Deferring antiviral therapy for hepatitis C until a person progresses to advanced liver disease has clear drawbacks including lower treatment effectiveness and an increased risk of clinical events and death, according to a study of US veterans presented at the European Association for the Study of the Liver (EASL) 50th International Liver Congress last month, in Vienna, Austria.
Over years or decades, chronic hepatitis C virus (HCV) infection can lead to serious liver disease including cirrhosis, hepatocellular carcinoma (liver cancer) and need for a liver transplant. When the standard of care for hepatitis C was interferon-based therapy – with its long course of treatment, poor tolerability and only modest cure rate – experts generally recommended delaying treatment until a patient developed advanced disease.
Now that much more effective and well-tolerated interferon-free direct-acting antiviral therapy is available, a growing number of providers and advocates think everyone living with hepatitis C should be eligible for treatment. But treatment is still often limited to the sickest patients due to the high cost of the new drugs.
Jeffrey McCombs, a health economist at the Schaeffer Center for Health Policy and Economics in Los Angeles, and colleagues, compared treatment outcomes for people with hepatitis C treated before or after development of advanced liver disease.
The aim of the study, McCombs explained, was to provide information for insurers and other payers about the risks of deferring treatment. "Can we eradicate this disease – an opportunity that doesn't come along often in medicine – without breaking the bank?" he asked. To date, many providers and payers have employed a 'watchful waiting' approach, monitoring patients and starting therapy only when they show signs of disease progression. This study, McCombs said, tried to answer "what do you watch and how long can you wait?"
This retrospective analysis looked at data from US Veterans Administration electronic records collected from 1999 through to 2010 – prior to the interferon-free treatment era. Hepatitis C prevalence in this population is estimated to be around 5%.
A previous study found that HCV viral suppression reduced the risk of liver disease events by 27% and deaths by 45%. Compared to people with HCV genotype 1, those with genotype 2 had a lower risk of progression and death, while those with genotype 3 did worse. Treatment effectiveness decreased if patients started therapy only after they developed abnormal laboratory values including albumin, platelet count, and ALT and AST liver enzyme levels.
The researchers determined liver disease progression using FIB-4, a non-invasive index calculated using patient age, platelet count and ALT and AST levels. This allows estimation of liver fibrosis using available laboratory tests for patients without liver biopsies. FIB-4 <1.45 indicates absent to mild fibrosis (Metavir F0-F1) while >3.25 indicates fibrosis or cirrhosis (F3-F4). According to prior research, FIB-4 >1.45 doubles the risk of clinical events and death, while FIB-4 >3.25 quadruples the risk, McCombs said.
The present analysis included 187,860 veterans (predominantly men) with chronic hepatitis C who had available FIB-4 data. The main outcome measures were time to death and time to a composite clinical events outcome that combined cirrhosis, decompensation, HCV-related hospitalisation, hepatocellular carcinoma and death.
Over the entire study period – at a time when hepatitis C treatment was poorly tolerated and not highly effective – 25% of patients started therapy and only 16% of those treated (or 4% of the study population overall) achieved undetectable HCV viral load.
The analysis showed that starting treatment with FIB-4 <1.00 was associated with a 41% reduction in clinical events and a 36% reduction in mortality. People who started therapy with FIB-4 <1.45 saw reductions of 39% and 40%, respectively, while those who started while FIB-4 was still <3.25 had a 34% lower risk of clinical events and a 45% lower risk of death.
Outcomes were not so good for individuals who delayed treatment until after they had progressed to advanced disease. People who waited until they reached FIB-4 >3.25 saw only an 11% reduction in clinical events and a 25% reduction in mortality.
Poorer outcomes are attributable in part to the fact that the likelihood of achieving viral suppression with interferon-based therapy is lower once someone develops cirrhosis. (This is also true for interferon-free treatment, though cure rates even for people with the most advanced disease are high using the newest direct-acting antivirals.) People who were treated early and achieved undetectable viral load saw about a 33-35% reduction in clinical events and 21-24% reduction in mortality, regardless of whether they started with FIB-4 <1.00, <1.45 or <3.25.
But advanced liver disease may not be fully reversible even if sustained virological response is achieved. Among people who delayed treatment until after FIB-4 reached >3.25, reductions in clinical events and death were only 13% and 24%, respectively, even if they achieved viral suppression.
Looking at another measure of treatment effectiveness – the 'number needed to treat' to achieve a desired outcome – while 180 people had to be treated with FIB-4 <3.25 in order to prevent a single death, this rose to 325 people who waited until FIB-4 reached >3.25.
"Delaying treatment until after a patient’s FIB-4 level exceeds 3.25 has a clear detrimental effect on treatment effectiveness," the researchers concluded.
The benefits of treatment are diminished if treatment is delayed," McCombs summarised. "If you treat too late it is not going to be as effective." This is something to discuss with payers, he added, since saving money now by delaying treatment may result in greater costs in the future.
Another recent analysis of people in Switzerland with HIV and HCV co-infection likewise showed that people who delay hepatitis C treatment remain at risk for liver failure, hepatocellular carcinoma and liver-related death even after being cured, with outcomes worsening the longer it is put off.
McCombs J et al. Can hepatitis C treatment be safely delayed?: Evidence from the Veterans Administration Healthcare System. EASL 50th international liver Congress, Vienna, abstract O005, 2015.