Since our last post in July, 2014, about sofosbuvir (Sovaldi, Gilead), the $1000 pill proclaimed to be a wonder drug for the treatment of hepatitis C, the marketing juggernaut for new antiviral drugs for this condition continues to roll along.
For example, I just got a notice to look at a Gilead website which proclaims
HCV can be cured
In October, Gilead got permission so sell Harvoni, a new combination drug that includes sofosbuvir and ledipasvir, hailed as a once daily pill that can cure hepatitis C, for a mere $94,500 for a typical treatment course. (See this article in the Wall Street Journal.) Meanwhile, AbbeVie launched its own antiviral treatment for hepatitis C, Viekira Pak, (ombitasvir, paritaprevir, and ritonavir tablets plus dasabuvir tablets) priced just under sofosbuvir, but still very expensive. (See this Bloomberg article.)
Media coverage of these developments suggests that there is no controversy about the curative, nay lifesaving properties of these new drugs. For example, a Wall Street Journal article about how Express Scripts will only pay for the slightly less expensive Viekira Pak referred to Sovaldi, Harvoni, and the Viekira Pak as "lifesaving medicines," and later noted, "Both Gilead’s Harvoni and AbbVie’s Viekira Pak have been shown in clinical trials to cure as many as 90% of patients..."
Never Mind the Evidence from Clinical Research, or Lack Thereof
Nearly all cases of hepatitis C can be cured, and one of the best hopes for a cure is sofosbuvir, maybe plus ledipasvir?
Never mind that the prominent published studies of sofosbuvir plus ledipasvir(1-3) did not compare this combination to any other drugs. They simply compared different durations of treatment with the combination, plus minus other drugs. So whether this combination is better than any other treatment, and even whether the apparently high rate of "cure," really suppression of virus detectable in blood samples at 12 weeks, would apply to patients less highly selected than those in the study was unclear.
Of course, like every other trial of antiviral drugs for hepatitis C, these studies only assessed whether the drugs causes a "sustained virological response," that is, made the virus undetectable in patients' blood for 12 weeks. They did not assess whether the virus reappeared after that, and certainly did not assess whether the drugs affected the development of the dreaded complications of hepatitis C infection, that is cirrhosis, liver failure, liver cancer, and death. In the absence of controlled trials that assessed these long term clinical outcomes, the assertions that these drugs are curative or lifesaving do not appear to be well substantiated.
It is not even obvious that the new sofosbuvir based regimens are better than the old peg-interferon based regimens. As we noted here, there apparently has only been one published study that compared sofosbuvir to another antiviral drug, peg-interferon. That study had multiple methodologic problems, most of which appeared likely to make sofosbuvir look better, but nonetheless did not show sofosbuvir to be clearly more effective or safer than this, or any other alternative. (See posts here and here.)
In October, a cost-effectiveness analysis appeared that was used to make the case that expensive drugs like sofosbuvir could nevertheless be cost-effective.(4) It showed that the drugs increased quality adjusted life expectancy for a relatively modest cost.
Never mind that the analysis was based on the highly questionable assumption, that "treatment resulting in cure [presumably meaning sustained virological response] could leave patients with residual fibrosis consistent with their stage at the time but without additional progression." [Italics added.] This assumption was completely unsupported by randomized controlled trial data. As Chavez-Tapia et al wrote in a December, 2014, letter to JAMA,(5) "SVR is poorly correalted with clinical outcomes in randomized controlled trials, and even though efforts have been made to correlate it with mortality, evidence to date is insufficient to assert that SVR will translate into improved quality of life or life expectancy."
Is the evidence supporting the Viekira Pak any better?
Not obviously. The prominent November, 2014, New England Journal of Medicine study by Ferenci et al of the drugs within the Viekira Pak also equated 12 week SVR with cure, also failed to allow patients long-term, and also failed to assess clinically important complications of hepatitis C such as cirrhosis, liver failure, liver cancer, and death. Furthermore, the study did not compare the Viekira Pak with any other treatment option, e.g., one containing sofosbuvir or peg-interferon, or to placebo.(6) Thus, assertions that the Viekira Pak is curative or lifesaving also do not appear to be substantiated by evidence from well-designed long-term clinical trials.
However, the lack of evidence so far as not discouraged the breathless claims, and the acceptance of these claims in the media, and probably by many physicians.
Another Skeptical Review
However, one bit of common sense about all this just appeared in the form of a 2015 article in the French journal Prescrire International.(7) The full article requires a subscription, but a summary is available on the web, and includes the following dry but telling language:
Sofosbuvir’s initial clinical evaluation includes several comparative trials. But these trials investigate its harm-benefit balance in a minimal way. Sofosbuvir has not been compared directly with a viral protease inhibitor in a randomised clinical trial. The evaluation of sofosbuvir in patients infected with a genotype 1 HCV and suffering from cirrhosis is very poor.
Clinical trials have shown that the addition of sofosbuvir to various drug combinations increases their virological efficacy, but there is no guarantee of success.
In practice, in patients with liver damage requiring antiviral drug therapy, sofosbuvir seems to be at least as effective and less harmful than viral protease inhibitors such as boceprevir. Its use makes it possible to reduce the duration of treatment by several months. But there is a great deal of uncertainty as to its adverse effects and its interactions. In genotype 1 cases, the addition of sofosbuvir to the peginterferon alfa + ribavirine combination is an option. In genotype 2 or 3 cases, sofosbuvir is an alternative to peginterferon alfa. However, given the slow progress of hepatitis C and the many unknowns surrounding sofosbuvir, it is a reasonable option to await further clinical evidence to be available.
Meanwhile, more skepticism about the sky high pricing of these new antiviral drugs appeared in the form of a lawsuit by the Southeastern Pennsylvania Transportation Authority (SEPTA) for price gouging that allegedly violates antitrust laws.
But even the coverage of this lawsuit, like nearly all the other coverage of Sovaldi, Harvoni, and competing drugs, assumed that these drugs are miracle cures, e.g., see this Wall Street Journal article. As we discussed in detail before (look here, here, here, here, here and here) there is no good evidence that any of these new treatments prevents cirrhosis, liver failure, liver cancer, or death due to hepatitis C, and their long-term safety is unclear. Similar points have been made by rigorous reviews in Germany, in the US, and now in France. Yet the antiviral spin continues without regard to evidence, or the lack thereof, from good clinical research. I would like to hope that each new added bit of skepticism, now including the Prescrire International review, will have some effect. But that may be wishful thinking, since most of what goes on in the health care "industry" now seems less than fully reality based.
As we said before, the Sovaldi (and now Harvoni, Viekira Pak, etc) case is a signal example of how our health care system is awash in marketing hype and public relations buzz that has swamped rational skeptical thinking about logic and evidence. That marketing and PR is ever enriching managers while it will send the rest of us, health care professionals included, to the poor house. And all the money we spend will likely not buy us the promised miracles and triumphs.
It is disappointing that so many physicians and other health professionals have been caught up in this hype and spin, probably abetted by their wishful thinking about cures of hepatitis C, and perhaps also abetted by financial conflicts of interest. Yet to protect the best interests of their patients, they should be rigorously skeptical of illogical or evidence-free arguments made to further vested financial interests.
As we have said until blue in the face, true health care reform would bring some skeptical thinking and regard for evidence and logic into the health policy discussion.
1. Afdhal N, Reddy KR, Nelson DR et al. Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection. N Engl J Med 2014; 370: 1483-98. Link here.
2. Afdhal N, Zeuzern S, Kwo P et al. Lepipasvir and sofosbuvir for untreated HCV genotype 1 infection. N Engl J Med 2014; 370: 1889-98. Link here.
3. Kowdley KV, Gordon SC, Reddy KR et al. Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis. N Engl J Med 2014; 370: 1879 - 1888. Link here.
4. Liu S, Watcha A, Holodniy M et al. Sofosbuvir-based treatment regimens for chronic genotype 1 hepatitis C virus infection in the U.S. incarcerated populations: a cost-effectiveness analysis. Ann Intern Med 2014; 161: 546 - 553. Link here.
5. Chavez-Tapia NC, Barrientos-Gutierrez TB, Uribe M. Assessment of outcomes of hepatitis C treatment. JAMA 2014; 312: 2570-2571. Link here.
6. Ferenci P, Bernstein D, Lalezari J et al. ABT-450/r–Ombitasvir and Dasabuvir with or without Ribavirin for HCV. N Engl J Med 2014; 370:1983-1992. Link here.
7. Sofosbuvir (Sovaldi), active against hepatitis C virus, but evaluation is incomplete. Prescrire Int 2015; 24: 5- 10. Link here.