Quality of life after hepatitis C cure

Quality of life can be severely impaired in people with chronic hepatitis C, especially in people with cirrhosis. Fatigue, insomnia, problems in physical functioning, depression, anxiety and mood disorders are reported by a substantial proportion of people with hepatitis C.

Patient-reported outcomes such as fatigue, vitality and mental health improve substantially in the two years following hepatitis C cure for people with cirrhosis, but people with cirrhosis are less likely than others to experience rapid resolution of severe fatigue after successful hepatitis C treatment, according to two studies from the Center for Outcomes Research in Liver Diseases reported last month at the 2018 International Liver Congress in Paris.

One study looked at improvement in measures of physical and mental quality of life including vitality, physical functioning, fatigue, depression and anxiety. Younger people, those without type 2 diabetes and those with compensated cirrhosis experienced greater improvement in quality of life measures over two years of follow-up after achieving sustained virologic response.

A study of changes in reported fatigue before and after sofosbuvir-based treatment in clinical trials found that around half of people with severe fatigue prior to treatment had experienced some improvement 12 weeks after completing treatment. Improvement was more likely in younger people, those without cirrhosis and those with fewer co-morbidities.

Portal hypertension after hepatitis C cure

Portal hypertension – high blood pressure in the portal veins – develops as a consequence of cirrhosis. As pressure rises in the veins that flow into the liver the veins become enlarged. These enlarged veins are called varices. If varices develop at the junction of the stomach and the oesophagus or in other places they are prone to bleed as they grow larger. Bleeding from varices can be life-threatening.

Two studies presented at The International Liver Congress reported on the evolution of portal hypertension and varices after successful hepatitis C treatment and attempted to identify predictors of regression or progression.

An Austrian study of 77 people with portal hypertension found that although portal hypertension improved in two-thirds of people, only 24% of individuals with clinically significant portal hypertension experienced a return to normal portal vein pressure within two years of being cured of hepatitis C. Liver decompensation occurred in ten out of 77 people after treatment and lack of improvement in portal hypertension after treatment was a significant predictor of decompensation during the follow-up period.

An Italian study of 280 people with Child-Pugh A cirrhosis who had been cured of hepatitis C found that varices could still develop after being cured of hepatitis C in people with no evidence of varices prior to treatment.

In those who already had varices prior to treatment, it was unusual for varices to disappear but also unusual for them to get worse (only 16% of people progressed).

These findings show that although direct-acting antiviral treatment is highly effective in curing hepatitis C, the underlying liver damage is less easy to repair, and a minority of people will suffer serious events such as decompensation despite successful treatment with direct-acting antivirals.

Cardiovascular disease risk and sustained virologic response

Successful hepatitis C virus therapy reduces the risk of a serious cardiovascular event in people with compensated liver cirrhosis, French investigators report in the American Heart Journal. A sustained virological response (SVR) was associated with a reduction in the risk of a major adverse cardiovascular event such as stroke and heart attack.

Chronic infection with hepatitis C increases the risk of cardiovascular events such as heart attack or stroke, probably due to inflammation.

To find out what effect curing hepatitis C has on the risk of cardiovascular disease, French investigators looked at a cohort of patients with cirrhosis treated for hepatitis C between 2006 and 2012 and followed for just under five years. They found that curing hepatitis C reduced the risk of a cardiovascular event by 65%. Asian ethnic origin, arterial hypertension, and low serum albumin each predicted an increased risk of a cardiovascular event.

Myrcludex: treatment for hepatitis delta

Heiner Wedemeyer at The International Liver Congress, 2018. Photo by Liz Highleyman.

Hepatitis delta is a small defective virus that can only replicate in the presence of hepatitis B virus (HBV). Over years or decades, chronic hepatitis B can lead to advanced liver disease including cirrhosis and liver cancer, and disease progression is more rapid and more severe in people co-infected with both HBV and hepatitis delta virus (HDV). Estimates suggest that people with both viruses are five times more likely to develop cirrhosis and liver cancer than those with HBV alone.

There is no approved therapy for hepatitis delta. Hepatitis B antivirals such as tenofovir or entecavir are inefficient against HDV, and peg-interferon-based treatment has only shown limited and temporary efficacy in a subset of patients.

Novel treatments for hepatitis delta are being investigated in clinical studies.

Myrcludex is a drug which binds to the receptor that hepatitis delta uses to enter liver cells. A phase 2b trial presented at The International Liver Congress showed that Myrcludex used in combination with tenofovir disoproxil reduced hepatitis delta levels in blood and in liver cells after 24 weeks of treatment. Levels of hepatitis delta rebounded soon after treatment was discontinued. Professor Heiner Wedemeyer of Hannover Medical School said that modelling studies suggest that two to three years of treatment with Myrcludex might be needed to eliminate HDV RNA.

Tenofovir alafenamide as treatment for hepatitis B

Tenofovir disoproxil (TDF) is a recommended antiviral treatment for chronic hepatitis B infection. Although the drug is well tolerated by most people, it can harm the kidneys and bones.

Tenofovir alafenamide (TAF) is a new pro-drug formulation that produces high levels of the active drug in hepatocytes with smaller doses than TDF, which means lower levels in the blood and less drug exposure for the kidneys and bones.

Long-term follow-up of people who have taken TAF is essential to show whether the drug reduces the risk of kidney or bone problems in people with hepatitis B.

At The International Liver Congress Edward Gane of Auckland Clinical Studies in New Zealand presented findings from a pooled analysis of bone and kidney safety in two head-to-head phase 3 studies. This analysis compared TAF and TDF, focusing on the subgroup of participants with risk factors for kidney or bone toxicity.

Risk factors included age over 60 years, osteoporosis (serious bone loss) at the hip or spine, obesity (body mass index > 30) and co-morbidities including high blood pressure, diabetes, cardiovascular disease or hyperlipidaemia (elevated blood fat levels). Also included were various measures of kidney function impairment.

About 60% of the participants in the registration studies had at least one risk factor.

Participants were exposed to TAF or TDF for 144 weeks.

Bone mineral density at the hip and spine remained stable in people originally randomised to TAF but declined in those who started on TDF. After switching from TDF to TAF at 96 weeks, bone density rose again and approached baseline levels by 144 weeks. Bone density patterns were similar in people with no risk factors and those with > 1 risk factors.

Kidney function also remained stable in people who were on TAF throughout the study. Among those assigned to tenofovir, eGFR declined through week 96 but returned to near baseline levels after switching to TAF. Again, kidney function patterns were similar in the no risk factors and > 1 risk factors groups.

Experimental treatment for hepatitis B

Edward Gane at The International Liver Congress, 2018. Photo by Liz Highleyman.

Although tenofovir is highly effective in suppressing hepatitis B virus (HBV) replication it does not cure the infection. New types of drugs are being developed that can interrupt different stages of the virus lifecycle. The long-term aim is to develop treatment combinations that can improve the clearance of hepatitis B surface antigen, suppress viral replication and promote immune control of hepatitis B.

Studies of two experimental antiviral drugs were presented at The International Liver Congress.

RO7049389, being developed by Roche, causes production of defective HBV core proteins that lead to assembly of a defective nucleocapsid, the shell that encloses viral genetic material. A phase 1b study of the safety and antiviral activity of the drug showed no serious adverse events and substantial antiviral activity when the drug was given at various doses for 28 days.

JNJ-379, being developed by Janssen, is a capsid inhibitor with a dual mode of action. It appears to interfere with both disassembly of the capsid when the virus enters a cell – necessary to release viral DNA – and assembly of capsids for newly produced HBV particles. A phase 1b study showed substantial reductions in HBV DNA levels after 28 days. A phase 2a study of both previously untreated and virally suppressed people with chronic hepatitis B is underway to further evaluate JNJ-379 alone and in combination with nucleoside/nucleotide analogues.

Hepatitis C elimination in Georgia

Georgia is a small country with a very high burden of hepatitis C: around 5% of the population had chronic hepatitis C in 2015, or 150,000 people out of a population of 3.7 million.

Georgia launched a national elimination plan in 2015, aiming to reduce prevalence of hepatitis C by 90% by 2020. The ambitious programme is supported by free medication from Gilead Sciences. The predominant hepatitis C genotypes are types 1, 2 and 3, enabling all people to be treated with sofosbuvir/ledipasvir (Harvoni).

A total of 48,764 people had been diagnosed with hepatitis C by March 2018, 93% had started treatment and of those who have completed treatment, 98.3% have been cured of hepatitis C.

Although these results are impressive, modelling shows that Georgia will need to triple the number of people starting treatment during 2018 to achieve its target of a 90% reduction in hepatitis C prevalence by 2020.

Treatment for hepatitis C in Africa

Delivery of treatment for hepatitis C is feasible and effective in a resource-limited setting in sub-Saharan Africa, findings from a study in Rwanda show. The results were presented at The International Liver Congress.

The prevalence of hepatitis C ranges from less than 1% in southern Africa to around 8% in central Africa. Prevalence in eastern Africa is approximately 3%, according to a synthesis of prevalence estimates published in 2016.

Treatment for hepatitis C in sub-Saharan Africa has been extremely limited due to the cost of medication, lack of information about prevalence and under-resourced health systems.

The availability of generic versions of direct-acting antivirals to low-income countries now makes it possible for countries to begin offering treatment for hepatitis C. Rwanda is amongst the first to carry out a pilot study.

The Simplifying Hepatitis C Antiviral Therapy in Rwanda for Elsewhere in the Developing World (SHARED) study was a proof-of-concept pilot of direct-acting antiviral treatment. Three hundred people received treatment. The cure rate was 87%.

But, the study also found a subgroup of people who were much less likely to be cured by treatment with sofosbuvir and ledipasvir. These people were classified as reactive to both genotypes 1 and 4 (at the same time); most of these later turned out to have a variant genotype 4r. Only 54% of people with genotype 4r cleared their virus with sofosbuvir/ledipasvir treatment. In other variant genotypes, cure rates were much higher, between 87 and 100%. This indicates the importance of field implementation studies for identifying the diversity of viral genotypes and treatment responses across genotypes as direct-acting antivirals become available in lower-income countries.

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