HIV coinfection shortens the survival of patients with hepatitis C virus-related decompensated cirrhosis^†

Study Design and Data Collection.

Data on survival from a cohort of patients with decompensated HCV-related cirrhosis who attended eight hospitals in Andalusia (in southern Spain) and who were followed thereafter were analyzed retrospectively in this survey. Eligible patients were identified by using the database of the clinical documentation services of each hospital. The codes of the International Classification for Diseases (ICD-9) for cirrhosis, each type of hepatic decompensation, viral hepatitis, and liver primary carcinoma were used as search terms. A common database was created to collect the data. The study was designed to detect a difference of 18 months in the median survival time (30 vs. 48 months), with a type I and type II error rate of 0.05 and 0.1, respectively. The computed accrual time of patient recruitment was 6 years, and the minimum follow-up was 1 day. A ratio of control to cases of 6 was considered. The minimum sample size thus calculated was 1,079 patients. The program PS Power and Sample Size Calculations, version 2.1.30 (http://www.mc.vanderbilt.edu/prevmed/ps/index.htm), was used for this calculation.

Patients and Follow-Up.

In this study, patients with decompensated cirrhosis who was seen at each participant hospital were analyzed from January 1997 to December 2002, provided that they fulfilled the following inclusion criteria: (1) older than 18 years of age; (2) positive serum anti-HCV; (3) detectable plasma HCV-RNA; (4) no evidence of metabolic or autoimmune liver disease according to clinical history, appropriate laboratory tests, and—when available—histological examination; and (5) no previous decompensation of liver disease. All eligible patients who were consecutively seen at the participant hospitals in the study period, regardless of HIV serostatus, were included in the analysis.

During the follow-up, all patients received similar care. The guidelines of the Spanish Association for the Study of the Liver (www.aeeh.org) were followed by both hepatologists and nonhepatologists. Patients were assessed at least every 6 months for symptoms and signs of hepatic decompensation. Ultrasound abdominal examinations for HCC screening were performed at least every 6 months. Portal hypertensive gastrointestinal bleeding (PHGB),14 ascites, hepatorenal syndrome,15 and spontaneous bacterial peritonitis16 were managed according to reported consensus. Namely, primary prophylaxis for PHGB was performed using beta-blockers (nadolol or propanolol). After PHGB, beta-blockers plus nitrates were used. Norfloxacin was administered in patients with spontaneous bacterial peritonitis for life and in those with an episode of PHGB for 1 week. No treatment other than lactitol or lactulose was prescribed after bouts of hepatic encephalopathy (HE). Liver transplantation was considered in HIV-uninfected patients with Child-Turcotte-Pugh class B or C and no contraindications. Likewise, transplantation was regarded as a therapeutic option in patients with HCC and unique tumors or three or fewer nodules with a diameter of less than 3 cm and no extension data.

All HIV-infected individuals who survived the first hepatic decompensation episode and who were candidates for HIV therapy were prescribed highly active antiretroviral therapy throughout the follow-up. Combinations included nucleoside analogues, protease inhibitors, or nonnucleoside retrotranscriptase inhibitors, as they became available. Drug combinations were made according to the recommendations of international guidelines applicable at the time of prescription.

In patients who acquired HCV through the sharing of needles or via blood transfusion, the duration of HCV infection was estimated. This value was calculated as the time elapsed from either the date of the first blood transfusion or the first year of needle-sharing to the date of the first liver decompensation.

Diagnostic Criteria.

Cirrhosis was diagnosed via histological examination or by the combination of clinical, biochemical, and ultrasound imaging data agreeing with such a diagnosis. Cirrhosis cases that presented with ascites, PHGB, HE, nonobstructive jaundice, spontaneous bacterial peritonitis, or HCC were classified as decompensated. The event that led the patient to the hospital was considered as the type of the first hepatic decompensation in the analysis. When more than one complication was present simultaneously, what dominated the clinical picture in the opinion of the attending physician was considered as the first hepatic decompensation.

Ascites was always proven by ultrasound examination or paracentesis. PHGB was diagnosed according to the Baveno criteria.14 HE was defined as an episode of mental confusion related by the patient or their relatives, or detection of disorientation by a physician in the absence of any other likely nonhepatic causes. Patients were classified as having nonobstructive jaundice if the plasma bilirubin level was equal or greater than 5 mg/dL and the ultrasound examination showed normal bile ducts. Spontaneous bacterial peritonitis was diagnosed when the polymorphonuclear count of the ascitic fluid was greater than 250 cells/μL or bacteria grew in the ascitic fluid culture, and no clinical or image data of secondary peritonitis were present. The diagnosis of HCC was made according to the criteria proposed by the panel of experts of the European Association for the Study of the Liver.17 Hepatorenal syndrome was defined as proposed by Ginés and colleagues.18

The model for end-stage liver disease (MELD) score was calculated using the following formula: 3.8Lnbilirubin + 9.6Lncreatinine + 11.2LnINR + 6.4.19

Life Status and Cause of Death Determinations.

To establish the vital status of the patients and the cause of death, the clinical records and the database of each participant hospital were used. Persons lost to follow-up or their next of kin were contacted via telephone whenever possible. The regional death registry was consulted to obtain the date and cause of death when a patient was lost to follow-up.

Death was classified as liver-related if it was a consequence of HCC, PHGB, hepatorenal syndrome, HE, or spontaneous bacterial peritonitis or whenever liver failure had a key role in death. AIDS was considered the cause of death when there was a life-threatening disease defining the clinical stage C of the 1993 Centers for Disease Control and Prevention classification. Otherwise, the cause of death was categorized as “other.”

Laboratory Procedures.

Serum HCV antibodies were identified via enzyme immunoassay (EIA; Ortho Diagnostic System, Raritan, NJ). HCV-RNA was detected either via qualitative polymerase chain reaction (Amplicor HCV or Cobas Amplicor HCV; Hoffmann-La Roche, Basel, Switzerland) or quantitative polymerase chain reaction (Amplicor HCV Monitor or Cobas Amplicor HCV Monitor; Hoffmann-La Roche). HCV genotype was determined via line-probe assay (INNOLiPA HCV; Innogenetics, Ghent, Belgium). HIV antibodies were tested via enzyme immunoassay (Genscreen HIV-1/2; Pasteur Diagnostics, Paris, France) and confirmed via Western blot analysis (New LAV Blot I; Pasteur Diagnostics). Plasma HIV RNA was measured via polymerase chain reaction assay (Amplicor HIV Monitor test; Hoffmann-La Roche). Serum hepatitis B surface antigen was detected via enzyme immunoassay (HBsAg Abbott Axsyn System; Abbott Científica S.A., Madrid, Spain). Hepatitis D virus (HDV) antibodies were also tested via enzyme immunoassay (Delta Bioelisa HDV; Biokit, Barcelona, Spain).

Statistical Methods.

Continuous variables are expressed as the median (Q1-Q3) and survival times as median. When the median survival was not reached, a value of more than 72 months is given, because 72 months was the maximum possible follow-up in this study. Categorical variables are presented as numbers (percentage). Survival estimates at different time points are expressed as the cumulative proportion of survivors at the end of the period. Comparisons between categorical variables were made using the χ² test or the Fisher test. For continuous variables, the Student t test was used if homocedasticity and normal distributions were proven. The Mann-Whitney U test was used otherwise.

For survival analysis, data were censored at the date of death or when the last information on life status was obtained and no later than December 31, 2002. For patients who underwent liver transplantation, the date of censoring was that of the surgical procedure.

The survival time was calculated from the date of the first decompensation to death or censoring date. The univariate analysis of survival was performed using the Kaplan-Meier method. Curves were compared using the log rank test. Continuous variables were dichotomized taking the median as the cutoff value, except for alpha fetoprotein, whose cutoff value was 20 ng/mL. Estimates of survival at different times of the follow-up were obtained using life tables. Independent prognostic factors for survival were identified by a stepwise forward Cox regression model, where covariates were entered if a difference with P < .1 was detected in the univariate analysis. MELD score was treated as a continuous variable in the Cox regression.

The statistical analysis was performed using the SPSS statistical software package, version 11 (SPSS, Chicago, IL).

Ethical Aspects.

The study was designed and performed according to the Helsinki Declaration and was approved by the ethics committee of each participating hospital.

Characteristics of the Study Population.

One thousand two hundred seventeen HCV-infected patients with decompensated cirrhosis and fulfilling the inclusion criteria attended the participating hospitals during the study period; 180 of these (15%) were seropositive for HIV. The most relevant demographic, virological, and clinical characteristics of HIV-coinfected and HIV-uninfected patients are shown in Table 1. In 218 (21%) HCV-monoinfected patients and in 41 (23%) HIV-coinfected subjects (P = .59), the diagnosis of cirrhosis had been made via biopsy.

The median follow-up of the population studied was 13 months (interquartile range: 4–33). Seventeen (9%) HIV-infected patients and 891 (86%) individuals without HIV infection were followed at Hepatology units. The remaining subjects received care at Internal Medicine or Infectious Diseases units. Eighty-seven (7%) patients, all of them HIV-seronegative, underwent a liver transplant. Seventy-seven patients (43%) with HIV infection were prescribed highly active antiretroviral therapy. Fifty-two (29%) HIV-infected patients were in Centers for Disease Control and Prevention class A, 43 (24%) were in class B, and 85 (47%) were in class C. The median CD4+ cell count of HIV-coinfected patients at baseline was 191 cells/μL (interquartile range: 75–342). Plasma HIV RNA load determinations were available in 163 HIV-infected patients at the time of the first hepatic decompensation. Twenty-four (15%) patients showed concentrations below 200 copies/mL. The median value in individuals with detectable levels was 4.16 log copies/mL (interquartile range: 2.84–4.92).

The frequencies of specific types of decompensation are shown in Table 2.

Causes of Death.

In 225 (18%) individuals, 13 (7%) HIV-infected and 212 (20%) uninfected, the life status could not be determined at the close of the study. The vital status and, when appropriate, the cause of death, were obtained through the regional death registry in 14 (8%) HIV-infected and 73 (7%) HCV-monoinfected patients and via telephone contact in 3 (2%) HIV-coinfected and 31 (3%) HIV-uninfected subjects. In the remaining cases, these data were obtained from clinical records or hospital databases. Autopsies were available in 8 (4%) HIV-coinfected and 34 (3%) monoinfected individuals.

Three hundred eighty-six (37%) patients without HIV infection and 100 (56%) HIV-infected individuals died during the follow-up. Liver disease was the cause of death in 332 (86%) monoinfected individuals and in 81 (81%) coinfected patients; AIDS accounted for 5% of deaths in the latter group. The frequencies of the events that led to death due to liver disease were different in patients with and without HIV infection (see Table 2). Specifically, HE and spontaneous bacterial peritonitis were more frequent among HIV-coinfected individuals, whereas HCC accounted for a greater percentage of cases among monoinfected patients. The characteristics of patients who died are shown in Table 3.

Survival.

The survival of HIV/HCV-coinfected patients was shorter than that of monoinfected subjects (Fig. 1; Table 4). The 1-year, 2-year, and 5-year survival estimates were 74%, 61%, and 44%, respectively, among individuals without HIV coinfection and 54%, 40%, and 25%, respectively, among coinfected patients. Other baseline factors that predicted survival in the univariate analysis were Child-Turcott-Pugh class, MELD score, older age, the event that defined the first decompensation episode, the number of simultaneous complications, and a positive result of serum HDV antibody testing (Fig. 2; see Table 4).

The median survival was shorter in patients harboring baseline plasma levels of alpha fetoprotein greater than or equal to 20 ng/mL (30 vs. 63 months; P < .001). However, this parameter did not remain associated with survival after adjusting for the presence of HCC throughout the follow-up. Thus the median survival of 553 patients without HCC and a baseline alpha fetoprotein plasma level of below 20 ng/mL was more than 72 months, whereas this value was 60 months in 169 patients without HCC and alpha fetoprotein plasma levels of 20 ng/mL or more (P = .16). In 215 patients who developed HCC throughout the entire follow-up, the corresponding median survivals were 37 months and 11 months, respectively (P = .003).

The unit that provided care to the patient, the route of HCV infection, prior interferon therapy (either alone or with ribavirin), and the use of intravenous drugs during the follow-up also predicted survival in the univariate analysis (see Table 4). Conversely, gender, daily alcohol intake, HBV coinfection, HCV genotype, plasma HCV RNA load, the procedure of cirrhosis diagnosis, and the hospital where the patient was recruited and followed were not associated with survival.

In the multivariate analysis, HIV infection, a poorer Child-Turcotte-Pugh class, MELD score, more than one event at the first hepatic decompensation, older age, and seropositivity for anti-HDV at baseline—as well as the presence of HE as the first decompensation of cirrhosis—independently predicted survival (see Table 4).

The impact of the length of HCV infection on survival was assessed in the subgroup of 338 patients in whom this time could be estimated. The median survival in patients with a duration of HCV infection longer than 18 years was 44 months, whereas it was 30 months in those who had been infected for 18 years or less (P = .01). However, this parameter did not remain as an independent predictor of survival in a Cox regression analysis limited to this subgroup of patients (P = .41).

An analysis restricted to the subgroup of patients in whom survival data were collected from clinical records or databases yielded the same results as that performed in the entire population.