We found that chronic HBV, HCV, and liver disease were frequent diagnoses among HIV-infected people followed in the ASD project from 1998 to 2004. Roughly one person out of a hundred people followed for a year was diagnosed with liver disease, two per 100 followed for a year were diagnosed with chronic HBV, and five out of a hundred were diagnosed with HCV. We observed relatively low rates of HBV and HCV screening, especially in earlier years of observation, despite consistent recommendations that all HIV-infected patients be screened for both infections in the guidelines for the treatment of HIV and prevention of opportunistic illness (including screening of HBV prior to administration of vaccine) covering 1998-2004[13
]. Fortunately, over the observation period, increasing proportions of individuals were screened for HBV and HCV. Diagnoses of HBV and HCV also increased over the seven years of the study. Among individuals who died, liver disease was present at any point in nearly 10%, and liver disease was listed as a contributing factor or as a new or ongoing diagnosis within six months of death in 1% of deaths. The overall prevalence of liver disease was about 1% each year-this increased only slightly over the seven years. As expected, IDU was associated with all three outcomes examined by multivariate analyses (chronic HBV, HCV, and liver disease). Hemophilia, and thus an exposure to unscreened blood products, was most strongly associated with HCV, and alcohol use was associated with liver disease.
Other researchers have found high rates of liver diseases and viral hepatitis among HIV-infected persons, especially HIV-infected hemophiliacs and injection drug users. The prevalence of HBV and HCV infection varies within HIV-infected cohorts largely due to the underlying prevalence of these infections in the general populations from which the cohorts are drawn and the proportion of IDU included. Relative to the 8% with chronic HBV and the 19% with HCV in our cohort, a New York City HIV clinic following 5639 people living with HIV from 1999 until 2007, found that 4% were HBV-infected and 25% were HCV infected[14
]. The HIV Outpatient Survey (HOPS) conducted at 10 facilities in eight U.S. cities followed 7618 HIV-infected individuals 1996-2007 and found a 24% prevalence of HCV[15
]. In a serological study of incarcerated individuals in three U.S. cities, of those who were HIV-infected, 38% were co-infected with HCV and 8% were HBsAg positive[16
The D:A:D Study followed 23 441 individuals on three continents between 1999 and 2004, finding a 23% prevalence of HCV and a 7% prevalence of active HBV[17
]. In this study, HCV was associated with a seven-fold excess risk of liver-related deaths (e.g. hepatocellular carcinoma, end stage liver disease, or hepatic failure) and active HBV was associated with a four-fold excess risk of liver-related deaths. This compares to our similar finding of liver related deaths occurring over four times more frequently among individuals infected with HCV or chronic HBV relative to uninfected individuals. In the Swiss HIV Cohort Study, 37% of 3111 people living with HIV were HCV-infected; this included 92% of IDU and 7% of those with other HIV risks[18
]. In this study, 9% of HCV-co-infected individuals died relative to 4% of those without HCV. Of the deaths among HCV-infected individuals, 16% were possibly to definitely associated with end-stage liver disease relative to 5% of deaths among HIV-infected individuals without HCV[18
]. In the Multicenter Cohort Study of MSM, about 8% of HIV-infected men followed between 1984 and 2000 were HBsAg positive, and liver-related mortality was about seven times higher (14 deaths per 1000 person-years) among HBsAg positive men relative to HBsAg negative men (two deaths per 1000 person-years)[19
Of 755 people living with HIV evaluated following initiation of antiretrovirals at one Italian HIV clinic, 3% developed severe hepatotoxicity (4/100 person-years). Nearly all (96%) of these patients had evidence of HCV infection (relative to 67% without hepatotoxicity), 19% had evidence of HBV, and 19% had a history of alcohol abuse (relative to 7% and 13% prevalence of these diagnoses among those without hepatotoxicity, respectively)[20
]. This is consistent with our finding of no excess risk of liver disease for individuals prescribed antiretrovirals once these other factors (HCV, HBV, alcohol use, etc
.) were controlled for by multivariate analyses. In a Veteran’s Affairs cohort with comprehensive evaluations of 299 HIV-infected individuals over 6 mo, 27% had abnormal liver functions and for 51% of these, no underlying cause was established. Among the remainder, 30% had non-alcoholic fatty liver disease as a diagnosis, alcohol was attributed to 13%, chronic HBV to 9% and chronic active HCV to 5%[21
Studies of HIV-infected hemophiliacs include a cohort study of 158 HIV-infected hemophiliacs followed in the pre- and post-HAART eras[22
]. The predominant cause of non-AIDS mortality in both periods was end-stage liver disease (ESLD). Of 223 HIV-infected hemophiliacs without clinical AIDS, 9% of those co-infected with HCV developed liver failure after 10-20 years[23
]. In Germany, 144 HIV and HCV co-infected hemophiliacs were examined, and the authors concluded that declining immune function may be associated with progression of liver failure[24
Relative to the increase in HCV screening that we observed (from 11% to 69%), the HOPS study documented a very similar trend-HCV screening increasing from 11% to 77% from 1996 to 2007[15
]. However, even if patients are screened, few receive ongoing screening despite ongoing risk, fewer than half are evaluated, and a minority are treated, reflecting the many hurdles that HIV and HCV and HIV and HBV co-infected patients must surmount to be appropriately managed and treated for HBV and HCV when indicated[25,26
Although the number of liver cancers we observed was small (n
= 25), all 21 with hepatitis screening documented were HBV or HCV-infected. Our study was not designed to compare the occurrence of liver cancer among people living with HIV relative to the general population, but other researchers have found three to six fold excess risk of liver cancer associated with HIV infection[27,28
Limitations of our analyses included that the data were collected solely by medical record review. Collecting data by chart review rather than targeted medical examinations, may have introduced errors. Exposures and diagnoses may have been missed, especially if an individual sought medical care at facilities other than those included in ASD. Other diseases recorded may have been in error, such as mistaking a “rule out” diagnosis with a true diagnosis. Further, the use of ICD-9 codes to define liver disease likely resulted in some losses of sensitivity and specificity (for example, including a code such as 571.4-chronic hepatitis-which might have included viral hepatitis infections without any known liver damage). Similarly ICD-9 code 571 includes both fatty liver and nonalcoholic steatohepatitis (NASH), which could not be distinguished from each other without additional information. Information on performance of liver biopsy was not collected, and biopsies were not likely to have been frequently performed, leaving us to rely upon broad clinical diagnoses rather than histological diagnoses. HBV and HCV were particularly difficult diagnoses to ascertain through chart review because of under-diagnosis-especially of asymptomatic infections, false negative screening tests due to low or transient antibody production[29-31
], and abstractor (and practitioner) confusion regarding distinguishing markers of acute, chronic, and chronic active or chronically persistent infection. Observed trends in HBV and HCV diagnoses could have been caused by increases in screening, not increases in incidence and prevalence. Some known predisposing conditions of certain liver disease (such as obesity) were not routinely collected. Deaths and causes of death may have been under-ascertained as well, as some ASD sites linked to core surveillance and national death index data and others did not. Finally, although ASD data collection ended in 2004, we believe there have been no major changes in hepatitis screening, HBV vaccination, or liver disease trends among HIV-infected individuals and that our findings remain highly relevant today.
Despite its limitations, ASD provided a large single cohort in a contemporary HAART era, collected with a consistent protocol and including a wealth of data on the screening and diagnosis HBV and HCV and liver disease and mortality as outcomes. Although HIV case reporting was not required throughout the U.S. during the period of our study, the socio-demographic characteristics (age, gender, race-ethnicity, and HIV risk category) of 38 398 newly diagnosed HIV cases in 2004 for the 34 states and five dependent areas, with name-based reporting at that time, were highly similar to the characteristics of ASD, suggesting ASD was largely representative of national HIV cases at this time[32
In conclusion, patients with HIV and liver disease had a much higher mortality compared to those with HIV without a liver disease diagnosis. Although HBV vaccination rates have improved and screening rates for HBV and HCV have climbed steadily, they are still inadequate, and efforts are needed to improve vaccination and screening rates. The high rates of incident HCV (5/100 person-years) indicate that individuals at risk should be screened and while remaining at risk, re-screened on a regular basis. Similarly, a sizable HBV incidence (2/100 person-years) supports improved screening and vaccination[33
]. Further studies are needed to determine the optimal frequency of repeated HCV screening among those with ongoing risk, as well as a frequency to re-visit HBV vaccination among unvaccinated individuals. Until better data are available, annual screenings for HCV and HBV vaccination discussions are suggested. Treatment of HBV and HCV should be considered for all HIV co-infected individuals.