minorities represent the majority of chronic hepatitis C cases in the Los Angeles County Hepatitis Clinic. Asians, Latinas, and African Americans are less likely to report injection drug use as a risk factor for hepatitis C virus. Latinos seem to have faster liver fibrosis progression rates than either African Americans or whites.