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Rapid Progression to Decompensated Cirrhosis and Death in HIV-infected Men with Newly-acquired HCV Infection
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Reported by Jules Levin
AASLD
Nov 2 2010 Boston
"HCV infection of HIV-infected men who have sex with men (MSM) is an emerging world-wide epidemic. We have previously reported rapid onset of liver fibrosis in these patients in New York City....'decompensation seen here with in 1-6 years'. ...... These 4 cases show that early onset fibrosis after HCV infection of HIV-infected men is not benign, does not spontaneously resolve, and can quickly progress to cirrhosis, liver failure, and death. Three of the patients were part of a cohort of 14 persistently infected patients, suggesting that this phenomenon is not rare. Progression may be more rapid in those with AIDS (CD4 count 200) at the time of HCV infection, but even those with well-controlled HIV infection progress far more rapidly than expected. It is therefore essential to identify and treat all HIV-infected men with new HCV infection to prevent these dire outcomes......elevation of liver transaminases (AST 332 IU/L, ALT 367 IU/L), ......He reported having had unprotected receptive an al intercourse with multiple men over the prior year and had injected crystal methamphetamine on multiple occasions and shared injection works once in the prior month. He reported moderate (50 g ram s/day ) alcohol use intermittently for many years...... health declined quickly and he died of liver failure in June 2009, 7 years after presentation with HCV infection."
Daniel S. Fierer,1* Douglas T. Dieterich,1* M. Isabel Fiel,1 Andrea D. Branch,1* Kristen Marks,2 Dahlene Fusco,2 Ricky Hsu,3 Davey Smith,4 and Joshua Fierer4
Departments of 1*Medicine and 1Pathology, Mount Sinai School of Medicine; 2Weill Cornell Medical College; and 3St. Vincent's Medical Center (New York, NY); and 4University of California, San Diego, VA Medical Center
(San Diego, CA)
AUTHOR CONCLUSIONS
4 HIV-infected men developed decompensated cirrhosis within 6 years of HCV infection
· This phenomenon is not rare:
· Patients 1-3 were part of a cohort of 14 HIV-infected men with documented new HCV infection in New York who remained HCV-viremic for at least 2 years [21% of this group]. The 4th patient was identified in San Diego.
· Patient 2 was one of only 2 patients who remained HCV-viremic from our original cohort in which 9 of 11 patients had rapid-onset fibrosis after new HCV infection [50% of this group].
· More immunocompromise [AIDS, low CD4 count, %) at the time of HCV infection appears to be associated with more rapid progression to liver failure [patients 1-3 had the lowest CD4% of the 14 patients who remained viremic].
· Older age at time of infection may also have contributed [patients 2 and 4 were older than the median age of the 14 patients who remained viremic].
· Other known (alcohol consumption by patients 2 and 4) and unknown co-factors factors may have contributed to the rapid progression in these patients.
· It is therefore essential to identify, treat, and cure all HIV-infected men with new HCV infection to prevent these dire outcomes.
ABSTRACT
Background: HCV infection of HIV-infected men who have sex with men (MSM) is an emerging world-wide epidemic. We have previously reported rapid onset of liver fibrosis in these patients in New York City. As most of our patients then received curative early HCV treatment and follow-up was short, in that report we could not determine if fibrosis continued to progress rapidly in the few who remained persistently infected.
Methods: HIV-infected MSM with new HCV infection who remained persistently infected were followed longitudinally. Needle liver biopsy was performed early in the course of HCV infection; Scheuer system (0-4) was used to stage fibrosis. New HCV infection was defined as new ALT elevation with HCV viremia and seroconversion.
Results: Four HIV-infected MSM with new HCV infection progressed to decompensated cirrhosis within 14 mo to 6 yr after first-noted ALT elevation (Table). All 4 patients had genotype 1a infection. All had undergone liver biopsy early in the course of HCV infection (table). Histopathology was consistent with damage from viral hepatitis. None had nodular regenerative hyperplasia or hepatoportal sclerosis. Patients 2 and 4 had mild-moderate steatohepatitis. Serial imaging studies from the time of biopsy showed progression from mildly abnormal livers to small nodular livers in all patients. Further, clinical progression continued to be rapid after the diagnosis of decompensated cirrhosis: patient 1 underwent liver transplantation 10 months later, patients 2 and 4 died from liver failure 2 and 6 months later, respectively, and patient 3 has intractable ascites and hydrothorax. Three of these patients (1-3) were part of a cohort of 14 HIV-infected MSM with new HCV infection who remained HCV-viremic for at least 2 years.
Conclusions: These 4 cases show that early onset fibrosis after HCV infection of HIV-infected men is not benign, does not spontaneously resolve, and can quickly progress to cirrhosis, liver failure, and death. Three of the patients were part of a cohort of 14 persistently infected patients, suggesting that this phenomenon is not rare. Progression may be more rapid in those with AIDS (CD4 count 200) at the time of HCV infection, but even those with well-controlled HIV infection progress far more rapidly than expected. It is therefore essential to identify and treat all HIV-infected men with new HCV infection to prevent these dire outcomes.
DETAILED CASE REPORTS
Case 1: A 39 year old man with AIDS underwent routine laboratory testing with his primary care physician in February 2008, which showed new elevation of liver transaminases (ALT 529 U/L, AST 306 U/L) and a normal total bilirubin (0.9 mg/dL). He was asymptomatic. Three months later he became jaundiced and had tan-colored stool. Evaluation for acute viral hepatitis infections including HCV Ab was negative; his CD4 count was 53 (3%) cells/µL and his last HIV VL was < 400 copies/mL. His antiretroviral (ARV) regimen was stopped. Seven months after his first-noted ALT elevation his liver transaminases (ALT 331 U/ L, AST 540 U/L) and total bilirubin (4.3 mg/dL) remained elevated; HCV Ab testing was again negative but HCV VL was found to be 6,144,372 IU/mL (genotype 1a), confirming the diagnosis of early HCV infection. Prior HCV Ab testing was negative twice in within 12 months and his liver transaminases were normal at those times. He reported having had unprotected receptive anal intercourse with multiple men over the prior year but never injected drugs and drank no alcohol. Percutaneous liver biopsy was performed 8 months after first noted ALT elevation, which showed stage 3 fibrosis but no steatohepatitis or other injur y. ARVs were restar ted. He began HCV treatment with pIFN/RBV 11 months after his first-noted ALT elevation but had no significant decline in viremia after almost 5 months and treatment was discontinued June 2009. Within a month after stopping treatment he had new mild gynecomastia and hepatomegaly, and laboratory testing showed an albumin of 2.9 mg/dL, INR of 1.6, platelet count of
138,000 cells/µL, and persistently elevated transaminases (ALT 120 U/L, AST 204 U/L); HCV Ab testing was now positive . Four months later he had pedal edema and endoscopy showed small esophageal varices, confirming portal hypertension. His albumin was 1.8 g/dL, total bilirubin 11.6 mg/dL, INR 3.5, platelet count 85,000 cells/µL (MELD score of 30), CD4 count 173 (14%) cells/
µL, and HIV VL < 48 copies/mL. He rapidly developed ascites, a right pleural effusion, his MELD score increased to 34, and he underwent liver transplantation under an NIH protocol, just seven months after onset of clinical cirrhosis and 2 years after his first-noted ALT elevation. At surgery he had a small cirrhotic liver.
Case 2: A 55 year old man with AIDS underwent routine laboratory testing with his primar y care physician in January 2006, which showed elevation of his liver transaminases (ALT 436 U/mL, AST 220 U/mL), a normal total bilirubin (0.6 mg/dL), seroconversion to HCV antibody positivity, and genotype 1 HCV, with a VL of 26,600,000 IU/mL. He was asymptomatic. Testing for other causes of hepatitis including other acute viral hepatitis infections was negative. His CD4 count was 200 (7%) cells/µL and HIV VL was < 50 copies/mL. Prior HCV Ab testing was negative 3 1/4 years earlier and HCV VL was undetectable
2 1/2 years earlier. His liver transaminases had been mildly elevated (range 49 to 107 U/L) over the prior 2 years with negative hepatitis serologies at that time. He denied sex in the prior year or ever injecting drugs. He did report receiving intravenous injection with vitamin preparations on multiple occasions from a non-physician "alternative" practitioner in the prior year. He reported that he stopped drinking alcohol a few years ago but had a history of significant (unquantified) alcohol use.
Four months after his first-noted ALT elevation he underwent percutaneous liver biopsy that showed grade 2 inflammation and stage 2 fibrosis, with concomitant grade 2 steatohepatitis. He refused treatment for his HCV infection. His liver transaminases peaked at the time of liver biopsy (ALT 622 U/L, AST 343 U/L)
and subsequently remained in the 200 to 300 U/L range. Six months after presenting with HCV infection he stopped ART for three months and his CD4 count declined to 92 (4%) cells/µL; he restarted ART with subsequent re-suppression of HIV viremia but his CD4 count never improved beyond 187 (5%) cells/µL. Nineteen months after his fir st- noted ALT elevation, an
abdominal CTscan showed mild to moderate hepatosplenomegaly. In June 2008, 2 1/2 years after his first noted ALT elevation, he presented with ascites. EGD showed esophageal varices and 2 months later abdominal CT scan showed a shrunken cirrhotic liver. He underwent initial evaluation for liver transplantation and had a MELD score of 19. He did not return for further evaluation and died in 2 months later in October 2008, 2 years and 9 months after his first-noted ALT elevation.
Case 3: A 40 year old man with AIDS underwent routine laboratory testing with his primary care physician in August 2004, which showed new elevation of liver transaminases (ALT 114 U/L, AST 78 U/L) and normal total bilirubin (0.6 mg/dL), a negative HCV Ab test, and an HCV VL of 10,700,000 IU/mL (genotype 1a). He was asymptomatic . Testing for other causes of hepatitis including other acute viral hepatitis infections was negative . Prior HCV Ab testing was negative 2 years earlier and his liver transaminases were normal over that period. His CD4 count was 381 (15%) cells/µL and his HIV VL was 155 copies/mL. He reported having had unprotected receptive anal intercourse with multiple men over the prior year but never injected drugs. He denied prior significant alcohol use. His HIV history was significant for taking ARVs only intermittent, initially including ddI and d4T, and for Candida esophagitis and rectal Kaposi sarcoma (KS) in 2002.
He refused HCV treatment. HCV serology was not repeated until 28 months later at which time it was positive. He tolerated ARVs poorly resulting in poor adherence and his CD4 count fell to 114 (7%) cells/µL. Forty months after his first-noted ALT elevation, in December 2007, he developed symptomatic cholelithiasis and underwent cholecystectomy. Intra-operative liver biopsy showed grade 4 inflammation and stage 3 fibrosis but no peri-sinusoidal fibrosis that would indicate old d4T or ddI toxicity. One month later, in January 2008, he received only a single dose of pIFN, tolerated it poorly, and refused further treatment.
Two weeks after attempting IFN treatment he developed massive ascites
requiring hospital admission, 3 1/2 years after his new HCV infection. He required large-volume paracentesis (LVP) on a monthly basis despite diuretic therapy. Forty-five months after first-noted ALT elevation, in May 2008, barium swallow showed small esophageal varices. Four months later he underwent repeat liver biopsy via transjugular route that showed grade 3 inflammation and stage 4 fibrosis, but no other etiology for liver failure.
He tolerate his ARV regimens poorly and his CD4 count never increased to 200 cells/µL. Over the next year he had a cutaneous KS recurrence and developed a large symptomatic right pleural effusion that was refractory to repeated therapeutic thoracentesis and sclerosis procedures. He was evaluated for liver transplant under an NIH protocol but has remained ineligible due to his low CD4 count. He continues to require biweekly LVP, and we are continuing to follow him.
Case 4: A 54 year old man with asymptomatic HIV infection underwent routine laboratory testing with his primary care physician in June 2002, which showed
elevation of liver transaminases (AST 332 IU/L, ALT 367 IU/L), normal total bilirubin (1.0 mg/dL), and a serologic negative evaluation for acute viral hepatitis,
including HCV Ab. He was initially asymptomatic but became jaundiced 4 weeks later (total bilirubin of 5.3 mg/dL), at which time his HCV VL was 2,410 IU/mL (genotype 1a). Three weeks later he was no longer jaundiced, his HCV Ab was retested and was then positive, and HCV VL was > 500,000 IU/mL. His CD4
count was 442 (40%) cells/µL and HIV VL was 221 copies/mL. Prior HCV Ab testing was negative twice over the previous 4 years and he had normal
liver transaminases over that period, the last measurement four months prior. He reported having had unprotected receptive an al intercourse with multiple men over the prior year and had injected crystal methamphetamine on multiple occasions and shared injection works once in the prior month. He reported moderate (50 g ram s/day ) alcohol use intermittently for many years.
He did not continue in regular care for either his HIV or new HCV infection due to his addiction to crystal methamphetamine , and to some extent his intermittent alcohol use, although he did continue to take ARVs. He underwent percutaneous liver biopsy December 2005, 3 1/2 years after his new HCV infection, which showed grade 2 inflammation and stage 3 fibrosis, with concomitant grade 1 steatohepatitis. Eleven months later, in November 2006, he underwent repeat liver biopsy, which showed grade 3 inflammation and stage 4 fibrosis, with no change in grade 1 steatohepatitis. In December 2008 he had new onset peripheral edema and ascites. His health declined quickly and he died of liver failure in June 2009, 7 years after presentation with HCV infection.
Materials & Methods
Study population
We enrolled and followed HIV-infected MSM with new HCV infection. Written informed consent was obtained from all patients.
Clinical protocol
New HCV infection was defined as new ALT elevation with HCV viremia and seroconversion. Patients who failed or refused treatment and who remained viremic for more than 2 years (that is, without spontaneous clearance) were followed.
Liver biopsy
Percutaneous liver biopsies were performed using 18 gauge x 100 mm Jamshidi Menghini needles (Allegiance Healthcare Corp., McGaw Park, Ill.). Specimens were formalin fixed, paraffin embedded, and treated with hematoxylin-eosin and trichrome stains. The Scheuer criteria for chronic HCV infection and Brunt criteria (grade 0-3) for steatohepatitis were applied. Immunostains for HBsAg and HBcAg were performed.
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