HIV not a risk factor for fibrosis progression in people with hepatitis C

HIV co-infection is not associated with accelerated progression of liver fibrosis in people with hepatitis C virus (HCV) infection, according to US research published in the online edition of the Journal of Infectious Diseases. Factors linked with fibrosis progression were low fibrosis stage at baseline and flares in alanine aminotransferase (ALT) levels.

The major strengths of the study were its large sample size and the fact that participants had at least two liver biopsy results during follow-up, Dr Daniel S Fierer of Mount Sinai Hospital, New York, commented in an accompanying editorial.

HCV is a leading cause of serious liver disease. The infection can cause progressive liver fibrosis, cirrhosis, liver cancer and death. Effective therapies are now available. However, these treatments are costly and it is therefore necessary to prioritise people in greatest need, especially those experiencing rapid fibrosis progression.

Glossary

fibrosis

Thickening and scarring of connective tissue. Often refers to fibrosis of the liver. See also ‘cirrhosis’, which is more severe scarring.

biopsy

A procedure to remove a small sample of tissue so that it can be examined for signs of disease.

cirrhosis

Severe fibrosis, or scarring of organs. The structure of the organs is altered, and their function diminished. The term cirrhosis is often used in relation to the liver. 

inflammation

The general term for the body’s response to injury, including injury by an infection. The acute phase (with fever, swollen glands, sore throat, headaches, etc.) is a sign that the immune system has been triggered by a signal announcing the infection. But chronic (or persisting) inflammation, even at low grade, is problematic, as it is associated in the long term to many conditions such as heart disease or cancer. The best treatment of HIV-inflammation is antiretroviral therapy.

alanine aminotransferase (ALT)

An enzyme found primarily in the liver. Alanine aminotransferase may be measured as part of a liver function test. Abnormally high blood levels of ALT are a sign of liver inflammation or damage from infection or drugs.

As the factors associated with the progression of liver fibrosis in the context of HCV infection are poorly understood, investigators from Cornell Medical College, New York, designed a retrospective study to determine the rates and risk factors for disease progression. The research involved 378 people with HCV infection who had two or more liver biopsies between 1997 and 2013. The investigators analysed the effect of demographic, epidemiological and virologic factors on progression of fibrosis.

Individuals had a mean age of 48 years, 59% were male, 60% were white and 87% had HCV genotype 1 infection. Approximately a third – 31% – had co-infection with HIV.

At the time of first biopsy, 36% of people had mild (grade 1) liver inflammation, 57% had moderate (grade 2) inflammation and 7% had severe (grade 3) inflammation. Fibrosis was absent in 12% of individuals (stage 0), whereas 32% had stage 1 (mild) fibrosis, 39% had stage 2 (moderate) fibrosis and 16% had stage 3 (severe) fibrosis.

Fibrosis stage 2 and above was associated with elevated inflammation at the time of the first biopsy (OR = 9.00; 95% CI, 5.53-14.64, p < 0.001). Fatty liver disease (steatosis) was present in the majority – 59% – of people and this was associated with both higher fibrosis stage (OR= 2.39; 95% CI, 1.38-4.14, p = 0.002) and higher inflammation (OR = 4.07; 95% CI, 2.26-7.35, p < 0.001) at initial biopsy.

A total of 558 consecutive biopsy pairs were available for analysis. Mean duration between first and last biopsies was 7 years, and the mean period between adjacent biopsies was 4 years.

During follow-up, 57% of people advanced at least one biopsy stage, 16% progressed two stages and 7% developed cirrhosis.

After controlling for potential confounders, factors associated with fibrosis progression were no/mild fibrosis at first biopsy (OR = 13.51; 95% CI, 7.44-24.53, p < 0.001) and at least one ALT flare (200u/l threshold) during follow-up (OR = 2.64; 95% CI, 1.30-5.36, p = 0.007).

The estimated progression rate from fibrosis stages 0 to 1 was highest – three times higher than the rate of progression between stages 2 and 3.

Individuals remained at stage zero for an average of 2.55 years and at stage 2 for an average of 18.4 years.

Analysis of the subset of study participants who developed cirrhosis showed that progression occurred in a mean of eight years of follow-up. Factors associated with progression were genotype 3 infection (p = 0.04), ALT level (p < 0.001). Higher fibrosis stage at first biopsy and lower baseline platelet count were both of borderline significance.

“We did not observe an association between fibrosis progression and HIV co-infection,” comment the investigators. “This could potentially be explained by well-controlled HIV viremia in co-infected patients.”

The authors also point out that their findings call into question the assumption that fibrosis progresses at a steady, or linear, rate, and they conclude, “we found varying stage-specific progression rates in patients with chronic hepatitis C.”

In an accompanying editorial, Daniel S Fierer of Mount Sinai Hospital, New York, said that understanding factors associated with fibrosis progression in people with HCV infection was “a crucial medical issue.” However, he was not convinced that all people with HIV/HCV co-infection even in the modern antiretroviral era have a low risk of fibrosis progression. Citing his own research in HIV-positive gay men who acquired HCV via sexual transmission, he noted that many of these people experienced rapid fibrosis progression, suggesting that the acquisition of HCV after HIV is more harmful to the liver than vice versa.

“The available evidence is that they rapidly progress to having moderate levels of fibrosis, and some of those with the most immunocompromise experience further rapid progression to cirrhosis,” writes Fierer. Yet Zeremski and colleagues report that progression from mild or no cirrhosis to moderate fibrosis was the most frequently-observed form of progression in their study, suggesting that what Fierer and colleagues are observing is a common pattern regardless of HIV status, and that Fierer's cohort are distinctive more for having well-established dates of HCV infection than for their previous HIV infection.

References

Zeremski M et al. Fibrosis progression in patients with chronic hepatitis C virus infection. J Infect Dis, online edition, 2016.

Fierer DS et al. The order of addition of immunocompromise: the effects of HIV infection on fibrosis progression of hepatitis C-infected patients. J Infect Dis, online edition, 2016.