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Hepatic Decompensation in Antiretroviral-Treated Patients Co-Infected With HIV and Hepatitis C Virus Compared With Hepatitis C Virus-Monoinfected Patients: A Cohort Study
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Ann Intern Med. 18 March 2014
"the increased rate of hepatic decompensation among co-infected patients should prompt earlier consideration of initiation of HCV therapy to try to reduce the risk for liver complications......Providers might also address modifiable risk factors, such as diabetes, to try to decrease the risk for end-stage liver disease......
.........In this study, antiretroviral-treated patients co-infected with HIV and HCV had higher rates of hepatic decompensation and severe liver events than HCV-monoinfected patients. Co-infected patients who maintained HIV RNA levels less than 1000 copies/mL or less than 400 copies/mL over the median 6.8 years of follow-up still had higher rates of decompensation, suggesting that HIV viral suppression below these thresholds with ART is not sufficient to reduce rates of end-stage liver disease to those of HCV-monoinfected patients. Furthermore, among patients with minimal or no fibrosis at baseline, the risk for decompensation remained higher for co-infected patients. Rates of decompensation were highest for patients with pre-ART CD4 counts less than 0.200 x 109 cells/L compared with monoinfected patients. Finally, among co-infected patients receiving ART, baseline advanced liver fibrosis, severe anemia, diabetes, and nonblack race were each associated with higher rates of decompensation........
........The mechanisms for the higher rates of hepatic decompensation in co-infected patients receiving ART remain unclear. HIV-related immune dysregulation, HIV-mediated depletion of CD4 cells in the gastrointestinal tract with resultant microbial translocation, oxidative stress related to co-infection with HIV and HCV, and HIV-induced hepatocyte apoptosis have been implicated in the pathogenesis of progressive hepatic disease in patients co-infected with HIV and HCV (13). Other cofactors, such as hepatic steatosis and cumulative exposure to potentially hepatotoxic medications, particularly selected antiretroviral drugs (39-41), might also accelerate liver disease progression in co-infected patients........
.......We identified several important factors associated with hepatic decompensation in co-infected patients. Diabetes is associated with hepatic steatosis (48), which could promote hepatic inflammation and accelerate liver fibrosis progression (49). Diabetes might also induce hepatic fibrosis independent of steatosis via stimulation of hepatic stellate cells by insulin (50-51). Severe anemia might be a marker of advanced HCV-associated liver disease, potentially indicating blood loss from variceal bleeding. Alternatively, anemia may be a marker for systemic inflammation (52), which may promote hepatic fibrosis. Nonblack HCV-infected patients have been reported to have stronger HCV-specific immunity than black patients (53), which could result in increased immune-mediated hepatic inflammation and accelerated liver fibrosis progression."
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Hepatic Decompensation in Antiretroviral-Treated Patients Co-Infected With HIV and Hepatitis C Virus Compared With Hepatitis C Virus-Monoinfected Patients: A Cohort Study
Ann Intern Med. 2014
Vincent Lo Re III, MD, MSCE; Michael J. Kallan, MS; Janet P. Tate, ScD; A. Russell Localio, PhD; Joseph K. Lim, MD; Matthew Bidwell Goetz, MD; Marina B. Klein, MD, MS; David Rimland, MD; Maria C. Rodriguez-Barradas, MD; Adeel A. Butt, MD, MS; Cynthia L. Gibert, MD, MS; Sheldon T. Brown, MD; Lesley Park, MPH; Robert Dubrow, MD, PhD; K. Rajender Reddy, MD; Jay R. Kostman, MD; Brian L. Strom, MD, MPH; and Amy C. Justice, MD, PhD
Abstract
Background: The incidence and determinants of hepatic decompensation have been incompletely examined among patients co-infected with HIV and hepatitis C virus (HCV) in the antiretroviral therapy (ART) era, and few studies have compared outcome rates with those of patients with chronic HCV alone.
Objective: To compare the incidence of hepatic decompensation between antiretroviral-treated patients co-infected with HIV and HCV and HCV-monoinfected patients and to evaluate factors associated with decompensation among co-infected patients receiving ART.
Design: Retrospective cohort study.
Setting: Veterans Health Administration.
Patients: 4280 co-infected patients who initiated ART and 6079 HCV-monoinfected patients receiving care between 1997 and 2010. All patients had detectable HCV RNA and were HCV treatment-naive.
Measurements: Incident hepatic decompensation, determined by diagnoses of ascites, spontaneous bacterial peritonitis, or esophageal variceal hemorrhage.
Results: The incidence of hepatic decompensation was greater among co-infected than monoinfected patients (7.4% vs. 4.8% at 10 years; P < 0.001). Compared with HCV-monoinfected patients, co-infected patients had a higher rate of hepatic decompensation (hazard ratio [HR] accounting for competing risks, 1.56 [95% CI, 1.31 to 1.86]). Co-infected patients who maintained HIV RNA levels less than 1000 copies/mL still had higher rates of decompensation than HCV-monoinfected patients (HR, 1.44 [CI, 1.05 to 1.99]). Baseline advanced hepatic fibrosis (FIB-4 score >3.25) (HR, 5.45 [CI, 3.79 to 7.84]), baseline hemoglobin level less than 100 g/L (HR, 2.24 [CI, 1.20 to 4.20]), diabetes mellitus (HR, 1.88 [CI, 1.38 to 2.56]), and nonblack race (HR, 2.12 [CI, 1.65 to 2.72]) were each associated with higher rates of decompensation among co-infected patients.
Limitation: Observational study of predominantly male patients.
Conclusion: Despite receiving ART, patients co-infected with HIV and HCV had higher rates of hepatic decompensation than HCV-monoinfected patients. Rates of decompensation were higher for co-infected patients with advanced liver fibrosis, severe anemia, diabetes, and nonblack race.
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Editors' Notes
Context
· Patients with HIV are often co-infected with hepatitis C virus (HCV). Whether treatment of HIV with antiretroviral therapy (ART) can improve HCV outcomes is a topic of interest.
Contribution
· In a Veterans Affairs study, patients co-infected with HIV and HCV who had HIV RNA levels less than 1000 copies/mL had a lower rate of hepatic decompensation than those with less HIV suppression. However, the rate was still higher than that in HCV-monoinfected patients.
Caution
· Few women were studied.
Implication
· Patients co-infected with HIV and HCV remain at greater risk for poor outcomes from HCV infection than HCV-monoinfected patients despite viral suppression by ART.
-The Editors
Co-infection with chronic hepatitis C virus (HCV) occurs in 10% to 30% of HIV-infected patients (1-4). The course of chronic HCV is accelerated in patients co-infected with HIV, with more rapid progression of liver fibrosis than in HCV-monoinfected patients (5-7). Consequently, HCV-related liver complications, particularly hepatic decompensation (defined by the presence of ascites, spontaneous bacterial peritonitis, variceal hemorrhage, or hepatic encephalopathy [8]), have emerged as important causes of illness in co-infected patients (9-10).
Despite the importance of HCV-related end-stage liver disease, few longitudinal studies have evaluated the incidence and determinants of hepatic decompensation among patients co-infected with HIV and HCV during the antiretroviral therapy (ART) era. Previous studies suggest that ART slows progression of HCV-associated liver fibrosis, possibly by reducing HIV-related inflammation and immune dysfunction and inhibiting the ability of HIV to directly infect hepatocytes (10-13). However, whether rates of hepatic decompensation and other severe liver events (for example, hepatocellular carcinoma [HCC] or liver-related death) in co-infected patients receiving ART are similar to those in HCV-monoinfected patients remains unclear. Furthermore, the determinants of hepatic decompensation among co-infected patients receiving ART are unknown.
Determination of these factors could help define the mechanisms of decompensation in co-infected patients and could suggest interventions to reduce the risk for end-stage liver disease in this population.
We first compared the incidence of hepatic decompensation between antiretroviral-treated patients co-infected with HIV and HCV and HCV-monoinfected patients. We hypothesized that rates of decompensation would remain higher in co-infected patients despite ART. We then evaluated host and viral factors associated with decompensation among co-infected patients.
Results
Patient Characteristics
Between 1997 and 2010, a total of 10 359 patients (4280 antiretroviral-treated patients co-infected with HIV and HCV and 6079 HCV-monoinfected patients) met our inclusion criteria (Figure 1). Absence of HCV RNA assessment was the most common reason for exclusion from both cohorts. There were no clinically relevant differences in the characteristics between included patients (Table 1) and those excluded due to absence of HCV RNA assessment in either cohort.
Table 1 summarizes the baseline cohort characteristics. Co-infected and monoinfected patients were similar in age, race/ethnicity, diabetes, history of alcohol dependence or abuse, and history of injection or noninjection drug use. Most patients in both cohorts were infected with HCV genotype 1. Co-infected patients more commonly had a high HCV RNA level. Follow-up was shorter for co-infected than monoinfected patients (6.8 vs. 9.9 years; P < 0.001). During follow-up, 330 (7.7%) co-infected and 505 (8.3%) monoinfected patients initiated HCV therapy and were censored.
Baseline ART regimens prescribed to co-infected patients reflected the antiretroviral drugs used at the time of entry into the VACS-VC (Table 1). A relatively small number (162 [3.8%]) was prescribed a combination of abacavir, lamivudine, and zidovudine as the baseline regimen. Among the 241 co-infected patients who were positive for hepatitis B surface antigen, 207 (85.9%) received lamivudine alone, tenofovir plus emtricitabine, or tenofovir plus lamivudine as part of their baseline regimen. Co-infected patients had a median of 2.8 HIV RNA results (interquartile range [IQR], 1.8 to 3.8 results) measured each year during follow-up to assess HIV virologic response.
Hepatic Decompensation
Hepatic decompensation occurred more frequently in antiretroviral-treated co-infected patients (271 [6.3%]) than among monoinfected patients (305 [5.0%]) (P = 0.004). At the time of initial decompensation, variceal hemorrhage was less common among co-infected patients (71 [26.2%] vs. 168 [55.1%]; P < 0.001).
However, similar proportions of co-infected and monoinfected patients presented with ascites (226 [83.4%] vs. 236 [77.4%]; P = 0.070) and spontaneous bacterial peritonitis (48 [17.7%] vs. 68 [22.3%]; P = 0.171). Among those who presented with ascites, similar proportions of co-infected and monoinfected patients had the diagnosis recorded in the inpatient setting (145 [64.2%] vs. 133 [56.4%]; P = 0.087).
After adjustment for age, race/ethnicity, diabetes, BMI, history of alcohol abuse and injection or noninjection drug use, and VA center patient volume, co-infected patients receiving ART had a higher rate of decompensation than monoinfected patients (HR, 1.83 [95% CI, 1.54 to 2.18]). This association was almost identical when we expanded our outcome to include events from VA, Medicare, or Medicaid data (HR, 1.85 [CI, 1.59 to 2.18]) and remained when we treated death as a competing risk (HR, 1.56 [CI, 1.31 to 1.86]). Hazard ratios that were adjusted for informative censoring differed little (data not shown).
The standardized cumulative incidence of decompensation was higher among co-infected than monoinfected patients at 10 years (7.4% vs. 4.8%; P < 0.001) (Figure 2 [top]).
In subgroup analyses, rates of decompensation remained higher in co-infected patients who maintained HIV RNA levels less than 1000 copies/mL throughout follow-up compared with monoinfected patients (Table 2 and Figure 2 [middle]).
Similar results were observed when co-infected patients with HIV RNA levels less than 400 copies/mL throughout follow-up were compared with HCV-monoinfected patients (data not shown). Across strata of pre-ART CD4 cell count, the HR for decompensation was highest for co-infected patients with a pre-ART CD4 count less than 0.200 x 109 cells/L compared with monoinfected persons (Table 2 and Figure 2 [bottom]). Among those with a baseline FIB-4 score less than 1.45, the risk for decompensation remained higher in co-infected than monoinfected patients (adjusted HR, 1.98 [CI, 1.23 to 3.18]).
Hepatocellular Carcinoma
The proportions of co-infected and monoinfected patients who developed HCC were similar (74 [1.7%] vs. 100 [1.6%]; P = 0.74). After adjustment for age, race, diabetes, BMI, alcohol abuse, injection or noninjection drug use, and VA center patient volume, rates of HCC were higher for co-infected patients (HR, 1.60 [CI, 1.16 to 2.21]). This association did not remain significant in a competing risk analysis (Table 2). Median survival after HCC diagnosis was shorter for co-infected patients (8.7 months [IQR, 2.3 to 27.3 months] vs. 14.2 months [IQR, 3.8 to 101.8 months]), but this difference was not significant (P = 0.22). There were no important differences in age at diagnosis, race, BMI, diabetes, or alcohol abuse between co-infected and monoinfected patients with HCC (Appendix Table 1).
Hepatocellular Carcinoma
The proportions of co-infected and monoinfected patients who developed HCC were similar (74 [1.7%] vs. 100 [1.6%]; P = 0.74). After adjustment for age, race, diabetes, BMI, alcohol abuse, injection or noninjection drug use, and VA center patient volume, rates of HCC were higher for co-infected patients (HR, 1.60 [CI, 1.16 to 2.21]). This association did not remain significant in a competing risk analysis (Table 2). Median survival after HCC diagnosis was shorter for co-infected patients (8.7 months [IQR, 2.3 to 27.3 months] vs. 14.2 months [IQR, 3.8 to 101.8 months]), but this difference was not significant (P = 0.22). There were no important differences in age at diagnosis, race, BMI, diabetes, or alcohol abuse between co-infected and monoinfected patients with HCC (Appendix Table 1).
Severe Liver Events and Death
Severe liver events were more common in co-infected than monoinfected patients (373 [8.7%] vs. 433 [7.1%]; P = 0.003), and co-infected patients had a higher risk for this end point (Table 2). Liver transplantation was less common among co-infected patients (5 [0.1%] vs. 26 [0.4%]; P = 0.004).
Death occurred more frequently among co-infected patients (1407 [32.9%] vs. 934 [15.4%]; P < 0.001), and HIV/AIDS (46.3%) was most commonly recorded as the underlying cause of death in this cohort. Liver disease (20.1%) was most commonly recorded as the cause of death in monoinfected patients (Appendix Table 2).
Factors Associated With Decompensation Among Co-infected Patients
Baseline advanced hepatic fibrosis, baseline hemoglobin level less than 100 g/L, diabetes, and nonblack race were risk factors for decompensation (Table 3). The hazard for HIV viremia copy-years greater than 6 log copy-years/mL was approximately twice that of the reference group (<2 log copy-years/mL), but these results did not approach statistical significance.
Discussion
In this study, antiretroviral-treated patients co-infected with HIV and HCV had higher rates of hepatic decompensation and severe liver events than HCV-monoinfected patients. Co-infected patients who maintained HIV RNA levels less than 1000 copies/mL or less than 400 copies/mL over the median 6.8 years of follow-up still had higher rates of decompensation, suggesting that HIV viral suppression below these thresholds with ART is not sufficient to reduce rates of end-stage liver disease to those of HCV-monoinfected patients. Furthermore, among patients with minimal or no fibrosis at baseline, the risk for decompensation remained higher for co-infected patients. Rates of decompensation were highest for patients with pre-ART CD4 counts less than 0.200 x 109 cells/L compared with monoinfected patients. Finally, among co-infected patients receiving ART, baseline advanced liver fibrosis, severe anemia, diabetes, and nonblack race were each associated with higher rates of decompensation.
Our analyses examining the risk for decompensation between co-infected and monoinfected patients did not control for baseline stage of hepatic fibrosis because the development of liver fibrosis is in the causal pathway to hepatic decompensation. Thus, controlling for baseline hepatic fibrosis could adjust away an association between treated HIV and decompensated cirrhosis. We conducted a secondary analysis restricted to patients with minimal or no liver fibrosis (FIB-4 score <1.45) at baseline. Antiretroviral-treated co-infected patients continued to have an increased risk for hepatic decompensation compared with monoinfected patients.
The mechanisms for the higher rates of hepatic decompensation in co-infected patients receiving ART remain unclear. HIV-related immune dysregulation, HIV-mediated depletion of CD4 cells in the gastrointestinal tract with resultant microbial translocation, oxidative stress related to co-infection with HIV and HCV, and HIV-induced hepatocyte apoptosis have been implicated in the pathogenesis of progressive hepatic disease in patients co-infected with HIV and HCV (13). Other cofactors, such as hepatic steatosis and cumulative exposure to potentially hepatotoxic medications, particularly selected antiretroviral drugs (39-41), might also accelerate liver disease progression in co-infected patients.
We found that variceal hemorrhage was less commonly an initial presenting decompensation event among co-infected patients. A similar finding was reported in a cohort study of Spanish patients who were co-infected with HIV and HCV (42). Prior studies have suggested that HIV infection is associated with protein C deficiency (43-45) and protein S deficiency (46), which can promote hypercoagulability and reduce the likelihood of variceal bleeding among co-infected patients.
We found a higher rate of HCC in co-infected patients receiving ART than in HCV-monoinfected patients, but this difference was not statistically significant after adjustment for competing risk. A prior cohort study conducted between 1992 and 2000 showed that co-infection with HIV and HCV was not associated with an increased risk for HCC compared with HCV monoinfection in either the pre-ART or ART eras (47). As life expectancy continues to increase among patients co-infected with HIV and HCV, clinically important differences in rates of HCC may become apparent in the future.
We identified several important factors associated with hepatic decompensation in co-infected patients. Diabetes is associated with hepatic steatosis (48), which could promote hepatic inflammation and accelerate liver fibrosis progression (49). Diabetes might also induce hepatic fibrosis independent of steatosis via stimulation of hepatic stellate cells by insulin (50-51). Severe anemia might be a marker of advanced HCV-associated liver disease, potentially indicating blood loss from variceal bleeding. Alternatively, anemia may be a marker for systemic inflammation (52), which may promote hepatic fibrosis. Nonblack HCV-infected patients have been reported to have stronger HCV-specific immunity than black patients (53), which could result in increased immune-mediated hepatic inflammation and accelerated liver fibrosis progression.
Our results suggest that the highest level of HIV viremia copy-years (>6 log copy-years/mL of HIV RNA) might increase the risk for hepatic decompensation. However, plasma viral loads were measured infrequently in many patients, with variable numbers and timing. Given our additional finding of a higher risk for decompensation in co-infected patients with pre-ART CD4 counts less than 0.200 x 109 cells/L than in monoinfected patients, suppression of HIV while receiving ART and resultant immune reconstitution should remain a key goal for patients co-infected with HIV and HCV to possibly reduce the risk for end-stage liver disease.
Neither hepatitis B infection nor HCV RNA level was associated with hepatic decompensation among co-infected patients. Most co-infected patients (85.9%) who were positive for hepatitis B surface antigen received hepatitis B-active ART, and this might have mitigated the association between hepatitis B and decompensation. Future analyses should test this hypothesis. Moreover, although several studies in HCV-monoinfected patients have suggested that higher HCV RNA levels are associated with more advanced liver fibrosis (54-56) or death from end-stage liver disease (57), most have found no association between HCV RNA level and liver disease severity (58-62). Our results are consistent with these findings.
Our results have important clinical implications. The finding that antiretroviral-treated co-infected patients who maintained an HIV RNA level less than 1000 copies/mL had lower rates of hepatic decompensation than those who did not achieve HIV suppression below this level suggests that suppression of HIV RNA with ART is an important factor in slowing progression of HCV-related liver fibrosis. This observation supports current management guidelines that recommend initiation of ART among patients co-infected with HIV and HCV, regardless of CD4 cell count (16, 63). Furthermore, the increased rate of hepatic decompensation among co-infected patients should prompt earlier consideration of initiation of HCV therapy to try to reduce the risk for liver complications (19-20). Recent clinical trials evaluating boceprevir- and telaprevir-based antiviral therapy among patients co-infected with HIV and HCV genotype 1 show sustained HCV virologic response rates that are similar to those of HCV-monoinfected patients (64-65). Providers might also address modifiable risk factors, such as diabetes, to try to decrease the risk for end-stage liver disease.
This study has several potential limitations. First, decompensation outcomes could have been misclassified. However, hepatic decompensation was identified using a validated definition (21). We might have underestimated the number of decompensation events because our definition did not include hepatic encephalopathy; however, the negative predictive value of our validated definition exceeded 99% (21). In addition, the incidence rates of decompensation among co-infected (9.5 per 1000 person-years) and monoinfected (5.7 per 1000 person-years) patients in this study were similar to those reported in other cohorts of co-infected (11.6 per 1000 person-years [10]) and monoinfected (3.4 per 1000 person-years [62]) patients. The potential exists for differential ascertainment of outcomes if patients in one of the cohorts more frequently presented to non-VA hospitals for care. To address this issue, we evaluated incident decompensation events within the VA system and in the U.S. Medicare and Medicaid programs, as well as liver-related deaths within a composite severe liver event outcome. The association between antiretroviral-treated co-infection and these composite end points remained in both analyses. Second, residual confounding by unmeasured factors (for example, duration of HCV infection or alcohol dependence or drug use during follow-up) is possible. However, sensitivity analyses (Supplement 4) suggested that our results were robust to the potential bias from unobserved confounders. Third, the median follow-up among the monoinfected patients was longer than that for the co-infected patients. However, both cohorts included patients in all age groups and produced risk sets of adequate size for all combinations of decompensation risk factors across age groups; therefore, they covered the spectrum of risk among young, middle-aged, and older HCV-infected patients. Finally, our study sample predominantly comprised male U.S. veterans, so results may not be generalizable to women. Because progression of HCV-related liver fibrosis differs by sex (60, 66-67), future epidemiologic analyses should evaluate end-stage liver disease events among women co-infected with HIV and HCV and HCV-monoinfected women.
This study has several strengths. It is, to our knowledge, the largest study to evaluate liver-related events among antiretroviral-treated co-infected patients and to compare outcomes with those of HCV-monoinfected persons. It had a long duration of follow-up, evaluated validated end points (21), accounted for time-varying covariates, and identified decompensations and liver-related deaths outside the VA system, ensuring that few outcomes were missed.
In conclusion, we found that patients co-infected with HIV and HCV who were receiving ART had higher rates of hepatic decompensation and severe liver events than HCV-monoinfected patients. Among co-infected patients receiving ART, baseline advanced liver fibrosis, severe anemia, diabetes, and nonblack race were associated with higher rates of decompensation. Clinicians should address modifiable risk factors and consider treatment of HCV infection in co-infected patients to reduce rates of hepatic decompensation.
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