Bruno, Raffaele MD*; Sacchi, Paolo MD*; Puoti, Massimo MD†; Maiocchi, Laura MD*; Patruno, Savino MD*; Carosi, Giampiero MD†; Filice, Gaetano MD*
Progressive chronic liver disease associated with hepatitis B virus (HBV) or hepatitis C virus (HCV) infection is a leading cause of morbidity and mortality in patients infected with HIV. As many as one third of all HIV-infected individuals are coinfected with HCV, and 10% to 45% of these patients will die from complications associated with HCV-related liver disease.1,2 Findings from a recent large cohort study involving more than 23,000 HIV-infected patients from North America and Europe indicated that liver disease was the second leading cause of death, after complications of AIDS.3
Numerous studies have shown that infection with HIV exacerbates the natural history of chronic HBV and HCV infection. Increased rates of liver fibrosis and progression to end-stage liver disease (ESLD) have been well documented in HIV-infected individuals coinfected with HBV4,5 and HCV.6-8 In prospective studies, HIV/HCV coinfection is associated with a higher cumulative incidence of ESLD and shorter survival times than is HCV monoinfection.4,9,10 A meta-analysis of studies involving HIV/HCV-coinfected patients reported a correlation between HIV coinfection and an increased risk for the progression of HCV-related liver disease.11 Findings from more recent studies involving patients with decompensated liver disease have further demonstrated that HIV coinfection is associated with a poor prognosis and marked reduction in survival.12
Data regarding the natural history of compensated cirrhosis in HIV patients coinfected with HBV and/or HCV is limited. The management of HIV-coinfected individuals with compensated advanced chronic liver disease is often complicated by a number of factors, including viral interactions, levels of immunodeficiency, and hepatotoxicity associated with antiretroviral therapy. A better understanding of the natural history of HBV- and HCV-related compensated cirrhosis in HIV-infected patients could further improve strategies for surveillance and disease management in this patient population.
In this study we describe the incidence and type of liver-related complications in a cohort of HIV-infected patients with HBV- and/or HCV-related compensated cirrhosis observed over a 6-year period. In addition, we determined the survival of HIV-infected patients with and without HBV- and/or HCV-related compensated cirrhosis and the impact of highly active antiretroviral therapy (HAART) on patient outcome after the first decompensation in HIV-infected patients who had HBV- and/or HCV-related compensated cirrhosis.
Study Design and Data Collection
Data on the morbidity and mortality of liver-related complications from a cohort of HIV-infected patients with initially compensated HBV- and/or HCV-related cirrhosis who attended a single center and who were followed thereafter were analyzed retrospectively in this study. Eligible patients were identified through use of ICD-9 codes for cirrhosis and review of medical records. Data were collected in an electronic database. The minimum follow-up time was 0.96 years for HIV-monoinfected patients, 0.88 years for coinfected patients without cirrhosis, and 0.96 years for those with cirrhosis. All patients coinfected with HBV and or HCV underwent a liver biopsy at the beginning of the follow-up to stage and grade the extent of liver damage.
Patients and Follow-Up
In this retrospective analysis, HIV-coinfected patients with HBV- or HCV-related compensated cirrhosis were identified and followed from January 1999 to December 2004, provided they fulfilled the following inclusion criteria: (1) >18 years of age; (2) positive serum anti-HCV and/or hepatitis B surface antigen (HBsAg); (3) detectable plasma levels of HCV RNA or HBV DNA; (4) a histologic or clinical diagnosis of cirrhosis (defined as the presence of irregular margins on ultrasound, portal hypertension with laboratory evidence of advanced chronic liver disease, or a Child-Turcotte-Pugh score of 6 or 7 [Child class A] without clinical deterioration such as variceal bleeding, ascites, or hepatic encephalopathy); and (5) individuals with elevated alpha-fetoprotein levels (>200 ng/mL) without clinical or ultrasonographic evidence of hepatocellular carcinoma (HCC).
All patients were assessed every 3 months during their regular clinical care for clinical signs and symptoms of liver disease. Assessment included laboratory testing for alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin, albumin, and alpha-fetoprotein levels, as well as prothrombin time and complete blood counts including platelet, leukocyte, and hemoglobin levels. An abdominal ultrasound (US) was performed every 6 months after cirrhosis was diagnosed.
The development of major complications of cirrhosis during follow-up was defined according to international guidelines.13 Ascites was identified by examination of the abdomen and confirmed by imaging; gastrointestinal bleeding due to portal hypertension was confirmed by endoscopy in the presence of esophageal or gastric varices or portal hypertensive gastropathy; and hepatic encephalopathy was established by clinical parameters. Worsening of disease with decompensation was defined by the transition from Child class A to Child class B or C cirrhosis. The date when each of these events was observed was recorded.
Complications of cirrhosis were managed according to the current guidelines.14,15 Antiretroviral drugs were interrupted when necessary according to the prescription guidelines for each drug and the clinical condition of each patient.
The Pearson χ2 test was applied to determine differences in categorical variables between groups of patients, while continuous variables were compared using the Kruskal-Wallis test. The Kaplan-Meier product-limit method was used to estimate survival curves, and the comparison of survival between different groups of patients was carried out by means of the Gehan-Wilcoxon test. The variables analyzed for influence on overall survival and event-free survival (EFS) in cirrhotic patients were gender, age, albumin concentration, genotype, therapy, and CD4 cell count (<350 vs. ≥350 cells/mm3).
Between 1999 and 2004, 392 HIV-infected patients were followed for ≥6 months. Baseline demographic characteristics among the study groups are shown in Table 1. The study populations were predominately male and had a median age ranging from 35 to 37 years. Among these patients, 140 (36%) infected with HIV alone and 183 (47%) coinfected with HIV and HCV did not have cirrhosis and served as control populations for the purposes of this study. Of the total population, 69 coinfected patients (18% of the total population; 7 who were coinfected with HBV, 59 who were coinfected with HCV, and 3 who were coinfected with both HBV and HCV) were identified as having had initially compensated cirrhosis. A significantly higher proportion of coinfected individuals with HBV- and/or HCV-related compensated liver disease were male (P < 0.0001), had CD4 cell counts of <350 cells/mm3 (P < 0.0001), and were not receiving HAART therapy (P < 0.0001), compared with HIV-infected individuals without HCV infection and HIV/HCV-coinfected individuals without cirrhosis. Among the 69 HIV-infected individuals with HBV- and/or HCV-related compensated liver disease, 23 (33%) had HCV genotype 3. None of these patients received anti-HCV therapy.
Causes of Death
A total of 5 patients (3.6%) with HIV monoinfection, 8 patients (4.4%) with HIV/HCV coinfection without cirrhosis, and 22 patients (31.9%) with HBV- and/or HCV-related compensated cirrhosis died during the follow-up period. Liver disease was the cause of death in all-coinfected individuals with HBV- and/or HCV-related compensated cirrhosis. No liver-related deaths were observed among the 140 HIV-monoinfected individuals or the 183 HIV/HCV-coinfected individuals without cirrhosis.
Incidence of Hepatic Complications During Follow-Up
Using the Kaplan-Meier method, a marked difference in the cumulative incidence of liver-related complications in HIV-coinfected patients who had compensated cirrhosis of viral etiology was observed during the 6-year follow-up period (Fig. 1). The most frequently reported complications were ascites, which occurred in 27 (39.1%) patients; jaundice in 27 (39.1%); and hepatic encephalopathy in 15 (21.7%). Occurring at a lower frequency were hepatorenal syndrome in 13 patients (18.8%), HCC in 9 (13%), and gastrointestinal bleeding in 8 (11.6%).
All 3 (33.3%) subjects with triple infection (HIV-HBV-HCV) developed HCC during follow-up.
A marked reduction in survival was observed in HIV-coinfected patients with HBV- and/or HCV-related compensated cirrhosis compared with HIV-monoinfected patients and HIV-coinfected patients without cirrhosis. The 5-year survival rate for coinfected patients with HBV- and/or HCV-related compensated cirrhosis was 71.5%, compared with 97.1% for either HIV-monoinfected patients or HIV/HCV-coinfected patients without cirrhosis (P < 0.0001) (Fig. 2).
The mortality per 1000 person-years was 71.3 (95% confidence interval [CI], 47 to 108) in HIV-infected patients with HBV- and/or HCV-related 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.
During the follow-up period, the number of cases of decompensated cirrhosis increased from 4 in 1999 to 44 and 53 in 2003 and 2004, respectively. Survival rates after the first event of decompensation were 48% at 1 year and 18.1% at 3 years (Fig. 3).
The median EFS to the first event of decompensation in HIV/HBV- or HIV/HCV-coinfected patients with cirrhosis was 4.3 years (Fig. 4). The median time to the second decompensation event in these patients was 2.3 months (Fig. 5).
Impact of HAART on Survival
In univariate and multivariate analyses, the administration of HAART after the first event of decompensation was associated with improved survival in HIV-infected patients with HBV- and/or HCV-related compensated liver disease. As shown in Figure 6, survival was significantly longer in coinfected patients who were prescribed HAART than in patients who were not. The cumulative probability of survival in coinfected patients receiving HAART was 61.1% at 1 year and 26.2% at 3 years, compared with 26.7% at 1 year and 0% at 3 years in patients not receiving HAART (P < 0.0001). The longest survival time was 4.6 years and 1.7 years in the 2 groups. Other variables, including gender, age, serum albumin concentration, genotype, and baseline CD4 cell count, did not have an effect on survival.
Neither CD4 count nor HIV RNA levels were significantly associated with decompensation or death (P < 0.46). There was no statistical difference in CD4 cell count and HIV RNA level between dead and alive patients at the last observation time point.
The findings of the present study show that HCV/HIV-coinfected individuals have high rates of morbidity and mortality within the first 6 years after the diagnosis of compensated cirrhosis. In fact, approximately 30% of HCV/HIV-coinfected patients with compensated cirrhosis died during the 6-year follow-up period. Disease progression was associated with a marked reduction in survival, with a 3-year survival rate of 18% after the first event of decompensation.
The natural history of compensated cirrhosis in HCV-monoinfected individuals has been described previously.16,17 In long-term studies involving patients with chronic hepatitis C and compensated cirrhosis, the annual rate of disease progression to decompensation was 7%.17 In this patient population, the 5-year survival rate was 91% and the 10-year survival was 79%. The findings of the present study indicate that HIV coinfection significantly shortens the survival of patients with HCV-related compensated cirrhosis, with a 5-year survival rate of only 71.5%.
Our study shows that the median time of EFS to the first and second decompensation was 4.3 years and 2.3 months, respectively. Therefore, clinicians should be encouraged to treat chronic hepatitis early to prevent cirrhosis and decompensation.
In the present study, ascites and jaundice were the most common complications observed among HIV-infected patients with HCV-related compensated cirrhosis. This is in agreement with other studies involving patients with HBV- or HCV-related compensated cirrhosis where ascites was the first complication to occur and marked the progression to decompensated liver disease.18-20 However, studies involving more homogenous cohorts of HCV-infected patients with compensated cirrhosis who were followed for longer duration found that HCC is another major complication to develop during the compensated phase of the cirrhosis. In fact, in a recent study that followed 312 patients with chronic hepatitis C and initially compensated cirrhosis for 10 years, HCC was the most frequent complication (21%), followed by ascites (19.5%), gastrointestinal bleeding (4.5%), and hepatic encephalopathy (1.9%).16
In our study, HCC was not one of the principal causes of decompensation and in 33.3% of cases it seemed to be associated with HIV, HCV, and HBV triple infection.
Coinfection with HIV has been associated with a marked reduction in the survival of patients with HCV-related ESLD.12,21 In a retrospective cohort study that compared the survival of HCV-monoinfected and HIV/HCV-coinfected patients with decompensated cirrhosis, the median survival rate of patients with HIV/HCV coinfection was considerably shorter than that of patients with HCV monoinfection (16% vs. 48%; P < 0.001).21 In this study, nearly half of the coinfected patients died within 1 year of developing decompensated liver disease. In another recent prospective cohort study involving 153 HIV/HCV-coinfected patients with ESLD, the cumulative survival at 1 year and at 3 years was 38% and 18%, respectively.12 Similarly, in the present study, the 1-year survival rate after the first event of decompensation was 48% in HIV-infected patients coinfected with HBV and/or HCV.
Findings from recent studies suggest that HAART may reduce liver-related mortality in HIV/HCV-coinfected patients.12,22,23 Merchante and colleagues12 reported that the prognosis of HIV/HCV-coinfected patients was significantly worse in absence of HAART. In this study, the cumulative probability of survival in patients receiving HAART was significantly improved compared with those not treated with HAART (hazard ratio [HR] = 0.5; range 0.3 to 0.9, P = 0.03). In agreement with these findings, we found that patients treated with HAART after the first event of decompensation had significantly improved their survival compared with those who did not receive HAART (HR = 0.19; P < 0.028). These results suggest that HAART-associated immune restoration may positively influence the natural history of liver disease, even in the absence of complete virologic control of HIV. Data analysis in our study may be limited by the potential bias of the retrospective design and small sample size. Another possible bias may be that HAART could be continued in patients with better liver function at the time of decompensation. However, prospective studies require years to complete, and HIV coinfection has been shown to accelerate the progression of HBV- and/or HCV-related liver disease. Thus, the current retrospective analysis allowed for an investigation of survival rates and the incidence of complications in a population of patients with the potential for accelerated mortality. The findings of this study are relevant and useful, although there remains a need for larger prospective studies to be carried out.
In summary, our results indicate that significant morbidity and mortality occurs during the first 5 years after the diagnosis of compensated cirrhosis in HIV-coinfected patients. In contrast to HCV-monoinfected patients, in whom HCC is reported to be the most frequent first complication and a major cause of liver-related death, our findings indicate that ascites and jaundice are the most frequent initial complications in HIV-infected individuals with HBV- and/or HCV-related compensated cirrhosis. In this cohort of patients, the maintenance of HAART therapy after first decompensation was associated with improved survival. These results suggest that strategies for early intervention are needed to prevent disease progression in HIV-infected patients with concurrent HBV and/or HCV infection.
We are indebted to Dr. Cristiana Pascutto for assistance with the statistical analysis.
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