Faculty Bibliography

Hepatoportal sclerosis (HPS) is one of several entities known to cause noncirrhotic portal hypertension. To date, its etiology is unknown. There have been increasing reports of HPS occurring in patients with human immunodeficiency virus (HIV), and the US Food and Drug Administration (FDA) recently issued an advisory regarding the development of noncirrhotic portal hypertension in association with didanosine (ddI) use. We report on a patient with HIV who had taken ddI for 4 years and who developed portal hypertension. Histopathological review of paired liver biopsies showed an initial drug hepatotoxicity, microvascular liver injury, and the presence of HPS. Despite cessation of ddI, the latter biopsy showed resolution of the drug-induced injury, but it also showed progression of the HPS. The patient's portal hypertension also progressed suggestive of an unremitting vascular injury. This case demonstrates the development of HPS resulting from a drug-induced microvascular injury. The paired biopsies demonstrate that the initial vascular injury may disappear but that the portal hypertension and HPS progress.

BACKGROUND & AIMS: Few studies evaluated the efficacy of HCV re-treatment and the predictors of response in HIV/HCV co-infected patients. The role of insulin resistance as a predictor of response in this population is unknown. The aim of this study is to evaluate the safety and efficacy of pegylated interferon-alpha-2a and ribavirin in re-treatment of HIV/HCV co-infected patients, predictors of sustained virological response, including insulin resistance, and the relationship between insulin resistance and liver histology. METHODS: This prospective, multi-centered study included HIV/HCV co-infected patients with prior interferon-based treatment failure. Patients received pegylated interferon-alpha-2a and ribavirin for 48 weeks. Serum HCV RNA was measured 24 weeks post treatment to assess sustained virological response. Insulin resistance was defined as HOMA-IR >2. Correlations between baseline insulin resistance and steatosis, and/or cirrhosis were determined. RESULTS: Sustained virological response was achieved in 14/96 (15%) patients. 35% of patients with HOMA-IR < 2 (6/17) achieved sustained virological response vs 14% (5/36) of those with HOMA-IR between 2-4, and 7% (3/41) of those with HOMA-IR > 4 (p = 0.01). In multivariable analysis, insulin resistance and log HCV RNA were negatively associated with sustained virological response [AOR 0.17; 95% CI 0.05-0.64, p = 0.009, and AOR 0.36; 95% CI 0.14-0.93, p = 0.04, respectively]. Steatosis and cirrhosis correlated with insulin resistance (p = 0.02 and 0.03, respectively) but neither independently predicted sustained virological response. Discontinuations due to severe adverse events occurred in 8% of cases, and 2 patients died of unrelated causes. CONCLUSIONS: In HIV/HCV co-infected patients undergoing re-treatment, sustained virological response rate is low; those patients without insulin resistance are significantly more likely to achieve sustained virological response

Background: SVR in hepatitis C virus (HCV)-infected patients is associated with improvements in liver histology and reduced risk of hepatocellular carcinoma and liver-related mortality. Data regarding long-term durability of SVR and incidence of liver-related morbidity/ mortality following peginterferon-based treatment are limited. This prospective long-term follow-up study of a large diverse cohort of patients assessed the durability of SVR and the incidence of significant clinical events in patients achieving an SVR following interferon-based treatment. Methods: HCV-infected patients recruited from 10 trials of interferon- based therapies +/- ribavirin were assessed for significant liverrelated clinical events. In HCV RNA serum-negative patients (<50IU/mL at the final week 24 follow-up assessment), the durability of undetectable serum HCV RNA was assessed. The efficacy population consisted of (a) all patients previously treated with conventional/pegylated interferon +/- ribavirin and (b) the subset of naive patients previously treated with peginterferon alfa-2a (40 kD) +/- ribavirin, all with undetectable HCV RNA at the last visit of the original study. Results: Among 1,724 patients evaluable for safety, 25 significant clinical events were detected in 21 (1.2%) patients: ascites (n = 5), encephalopathy (n = 4), hepatic malignancy (n = 1) and death (n = 15; 3 hepatic related). Of the 21 patients, 8 had significant hepatic-related clinical events, of whom 4 had baseline cirrhosis. No liver transplantations were reported. In the efficacy population, 99% (1331/1343) of patients previously treated with peginterferon alfa-2a +/- ribavirin continued to have undetectable HCV RNA after mean follow-up 3.9 years. Less than 1% (12/1343) of patients in the peginterferon alfa-2a +/- ribavirin group became HCV RNA detectable after a mean of 1.8 years. Conclusion: SVR achieved with peginterferon alfa-2a +/- ribavirin should be considered a cure for HCV and is associated with a low incidence of significant clinical events

BACKGROUND & AIMS: A sustained virologic response (SVR) to therapy for hepatitis C virus (HCV) infection is defined as the inability to detect HCV RNA 24 weeks after completion of treatment. Although small studies have reported that the SVR is durable and lasts for long periods, it has not been conclusively shown. METHODS: The durability of treatment responses was examined in patients originally enrolled in one of 9 randomized multicenter trials (n = 1343). The study included patients who received pegylated interferon (peginterferon) alfa-2a alone (n = 166) or in combination with ribavirin (n = 1077, including 79 patients with normal alanine aminotransferase levels and 100 patients who were coinfected with human immunodeficiency virus and HCV) and whose serum samples were negative for HCV RNA (<50 IU/mL) at their final assessment. Patients were assessed annually, from the date of last treatment, for a mean of 3.9 years (range, 0.8-7.1 years). RESULTS: Most patients (99.1%) who achieved an SVR had undetectable levels of HCV RNA in serum samples throughout the follow-up period. Serum samples from 0.9% of the patients contained HCV RNA a mean of 1.8 years (range, 1.1-2.9 years) after treatment ended. It is not clear if these patients were reinfected or experienced a relapse. CONCLUSIONS: In a large cohort of patients monitored for the durability of an SVR, the SVR was maintained for almost 4 years after treatment with peginterferon alfa-2a alone or in combination with ribavirin. In patients with chronic hepatitis C infection, the SVR is durable and these patients should be considered as cured

Parathyroid hormone (PTH) elevations are associated with reduced bone mineral density and adverse health outcomes and have been reported in patients with HIV infection. We aimed to examine the impact of vitamin D status and tenofovir (TDF) use on PTH levels among HIV-infected patients receiving combination antiretroviral therapy (cART). Demographics, medication and supplement use, and clinical data, including 25-hydroxyvitamin D [25(OH)D] and PTH, were collected on 45 HIV-infected men on ART. Suboptimal vitamin D status was defined as 25(OH)D < 30 ng/ml. The relationship between antiretroviral agents, suboptimal 25(OH)D, and PTH levels was examined. Among subjects with suboptimal vitamin D status, PTH values greater than or equal to the ULN (87 pg/ml) were more common among TDF users than nonusers: 41% versus 0% (p = 0.018); and median PTH was higher in TDF users: 80 pg/ml versus 55 pg/ml (p = 0.02). Among TDF users, PTH was higher in the group with suboptimal 25(OH)D (p = 0.045). Multivariable linear regression showed that PTH was independently and directly related to TDF use (p = 0.017) and inversely related to 25(OH)D (p = 0.017). PTH was not related to the estimated glomerular filtration rate (p = 0.9). In this cross-sectional study of HIV-infected men on ART, the use of TDF and the level of 25(OH)D were independently associated with PTH levels. Because TDF is a potent and widely used antiretroviral drug, information about cofactors that may exacerbate its side effects is of significant clinical value.

Hepatitis B virus (HBV) infection is an important health problem and a major cause of chronic hepatitis that can lead to cirrhosis and hepatocellular carcinoma. Durable viral suppression has been documented to lower the risk of hepatocellular carcinoma and disease progression. Treatment of chronic HBV infection remains a major clinical challenge because long-term use with approved oral antiviral agents is associated with drug resistance. Antiviral resistance can result in poor clinical outcomes; therefore first-line therapy with the most potent agent(s) is recommended to lower the risk. Early detection of resistance is paramount to possibly reduce the risk of liver-related morbidity and mortality. It is important that clinicians monitor for therapeutic efficacy and resistance, so as to optimize the management of chronic HBV.

Infection with HCV is one of the most challenging co-morbidities emerging in HIV-infected patients in the post-antiretroviral therapy era. The co-infected population differs from the HCV mono-infected population in several aspects. HIV accelerates hepatic fibrosis progression, cirrhosis, end-stage liver disease, the development of hepatocellular carcinoma and death. Co-infected patients have a lower likelihood of achieving sustained virological response to treatment compared with mono-infected ones. A growing number of co-infected patients have a past history of nonresponse or relapse along with advanced liver disease. The simultaneous treatment of HCV and HIV may be associated with the occurrence of drug interactions, overlapping toxicities, and increased incidence and severity of side effects. This population is sorely in need of treatment. State-of-the-art management requires different strategies to achieve a cure with minimal adverse events. This review focuses on specific treatment challenges encountered in the current treatment of HCV in HIV-seropositive individuals

Chronic HBV infection is an important public health problem worldwide and in the United States. A treatment algorithm for the management of this disease, published previously by a panel of U.S. hepatologists, has been revised on the basis of new developments in the understanding of the disorder, the availability of more sensitive molecular diagnostic tests, and the licensure of new therapies. In addition, a better understanding of the advantages and disadvantages of new treatments has led to the development of strategies for reducing the rate of resistance associated with oral agents and optimizing treatment outcomes. This updated algorithm was based primarily on available evidence by using a systematic review of the literature. Where data were lacking, the panel relied on clinical experience and consensus expert opinion. The primary aim of antiviral therapy is durable suppression of serum HBV DNA to low or undetectable levels. Assays can now detect serum HBV DNA at levels as low as 10 IU/mL and should be used to establish a baseline level, monitor response to antiviral therapy, and survey for the development of drug resistance. Interferon alfa-2b, lamivudine, adefovir, entecavir, peginterferon alfa-2a, telbivudine, and tenofovir are approved as initial therapy for chronic hepatitis B and have certain advantages and disadvantages. Although all of these agents can be used in selected patients, the preferred first-line treatment choices are entecavir, peginterferon alfa-2a, and tenofovir. Issues for consideration for therapy include efficacy, safety, rate of resistance, method of administration, and cost