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HIV+ People Who Get Hepatitis C May Experience Rapid Liver Disease Progression


People with HIV, especially those with advanced immune suppression, who become coinfected with hepatitis C virus (HCV) may experience rapid progression to decompensated cirrhosis and liver-related death, Mt. Sinai researchers reported in the December 21, 2012, advance edition of Clinical Infectious Diseases.

Since around 2000 clinicians in Europe, Australia, and the U.S. have been reporting outbreaks of presumed sexually transmitted acute hepatitis C among HIV positive men who have sex with men (MSM), including those with well-preserved immune function. Similar outbreaks have not been seen among HIV negative gay/bisexual men, and the exact risk factors are not yet fully understood.

Hepatitis C can lead to severe liver disease including advanced fibrosis, cirrhosis (scarring), and liver cancer, but this typically takes many years or decades. Ultimately, hepatitis C can result in decompensated cirrhosis (when the liver cannot carry out its essential functions), liver transplantation, or liver-related death.

At the 2007 Retrovirus Conference, Daniel Fierer from Mount Sinai in New York City first reported that biopsies revealed unusually rapid liver disease progression in a cohort of HIV positive gay/bisexual men recently infected with HCV. Fierer presented an overview of coinfection and rapid disease progression at the International AIDS Conference this past summer.

His findings have generated some controversy, however. Researchers in Europe, using the non-invasive FibroScan method for evaluating liver damage, interpreted their findings as showing transient acute inflammation -- but not unusually severe fibrosis -- in a similar population.

For the latest report, Fierer and his group looked at longer-term natural history of liver disease progression in a subset their coinfection cohort. The researchers initially studied 11 patients, later expanding their biopsy series to include 29 men with longer follow-up (up to 2 years after HCV infection). Most of these men were treated with interferon-based therapy and achieved sustained virological response, which typically halts progression of liver damage. The present report describes 4 men who were not cured and whorapidly developed decompensated cirrhosis.

Case Reports

Case 1: 39-year-old man with AIDS who showed new liver enzyme elevations on a lab test in February 2008. His CD4 T-cell count was 53 cells/mm3, he had recently started antiretroviral therapy (ART) using efavirenz, tenofovir, and emtricitabine (the drugs in Atripla), and he achieved undetectable HIV viral load. He reported unprotected receptive anal sex with several men in the prior year but no drug or alcohol use. 3 months later he developed jaundice, but tested negative for HCV antibodies. A liver biopsy at 8 months showed stage 3 (advanced) fibrosis. He started but discontinued interferon-based therapy after 5 months due to non-response. Within a month after stopping he developed an enlarged liver. At this point he tested HCV antibody positive; RNA testing showed he had HCV genotype 1a. 4 months later -- or 17 months after the suspected time of initial HCV infection -- he developed decompensated cirrhosis with esophageal varices and a MELD score of 30. He then developed ascites (abdominal fluid accumulation) and underwent liver transplantation; his removed liver showed cirrhosis. He recovered slowly but "has remained clinically well" during the subsequent 2.5 years.

Case 2: 55-year-old man with AIDS who had routine lab tests showing elevated liver enzymes in January 2006 and tested positive for HCV antibodies and HCV RNA (also genotype 1a). His CD4 count was 200 cells/mm3, his ART regimen consisted of tenofovir/emtricitabine (Truvada) plus ritonavir-boosted lopinavir (Kaletra), and he achieved undetectable HIV viral load. He reported receiving intravenous vitamin preparations but denied ever using illegal drugs; though he had a history of significant alcohol use, he said he had stopped drinking a few years earlier. A biopsy done 4 months after acute hepatitis C diagnosis showed grade 2 liver inflammation, stage 2 (moderate) fibrosis, and grade 2 steatohepatitis (fatty liver). He declined hepatitis C treatment. He interrupted ART for 3 months and his CD4 count fell to 92 cells/mm3. He restarted ART, substituting ritonavir-boosted atazanavir (Reyataz), and while his HIV viral load was re-suppressed, his CD4 count never rose above 187 cells/ mm3. 19 months after acute HCV diagnosis a CT scan revealed liver and spleen enlargement, and 10 months later he developed ascites and esophageal varices. While he underwent initial evaluation for liver transplantation (with a MELD score of 19), he did not return for further assessment and died 2 months later from liver failure.

Case 3: 40-year-old man with AIDS who underwent routine lab testing in August 2004 showing newly elevated liver enzymes. He had a negative HCV antibody test, high HCV viral load, and genotype 1a. His CD4 count was 381 cells/mm3 and his ART regimen consisted of tenofovir (Viread), nevirapine (Viramune), and lopinavir/ritonavir; he had taken stavudine (d4T; Zerit) and didanosine (ddI; Videx) in the past, both of which can cause liver toxicity. He reported unprotected receptive anal sex with multiple men, said he never injected drugs or drank alcohol heavily, but had used methamphetamine in the past. He refused hepatitis C treatment. He tolerated ART poorly and his CD4 count fell to 114 cells/mm3, thereafter never rising above 200 cells/mm3. Just over 3 years after diagnosis of acute HCV infection he underwent cholecystectomy (gallbladder removal), at which time a liver biopsy showed grade 4 inflammation and stage 3 fibrosis, of a type not associated with antiretroviral drug toxicity. He then received a single dose of pegylated interferon but stopped due to side effects. Soon thereafter he develop decompensated liver disease with ascites and esophageal varices. A repeat liver biopsy showed grade 3 inflammation and stage 4 fibrosis (cirrhosis). He was ineligible for liver transplantation due to low CD4 count and uncontrolled HIV infection, and he died from liver failure 8 years after initial acute hepatitis C diagnosis.

Case 4: 54-year-old man who underwent routine lab testing in June 2002, which revealed new liver enzyme elevations and a negative HCV antibody test. He had asymptomatic HIV infection with a CD4 count of 442 cells/mm3 and was on a single-class ART regimen of zidovudine (AZT; Retrovir), lamivudine (3TC; Epivir), and abacavir (Ziagen). He reported unprotected receptive anal sex with multiple men, had injected crystal methamphetamine multiple times, shared injection equipment once, and reported moderate alcohol use. 4 weeks later he developed jaundice, and 3 weeks after that he tested positive for HCV antibodies and had genotype 1a. He did not receive consistent medical care for HIV or hepatitis C, though he remained on ART. A liver biopsy 3.5 years after acute hepatitis C diagnosis revealed grade 2 inflammation, stage 3 fibrosis, and grade 1 steatohepatitis. A repeat biopsy 1 year later showed grade 3 inflammation, stage 4 fibrosis, and grade 1 steatohepatitis. He returned for medical care 6.5 years after HCV diagnosis due to new onset edema and ascites, his health declined rapidly, and he died of liver failure 7 months later.

Overall Findings

  • 3 of the 4 men had AIDS at the time they were infected with HCV, indicating advanced immune suppression.
  • All 4 were infected with HCV genotype 1a.
  • All 4 patients developed decompensated cirrhosis within 17 months to 6 years after initial HCV infection.
  • 3 of the men died within 8 years of HCV infection.
  • The remaining patient survived after a liver transplantation performed 2 years after HCV infection.
  • The most rapid liver disease progression occurred in the 2 men who had the lowest CD4 counts at the time of HCV infection. 
  • Some patients had other causes of liver injury such as heavy alcohol use, but liver histopathology most closely resembled HCV-related damage.

"Primary HCV infection resulted in decompensated cirrhosis and death within 2 to 8 years in 4 HIV-infected men," the study authors concluded. "The rapid-onset of fibrosis due to primary HCV infection in HIV-infected men cannot therefore be considered benign."

"The rate of continued progression to liver failure may be proportional to the degree of underlying immunocompromise caused by HIV infection," they suggested. "More research is needed to better define the mechanisms behind accelerated liver damage."

"We do not know the precise mechanism(s) that caused HCV to take such a rapid course in these four men but we hypothesize that they fit into a model of highly accelerated progression to liver failure after HCV infection previously suggested by clinical experience with other immunocompromised patient cohorts," they elaborated in their discussion.

"[E]ven in this small series of 4 men there is a suggestion that the lower the CD4 count at the time of primary HCV infection, the higher the rate of progression to liver failure," they continued. "Taken together with the prior literature, these observations suggest that the rate of progression of HCV-induced liver disease is greatly accelerated if patients are immunocompromised, including by HIV infection, at the time of acquisition of HCV infection."



DS Fierer, DT Dieterich, MI Fiel, et al. Rapid Progression to Decompensated Cirrhosis, Liver Transplantation, and Death in HIV-infected Men after Primary HCV Infection.Clinical Infectious Diseases. December 21, 2012 (Epub ahead of print).