Miriam E. Tucker

November 15, 2013

Washington, DC — Achieving an undetectable hepatitis C viral load is associated with decreased liver morbidity and death, a large observational study using Veterans Affairs (VA) data finds.

"New therapies are needed to increase treatment rates and increase treatment effectiveness," said Jeffrey McCombs, PhD, from the University of Southern California School of Pharmacy in Los Angeles.

Dr. McCoombs presented the results here at The Liver Meeting 2013. The findings were simultaneously published online in JAMA Internal Medicine.

Dr. McCombs and his team used electronic medical records data from the VA National Clinical Case Registry for hepatitis C virus from 1999 through 2010, which includes 360,857 patients.

A total of 128,769 people met the selection criteria with a detectable viral load (>25 IU/mL) at baseline and their viral genotype recorded.

Patients were 97% male, 51% white, and 31% black, with an average age of 52 years. The majority of patients, 79%, were infected with hepatitis C genotype 1, 12% with genotype 2, and 8% with genotype 3.

Twelve percent also had diabetes and 16% had a prior hospital admission.

Primary outcomes were time to death and time to a composite liver event, including compensated and decompensated cirrhosis, hepatocellular carcinoma, or liver-related hospitalization.

Dr. McCombs explained that the time from undetectable viral load to first event was used instead of sustained viral response — the gold standard of treatment success — because it is much easier to obtain. Viral response requires the determination of the time at which the patient maintained consistent viral load suppression for a minimum of 6 months following the termination of treatment.

Only 1 in 4 Treated

In all, just 24% of patients had been treated previously for hepatitis C, and only 16% of those treated achieved an undetectable viral load.

Of the entire study population, only 4% achieved an undetectable viral load.

Overall, viral load suppression reduced the risk for future liver events by 27% and death by 45%.

"This verifies earlier findings that viral load reduction through treatment can significantly reduce the risk of adverse patient outcomes," Dr. McCombs said.

Male sex significantly increased the risk for the composite clinical outcome by 11% and the risk for death by 58%. Both diabetes and prior hospital admissions increased these risks as well.

Compared with whites, black patients had a 35% lower risk for the composite endpoint and a 28% lower risk for death. And compared with patients who had hepatitis C genotype 1, those with genotype 2 were at lower risk: 23% for the composite event and 20% for death.

This has left me, and many clinicians, in the odd position of feeling that patients are either too healthy or too sick for hepatitis C treatment. Dr. Mitchell Katz

In an accompanying article, JAMA Internal Medicine deputy editor Mitchell Katz, director of the Los Angeles County Department of Health Services, writes, "The authors demonstrate that patients who do achieve viral suppression, which almost always required  treatment, fared significantly better."

He adds, "The critical issue going forward is whether the new drugs that have been released (eg, hepatitis C protease inhibitors) or are likely to be approved soon (eg, hepatitis C nucleotide polymerase inhibitor) can achieve sustained viral suppression in a high percentage of patients without serious adverse effects."

Can these treatments "be made available without breaking the bank of safety net health systems across the country that care for large numbers of patients with hepatitis C?" Dr. Katz questions. "I certainly hope so," he writes.

Dr. Katz also notes that the low rate of treatment seen in the VA database probably reflects the fact that current treatments aren't very effective in clearing the infection and have serious adverse effects.

He explains that he often feels he is "between a rock and a hard place" when it comes to treating patients with hepatitis C. For patients who are healthy, despite their infection, it may be worthwhile to wait for better treatments, whereas patients with severe liver damage may not be able to tolerate the adverse effects of treatment; for those patients, it is unclear whether suppressing the virus would even improve their outcomes.

"This has left me, and many clinicians, in the odd position of feeling that patients are either too healthy or too sick for hepatitis C treatment," writes Dr. Katz. "It undoubtedly explains why in this VA cohort only 24% of patients had received treatment at any time."

Sustained Viral Response

During the question-and-answer period at the meeting, audience members questioned the study's methods, given its assumption that the patients are all at equal risk going in, which may not be the case.

"Especially when you have relatively low response rates, there's a big difference between those who do and don't respond, before you ever treat them," said Andrea Branch, MD, from the Icahn School of Medicine at Mount Sinai, New York.

She urged Dr. McCombs and his team to compare long-term outcomes in the relapsers with those in patients who actually achieve a sustained viral response.

"That gives you a chance to look at people who have the physiology necessary to respond to treatment with dramatic suppression of virus, but who remain viremic afterward," she explained.

Dr. Branch said other studies have shown that the patients who first suppress the virus, but then relapse and don't achieve a sustained viral response, tend to have long-term outcomes, such as liver cancer and mortality, similar to those in patients who do achieve a sustained response, even though they become hepatitis C load positive again.

"I think it's really important when doing outcomes to tease out patients who never suppress the virus with those who are capable of suppressing it," even if they later relapse, stressed Dr. Branch. "It's a marker of those healthy enough to respond to therapy by becoming viral-load negative. Those people are different from the population who don't become viral-load negative."

But, she added, "as more and more people have a sustained viral response, this will become less of an issue because the more potent the antiviral drugs, the less significant the underlying physiology in achieving viral suppression."

Dr. McCombs replied that the VA dataset would allow for this analysis.

"I would very much encourage you to do that and would be very interested in what you find," Dr. Branch said.

This study was funded by Bristol-Myers Squibb. Dr. McCombs received salary and travel support under the terms of the research grant between Bristol-Myers Squibb and the University of Southern California. Dr. Branch has received research support from Gilead Sciences, the National Institute of Drug Abuse, and the National Institute of Diabetes and Digestive and Kidney Diseases. Dr. Katz has disclosed no relevant financial relationships.

The Liver Meeting 2013: American Association for the Study of Liver Diseases (AASLD). Abstract #246. Presented November 5, 2013.

JAMA Intern Med. Published online November 5, 2013. Abstract  Editorial


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