Liver fibrosis regression after hepatitis C treatment linked to reduced complications and death in people with HIV and HCV co-infection

Laurence Brunet at IAS 2015. Photo by Liz Highleyman, hivandhepatitis.com

People with HIV and HCV co-infection, with liver cirrhosis, who achieve sustained virological response (SVR) and experience an improvement in liver fibrosis are less likely to develop liver disease complications or die from liver-related causes – and in some cases fibrosis regression is beneficial even in the absence of a cure – according to a presentation at the Eighth International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention (IAS 2015) last week in Vancouver, Canada.

A related study looked at predictors of liver fibrosis progression in people with HIV and HCV co-infection, finding that use of certain NRTI ‘backbone’ antiretroviral drugs and HIV protease inhibitors may increase the risk.

Liver fibrosis progression

Over years or decades, chronic hepatitis C virus (HCV) infection can lead to liver fibrosis (build-up of collagen and other scar material), cirrhosis (scar tissue replacing functional liver cells), liver cancer and the need for a liver transplant.

People living with HIV who have HCV tend to experience more aggressive liver disease progression than people with HCV alone, especially if they have advanced immune system damage. In the era of effective antiretroviral therapy (ART), liver disease is now a leading cause of illness and death among people with HIV.

Glossary

fibrosis

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

sustained virological response (SVR)

The continued, long-term suppression of a virus as a result of treatment. In hepatitis C, refers to undetectable hepatitis C RNA after treatment has come to an end. Usually SVR refers to RNA remaining undetectable for 12 or 24 weeks after ending treatment and is considered to be a cure (SVR12 or SVR24).

regression

Improvement in a tumour. Also, a mathematical model that allows us to measure the degree to which one of more factors influence an outcome.

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. 

disease progression

The worsening of a disease.

The reasons for increased disease progression among people with co-infection are not fully understood, but may include immune dysfunction, persistent inflammation or metabolic changes related to chronic HIV infection, and ART toxicities. Most modern antiretrovirals are well-tolerated and usually do not cause liver toxicity in the way that some older medications did, but subtle harmful effects may occur over time.

Laurence Brunet of McGill University and fellow investigators with the Canadian Co-Infection Cohort Study performed a longitudinal analysis of liver fibrosis progression among cohort participants who used HIV protease inhibitors or non-nucleoside reverse transcriptase inhibitors (NNRTIs).

The researchers estimated liver fibrosis using the AST-to-Platelet Ratio Index (APRI), a non-invasive biomarker index based on aspartate aminotransferase – an enzyme that rises with liver inflammation – and platelet count. APRI is not as accurate as a liver biopsy or FibroScan (ultrasound transient elastometry), but it can be calculated from routine laboratory test results found in patients’ medical records.

This analysis included 348 cohort members with HIV and HCV co-infection who started ART in the year 2000 or later. A majority were men, the median age was in the mid-40s and they had been on ART for about two years. About a third had a history of injecting drugs and more than half reported alcohol use, another risk factor for liver damage. People who were on hepatitis C treatment and those with hepatitis B triple infection were excluded.

The study was restricted to people who used an ART ‘backbone’ of either tenofovir/emtricitabine (the drugs in Truvada) or abacavir/lamivudine (the drugs in Kivexa or Epzicom); some older drugs in this class can cause liver damage related to mitochondrial toxicity. In addition, as an ‘anchor’ drug, about 30% used an NNRTI (92% of whom took efavirenz [Sustiva]) and 70% used a HIV protease inhibitor (56% atazanavir [Reyataz], 29% lopinavir/ritonavir [Kaletra] and 15% darunavir [Prezista]).

Changes in APRI scores varied by regimen, though the differences were not large. Protease inhibitors were associated with a higher rate of APRI increase per five years than NNRTIs, while the abacavir backbone was associated with a higher rate than the tenofovir backbone:

  • NNRTI/tenofovir/emtricitabine: +3%
  • NNRTI/abacavir/lamivudine: +11%
  • Protease inhibitor/tenofovir/emtricitabine: +8%
  • Protease inhibitor/abacavir/lamivudine: +16%

"Fibrosis development [was] more influenced by [NRTI] backbone than class of anchor agent," the researchers concluded. However, most people did not progress to significant fibrosis over this five-year follow-up period.

"Since liver disease is a major cause of illness in HIV-positive people, it would be beneficial if we can find [antiretroviral] regimens not associated with fibrosis over time," Burnet suggested.

Fibrosis regression

At the same abstract session, Santiago Moreno of Ramon y Cajal Hospital in Madrid presented findings from a study of liver fibrosis regression after hepatitis C treatment in people with HIV and HCV co-infection, and how this influences liver-related complications, hospital admissions and death.

Several studies of people with HCV monoinfection have shown that successful treatment with interferon-based therapy can halt or even partially reverse liver fibrosis, and this improvement is associated with a reduction in liver disease complications and death over time. However, even people who have been cured of HCV are not completely protected against developing liver-related complications or liver cancer. Direct-acting antiviral agents in interferon-free regimens have not yet been around long enough to have long-term data on outcomes.

Less is known about disease progression after hepatitis C treatment in people with HIV and HCV co-infection. But a study presented at this year's Conference on Retroviruses and Opportunistic Infections (CROI) showed that people with co-infection remain at risk for liver failure, liver cancer and liver-related death even after being cured, with outcomes worsening the longer treatment is delayed.

Moreno's team compared the incidence rate and time to develop complications and death in co-infected people with cirrhosis, according to whether they achieved sustained virological response and liver fibrosis regression using interferon-based therapy.

This study included 133 people with co-infection treated with pegylated interferon and ribavirin at Ramon y Cajal Hospital since 2004. More than three-quarters were men and the average age was 42 years. Most (59%) had HCV genotype 1, followed by 3 (34%), 4 (17%) and 2 (3%). They had been living with HCV for more than 20 years and were followed-up for nearly seven years after hepatitis C treatment.

Participants had a liver biopsy or transient elastography done at baseline, and follow-up elastography scans were done starting in 2006. Fibrosis regression was defined as a 1-point decrease in Metavir score, as estimated by transient elastography liver stiffness measurements.

Overall, 42 participants, or 32%, achieved SVR, with the rest being non-responders or relapsers. While cure rates using the new interferon-free direct-acting antivirals are typically above 90%, SVR rates below 50% are not unusual for people with co-infection using interferon and ribavirin.

A total of 37 participants experienced fibrosis regression, which was much more likely to occur in people who were cured (55%) compared to those without sustained response (15%).

Fibrosis regression rates among people with SVR were 22%, 9%, 52% and 17% for HCV genotypes 1, 2, 3 and 4, respectively. Among the 14 people who showed fibrosis regression without SVR, 79% had genotype 1, with a single study participant with each of the other three genotypes. Regression without SVR was relatively more likely among relapsers – those who had undetectable HCV at the end of therapy but saw the virus rebound after stopping treatment.

Overall, people who achieved SVR were less likely than people who were not cured to experience liver-related complications, hospitalisation, liver-related death or death due to any cause. But fibrosis regression also played a major role.

Among people with SVR, rates of liver-related complications and hospitalisation were much lower than rates for people without SVR. Within the SVR group, fibrosis regression conferred an added advantage, but it did not make much difference among those without SVR. Looking at liver-related or all-cause death, however, the risk was much lower for people with fibrosis regression in both the SVR and non-SVR groups. In fact, death rates were higher for people who were cured but did not experience fibrosis regression (FR) than for those who had regression without SVR.

                                    SVR+FR          SVR/no FR     No SVR/FR    No SVR or FR

All-cause death          17%                32%                14%                48%   

Liver-related death   4%                  16%                7%                  38%   

Liver complications  4%                  11%                36%                43%

Hospitalisation          9%                  16%                29%                30%

Fibrosis regression was the only factor significantly associated with lower risk of death in a multivariate analysis, with a 64% reduction in the risk of all-cause death (adjusted hazard ratio [HR] 0.36) and a 85% reduction in liver-related death (HR 0.15). Both fibrosis regression and SVR were associated with lower likelihood of liver-related complications, cutting the risk by 91% (HR 0.09) and 76% (HR 0.24), respectively.

"Our study clarifies the risk of complications after therapy in HIV-infected patients with cirrhosis, showing a lower rate if fibrosis regression is attained in addition to SVR," the researchers concluded.

"Of clinical application, [transient elastography liver stiffness measurement] is useful in demarcating cirrhotic patients at a high risk for complications after therapy and who would require a more frequent check-up," they added. "Sequential [transient elastography] after therapy could be useful in the management of the patients, irrespective of achieving SVR."

References

Brunet L et al. A longitudinal analysis of liver fibrosis progression among NNRTI and PI users in the Canadian co-infection cohort study. 8th International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention (IAS 2015), Vancouver, abstract TUAB0201, 2015.

You can download the slides of this presentation from the conference website.

A webcast of this presentation is available on the conference YouTube channel.

Casado JL et al. (Moreno S presenting) Liver fibrosis regression after anti-HCV therapy and the rate of death, liver-related death, liver-related complications, and hospital admissions in HIV/HCV co-infected patients with cirrhosis. 8th International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention (IAS 2015), Vancouver, abstract TUAB0204, 2015.

You can download the slides of this presentation from the conference website.

A webcast of this presentation is available on the conference YouTube channel.

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