Liver Disease Is a Growing Cause of Death for HIV Positive People in France, but Has Leveled Off in Spain

By Liz Highleyman

Effective combination antiretroviral therapy (ART) has dramatically reduced overall mortality among people with HIV, especially deaths related to opportunistic illnesses. As HIV positive people live longer, however, they are more prone to progressive diseases that develop over time, including non-AIDS-defining cancers and liver disease.

Due to overlapping transmission routes, many people with HIV are coinfected with chronic hepatitis B virus (HBV) or hepatitis C virus (HCV), which over time can lead to advanced liver disease including cirrhosis and hepatocellular carcinoma (HCC), a form of primary liver cancer.

As reported in the February, 2009 advance online edition of HIV Medicine, researchers with the GERMIVIC Joint Study Group Network (Mortavic 2005 Study in collaboration with the Mortalité 2005 survey, ANRS EN19) evaluated trends in the proportion of deaths caused by end-stage liver disease (ESLD) among HIV positive adults in France between 1995 and 2005.

In 2005, 34 medical departments across the country prospectively recorded all deaths among approximately 24,000 HIV positive patients. A total of 313 deaths were reported, with complete case report information available for 287. Results were compared with those of 4 previous cross-sectional surveys conducted using the same methodology since 1995.

Results

At the time of death, 62% of patients who died in 2005 had undetectable HIV viral load and the median CD4 count was 237 cells/mm3, indicating moderately advanced immune suppression.

Among the 287 deaths with complete information, 100 (35%) were due to AIDS-related causes, down from 92% in 1995.

Half as many deaths -- 48 (17%) -- were due to ESLD.

ESLD was the most common cause of non-AIDS-related mortality, accounting for 26% of such deaths.

The vast majority of patients who died from ESLD had viral hepatitis, with 75% having HCV and 27% having HBV (some had both).

Patients with both HBV and HCV in addition to HIV had a higher mortality rate than those with HIV-HBV or HIV-HCV coinfection.

Heavy alcohol consumption was reported in nearly half the patients (48%) who died from ESLD, including 4 deaths attributed to alcohol in people without viral hepatitis.

Among the deaths due to ESLD, three-quarters were due to cirrhosis and one-quarter were due to HCC (7 related to HCV, 5 related to HBV).

17 patients with HCV (47%) whose deaths were ESLD-related had previously received interferon/ribavirin treatment.

Other causes of death included non-AIDS-related malignancies other than liver cancer (15%), cardiovascular diseases (6%), and other causes including accidents and suicide (28%).

Compared with other causes, patients who died from ESLD were more likely to be injection drug users, to have a high alcohol intake, to have previously received hepatitis C treatment, and to have better control of HIV infection.

From 1995 to 2005, the proportion of deaths due to ESLD increased 11-fold, from 2% to 17% (P < 0.001).

The proportion of deaths caused by HCC increased from 5% in 1995 to 25% in 2005 (P = 0.0337).

"Over the 10 years from 1995 to 2005, the proportion of deaths caused by hepatitis C virus-related ESLD has increased in HIV-infected patients," the study authors concluded.

This was despite the fact that the proportion of patients treated for hepatitis C increased over the study period, to 47% by 2005. Percentages of people receiving combination ART also rose over time, as did the median CD4 cell count (from 113 cells/mm3 in 1995 to 237 cells/mm3 in 2005).

Interestingly, a related study by Carla Núnez-Fernández from Hospital Carlos III in Madrid and colleagues, published the March 25, 2009 advance online edition of AIDS Research and Human Retroviruses, found that morbidity and mortality related to liver disease may have reached a plateau in Spain.

"Hospital admissions and deaths due to liver-related complications as result of chronic viral hepatitis are globally on the rise in HIV patients," the authors of the Spanish study wrote. "However, a steady decline in liver-related hospitalizations and deaths has occurred at our HIV clinic in Madrid since year 2003."

But, they added, "Hepatic complications are currently still responsible for 8.7% of all hospital admissions and one-third of in-hospital deaths, with hepatitis C virus infection by far the leading etiologic agent."

In their discussion, the French researchers said their findings "emphasize the importance of developing effective strategies for the prevention and early diagnosis and treatment of chronic HCV infection, routine screening for HCC and reduction of alcohol intake."

HCC screening may be done using blood biomarkers such as alpha-fetoprotein (AFP) or imaging methods such as ultrasound to detect tumors. When caught in the early stages, liver cancer is not as difficult to treat and has a higher survival rate.

Timely treatment of chronic hepatitis C can slow or halt liver disease progression and potentially even reverse existing damage, especially in people who achieve a sustained virological response (SVR), or viral clearance after completion of therapy. Most HIV-HBV coinfected patients today include drugs in their antiretroviral regimen that are dually active against both viruses (e.g., lamivudine [Epivir], tenofovir [Viread]). Though studies have produced mixed data, use of combination ART and higher CD4 counts also appear to be associated with slower liver disease progression.

Department of Internal Medicine, Archet Hospital Centre, University of Nice-Sophia Antipolis, Nice; Department of Internal Medicine, Cochin-Tarnier Hospital Centre, Paris; Institut National de la Santé et de la Recherche Médicale (INSERM) Unit 593, Victor Segalen University, Bordeaux 2; Institut de Santé Publique, d'Epidémiologie et de Développement (ISPED), Bordeaux; Department of Infectious Diseases, Tenon Hospital, Paris; INSERM, Unit 593, Bordeaux; Department of Internal Medicine, Bordeaux University Hospital; Department of Internal Medicine, Georges Pompidou European Hospital, Paris; Department of Infectious Diseases, Brabois University Hospital, Vandoeuvre-Les-Nancy; INSERM, CépiDc, Le Vésinet; INSERM, Unit 720, Paris; Pierre et Maris Curie University, Paris; Department of Internal Medicine, La Pitié Salp?trière Hospital Centre, Assistance Publique des Hopitaux de Paris and Centre National de la Recherche Scientifique, Pierre et Marie Curie University, Paris, France.

4/07/09

References

E Rosenthal, D Salmon-Céron, C Lewden, and others. Liver-related deaths in HIV-infected patients between 1995 and 2005 in the French GERMIVIC Joint Study Group Network (Mortavic 2005 Study in collaboration with the Mortalité 2005 survey, ANRS EN19). HIV Medicine. February 13, 2009 [Epub ahead of print]. (Abstract).

C Nunez-Fernandez, L Martin-Carbonero, ME Valencia, and others. Liver Complications Have Reached a Plateau as Cause of Hospital Admission and Death in HIV Patients in Madrid. AIDS Research and Human Retroviruses. March 25, 2009 [Epub ahead of print]. (Abstract).