Case report. Hepatitis B virus and HIV coinfection

Coinfection with HIV and hepatitis B virus (HBV) is more common than that with HIV and hepatitis C virus (HCV), although more attention has been given to HCV coinfection as a result of its higher frequency of chronic disease. Natural history studies with HIV-HCV coinfection have also shown more rapid progression of liver disease, and end-stage liver disease due to hepatitis C is now a leading cause of death in HIV-infected patients. Like HCV infection, HBV infection can also be associated with significant morbidity and mortality in patients with HIV infection. Fortunately, treatment options of hepatitis B are expanding and may have a clinical impact on slowing disease progression. A case study of a patient with severe HBV-HIV coinfection is presented to illustrate what is known about this increasingly problematic disease state.     

Early initiation of antiretroviral therapy: the current best way to reduce liver-related deaths in HIV/hepatitis C virus-coinfected patients

Approximately 25% to 35% of HIV-infected persons in developed countries are coinfected with hepatitis C virus (HCV). HCV liver disease is accelerated by HIV coinfection, especially at low CD4 cell counts. Highly active antiretroviral therapy (HAART) dramatically reduces HIV-related mortality, and liver disease has emerged as a major cause of death in HIV/HCV-coinfected persons. Anti-HCV therapy with pegylated interferon plus ribavirin can cure HCV infection in up to 40% of coinfected patients; however, only approximately 10% of coinfected patients are considered candidates. Hence, HCV therapy cures approximately 4% of coinfected patients. Eleven cohort studies have shown that HAART is associated with a reduced rate of progression of HCV liver disease, and 4 of these studies have demonstrated a reduction in liver-related mortality. Although offering HCV therapy to the few eligible HIV/HCV-coinfected patients is important, early initiation of HAART in coinfected patients has a greater public health impact in reducing liver-related mortality than in curing HCV infection in approximately 4% of these patients.     

Challenges in the treatment of HIV and HCV coinfection

HIV and hepatitis C virus (HCV) infections are pandemic illnesses that represent serious global public health problems. It is estimated that there are currently 38 million people infected with HIV and 60–180 million people infected with HCV worldwide. Owing to similar transmission pathways, HIV/HCV coinfection occurs frequently and, indeed, affects approximately a third of all European and North American HIV patients. With the successful introduction of highly active antiretroviral therapy (HAART) for the treatment of HIV in 1996, the morbidity and mortality owing to HIV declined drastically. As the prognosis of HIV infection has improved, liver disease caused by chronic infection with HCV has become increasingly important for mortality and morbidity among HIV/HCV-coinfected patients. Coinfection leads to accelerated progression of liver fibrosis and development of cirrhosis, as well as earlier emergence of hepatocellular carcinomas. Pegylated interferon and ribavirin combination therapy of HCV in coinfected patients showed reasonable sustained virological responses in randomized clinical trials, ranging from 27 to 44%, which, however, is substantially lower than in HCV monoinfected patients. Furthermore, cohort analyses have shown that HAART-induced immune reconstitution can improve the natural course of hepatitis C significantly and delay fibrosis progression. As pharmacokinetic drug–drug interactions and higher rates of hepatotoxicity following HAART initiation must be considered in HIV/HCV coinfection, specific treatment and management guidelines have been developed to optimize care in this clinically challenging group of patients.     

Treatment of HIV/HBV coinfection: clinical and virologic issues

Chronic hepatitis B affects nearly 10% of HIV-infected patients. Thus, approximately four million people worldwide are HBV/HIV coinfected. Hepatitis B virus (HBV) infection is a dynamic disease and coinfection with HIV impacts directly on the outcome of HBV infection, considerably complicating its natural history, diagnosis, and management. Hepatic necroinflammation is lower in HBV/HIV coinfection, yet liver damage, especially fibrosis, progresses at a faster rate than in HBV monoinfection. With improved control of HIV disease with HAART, liver disease has emerged as one of the leading causes of death in patients with HIV Anti-HBV therapy should be considered for all HIV/HBV-coinfected patients with evidence of liver disease, irrespective of the CD4 cell count. In coinfected patients not requiring HAART, HBV therapy should be based on agents with no HIV activity such as adefovir. In contrast, in patients with CD4 counts less than 350 cells/microl, the use of agents with dual anti-HIV and anti-HBV activity should be considered. Combination therapy should ideally be used to avoid or delay the development of antiviral resistance. Regular monitoring of patients is imperative to recognize reactivation and subsequent need for treatment, and to identify drug resistance and viral breakthrough early. Similar close monitoring is required for patients presenting with advanced HIV infection and reduced functional hepatic reserve due to HBV-related cirrhosis. Effective antiviral treatment can precipitate immune reconstitution disease resulting in serious hepatic flare and precipitating liver decompensation. Clearly, more data are needed to more effectively treat HIV/HBV coinfection.     

Influence of hepatitis G virus infection on liver disease

The influence of hepatitis G virus (HGV) infection on disease activity in hepatitis C related and unrelated liver disease was investigated in 254 individuals using an EIA polymerase chain reaction assay for HGV. One hundred patients had chronic hepatitis C, 26 primary biliary cirrhosis, and 30 alcoholic liver cirrhosis. In addition, 51 hepatitis B surface antigen (HBsAg)-positive and 47 anti-hepatitis C virus (HCV)-positive blood donors were screened. Hepatitis G virus was detected in 18% of patients with chronic hepatitis C, 13% of patients with alcoholic liver cirrhosis, 11 % of patients with primary biliary cirrhosis, 10% of anti-HCV-positive blood donors, and 2% of HBsAg-positive blood donors. Virus load and alanine aminotransferase (ALT) levels did not differ significantly in patients with HCV alone versus patients coinfected with HCV and HGV. However, mild liver fibrosis correlated with HGV coinfection. Hepatitis G virus did not influence ALT levels or liver damage in liver disease unrelated to viral infection.     

HIV/HCV Co-infection: Pathogenesis, Clinical Complications, Treatment, and New Therapeutic Technologies

World-wide, hepatitis C virus (HCV) accounts for approximately 130 million chronic infections, with an overall 3% prevalence. Four to 5 million persons are co-infected with HIV. It is well established that HIV has a negative impact on the natural history of HCV, including a higher rate of viral persistence, increased viral load, and more rapid progression to fibrosis, end-stage liver disease, and death. Whether HCV has a negative impact on HIV disease progression continues to be debated. However, following the introduction of effective combination antiretroviral therapy, the survival of coinfected individuals has significantly improved and HCV-associated diseases have emerged as the most important co-morbidities. In this review, we summarize the newest studies regarding the pathogenesis of HIV/HCV coinfection, including effects of coinfection on HIV disease progression, HCV-associated liver disease, the immune system, kidney and cardiovascular disease, and neurologic status; and effectiveness of current anti-HIV and HCV therapies and proposed new treatment strategies.     

Liver histopathology in patients with concurrent chronic hepatitis C and HIV infection

To investigate the influence of human immunodeficiency virus (HIV) coinfection on preexisting long-term chronic C hepatitis (HCV) 68 liver biopsies from 22 HIV/HCV-coinfected, 13 HIV and 33 HCV-monoinfected patients and 71 livers obtained at autopsy from 26 HIV/HCV-coinfected and 45 HIV-monoinfected patients were studied by histo- and immunohistochemistry. All HIV patients had reached the advanced stage of immunodeficiency (stage III CDC), except for 3 haemophiliacs (stage II CDC). HCV infection was associated with a higher degree of portal, periportal and lobular inflammation — regardless of whether there was concurrent HIV infection. HIV/HCV coinfection was associated with a significantly higher rate of granulocytic cholangiolitis than HCV and HIV monoinfection (P < 0.05), a histological feature uncommon in C hepatitis. In HIV/HCV coinfection cholestasis was a predominant histological feature. HCV monoinfection and HCV/HIV coinfection were associated with the highest fibrosis index. In HIV/HCV coinfection centrilobular fibrosis was significantly more marked than in HCV monoinfection (P < 0.05), suggesting an HIV associated fibrogenic effect. Patients with chronic C hepatitis showed a significantly increased rate of posthepatitic cirrhosis compared with the patients without HCV infection (P < 0.05). At autopsy, 10 of the 20 HIV/HCV-coinfected haemophiliacs had developed cirrhosis because of chronic C hepatitis, whereas cirrhosis was found in only 2 of 6 HIV/HCV-coinfected non-haemophiliacs (1 case of chronic B and C hepatitis, and 1 case of chronic alcohol abuse). No cirrhosis was observed in the 45 autopsy patients with HIV monoinfection. The findings suggest that HIV coinfection aggravates the course of preceding long-term chronic C hepatitis by a more marked (centrilobular) fibrosis. HIV/HCV-coinfected patients are threatened by a higher rate of posthepatitic cirrhosis —particularly in multitransfused haemophiliacs — and cholestatic hepatopathy.     

Psychiatric behavioral aspects of comanagement of hepatitis C virus and HIV

Coinfection with HIV hastens the progression of liver disease in persons with hepatitis C virus (HCV) infection. As mortality directly due to HIV continues to decrease among persons who are HIV-positive, coinfection with HCV has emerged as a leading cause of death. There is increasing attention to the need to actively treat HCV infection in HIV/HCV coinfected patients. Current HCV treatment with pegylated interferon and ribavirin achieves sustained viral response in up to 40% of coinfected patients but has numerous neuropsychiatric side effects. Providers are hesitant to begin HCV treatment in the coinfected population given the high prevalence of existing psychiatric illness, cognitive impairment, and substance use disorders. There is an urgent need for research into the psychiatric and behavioral predictors of HCV treatment adherence and virologic outcome, as well as into the optimal psychiatric management of the neuropsychiatric sequelae of HCV therapy.     

Low rates of active hepatitis B and C infections among adults and children living with HIV and taking antiretroviral therapy: A multicenter screening study in Lesotho

Lesotho presents the second-highest adult human immunodeficiency virus (HIV) prevalence globally. Among people living with HIV, data on hepatitis B virus (HBV) or hepatitis C virus (HCV) coinfection are limited. We report HBV and HCV coinfection data from a multicentre cross-sectional study among adult and pediatric patients taking antiretroviral therapy in 10 health facilities in Lesotho. Among 1318 adults screened (68% female; median age, 44 years), 262 (20%) had immunologically controlled HBV infection, 99 (7.6%) tested anti-HBs positive and anti-HBc negative, indicating vaccination, and 57 (4.3%) had chronic HBV infection. Among the patients with chronic HBV infection, 15 tested hepatitis B envelope antigen (HBeAg) positive and eight had detectable HBV viremia (median, 2 477 400 copies/mL; interquartile range, 205-34 400 000) with a mean aspartate aminotransferase-to-platelet ratio index of 0.48 (SD, 0.40). Prevalence of HCV coinfection was 1.7% (22 of 1318), and only one patient had detectable HCV viremia. Among 162 pediatric patients screened, three (1.9%) had chronic HBV infection, whereby two also tested HBeAg-positive, and one had detectable HBV viral load (210 copies/mL). Six of 162 (3.7%) had anti-HCV antibodies, all with undetectable HCV viral loads. Overall prevalence of chronic HBV/HIV and HCV/HIV coinfection among adults and children was relatively low, comparable to earlier reports from the same region. But prevalence of immunologically controlled HBV infection among adults was high. Of those patients with chronic HBV infection, a minority had detectable HBV-DNA.     

Evaluating liver fibrosis progression and the impact of antiretroviral therapy in HIV and hepatitis C coinfection using a noninvasive marker

The effects of highly active antiretroviral therapy (HAART) on progression of hepatic fibrosis in hepatitis C virus (HCV) coinfection with HIV are not well understood and are difficult to measure because of the need for repeated liver biopsy. We evaluated the evolution of a noninvasive measure of liver fibrosis, the alanine aspartyl transferase (AST)-to-platelet ratio index (APRI), longitudinally and determined its predictive value for hepatic outcomes in HIV-positive patients with and without HCV coinfection. A total of 673 HIV-positive patients without liver complications at baseline (540 with HIV only, 133 with HIV-HCV coinfection) were followed between 1991 and 2004 for a median of 4.6 years (3524 person-years). At baseline, HIV-HCV coinfection had a higher median APRI compared with HIV infection alone (0.59 vs. 0.33; P < 0.0001). The natural logarithm of the APRI [ln(APRI)] changed significantly over time, particularly among patients with HIV-HCV coinfection. The baseline ln(APRI) was predictive of liver complications (hazard ratio [HR] = 4.0, 95% confidence interval [CI]: 2.5 to 6.4 per log), as was HCV (HR = 4.5, 95% CI: 1.5 to 14). Cumulative HAART did not protect against liver complications, although it was significantly associated with progression of APRI scores in HIV-HCV coinfection and in HIV alone. In conclusion, the APRI may be a useful marker for longitudinal evaluation of the progression of liver disease in HIV-HCV coinfection.     

Natural history of compensated viral cirrhosis in a cohort of patients with HIV infection

BACKGROUND: The natural history of initially compensated cirrhosis in patients with HIV and concurrent hepatitis B virus (HBV) and/or hepatitis C virus (HCV) infection is poorly defined. This study was designed to investigate the incidence and type of liver-related complications and mortality in coinfected cirrhotic patients. METHODS: We retrospectively identified a cohort of patients coinfected with HIV and HCV or HBV and initially compensated viral cirrhosis. Time to decompensation and mortality from liver-related causes were recorded. RESULTS: Between 1999 and 2004, 392 HIV-infected patients underwent a follow-up of > or =6 months. Sixty-nine patients (17.6%) with initially compensated cirrhosis were identified (7 HBV positive, 59 HCV positive, and 3 positive for both HBV and HCV). The most frequent complication was ascites. The mortality was 71.3 per 1000 person-years (95% confidence interval [CI], 47 to 108) in HIV-infected patients with HBV and/or HCV compensated cirrhosis, 8 (95% CI, 4 to 16) in HIV/HCV-coinfected patients without cirrhosis, and 6.5 (95% CI, 2.7 to 15.5) in HIV-monoinfected patients. After the first event of decompensation, the survival rate was 48% at 1 year and 18.1% at 3 years. Treatment with HAART after the first event of decompensation was associated with an increased survival rate (61.1% and 26.2% at 1 and 3 years, respectively, vs. 26.7% and 0%; P < 0.0001). CONCLUSIONS: These results indicate significant morbidity and mortality during the 6 years after the diagnosis of compensated cirrhosis due to HBV and/or HCV in HIV-infected patients, identifying ascites as the most frequent complication.     

Hepatitis B virus (HBV) and hepatitis C virus (HCV) dual infection

Hepatitis B virus (HBV) and hepatitis C virus (HCV) infections account for a substantial proportion of liver diseases worldwide. Because the two hepatotropic viruses share same modes of transmission, coinfection with the two viruses is not uncommon, especially in areas with a high prevalence of HBV infection and among people at high risk for parenteral infection. Patients with dual HBV and HCV infection have more severe liver disease, and are at an increased risk for progression to hepatocellular carcinoma (HCC). Treatment of viral hepatitis due to dual HBV/HCV infection represents a challenge.     

Hepatitis in AIDS patients

The individuals with HIV infection are more susceptible to develop coinfections with infectious pathogens such as HCV and HBV. The routes of transmission of these pathogens are the same including sexual contact, injection drug use, or at birth from mother to an infant. The main reason of morbidity and mortality in HIV infected individuals is a liver disease in the context of antiretroviral therapy, and coinfection such as HCV and HBV complicates this condition. Nucleos(t)ide analogues are used for HBV infection management, and treatment of HCV infection is done by PegIFN and ribavirin combination and protease inhibitors. In this review, we focused on hepatitis B and C infections in HIV patients along with their therapies.     

Overt and hidden coinfection with hepatitis B and C viruses in chronic liver disease and porphyria cutanea tarda

The aim of this study was to assess the rate of hepatitis B virus (HBV) and hepatitis C virus (HCV) coinfection ("the coinfection") in chronic liver disease (CLD) and to reveal overt and hidden HBV infection in patients with antibodies to HCV (anti-HCV). A total of 209 untreated patients (64 with chronic hepatitis B, 79 with chronic hepatitis C and 66 with porphyria cutanea tarda (PCT)) were screened for serological markers of HBV and HCV infection in serum by third generation enzyme-linked immunosorbent assay (ELISA) methods and for HBV DNA and HCV RNA in serum by polymerase chain reaction (PCR). The rate of the overt coinfection in chronic hepatitis B was very low (2/64, 3%). However, in chronic hepatitis C, the rate of the hidden coinfection with HBV was relatively high (19/79, 24%); these patients had higher alanine transaminase (ALT) and asparagine transaminase (AST) levels in serum and a more advanced liver disease. In PCT patients, the rates of HBV and HCV infections were the same, 21% (14/66). In the PCT patients infected with HBV or HCV, the rate of the coinfection was 33% (7/21). The PCT patients with the coinfection had a high serum ALT level and the worst histological picture in the liver. The hidden HBV infection was more frequent than the overt one. The possibility of the overt or hidden coinfection in CLD renders a detailed analysis of all serum samples for both viruses mandatory. Vaccination against HBV infection should be offered to anti-HCV-positive individuals as well as to PCT patients not showing antibodies to HBV (anti-HBV).     

Virological and clinical aspects of HBV-HCV coinfection in HIV positive patients

In a long-term follow-up study the clinical and virological presentation of HBV/HCV coinfection in anti-HIV positive patients was evaluated. Plasma HBV-DNA, HCV-RNA, and HIV-RNA were determined by PCR in 5 HBsAg/anti-HCV/anti-HIV positive patients, in 4 HBsAg/anti-HIV positive patients and in 82 anti-HCV/anti-HIV positive patients first observed at a Unit of Infectious Diseases in Naples (Italy) from 1990 to 2000 (follow up 6-16 years). All five hepatitis B and C coinfected patients showed reciprocal inhibition of viral replication on admission and during the follow up. At the end of the follow up a clearance of HBsAg from serum was observed in four patients and a clearance of anti-HCV in one of them. In two patients after clearance of HBsAg, evidence of occult HBV infection was observed, at times associated with a hepatic flare. None of the four patients with HIV/HBV coinfection lost HBsAg and none of the 82 with HIV/HCV coinfection lost anti-HCV during the follow up. In anti-HIV positive patients HBV/HCV coinfection is characterized by reciprocal inhibition of viral replication, more evident in HBV expression in plasma and at times by progression to occult HBV infection.     

Chronic immune activation is a distinguishing feature of liver and PBMC gene signatures from HCV/HIV coinfected patients and may contribute to hepatic fibrogenesis

Hepatitis C virus/human immunodeficiency virus (HCV/HIV) coinfected patients demonstrate accelerated progression to severe liver injury in comparison to HCV monoinfected patients, although the underlying mechanisms are unclear owing to infection of separate tissue compartments with two distinct viral pathogens. Microarray analysis of paired liver biopsy and peripheral blood mononuclear cell (PBMC) specimens from HCV/HIV coinfected and HCV monoinfected patients identified a gene expression signature associated with increased inflammation and immune activation that was present only in liver and PBMC samples from coinfected patients. We also identified in these samples liver- and PBMC-specific signatures enriched with fibrogenic/hepatic stellate activation and proinflammatory genes, respectively. Finally, Bayesian networks were constructed by assimilating these data with existing data from liver and PBMC samples from other cohorts, augmenting enrichment of biologically important pathways and further indicating that chronic immune activation in HCV/HIV coinfection may exacerbate liver disease progression in coinfected patients.     

Management of hepatitis B in patients coinfected with the human immunodeficiency virus

The human immunodeficiency virus (HIV) and the hepatitis B virus share common routes of transmission, and hence, coinfection with these two viruses is common. Chronic hepatitis B does not influence the progression of HIV disease or the response to highly active antiretroviral therapy. It is clear, however, that HIV infection does impact the course of hepatitis B, as higher rates of chronic carriage, lower seroconversion rates, and accelerated progression towards cirrhosis have been observed. Vaccination against hepatitis B is less effective in HIV-infected individuals. Coinfected subjects have a poor response to interferon therapy. Lamivudine is more effective in coinfected subjects but must not be used as monotherapy because of the risk of resistance developing. Combination therapy with lamivudine and tenofovir has shown promise and is currently being investigated in clinical trials, while new drugs and other combinations are in development.     

The natural history of hepatitis C virus (HCV) infection

Hepatitis C virus (HCV) is a leading cause of chronic liver disease, cirrhosis, and hepatocellular carcinoma, as well as the most common indication for liver transplantation in many countries. Although the incidence of hepatitis C infection has dramatically decreased during the past decade, the worldwide reservoir of chronically infected persons is estimated at 170 million, or 3% of the global population. There is much controversy surrounding the natural history of hepatitis C infection. The rate of chronic HCV infection is affected by a person's age, gender, race, and viral immune response. Approximately 75%-85% of HCV-infected persons will progress to chronic HCV infection, and are at risk for the development of extrahepatic manifestations, compensated and decompensated cirrhosis, and hepatocellular carcinoma (HCC). The rate of progression to cirrhosis is highly variable, and is influenced by several factors, including the amount of alcohol consumption, age of initial HCV infection, degree of inflammation and fibrosis on liver biopsy, HIV and HBV coinfection, and comordid conditions. An estimated 10%-15% of HCV-infected persons will advance to cirrhosis within the first 20 years. Persons with cirrhosis are at increased risk of developing HCC. An understanding of the natural history of hepatitis C is essential to effectively manage, treat, and counsel individuals with HCV infection.     

Clinical and virological characteristics of hepatitis B or C virus co-infection with HIV in Indonesian patients

Hepatitis virus-related liver disease increases substantially the mortality rate of patients with HIV on highly active antiretroviral therapy (HAART). Therefore, early diagnosis of hepatitis B virus (HBV) and hepatitis C virus (HCV) is important. However, the prevalence of HBV and HCV infection in Indonesian patients infected with HIV is unknown. Therefore, this study examined the molecular and clinical characteristics of HBV and HCV in 126 patients infected with HIV, mostly on HAART, at Dr. Sardjito Hospital, Yogyakarta, Indonesia. The rates of triple infection, HIV/HCV co-infection, HIV/HBV co-infection, and mono-infection were 4.8%, 34.1%, 3.2%, and 57.9%, respectively. Seven HCV genotypes were detected, with genotypes 1a, 1b, 1c, 3a, 3k, 4a, and 6n found in 23 (52%), 1 (2%), 4 (9%), 5 (11%), 7 (16%), 3 (6%), and 1 (2%) patients, respectively, indicating multiple modes of transmission. HBV-DNA was detected in 2/10 patients with hepatitis B surface antigen; both patients were HAART naive. Univariate analysis revealed that male sex, higher education level, injection drug use, sexual contact, alanine aminotransferase ≥40 IU/L, and aspartate aminotransferase-to-platelet ratio index > 0.5 were associated with HCV co-infection. In multivariate analysis, injection drug use (OR: 26.52; 95% CI: 3.52-199.54) and alanine aminotransferase ≥40 IU/L (OR: 6.36; 95% CI: 1.23-32.89) were independently associated with HCV co-infection. HCV co-infection was common among Indonesian patients infected with HIV, particularly among injecting drug users, and was a risk factor for disease progression of HIV.     

Monitoring patients with chronic hepatitis during and after therapy

Hepatitis C is a major public health problem. General screening is not advisable and should be limited to risk groups. The gold standard for the assessment of disease severity is liver biopsy. AST and ALT do not correlate with histology. Serum HCV RNA by qualitative assay and HCV genotype should be determined prior to therapy. Response to antiviral therapy should be assessed by testing AST, ALT and qualitative HCV RNA. Repeat liver biopsy is not necessary. The incidence of HCC related to HCV infection is rising. Early detection by a cost effective screening program is essential. In patients with liver cirrhosis caused by hepatitis C, alpha fetoprotein and liver sonography should be done every 6 months. Upper GI endoscopy is recommended every 1-4 years in cirrhotic patients. Over 350 000 000 people are infected with HBV worldwide, and chronic HBV infection is the leading cause of liver cancer and tenth leading cause of death. HBs Ag, HBeAg and HBV DNA positive patients should be monitored for 6 months before treatment. Patients treated with antiviral therapy should be tested for HBAg, HBeAg and HBV DNA at the end of treatment and every 6 months thereafter to assess virologic response. Monitoring of serum HBV DNA is done by PCR. Patients treated with lamivudine should be tested for YMDD mutation. Ultrasound and AFP monitoring are recommended for detection of HCC, but results are not always reliable. Approximately 40% -70% of HIV infected patients have coinfection with HCV, HBV and HDV. HIV/HCV coinfected patients have an increased risk of progressive liver disease and should be treated accordingly.