The findings of a new analysis highlight the safety, tolerability, and high treatment response rates of US Food and Drug Administration (FDA)-approved oral direct-acting antiviral (DAA) regimens for patients with chronic hepatitis C virus (HCV) infection, especially for those with genotype 1 infection. However, despite these optimistic findings, some experts remain cautious.
Oluwaseun Falade-Nwulia, MBBS, MPH, from Johns Hopkins University School of Medicine, Baltimore, Maryland, and colleagues published the results of their systematic review of published trials of these agents online March 20 in the Annals of Internal Medicine.
"We found high [sustained virologic response (SVR)] rates for all FDA-approved DAA regimens, with some evidence of variable response influenced by specific patient and virus characteristics," the authors write.
"The evidence was robust for persons with genotype 1 infection, which is the most common genotype worldwide, infecting approximately 84 million persons."
In the United States, HCV infection is not only the leading indication for liver transplantation, but also causes more deaths annually than all other nationally notifiable infectious diseases combined.
However, advances in HCV therapy have led to FDA approval of several new oral interferon-free regimens for chronic HCV treatment.
Therefore, the researchers summarized published literature on the efficacy and safety of oral DAAs for treating chronic HCV infection.
They performed a systematic review of 42 published randomized controlled trials of 10 agents in all six HCV genotypes, as well as in patients with and without cirrhosis, previous treatment, HIV coinfection, and liver transplantation. They included trials in which patients had received at least 8 weeks of an FDA-approved interferon-free HCV regimen that comprised at least two DAAs, and for which the primary outcome was SVR. Regimens included inhibitors of HCV NS3 protease (grazoprevir, paritaprevir, and simeprevir), NS5A (daclatasvir, elbasvir, ledipasvir, ombitasvir, and velpatasvir), and NS5B polymerase (sofosbuvir and dasabuvir), as well as the oral antiviral ribavirin.
For HCV genotype 1 infection, the investigators analyzed 32 studies evaluating six DAA regimens and found SVR rates greater than 95% for most drug combinations and patient populations. These high SVR rates are particularly important in this population, in whom interferon therapy has typically produced poor treatment response rates.
In contrast, fewer regimens are available for HCV genotype 3 infection, which is the second most common HCV genotype worldwide. Among six studies that evaluated three DAA regimens for genotype 3 infection, the investigators found two of the regimens to be effective in this patient population: sofosbuvir plus velpatasvir or sofosbuvir plus daclatasvir for 12 weeks. In patients with cirrhosis, velpatasvir–sofosbuvir achieved higher SVR rates.
Few studies enrolled patients with HCV genotypes 2, 4, 5, or 6, but high SVR rates (>92%) "were observed for all regimens administered for at least 12 weeks." SVR rates exceeded 99% for patients who received velpatasvir–sofosbuvir. For genotype 4 infection, all the DAA regimens except paritaprevir–ritonavir–ombitasvir produced high SVR rates (93% - 100%) without ribavirin; treatment-naive patients experienced minimal adverse events.
These regimens also produced high SVR rates and minimal adverse events in patient populations historically considered difficult to cure, including those with HIV coinfection, decompensated cirrhosis, severe chronic kidney disease, and a liver transplant, the authors explain.
Overall, interferon-free, oral DAA regimens led to low rates of serious adverse events (<10%) and treatment discontinuation (<5%), even in patients with comorbid conditions such as HIV infection and cirrhosis, they add.
Nevertheless, the investigators also found that ribavirin still plays a key role in the optimal treatment of some patient populations, such as those with HCV genotype 1a or 3 infection, cirrhosis, or previous treatment experience.
The ease of dosing, safety profile, and effectiveness of these oral DAA regimens expands both the number of patients who can be treated for HCV infection and the pool of treating providers, the authors conclude. However, they stress that for rapid advances in these therapies to be beneficial, they must be "linked to efforts to improve rates of HCV detection, linkage to care, and access to DAA therapy."
"Hepatitis C Is Down but Not Out"
In an accompanying editorial, Jay H. Hoofnagle, MD, and Averell H. Sherker, MD, both from the National Institutes of Health, Bethesda, Maryland, acknowledge that these findings offer hope that HCV infection is fully treatable and potentially can be eliminated as a significant public health condition in the United States.
Nevertheless, they express some notes of caution.
"First, the response rates were close but not equal to 100%," the editorialists say, adding that 2% to 5% of patients with HCV infection will have virologic failure or relapse, amounting to tens of thousands of patients who might remain infected despite treatment.
Barriers to accessing care present an even more serious problem. Because it is often clinically silent, chronic HCV infection frequently goes undiagnosed until signs of advanced disease arise. And although screening for HCV infection is simple, it is not part of routine medical care, so improving screening rates among high-risk individuals remains a challenge. This problem is also compounded by the high cost of treatments, which poses a significant burden to private insurers and to the public healthcare system.
Although the all-oral HCV treatment regimens are typically associated with only mild adverse events, Dr Hoofnagle and Dr Sherker also highlight two serious adverse events that may arise, albeit rarely. In particular, they say at least two dozen cases of hepatitis B virus reactivation have been reported during oral antiviral therapy. Now the FDA requires a boxed warning recommending clinicians to screen and monitor for hepatitis B in all patients receiving DAAs.
Sudden hepatic decompensation during or shortly after successful HCV therapy is another potential serious adverse event, the editorialists say. Thus, clinicians should carefully monitor patients with cirrhosis during DAA treatment, and discontinue their therapy if signs of jaundice, ascites, or hepatic encephalopathy arise.
Last, Dr Hoofnagle and Dr Sherker stress that clearance of HCV infection does not guarantee patients will not develop chronic complications associated with the infection. Indeed, patients who achieve SVR after antiviral therapy still have a higher mortality rate overall than the general population. According to the editorialists, hepatocellular carcinoma (HCC) causes most of this excess mortality. Because HCC can arise even within the first year after HCV eradication, clinicians should closely monitor patients with HCV who have cirrhosis or advanced fibrosis, focusing on early detection of HCC.
Despite significant advances in treatment for individuals with HCV infection, several important issues therefore prevail in this patient population.
"Hepatitis C is down but not out," the editorialists conclude.
This study was funded partially through a research contract from the Patient-Centered Outcomes Research Institute (PCORI). Dr Falade-Nwulia has reported receiving funding from Johns Hopkins University and from the National Institutes of Health. One coauthor reports receiving grants from AbbVie, Bristol-Myers Squibb, Gilead Sciences, Janssen Pharmaceutical, and Merck, outside the submitted work. One coauthor reports receiving grants and personal fees from AbbVie, Bristol-Myers Squibb, Gilead Sciences, and Merck outside the submitted work. One coauthor reports receiving grants from the PCORI during the conduct of the study. One coauthor reports receiving grants from the National Institutes of Health and PCORI during the conduct of the study; grants from AbbVie, Gilead Sciences, Janssen Pharmaceutical, and Merck outside the submitted work; and personal fees from AbbVie, Cocrystal Pharma, Gilead Sciences, Janssen Pharmaceutical, Merck, and Trek outside the submitted work. The remaining authors and the editorialists have disclosed no relevant financial relationships.
Ann Intern Med. Published online March 20, 2017. Review full text, Editorial extract
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