Editorial

Remember risk-benefits of DAAs still lean heavily toward the benefits

A recent report questioning the safety of direct-acting antivirals in the treatment of hepatitis C garnered much attention due to its coverage in the New York Times; enough attention that our patients who have read the Times article have begun to question these treatments, including even some who have already been cured and are needlessly concerned about the potential for late-appearing side effects.

Ira M. Jacobson
Douglas T. Dieterich

Yet, we feel the benefits to these patients were wholly ignored and the flaws in the report not acknowledged.

The report came from the Institute for Safe Medical Practices and did not appear in a peer-review journal, with the critical outside analysis and interpretation that characterizes peer-reviewed studies. Though we have seen publications and presentations on decompensation and hepatitis B reactivation, the two main alleged problems associated with HCV therapy, the Times article failed to place these problems in any context by providing information about the enormous numbers of patients who have been treated with DAA treatment regimens for HCV infection. Without disputing the remote possibility of HBV reactivation, the need to be aware of it and, when appropriate, take action to prevent it, we and many colleagues with whom we have shared our experiences have never seen a patient with hepatitis B reactivation on HCV therapy, emphasizing its rarity.

Perhaps the most unfortunate insinuation comes from the ISMP authors, quoted in both our coverage and the Times article, implying that DAAs were approved too quickly based upon 12-week follow-up data indicating virologic cure without adequate focus on long-term benefits and risks. In actuality, many studies have demonstrated that HCV undetectability at follow-up week 12 is nearly always tantamount to virologic cure, and that marked long-term benefits of virologic cure accrue in the form of reduced risks of progressive liver failure and liver cancer.

The numbers presented by ISMP trend toward alarmist. They present 165 deaths out of 250,000 patients for a fatality rate of 0.00066. This is much lower than the mortality rates for patients who have significant liver disease from hepatitis C. The report fails to account for the background rate of decompensation and liver failure in patients with advanced cirrhosis as would occur to the natural history of the disease in the absence of treatment.

Additionally, there is a natural selection bias because sofosbuvir (Sovaldi, Gilead Sciences) and sofosbuvir/ledipasvir (Harvoni, Gilead Sciences) — the only medications cited in the Times article — are the most frequently used medications approved for use in patients with advanced cirrhosis. In the prescribing information for daclatasvir (Daklinza, Bristol-Myers Squibb), it is noted a that there is reduced efficacy in very advanced cirrhosis. The ISMP report notes “no data” for sofosbuvir/velpatasvir (Epclusa, Gilead Sciences) and “just a single case” for elbasvir/grazoprevir (Zepatier, Merck). Yet clinical trials such as the ASTRAL-4 study showed a very high level of efficacy for SOF/VEL in decompensated Child-Pugh B patients, maximized when given for 12 weeks with ribavirin while C-EDGE and C-SALT showed improvement in cirrhosis and overall SVR with grazoprevir/elbasvir. For the safety of patients, DAAs containing another drug class, protease inhibitors, are already contraindicated in treating these advanced patients.

Here at Mount Sinai, and in medical centers all over the country, we treat all types of patients and we are not seeing this level of complication from DAAs. Rather, we are distressed at this report and its portrayal in the mainstream media and our major concern is that it will scare patients away from being treated. The ones who need treatment the most are the ones whose livers are the sickest and those whose risk-benefit profiles still weigh on the side of treatment.

We have made great strides the diagnosis and treatment of HCV in this country, but we are having a hard time rounding up the last 5 or 6 million that need to be treated and this could deter them further.

HCV treatment now is all oral. It’s quite short — 8 to 12 weeks for the most part — and real-world data shows we can cure 98% to 99% of patients. The side effect profile is remarkably small. They consist mostly of headache and fatigue but not liver failure and death. Worldwide, more than 1 million people have been treated with the drugs in question and, in the United States, we have treated more than 500,000 people.

It is our firm belief that most of the morbidity in the study is from the disease process itself and not from the treatment.

We should always use drugs with caution, but the take on this seems to exaggerate the risk and we have concern it may dissuade patients who were on the fence from getting treated. In fact, at our institution, we are already beginning to witness patients on the launchpad for treatment who are becoming reluctant to pursue DAAs.

While we hope these repercussions will die out shortly, it speaks to the influence of an article in one of the world’s most influential newspapers, no matter the placement or basis.

Editor’s note: A version of this article originally appeared in HCV Next.

A recent report questioning the safety of direct-acting antivirals in the treatment of hepatitis C garnered much attention due to its coverage in the New York Times; enough attention that our patients who have read the Times article have begun to question these treatments, including even some who have already been cured and are needlessly concerned about the potential for late-appearing side effects.

Ira M. Jacobson
Douglas T. Dieterich

Yet, we feel the benefits to these patients were wholly ignored and the flaws in the report not acknowledged.

The report came from the Institute for Safe Medical Practices and did not appear in a peer-review journal, with the critical outside analysis and interpretation that characterizes peer-reviewed studies. Though we have seen publications and presentations on decompensation and hepatitis B reactivation, the two main alleged problems associated with HCV therapy, the Times article failed to place these problems in any context by providing information about the enormous numbers of patients who have been treated with DAA treatment regimens for HCV infection. Without disputing the remote possibility of HBV reactivation, the need to be aware of it and, when appropriate, take action to prevent it, we and many colleagues with whom we have shared our experiences have never seen a patient with hepatitis B reactivation on HCV therapy, emphasizing its rarity.

Perhaps the most unfortunate insinuation comes from the ISMP authors, quoted in both our coverage and the Times article, implying that DAAs were approved too quickly based upon 12-week follow-up data indicating virologic cure without adequate focus on long-term benefits and risks. In actuality, many studies have demonstrated that HCV undetectability at follow-up week 12 is nearly always tantamount to virologic cure, and that marked long-term benefits of virologic cure accrue in the form of reduced risks of progressive liver failure and liver cancer.

The numbers presented by ISMP trend toward alarmist. They present 165 deaths out of 250,000 patients for a fatality rate of 0.00066. This is much lower than the mortality rates for patients who have significant liver disease from hepatitis C. The report fails to account for the background rate of decompensation and liver failure in patients with advanced cirrhosis as would occur to the natural history of the disease in the absence of treatment.

Additionally, there is a natural selection bias because sofosbuvir (Sovaldi, Gilead Sciences) and sofosbuvir/ledipasvir (Harvoni, Gilead Sciences) — the only medications cited in the Times article — are the most frequently used medications approved for use in patients with advanced cirrhosis. In the prescribing information for daclatasvir (Daklinza, Bristol-Myers Squibb), it is noted a that there is reduced efficacy in very advanced cirrhosis. The ISMP report notes “no data” for sofosbuvir/velpatasvir (Epclusa, Gilead Sciences) and “just a single case” for elbasvir/grazoprevir (Zepatier, Merck). Yet clinical trials such as the ASTRAL-4 study showed a very high level of efficacy for SOF/VEL in decompensated Child-Pugh B patients, maximized when given for 12 weeks with ribavirin while C-EDGE and C-SALT showed improvement in cirrhosis and overall SVR with grazoprevir/elbasvir. For the safety of patients, DAAs containing another drug class, protease inhibitors, are already contraindicated in treating these advanced patients.

Here at Mount Sinai, and in medical centers all over the country, we treat all types of patients and we are not seeing this level of complication from DAAs. Rather, we are distressed at this report and its portrayal in the mainstream media and our major concern is that it will scare patients away from being treated. The ones who need treatment the most are the ones whose livers are the sickest and those whose risk-benefit profiles still weigh on the side of treatment.

We have made great strides the diagnosis and treatment of HCV in this country, but we are having a hard time rounding up the last 5 or 6 million that need to be treated and this could deter them further.

HCV treatment now is all oral. It’s quite short — 8 to 12 weeks for the most part — and real-world data shows we can cure 98% to 99% of patients. The side effect profile is remarkably small. They consist mostly of headache and fatigue but not liver failure and death. Worldwide, more than 1 million people have been treated with the drugs in question and, in the United States, we have treated more than 500,000 people.

It is our firm belief that most of the morbidity in the study is from the disease process itself and not from the treatment.

We should always use drugs with caution, but the take on this seems to exaggerate the risk and we have concern it may dissuade patients who were on the fence from getting treated. In fact, at our institution, we are already beginning to witness patients on the launchpad for treatment who are becoming reluctant to pursue DAAs.

While we hope these repercussions will die out shortly, it speaks to the influence of an article in one of the world’s most influential newspapers, no matter the placement or basis.

Editor’s note: A version of this article originally appeared in HCV Next.