Coinfection with hepatitis C virus (HCV) is present in one-third of all human immunodeficiency virus (HIV)-infected individuals in the United States and is associated with rapid progression of liver fibrosis and poor response to pegylated interferon (IFN) and ribavirin. In this study we examined gene expression profiles in peripheral blood mononuclear cells (PBMCs) from different groups of individuals who are monoinfected or coinfected with HIV and HCV. Data showed that HIV and HCV viremia up-regulate genes associated with immune activation and immunoregulatory pathways. HCV viremia is also associated with abnormalities in all peripheral immune cells, suggesting a global effect of HCV on the immune system. Interferon-alpha-induced genes were expressed at a higher level in PBMCs from HIV-infected individuals. HCV and HIV infections leave distinct profiles or gene expression of immune activation in PBMCs. HIV viremia induces an immune activated state; by comparison, HCV infection induces immunoregulatory and proinflammatory pathways that may contribute to progression of liver fibrosis. Conclusion: An aberrant type-I IFN response seen exclusively in HIV-infected individuals could be responsible for the poor therapeutic response experienced by HIV/HCV coinfected individuals receiving interferon-alpha-based current standard of care.(HEPATOLOGY 2009;50:34-45.).

A disease whose reputation is often worse than its reality, hepatitis C is usually benign. Most infected individuals do not experience symptoms requiring treatment, and roughly half of those treated will become free of detectable virus for an extended, perhaps permanent, period. Moreover, a growing body of data suggests that drug users can attain successful treatment outcomes, even when not completely abstinent. Addiction professionals belong in the forefront of prevention and management of this disease. We can assist our patients by helping them stabilize their lifestyles, correcting misperceptions about the disease, teaching prevention and health maintenance, promoting access to diagnosis and treatment, monitoring for treatment side effects, and providing encouragement to remain in treatment.

Spontaneous resolution of chronic hepatitis C virus (HCV) infection is exceedingly rare and poorly understood. As HCV and human immunodeficiency virus (HIV) have shared routes of transmission, HCV coinfection is estimated to affect 15%-30% of the HIV-positive population. We report 2 patients with HCV-HIV coinfection who underwent orthotopic liver transplantation at our center and had spontaneous clearance of their chronic HCV infection after transplantation without any anti-HCV treatment. Both patients showed no evidence of HCV recurrence for more than 3 years despite long-term immunosuppressant therapy. Spontaneous clearance of chronic HCV infection can occur in HIV-HCV-coinfected patients after liver transplantation. The mechanism of this phenomenon remains unclear. Liver Transpl 14:92-95, 2008.(c) 2007 AASLD.

BACKGROUND:: Previous studies of patients with hepatitis C virus (HCV) infection looking at the effect of human immunodeficiency virus (HIV) co-infection on biochemical parameters and HCV RNA level have shown conflicting results. Accurate characterization of the effect of HIV is important for evaluation and treatment of HCV in co-infected persons. METHODS:: We studied 315 HCV mono-infected and 75 HCV-HIV co-infected subjects to determine the effect of HIV on biochemical parameters and HCV RNA and to determine the predictors of elevated serum alanine aminotransferase (ALT) levels and HCV RNA levels. RESULTS:: The co-infected subjects were more likely to be African-American (55% vs 26%, P < 0.0005), have used injection drugs (68% vs 60%, P = 0.02), have detectable HCV RNA (84% vs 70.5%, P = 0.018), have HCV RNA levels >6 log10 IU/mL (60% vs 38%, P = 0.001), and have lower mean serum ALT levels (50.4 IU/mL vs 73.7 IU/mL, P = 0.006). In multivariable analyses, the following factors predicted an ALT level >50 IU/mL: log10 HCV RNA (OR, 1.15; 95% CI, 1.00 to 1.32); HIV co-infection (OR, 0.48; 95% CI, 0.25 to 0.89); and having ever been treated for HCV (OR, 1.92; 95% CI, 1.16 to 3.18). The only significant predictor of HCV RNA level >6 log10 IU/mL was HIV co-infection (OR, 2.75; 95% CI, 1.46 to 5.15). Significant predictors of having a detectable HCV RNA level were female sex (OR, 3.81; 95% CI, 1.18 to 12.25); HIV co-infection (2.45; 95% CI, 1.14 to 5.26); and ever being treated for HCV (OR, 1.96; 95% CI, 1.10 to 3.48). CONCLUSIONS:: HCV-HIV co-infected persons have higher HCV RNA levels but lower serum ALT levels than HCV mono-infected patients. Criteria for performing liver biopsy and treating HCV infection in co-infected patients may need to be revisited.

People with human immunodeficiency virus (HIV) infection are frequently infected with hepatitis C virus (HCV), because of the common transmission routes. Since the dissemination of hyperactive antiretrovirus therapy (HAART), the morbidity and mortality associated with HIV infection have declined. However, the reduction in mortality due to opportunistic infection has made HCV-associated liver diseases the leading cause of mortality in Western countries. A similar situation is assumed in Japan, but the status of coinfection with HIV and HCV is unclear. We conducted a nationwide survey to determine the prevalence of coinfection with HIV and HCV by distributing a questionnaire to the hospitals in the HIV/AIDS Network of Japan. Among 4877 patients reported to be HIV-positive, 935 (19.2%) were also positive for the anti-HCV antibody. Most (84.1%) of the patients coinfected with HIV and HCV were recipients of blood products. These data, for the first time, show the current status of coinfection with HIV and HCV in Japan. A detailed analysis of the progression and severity of liver diseases in the coinfected patients is expected.

BACKGROUND/GOALS: Many patients with a history of injection drug use (IDU) are excluded from hepatitis C virus (HCV) treatment. This prospective multicenter study aimed to determine the impact of IDU history on HCV treatment candidacy and outcomes. STUDY: Between 1999 and 2001, 4318 HCV-infected patients seen at 24 VA Medical Centers were evaluated for HCV treatment candidacy and followed prospectively. Univariate and multivariate logistic regression analyses were used to determine whether an IDU history was associated with HCV treatment candidacy, HCV treatment acceptance, early treatment discontinuation, and virologic response. RESULTS: Of 4318 participants, 2611 (61%) reported an IDU history. IDU history was not significantly associated with HCV treatment candidacy, acceptance, early discontinuation of therapy, or virologic response (all P values nonsignificant). Instead, reduced HCV treatment candidacy was independently associated with low-income [odds ratio (OR)=1.46, 95% confidence interval (CI)=1.22-1.74), education </=12 years (OR=1.23, 95% CI=1.03-1.46), and alcohol consumption >/=3 drinks/d (OR=2.08, 95% CI=1.68-2.57), whereas early discontinuation of HCV therapy was independently associated with low-income and consuming >/=3 alcoholic drinks/d. CONCLUSIONS: A history of IDU was not associated with HCV treatment candidacy or outcomes, supporting national guidelines to evaluate former IDUs on a case-by-case basis for HCV treatment.

Two hundred mentally ill adults receiving community-based outpatient psychiatric services were surveyed. Although 59% received an HIV test, only 41% received a hepatitis test. Clinic location and reports of unprotected sex were associated with receipt of an HIV test. Although no behavioral risk factors were associated with hepatitis testing, those with a comorbid medical condition were more likely to be tested. Only 15% of the sample was immunized against hepatitis B. Medical hospitalization was the only factor related to immunization. These results indicate an urgent need to improve access to HIV and hepatitis testing and related treatment.

Treatment for hepatitis C virus (HCV) is rarely received by injection drug users (IDU), particularly those co-infected with HIV. We propose a framework for understanding factors that affect utilization and adherence to HCV therapy among HCV mono-infected and HIV/HCV-co-infected IDU. Provision of treatment requires calculation of risks and benefits including evaluation of a number of time-varying factors that collectively determine a gradient of treatment eligibility, advisability and acceptability, the relative importance of which may differ in co-infected and mono-infected IDU. Treatment eligibility is determined by a number of non-modifiable and modifiable contraindications, the latter of which can change over time rendering patients who were once ineligible eligible. Among those eligible, treatment need can be assessed by liver biopsy and therapy may be deferred in those with no liver disease and started in those with significant liver disease. Among those with moderate disease, further consideration of treatment advisability (medical factors that affect treatment response) and acceptability (individual, provider and environmental barriers) is needed before treatment decisions are made. These factors are dynamic and thus should be continually evaluated even among those who may not initially appear to be ready for treatment. An evaluation of this framework is needed to determine applicability and feasibility. Until then, treatment decisions should be made on an individual basis after careful consideration of these issues by provider and patient and efforts to develop novel strategies for identifying IDU who need treatment most (alternatives to liver biopsy) and multidimensional approaches to deliver treatment for HCV while addressing other factors including HIV infection, depression and drug use should be continued.

Therapies for hepatitis B virus (HBV) have continued to evolve, and new therapies for hepatitis C virus (HCV) will soon be available in clinical practice. These medications for hepatitis C will mark the first time that direct antivirals that target HCV functions have been used. When such drugs are used as single agents, previously existing mutants with reduced susceptibility to them are rapidly selected. The relationship between these drug-resistant mutants and "wild-type" virus is unclear, but resistant strains likely have the potential to maintain the progression of liver disease despite successful treatment of "wild-type" virus. Resistant HBV and now HCV are already a clinical problem. The same issue was recognized very early in the development of therapy against HIV, with azidothymidine-resistant mutants detected within the first weeks of therapy. Clinical investigation and a progressive understanding of the pathogenesis of the disease overcame this challenge and led to the substantial and durable benefits of antiretroviral therapy that are evident today. To bring experts from the fields of HIV and viral hepatitis virology and therapy together for interactive discussions about how to apply the lessons from HIV to the further development of viral hepatitis therapy, the American Association for the Study of Liver Diseases held a single-topic conference entitled "Viral Hepatitis Therapy: Lessons to be Learned From HIV" on 24-26 July 2008. This article summarizes that conference.Am J Gastroenterol advance online publication, 19 January 2010; doi:10.1038/ajg.2009.726.

ABSTRACT: BACKGROUND: The risk and course of serum transaminase elevations (TEs) and clinical hepatic serious adverse event (SAE) development in ritonavir-boosted tipranavir (TPV/r) 500/200mg BID recipients, who also received additional combination antiretroviral treatment agents in clinical trials (TPV/r-based cART), was determined. METHODS: Aggregated transaminase and hepatic SAE data through 96 weeks of TPV/r-based cART from five Phase IIb/III trials were analyzed. Patients were categorized by the presence or absence of underlying liver disease (+LD or -LD). Kaplan-Meier (K-M) probability estimates for time-to-first US National Institutes of Health, Division of AIDS (DAIDS) Grade 3/4 TE and clinical hepatic SAE were determined and clinical actions/outcomes evaluated. Risk factors for DAIDS Grade 3/4 TE were identified through multivariate Cox regression statistical modeling. RESULTS: Grade 3/4 TEs occurred in 144/1299 (11.1%) patients; 123/144 (85%) of these were asymptomatic; 84% of these patients only temporarily interrupted treatment or continued, with transaminase levels returning to Grade [less than or equal to]2. At 96 weeks of study treatment, the incidence of Grade 3/4 TEs was higher among the +LD (16.8%) than among the -LD (10.1%) patients. K-M analysis revealed an incremental risk for developing DAIDS Grade 3/4 TEs; risk was greatest through 24 weeks (6.1%), and decreasing thereafter (>24-48 weeks: 3.4%,>48 weeks-72 weeks: 2.0%,>72-96 weeks: 2.2%), and higher in +LD than -LD patients at each 24-week interval. Treatment with TPV/r, co-infection with hepatitis B and/or C, DAIDS grade >1 TE and CD4+> 200 cells/mm3 at baseline were found to be independent risk factors for development of DAIDS Grade 3/4 TE; the hazard ratios (HR) were 2.8, 2.0, 2.1 and 1.5, respectively. Four of the 144 (2.7%) patients with Grade 3/4 TEs developed hepatic SAEs; overall, 14/1299 (1.1%) patients had hepatic SAEs including six with hepatic failure (0.5%). The K-M risk of developing hepatic SAEs through 96 weeks was 1.4%; highest risk was observed during the first 24 weeks and decreased thereafter; the risk was similar between +LD and -LD patients for the first 24 weeks (0.6% and 0.5%, respectively) and was higher for +LD patients, thereafter. CONCLUSION: Through 96 weeks of TPV/r-based cART, DAIDS Grade 3/4 TEs and hepatic SAEs occurred in approximately 11% and 1% of TPV/r patients, respectively; most (84%) had no significant clinical implications and were managed without permanent treatment discontinuation. Among the 14 patients with hepatic SAE, 6 experienced hepatic failure (0.5%); these patients had profound immunosuppression and the rate appears higher among hepatitis co-infected patients. The overall probability of experiencing a hepatic SAE in this patient cohort was 1.4% through 96 weeks of treatment. Independent risk factors for DAIDS Grade 3/4 TEs include TPV/r treatment, co-infection with hepatitis B and/or C, DAIDS grade >1 TE and CD4+> 200 cells/mm3 at baseline. US-NIH Trial registration number: NCT00144170.

BACKGROUND: Treatment guidelines recommend the use of peginterferon alfa-2b or peginterferon alfa-2a in combination with ribavirin for chronic hepatitis C virus (HCV) infection. However, these regimens have not been adequately compared. METHODS: At 118 sites, patients who had HCV genotype 1 infection and who had not previously been treated were randomly assigned to undergo 48 weeks of treatment with one of three regimens: peginterferon alfa-2b at a standard dose of 1.5 mug per kilogram of body weight per week or a low dose of 1.0 mug per kilogram per week, plus ribavirin at a dose of 800 to 1400 mg per day, or peginterferon alfa-2a at a dose of 180 mug per week plus ribavirin at a dose of 1000 to 1200 mg per day. We compared the rate of sustained virologic response and the safety and adverse-event profiles between the peginterferon alfa-2b regimens and between the standard-dose peginterferon alfa-2b regimen and the peginterferon alfa-2a regimen. RESULTS: Among 3070 patients, rates of sustained virologic response were similar among the regimens: 39.8% with standard-dose peginterferon alfa-2b, 38.0% with low-dose peginterferon alfa-2b, and 40.9% with peginterferon alfa-2a (P=0.20 for standard-dose vs. low-dose peginterferon alfa-2b; P=0.57 for standard-dose peginterferon alfa-2b vs. peginterferon alfa-2a). Estimated differences in response rates were 1.8%(95% confidence interval [CI],-2.3 to 6.0) between standard-dose and low-dose peginterferon alfa-2b and -1.1%(95% CI,-5.3 to 3.0) between standard-dose peginterferon alfa-2b and peginterferon alfa-2a. Relapse rates were 23.5%(95% CI, 19.9 to 27.2) for standard-dose peginterferon alfa-2b, 20.0%(95% CI, 16.4 to 23.6) for low-dose peginterferon alfa-2b, and 31.5%(95% CI, 27.9 to 35.2) for peginterferon alfa-2a. The safety profile was similar among the three groups; serious adverse events were observed in 8.6 to 11.7% of patients. Among the patients with undetectable HCV RNA levels at treatment weeks 4 and 12, a sustained virologic response was achieved in 86.2% and 78.7%, respectively. CONCLUSIONS: In patients infected with HCV genotype 1, the rates of sustained virologic response and tolerability did not differ significantly between the two available peginterferon-ribavirin regimens or between the two doses of peginterferon alfa-2b.(ClinicalTrials.gov number, NCT00081770.) Copyright 2009 Massachusetts Medical Society.

BACKGROUND & AIMS: Pegylated interferon alfa-2a/2b is used in combination with ribavirin to treat patients with chronic hepatitis C (CHC), although many do not achieve a sustained virologic response (SVR). Albinterferon alfa-2b, a recombinant protein consisting of interferon alfa-2b fused to human albumin, may increase drug exposure. This phase 2 study evaluated the safety/efficacy of albinterferon in CHC patients who had not responded to interferon-based regimens. METHODS: A total of 115 patients were assigned to 5 groups given 1200 mug albinterferon every 4 weeks or 900, 1200, 1500, or 1800 mug every 2 weeks, plus oral ribavirin, for 48 weeks. The primary efficacy end point was achievement of an SVR after 24 weeks. Treatment was extended to 72 weeks for 6 slow responders who were negative for hepatitis C virus RNA after 24 weeks. RESULTS: The types of adverse events were similar across groups; the overall discontinuation rate as a result of adverse events was 10.4%. Reductions in absolute neutrophil counts were less frequent in the every 4 weeks group and comparable among the every 2 weeks groups. The overall SVR rate was 17%(11% for previous nonresponders to pegylated interferon-alfa/ribavirin with genotype 1 infection). An SVR occurred in 3 of 6 slow responders by 72 weeks. The greatest reductions in hepatitis C virus RNA in nonresponders to pegylated interferon-alfa/ribavirin with genotype 1 infection were observed in the 1800-mug group. CONCLUSIONS: In patients with CHC who did not respond to interferon-based regimens, higher doses of albinterferon had significant early antiviral activity and a low incidence of adverse events, with the types of adverse events similar to those observed with interferon.

BACKGROUND: Adherence to chronic hepatitis C (CHC) treatment may be particularly challenging in methadone maintenance patients. We assessed the safety, tolerability, and efficacy of peginterferon alfa-2a/ribavirin treatment in methadone maintenance patients previously untreated for CHC. METHODS: Patients were randomized 1:1 to direct observed therapy (DOT) or self-administration (SA) of peginterferon alfa-2a. DOT patients were seen weekly at methadone clinics; SA patients were seen less frequently, only at investigative sites. Genotype 1-infected patients were treated for 48 wk with peginterferon alfa-2a (180 mug/wk)/ribavirin (1,000/1,200 mg/day); genotypes 2- and 3-infected patients were treated for 24 wk with peginterferon alfa-2a (180 mug/wk)/ribavirin (800 mg/day). RESULTS: Based on defined efficacy stopping rules, 77%(37/48) completed their targeted length of treatment, and 44%(21/48) achieved sustained virologic response (SVR). Two DOT and 3 SA patients were withdrawn for safety reasons and 6 and 9, respectively, for nonsafety reasons. Over 60% and 50% of each group were >80% compliant with the planned cumulative doses of peginterferon alfa-2a and ribavirin, respectively, and over 60% with overall treatment duration. SVR rates were 54%(13/24) for DOT and 33%(8/24) for SA; 23%(3/13) and 38%(6/16), respectively, for genotype 1 and 91%(10/11) and 25%(2/8), respectively, for genotypes 2 and 3. Stepwise logistic regression analysis, showed that DOT (vs SA; OR 3.27, 95% CI 0.90-11.91, P= 0.073) and Caucasian race (vs Other; OR 13.31, 95% CI 1.42-124.71, P= 0.023) were predictors of SVR. CONCLUSION: Peginterferon alfa-2a/ribavirin can be used safely and successfully in CHC patients receiving methadone maintenance.

Detection of liver disease among injection drug users is an important challenge because liver disease is common, usually unrecognized, and treatable in early stages. Many forms of liver disease occur in injection drug users (IDUs). However, commensurate with its exceedingly high prevalence among IDUs, much of the published literature (and accordingly the focus of this review) regards liver disease caused by chronic hepatitis C. Existing guidelines for detection of liver disease are presented in the context of the current standard of care. Since recent research shows these guidelines rarely contribute to the medical management of IDUs, special emphasis is given to novel approaches that, when coupled with advances in treatment, the authors believe could substantially reduce the medical and psychological consequences of injection drug use.

In the era of effective antiretroviral therapy (ART), liver disease is the second most common cause of death among persons with human immunodeficiency virus (HIV) infection. Liver disease-related deaths mostly result from chronic infection with hepatitis B virus (HBV) and/or hepatitis C virus (HCV). In addition, recent reports suggest that HCV infection may be transmitted sexually between HIV-infected men who have sex with men. Management of these conditions in HIV-infected persons requires careful consideration, balancing the potential benefits of therapy with the potential for significant treatment-related adverse effects (HCV infection) and viral resistance and/or hepatitis flares (HBV infection). Furthermore, several antiretroviral agents are active against HBV infection, including lamivudine, emtricitabine, tenofovir, and, more recently, entecavir. Despite the complexity and potential for antiretroviral-associated hepatotoxicity, ART usually is safe for patients with viral hepatitis coinfection, and, in some cases, treatment for HIV infection may be beneficial for the liver.

Persons at high risk for human immunodeficiency virus (HIV) infection are also likely to be at risk for other infectious pathogens, including hepatitis B virus (HBV) or hepatitis C virus (HCV). These are bloodborne pathogens transmitted through similar routes; for example, via injection drug use (IDU), sexual contact, or from mother to child during pregnancy or birth. In some settings, the prevalence of coinfection with HBV and/or HCV is high. In the context of effective antiretroviral therapy (ART), liver disease has emerged as a major cause of morbidity and mortality in HIV-infected persons. Further, coinfection with viral hepatitis may complicate the delivery of ART by increasing the risk of drug-related hepatoxicity and impacting the selection of specific agents (e.g., those dually active against HIV and HBV). Expert guidelines developed in the United States and Europe recommend screening of all HIV-infected persons for infection with HCV and HBV and appropriate management of those found to be chronically infected. Treatment strategies for HBV infection include the use of nucleos(t)ide analogues with or without anti-HIV activity and/or peginterferon alfa (PegIFN) whereas HCV treatment is limited to the combination of PegIFN and ribavirin (RBV). Current approaches to management of HIV-infected persons coinfected with HBV or HCV are discussed in this review.

OBJECTIVE: To describe the safety and tolerability of zidovudine, lamivudine, and efavirenz in a low-income setting. DESIGN: We conducted a prospective cohort study in a workplace HAART programme in South Africa, which uses a first-line regimen of efavirenz, zidovudine, and lamivudine and provides routine clinical and laboratory monitoring 6-monthly pre-HAART and at 2, 6, 12, 24, 36, 48 weeks during HAART. METHODS: We assessed the incidence of specified clinical and laboratory events (AIDS Clinical Trials Group grade 3 or higher) and associated regimen changes, hospitalizations, and deaths one year before HAART initiation and one year on-HAART using person-year analysis. RESULTS: Between November 2002 and October 2005, 853 subjects (98% male, median age 40 years, and median CD4 cell count at HAART initiation 186 cells/mul) met enrollment criteria. The incidence of events on-HAART was higher than pre-HAART for neutropenia and nausea/vomiting. Dizziness was common early after HAART initiation (not evaluated pre-HAART). Of those with neutropenia, 88% had no apparent clinical consequences. The incidence of anemia, hepatotoxicity, peripheral neuropathy, and rash was similar or higher pre-HAART than on-HAART. Mean hemoglobin rose during the time on-HAART and was higher at 24 and 48 weeks than at baseline (P < 0.001). DISCUSSION: This regimen was well tolerated with a short-term increase in neutropenia, nausea, and probably neurocerebellar events. Most significantly, in contrast to reports from high-income countries, we observed a long-term improvement in the hemoglobin concentration.

Liver disease is the most common non-AIDS-related cause of mortality in HIV-infected patients. HIV-infected patients with chronic liver disease progress more rapidly to cirrhosis, and those with hepatitis B virus or hepatitis C virus coinfection progress more rapidly from decompensation to death and are at increased risk of death from end-stage liver disease. With improvements in health associated with antiretroviral therapy, liver transplantation is increasingly an option in HIV-infected patients with end-stage liver disease. Elements of management of decompensated liver disease, including staging, treatment of variceal hemorrhage and ascites, and considerations in transplantation in the HIV-infected patient are discussed. This article summarizes a presentation made by Marion G. Peters, MD, at the International AIDS Society-USA continuing medical education program held in Chicago in May 2009. The original presentation is available as a Webcast at www.iasusa.org.

Nearly one fourth of individuals with human immunodeficiency virus (HIV) infection have hepatitis C virus (HCV) infection in the US and Western Europe. With the availability of highly active antiretroviral therapy and the consequent reduction in opportunistic infections, resulting in the prolongation of the life span of HIV-infected patients, HCV co-infection has emerged as a significant factor influencing the survival of HIV patients. Patients with HIV/HCV co-infection have a faster rate of fibrosis progression resulting in more frequent occurrences of cirrhosis, end-stage liver disease, and hepatocellular carcinoma. However, the mechanism of interaction between the two viruses is not completely understood. The treatment for HCV in co-infected patients is similar to that of HCV mono-infection; i.e., a combination of pegylated interferon and ribavirin. The presence of any barriers to anti-HCV therapy should be identified and eliminated in order to recruit all eligible patients. The response to treatment in co-infected patients is inferior compared to the response in patients with HCV mono-infection. The sustained virologic response rate is only 38% for genotype-1 and 75% for genotype-2 and -3 infections. Liver transplantation is no longer considered a contraindication for end-stage liver disease in co-infected patients. However, the 5 year survival rate is lower in co-infected patients compared to patients with HCV mono-infection (33% vs 72%, P = 0.07). A better understanding of liver disease in co-infected patients is needed to derive new strategies for improving outcome and survival.

PURPOSE OF REVIEW: Although the remarkable efficacy of biological therapy has resulted in significant success in rheumatic disease management, susceptibility to infections remains a concern. Here we review the latest publications on infectious complications of biological therapy in rheumatic diseases. RECENT FINDINGS: The recent data on anti-tumor necrosis factor agents show encouraging results in relation to infections. The majority of the infections are minor, and opportunistic infections including tuberculosis are rare. The incidence of infections decreases with time on biologic therapy. Vaccination is effective while on biological agents, although live vaccines should be avoided. Biologic therapy in the setting of HIV, HCV and HBV continues to be studied, but data are accumulating in support of a favorable safety profile. There are degrees of differential susceptibility to infection across the rheumatic diseases, which should be taken into account in weighing the infectious risks of biologics in the respective diseases. SUMMARY: Biological medications have a favorable safety profile but continued vigilance is appropriate. Most infectious reported episodes are minor and the risk of infection appears to decrease with duration of treatment.

Hepatitis-C virus (HCV) has infected an estimated 130 million people worldwide, most of whom are chronically infected. Infection is marked by both treatment- and non-treatment-related psychiatric symptoms. Symptoms associated with antiretroviral therapy, interferon-alpha (IFN-alpha), include acute confusional states, delirium, depression, irritability, and even mania. These psychiatric symptoms are further complicated by the high rate of substance abuse and comorbid HIV infection inherent to this population. Even in the absence of IFN-alpha therapy, comorbid depression, cognitive decline, and especially fatigue are common in patients suffering HCV. These comorbidities have significant effects on both treatments and outcomes, and thus are reviewed herein.

Abstract Autoimmune hepatitis (AIH) is a progressive, chronic hepatitis that has rarely been reported in HIV-infected individuals. Among patients who are candidates for hepatitis C virus (HCV) treatment, screening for AIH should be considered, because interferon has the potential to cause fulminant hepatic failure in the setting of immune-mediated injury. During a 4-year period, we identified four HIV-infected patients who were referred for evaluation of persistently elevated aminotransferases, two of whom were also infected with HCV. Serologic testing and the hepatic histologic appearance were consistent with AIH. Although each patient initiated treatment with corticosteroids and immunosuppressive agents, all four eventually developed life-threatening infectious or adverse metabolic effects that resulted in treatment discontinuation. Of note, one HIV/HCV co-infected patient was able to initiate HCV treatment with interferon after AIH remission was documented. While these cases illustrate that AIH can produce hepatic injury in virally infected individuals, we recommend that treatment for AIH in HIV-infected patients should be individualized after careful consideration of the potential risks and likely benefits.

Due to the introduction of active HIV antiretroviral treatment, AIDS-related morbidity and mortality have markedly decreased and liver diseases are now a major cause of morbidity and mortality in HIV-infected patients. Chronic liver injury encompasses a wide spectrum of diseases due to HCV and HBV coinfection, drug-related toxicity, and NASH. HIV-infected patients who are receiving treatment present with a high prevalence of metabolic complications and lipodystrophy. Those patients are at high risk of nonalcoholic fatty liver disease, the liver feature of the metabolic syndrome. This review will focus on (1) the liver injuries in HIV-infected patients;(2) both the current experimental and human data regarding PPAR and liver diseases;(3) the interactions between HIV and PPAR;(4) the potential use of PPAR agonists for the management of HIV-related liver diseases.

PURPOSE OF REVIEW: This review provides information on the natural history of end-stage liver disease in HIV/hepatitis C virus-coinfected patients from diagnosis to liver transplantation or death and summarizes recent developments in the epidemiology, management, and prognosis of end-stage liver disease and orthotopic liver transplantation in this population compared with the HIV-negative population. RECENT FINDINGS: Many studies have described epidemiological aspects, including the increasing incidence of end-stage liver disease, as a cause of non-AIDS-related death in the co-infected population in developed countries, whereas other reports have focused on the clinical presentation and prognosis of end-stage liver disease in this specific clinical setting. The medical management of end-stage liver disease should be the same as for the HIV-negative population, and orthotopic liver transplantation is the only therapeutic option for HIV-infected patients who are eligible for this procedure. SUMMARY: End-stage liver disease is becoming a major issue in the HIV/HCV-coinfected population because of its increasing frequency, especially now the prognosis of HIV infection has improved with combined antiretroviral therapy. Medical management is essential and should be considered a bridge to orthotopic liver transplantation. Nevertheless, many issues remain unclear and must be examined in further studies.

PURPOSE OF REVIEW: Persons with HIV are frequently coinfected with hepatitis C virus. We review recent data on the epidemiology and natural history of hepatitis C in HIV-infected persons. RECENT FINDINGS: One-quarter of persons with HIV in Europe and the USA also have hepatitis C, but its prevalence in other areas is under 10%. Outbreaks of acute hepatitis C among men having sex with men have been described in Europe. Hepatitis C is the cause of more than three-quarters of liver-related deaths in HIV-seropositive individuals; however, liver-related morbidity and mortality are declining or stable in the era of highly active antiretroviral therapy. The association between hepatitis C virus coinfection and non-liver-related morbidity and mortality is still controversial. HIV-induced immune depression is strongly associated with worse liver disease, but it still does not support an earlier initiation of highly active antiretroviral therapy in coinfected subjects. SUMMARY: Screening and management of hepatitis C virus coinfection should be mandatory in persons with HIV, especially in Europe and the USA, where prevention of blood exposure should also be pursued in patients with sexual risk behaviour. The results of ongoing randomized controlled trials are needed before recommending earlier initiation of highly active antiretroviral therapy in coinfected persons.

PURPOSE OF REVIEW: Highly active antiretroviral therapy dramatically reduces HIV-related morbidity and mortality. Liver disease has subsequently emerged as a major cause of death in HIV/hepatitis C virus-coinfected individuals. Whether HIV therapy also has a favourable impact on the course of liver disease needs to be explored and counterbalanced with toxicity issues related to the extended duration of antiretroviral therapy. RECENT FINDINGS: Recent cohort studies have shown that highly active antiretroviral therapy is associated with a reduced rate of progression of hepatitis C virus liver disease, with some also showing a reduction in liver-related mortality. Increased mortality from liver disease has been linked with the extended duration of antiretroviral therapy. Highly antiretroviral therapy-associated liver steatosis has been described as an emerging cause of liver cirrhosis. New possibly HIV therapy-related adverse events such as hepatoportal sclerosis have been reported. SUMMARY: Studies evaluating the impact of the early initiation of highly active antiretroviral therapy on liver disease in coinfected patients are urgently needed. The safety profile of currently available antiretroviral agents with regard to liver toxicity needs to be further elucidated in order to be able to recommend earlier HIV treatment in this particular patient population.