Hepatocellular carcinoma, human immunodeficiency virus and viral hepatitis in the HAART era

The incidence of hepatocellular carcinoma （HCC） in patients with human immunodeficiency virus （HIV） is rising. HCC in HIV almost invariably occurs in the context of hepatitis C virus （HCV） or hepatitis B virus （HBV） co-infection and, on account of shared modes of transmission, this occurs in more than 33% and 10% of patients with HIV worldwide respectively. It has yet to be clearly established whether HIV directly accelerates HCC pathogenesis or whether the rising incidence is an epiphenomenon of the highly active antiretroviral therapy （HAART） era, wherein the increased longevity of patients with HIV allows long-term complications of viral hepatitis and cirrhosis to develop. Answering this question will have implications for HCC surveillance and the timing of HCV/HBV therapy, which in HIV co-infection presents unique challenges. Once HCC develops, there is growing evidence that HIV co-infection should not preclude conventional therapeutic strategies, including liver transplantation.     

Hepatocellular carcinoma in patients co-infected with hepatitis C virus and human immunodeficiency virus

Hepatitis C virus (HCV) and human immunodeficiency virus (HIV) share a common route of transmission so that about one third of HIV infected individuals show HCV co-infection. Highly active antiretroviral therapy has offered a longer and better life to infected patients. While has removed AIDS-related diseases from the list of most common causes of death their place has been taken by complications of HCV infection, such as cirrhosis, end stage liver disease and hepatocellular carcinoma (HCC). HIV/HCV co-infection requires complex management, especially when HCC is present. Co-infected patients with HCC undergo the same therapeutic protocol as their mono-infected counterparts, but special issues such as interaction between regimens, withdrawal of therapy and choice of immunosuppressive agents, demand a careful approach by specialists. All these issues are analyzed in this minireview.     

Outcomes and management of viral hepatitis and human immunodeficiency virus co-infection in liver transplantation

Liver transplantation for human immunodeficiency virus(HIV)positive patients with viral hepatitis co-infection is increasingly offered in many North American and European liver transplant centers.Prior studies have demonstrated acceptable post-transplant outcomes and no increased risk of HIV complications in patients coinfected with hepatitis B virus(HBV).However,liver transplantation in HIV positive patients with hepatitis C virus(HCV)has poorer outcomes overall,requiring careful selection of candidates.This review aims to summarize the published literature on outcomes after transplant in HIV patients with HBV or HCV related end-stage liver disease and recommendations for management.In particular the pre-transplant factors impacting outcomes in HCV/HIV co-infected candidates and importance of multidisciplinary management will be discussed.     

慢性丙型肝炎患者混合或重叠感染其他病原体状况分析

目的了解丙型肝炎病毒（HCV）感染者混合或重叠感染乙型肝炎病毒（HBV）、人免疫缺陷病毒（HIV）和梅毒螺旋体（TP）的状况,为HCV感染的防治提供依据。方法采用ELISA法检测乙型肝炎病毒标志物、抗TP和抗HIV;采用化学发光法检测抗HCV;采用蛋白印迹法确认HIV感染。结果在169例HCV感染者中,重叠感染HBV 25例（14.8%）、HIV 4例（2.4%）、TP 9例（5.3%）,重叠感染HBV和TP 2例（1.2%）,重叠感染HBV和HIV 2例（1.2%）;静脉吸毒者重叠感染HIV（6.7%）和TP（11.1%）的比例均明显高于非静脉吸毒者（P〈0.05）;男性患者重叠感染HBV的比例（19.7%）明显高于女性患者（3.8%,P〈0.01）,女性患者重叠感染TP的比例（11.5%）明显高于男性患者（2.6%,P〈0.05）。结论随着感染方式的多元化,慢性丙型肝炎患者重叠感染其他病原体的情况更加常见。     

Human immunodeficiency virus and hepatitis C virus/hepatitis B virus co-infection in Southern Brazil: clinical and epidemiological evaluation

Hepatitis B virus, hepatitis C virus and human immunodeficiency virus share a similar transmission pathway and are often diagnosed in the same patient. These patients tend to have a faster progression of hepatic fibrosis. This cross-sectional study describes the demographic features and clinical profile of human immunodeficiency virus/hepatitis co-infected patients in Paraná, Southern Brazil. A total of 93 human immunodeficiency virus-infected patients attending a tertiary care academic hospital in Southern Brazil were included. Clinical, demographic and epidemiological data were evaluated. Hepatitis B virus and/or hepatitis C virus positive serology was found in 6.6% of patients. The anti-hepatitis C virus serum test was positive in 85% (79/93) of patients, and the infection was confirmed in 72% of the cases. Eighteen patients (19%) were human immunodeficiency virus/hepatitis B virus positive (detectable HBsAg). Among co-infected patients, there was a high frequency of drug use, and investigations for the detection of co-infection were conducted late. A low number of patients were eligible for treatment and, although the response to antiretroviral therapy was good, there was a very poor response to hepatitis therapy. Our preliminary findings indicate the need for protocols aimed at systematic investigation of hepatitis B virus and hepatitis C virus in human immunodeficiency virus-infected patients, thus allowing for early detection and treatment of co-infected patients.     

Non-initiation of hepatitis C virus antiviral therapy in patients with human immunodeficiency virus/hepatitis C virus co-infection

AIM: To assess whether reasons for hepatitis C virus(HCV) therapy non-initiation differentially affect racial and ethnic minorities with human immunodeficiency virus(HIV)/HCV co-infection.METHODS: Analysis included co-infected HCV treatment-na?ve patients in the University of North Carolina CFAR HIV Clinical Cohort(January 1, 2004 and December31, 2011). Medical records were abstracted to document non-modifiable medical(e.g., hepatic decompensation, advanced immunosuppression), potentially modifiable medical(e.g., substance abuse, severe depression, psychiatric illness), and non-medical(e.g., personal,social, and economic factors) reasons for non-initiation. Statistical differences in the prevalence of reasons for non-treatment between racial/ethnic groups were assessed using the two-tailed Fisher's exact test. Three separate regression models were fit for each reason category. Odds ratios and their 95%CIs(Wald's) were computed.RESULTS: One hundred and seventy-one patients with HIV/HCV co-infection within the cohort met study inclusion. The study sample was racially and ethnically diverse; most patients were African-American(74%), followed by Caucasian(19%), and Hispanic/other(7%). The median age was 46 years(interquartile range = 39-50) and most patients were male(74%). Among the 171 patients, reasons for non-treatment were common among all patients, regardless of race/ethnicity(50% with ≥ 1 non-modifiable medical reason, 66% with ≥1 potentially modifiable medical reason, and 66% with ≥ 1 non-medical reason). There were no significant differences by race/ethnicity. Compared to Caucasians, African-Americans did not have increased odds of nonmodifiable [adjusted odds ratio(a OR) = 1.47, 95%CI: 0.57-3.80], potentially modifiable(a OR = 0.72, 95%CI: 0.25-2.09) or non-medical(a OR = 0.90, 95%CI: 0.32-2.52) reasons for non-initiation.CONCLUSION: Race/ethnicity alone is not predictive of reasons for HCV therapy non-initiation. Targeted interventions are needed to improve access to therapy for all co-infected patients, including minorities.     

HBV/HIV重叠感染的抗病毒治疗

随着人类免疫缺陷病毒(human immunodeficiency virus,HIV)感染率快速增长,乙型肝炎病毒(hepatitis B virus,HBV)/HIV重叠感染成为一种临床易见疾病.HBV/HIV重叠感染使HBV和HIV的生物学行为发生改变,进而相互影响病情进展,使得HBV/HIV重叠感染患者的抗病毒...     

13例HIV/HBV重叠感染患者的实验指标分析

目的了解艾滋病病毒与乙型肝炎病毒（HIV/HBV）重叠感染患者的临床特征,分析HIV与HBV在疾病进展中的相互作用。方法回顾性分析、比较13例HIV/HBV重叠感染组、28例单纯HIV感染组、28例单纯HBV感染组患者,在免疫功能、肝脏功能及血常规方面的差异。结果免疫功能检测：CD4^＋T细胞计数和CD4^＋/CD8^＋T细胞比值表现为HIV/HBV重叠感染组〈单纯HIV组〈单纯HBV组（P〈0.01）;肝脏功能检测：HIV/HBV重叠感染组与单纯HIV感染组各项指标无显著性差异,而单纯HBV组的丙氨酸氨基转移酶（ALT）、天冬氨酸转氨酶（AST）、总胆红素显著高于（P〈0.01）或高于（P〈0.05）另外两组;血常规检测：HIV/HBV重叠感染组和单纯HIV组各指标无显著性差异,但与单纯HBV组比较,则红细胞和血红蛋白显著降低（P〈0.01）,血小板明显升高（P〈0.01）。结论研究结果初步提示,HIV与HBV重叠感染后,可能减轻患者的肝细胞损伤,进一步降低患者的免疫功能。     

Modification of the immune response against hepatitis B virus by the human immunodeficiency virus

Summary Hepatitis B virus and the human immunodeficiency virus are similarly transmitted. Individuals with preexisting HIV infection have a higher chance to become HBsAg carriers than do anti-HIV negative persons. Cytotoxic T cells with specificity for HBcAg, that are under the control of HBcAg-specific helper T cells, are responsible for liver injury. There is good evidence that HIV infection lowers inflammatory activity, is associated with milder liver histology, high levels of viral replication and low seroconversion rates. In addition interferon alpha therapy is less effective in anti-HIV positive subjects. The immune response against HBsAg is helper T-cell dependent and vaccination against hepatitis B is of low effectiveness. In addition, vaccination against hepatitis B may activate the HIV disease and is, therefore, presently not to be recommended.     

Co-infection of hepatitis B and hepatitis C virus in human immunodeficiency virus-infected patients in New York City,United States

AIM： To study the prevalence and risk factors associated with triple infection with human immunodeficiency virus （HIV）/hepatitis B virus （HBV）/hepatitis C virus （HCV） in an urban clinic population. METHODS： Retrospective chart review of 5639 patients followed at St. Luke＇s-Roosevelt Hospital HIV Clinic （Center for Comprehensive Care） in New York City, USA from January 1999 to May 2007. The following demographic characteristics were analyzed： age, sex, race and HIV risk factors. A multiple logistic regression analysis was performed to evaluate the influence of demographic factors on acquisition of these viruses. RESULTS： HIV/HBV, HIV/HCV and HIV/HBV/HCV infections were detected in 252/5639 （4.47%）, 1411/5639 （25.02%） and 89/5639 （1.58%） patients, respectively. HIV/HBV co-infections were associated with male gender （OR 1.711; P = 0.005）, black race （OR 2.091, P 〈 0.001）, men having sex with men （MSM） （OR 1.747, P = 0.001）, intravenous drug use （IDU） （OR 0.114, P 〈 0.001）, IDU and heterosexual activity （OR 0.247; P = 0.018）, or unknown （OR 1.984, P = 0.004）.HIV/HCV co-infections were associated with male gender （OR 1.241; P = 0.011）, black race （OR 0.788; P = 0.036）, MSM （OR 0.565; P 〈 0.001）, IDU （OR 8.956; P 〈 0.001）, IDU and heterosexual activity （OR 9.106; P 〈 0.001）, IDU and MSM （OR 9.179; P 〈 0.001）, or transfusion （OR 3.224; P 〈 0.001）. HIV/HBV/HCV coinfections were associated with male gender （OR 2.156; P = 0.015）, IDU （OR 6.345; P 〈 0.001）, IDU and heterosexual activity （OR 9.731; P 〈 0.001）, IDU and MSM （OR 9.228; P 〈 0.001）, or unknown （OR 4.219; P = 0.007）. CONCLUSION： Our study demonstrates that coinfection with HBV/HCV/HIV is significantly associated with IDU. These results highlight the need to intensify education and optimal models of integrated care, particularly for populations with IDU, to reduce the risk of viral transmission.     

Hepatitis C virus infection in the human immunodeficiency virus infected patient

Human immunodeficiency virus(HIV)and hepatitis C virus(HCV)share the same transmission routes;therefore,coinfection is frequent.An estimated 5-10 million individuals alone in the western world are infected with both viruses.The majority of people acquire HCV by injection drug use and,to a lesser extent,through blood transfusion and blood products.Recently,there has been an increase in HCV infections among men who have sex with men.In the context of effective antiretroviral treatment,liver-related deaths are now more common than Acquired Immune Deficiency Syndromerelated deaths among HIV-HCV coinfected individuals.Morbidity and mortality rates from chronic HCV infection will increase because the infection incidence peaked in the mid-1980s and because liver disease progresses slowly and is clinically silent to cirrhosis and end-stage-liver disease over a 15-20 year time period for 15%-20%of chronically infected individuals.HCV treatment has rapidly changed with the development of new direct-acting antiviral agents;therefore,cure rates have greatly improved because the new treatment regimens target different parts of the HCV life cycle.In this review,we focus on the epidemiology,diagnosis and the natural course of HCV as well as current and future strategies for HCV therapy in the context of HIV-HCV coinfection in the western world.     

Effect of IL-2 on hepatitis C virus RNA levels in patients co-infected with human immunodeficiency virus receiving HAART

The effect of interleukin-2 (IL-2) on the plasma levels of hepatitis C RNA (HCV-RNA) has varied in published reports. We measured the impact of IL-2 on plasma HCV RNA levels in 54 human immunodeficiency virus (HIV)/HCV coinfected patients enrolled in a randomized trial of 512 participants designed to compare the virologic and immunologic effects of cycled IL-2 plus antiretroviral therapy (ART) vs ART alone in the treatment of HIV in patients with CD4 cell counts > or =300 cells/mm(3). The mean decreases in average HCV RNA levels (copies/mL, log (10)) were 0.28 log in the IL-2 group (n = 26) and 0.04 log in the ART alone group (n = 28) at 12 months (P = 0.18). The changes in HCV RNA level were not associated with baseline or nadir CD4 cell counts, baseline aspartate aminotransferanse, CD4 cell response to IL-2, or changes in plasma HIV RNA values. Compared with those participants who only had HIV, the HIV/HCV co-infected patients did not have a significantly different CD4 cell response to IL-2 therapy. Intermittent IL-2 therapy does not produce a significant sustained decrease in plasma HCV RNA levels among patients co-infected with HIV/HCV who are on highly active ART.     

Pros and cons of liver transplantation in human immunodeficiency virus infected recipients

Before the introduction of combined highly antiretroviral therapy,a positive human immunodeficiency virus(HIV)serological status represented an absolute contraindication for solid organ transplant(SOT).The advent of highly effective combined antiretroviral therapy in 1996 largely contributed to the increased demand for SOT in HIV-positive individuals due to increased patients’life expectancy associated with the increasing prevalence of end-stage liver disease(ESLD).Nowadays,liver failure represents a frequent cause of mortality in the HIV-infected population mainly due to coinfection with hepatitis viruses sharing the same way of transmission.Thus,liver transplantation(LT)represents a reasonable approach in HIV patients with stable infection and ESLD.Available data presently supports with good evidence the practice of LT in the HIV-positive population.Thus,the issue is no longer"whether it is correct to transplant HIV-infected patients",but"who are the patients who can be safely transplanted"and"when is the best time to perform LT".Indeed,the benefits of LT in HIV-infected patients,especially in terms of mid-and long-term patient and graft survivals,are strictly related to the patients’selection and to the correct timing for transplantation,especially when hepatitis C virus coinfection is present.Aim of this article is to review the pros and cons of LT in the cohort of HIV infected recipients.     

Dried blood spots,valid screening for viral hepatitis and human immunodeficiency virus in real-life

AIMTo detect chronic hepatitis B (CHB), chronic hepatitis C (CHC) and human immunodeficiency virus (HIV) infections in dried blood spot (DBS) and compare these samples to venous blood sampling in real-life.METHODSWe included prospective patients with known viral infections from drug treatment centers, a prison and outpatient clinics and included blood donors as negative controls. Five drops of finger capillary blood were spotted on filter paper, and a venous blood sample was obtained. The samples were analyzed for HBsAg, anti-HBc, anti-HBs, anti-HCV, and anti-HIV levels as well as subjected to a combined nucleic acid test (NAT) for HBV DNA, HCV RNA and HIV RNA.RESULTSSamples from 404 subjects were screened (85 CHB, 116 CHC, 114 HIV and 99 blood donors). DBS had a sensitivity of > 96% and a specificity of > 98% for the detection of all three infections. NAT testing did not improve sensitivity, but correctly classified 95% of the anti-HCV-positive patients with chronic and past infections. Anti-HBc and anti-HBS showed low sensitivity in DBS (68% and 42%).CONCLUSIONDBS sampling, combined with an automated analysis system, is a feasible screening method to diagnose chronic viral hepatitis and HIV infections outside of the health care system.     

Alcohol use disorder and its impact on chronic hepatitis C virus and human immunodeficiency virus infections

Alcohol use disorder(AUD) and hepatitis C virus(HCV) infection frequently co-occur. AUD is associated with greater exposure to HCV infection, increased HCV infection persistence, and more extensive liver damage due to interactions between AUD and HCV on immune responses, cytotoxicity, and oxidative stress. Although AUD and HCV infection are associated with increased morbidity and mortality, HCV antiviral therapy is less commonly prescribed in individuals with both conditions. AUD is also common in human immunodeficiency virus(HIV) infection, which negatively impacts proper HIV care and adherence to antiretroviral therapy, and liver disease. In addition, AUD and HCV infection are also frequent within a proportion of patients with HIV infection, which negatively impacts liver disease. This review summarizes the current knowledge regarding pathological interactions of AUD with hepatitis C infection, HIV infection, and HCV/HIV co-infection, as well as relating to AUD treatment interventions in these individuals.     

Rates and impact of hepatitis on human immunodeficiency virus infection in a large African cohort

AIM:To determine the rates and impact of hepatitis B virus(HBV) and hepatitis C virus(HCV) infections on response to long-term highly active antiretroviral therapy(HAART) in a large human immunodeficiency virus(HIV) population in Nigeria.METHODS:HBV and HCV as well as HIV infections are endemic in sub Saharan Africa.This was a retrospective cohort study of 19 408 adults who were recruited between June 2004 and December 2010 in the AIDS Prevention Initiative in Nigeria in Nigeria programme at Jos University Teaching Hospital.Serological assays,including HBV surface antigen(HBsAg) and hepatitis C antibody were used to categorise hepatitis status of the patients.HBsAg was determined using enzyme immunoassay(EIA)(Monolisa HBsAg Ultra3;Bio-Rad).HCV antibody was tested using third generation EIA(DIA.PRO Diagnostic,Bioprobes srl,Milan,Italy).HIV RNA levels were measured using Roche COBAS Amplicor HIV-1 monitor test version 1.5(Roche Diagnostics,GmbH,Mannheim,Germany) with a detection limit of 400 copies/mL.Flow cytometry was used to determine CD4+ cell count(Partec,GmbH Munster,Germany).Comparison of categorical and continuous variables were achieved using Pearson’s χ 2 and Kruskal Wallis tests respectively,on MedCalc for Windows,version 9.5.0.0(MedCalc Software,Mariakerke,Belgium).RESULTS:With an overall hepatitis screening rate of over 90% for each virus;HBV,HCV and HBV/HCV were detected in 3162(17.8%),1983(11.3%) and 453(2.5%) HIV infected adults respectively.The rate of liver disease was low,but highest among HIV monoinfected patients(29,0.11%),followed by HBV coinfected patients(15,0.08%).Patients with HBV coinfection and triple infection had higher log 10 HIV RNA loads(HBV:4.6 copies/mL vs HIV only:4.5 copies/mL,P<0.0001) and more severe immune suppression(HBV:645,55.4%;HBV/HCV:97,56.7%) prior to initiation of HAART compared to HIV mono-infected patients(1852,48.6%)(P<0.0001).Of 3025 patients who were 4.4 years on HAART and whose CD4 cell counts results at baseline and end of follow up were available for     

Role of liver transplantation in human immunodeficiency virus positive patients

End-stage liver disease(ESLD) is a leading cause of morbidity and mortality amongst human immunodeficiency virus(HIV)-positive individuals. Chronic hepatitis B and hepatitis C virus(HCV) infection,drug-induced hepatotoxicity related to combined antiretro-viral therapy,alcohol related liver disease and non-alcohol related fatty liver disease appear to be the leading causes. It is therefore,anticipated that more HIV-positive patients with ESLD will present as potential transplant candidates. HIV infection is no longer a contraindication to liver transplantation. Key transplantation outcomes such as rejection and infection rates as well as medium term graft and patient survival match those seen in the non-HIV infected patients in the absence of co-existing HCV infection. HIV disease does not seem to be negatively impacted by transplantation. However,HIV-HCV coinfection transplant outcomes remain suboptimal due to recurrence. In this article,we review the key challenges faced by this patient cohort in the pre- and posttransplant period.     

Incidence of hepatocellular carcinoma in patients with chronic liver disease due to hepatitis B or C and coinfected with the human immunodeficiency virus: A retrospective cohort study

AIM To assess the incidence of hepatocellular carcinoma(HCC) in chronic liver disease due to hepatitis B virus(HBV) or hepatitis C virus(HCV) coinfected with human immunodeficiency virus(HIV).METHODS A retrospective cohort study was performed, including patients with chronic liver disease due to HBV or HCV, with and without HIV coinfection. Patients were selected in the largest tertiary public hospital complex in southern Brazil between January 2007 and June 2014. We assessed demographic and clinical data, including lifestyle habits such as illicit drug use or alcohol abuse, in addition to frequency and reasons for hospital admissions via medical records review.RESULTS Of 804 patients were included(399 with HIV coinfection and 405 monoinfected with HBV or HCV). Coinfected patients were younger(36.7 ± 10 vs 46.3 ± 12.5, P 0.001). Liver cirrhosis was observed in 31.3% of HIV-negative patients and in 16.5% of coinfected(P 0.001). HCC was diagnosed in 36 patients(10 HIV coinfected and 26 monoinfected). The incidence density of HCC in coinfected and monoinfected patients was 0.25 and 0.72 cases per 100 patient-years(95%CI: 0.12-0.46 vs 0.47-1.05)(long-rank P = 0.002), respectively. The ratio for the HCC incidence rate was 2.98 for HIV-negative. However, when adjusting for age or when only cirrhotic are analyzed, the absence of HIV lost statistical significance for the development of HCC. CONCLUSION In this study, the presence of HIV coinfection in chronic liver disease due to HBV or HCV showed no relation to the increase of HCC incidence.     

Hepatocellular carcinoma in patients with chronic hepatitis C virus infection without cirrhosis

AIM:To investigate and characterise patients with chronic hepatitis C virus(HCV) infection presenting with hepatocellular carcinoma(HCC) in the absence of cirrhosis.METHODS:Patients with chronic hepatitis C infection without cirrhosis presenting with HCC over a 2-year period were identified.The clinical case notes,blood test results and histological specimens were reviewed to identify whether additional risk factors for the development of HCC were present.RESULTS:Six patients(five male,one female) with chro...     

Prevention of hepatocellular carcinoma in chronic viral hepatitis B and C infection

Hepatocellular carcinoma(HCC)is a leading cause of cancer-related mortality worldwide,with the majority of cases associated with persistent infection from hepatitis B virus(HBV)or hepatitis C virus(HCV).Natural history studies have identified risk factors associated with HCC development among chronic HBV and HCV infection.High-risk infected individuals can now be identified by the usage of risk predictive scores.Vaccination plays a central role in the prevention of HBV-related HCC.Treatment of chronic HBV infection,especially by nucleoside analogue therapy,could also reduce the risk of HBV-related HCC.Concerning HCV infection,besides the advocation of universal precautions to reduce the rate of infection,pegylated interferon and ribavirin could also reduce the risk of HCV-related HCC among those achieving a sustained virologic response.Recently there has been mounting evidence on the role of chemopreventive agents in reducing HBV-and HCV-related HCC.The continued advances in the understanding of the molecular pathogenesis of HCC would hold promise in preventing this highly lethal cancer.