Reports that new treatments for the hepatitis C virus (HCV) dramatically outperform older therapies in patients who also have HIV have inspired both celebration and consternation.
Trials of interferon-free regimens that combine ribavirin with either sofosbuvir (Sovaldi) or a 3-drug cocktail from AbbVie achieved sustained virological response in up to 95% of coinfected patients.
Both regimens, moreover, produced significantly milder side effects than their predecessors, and there were none of the drug interactions that made those older HCV treatments undermine HIV medications.
The new results echo those from other recent trials, trials that have already transformed the treatment of patients with HCV alone, but the documented outcomes for coinfected patients may prove particularly important.
Roughly a quarter of all Americans with HIV also have HCV—about 275,000 people in all—and HIV speeds the progression of HCV. Coinfected patients thus develop serious liver disease more frequently and more quickly than people with HCV alone. Indeed, HIV coinfection more than triples the risk of liver disease, liver failure, and liver-related death from HCV.1
The shortcomings of older HCV treatments have helped make liver disease the leading non-AIDS cause of death for Americans with HIV,2 so news of significantly better medications certainly justifies celebration—unless you’re paying for those medications.
The $84,000 price tag of a 12-week course of sofosbuvir has already generated unprecedented criticism from virtually every organization that finances healthcare.3 The 24-week treatment for coinfected patients would cost twice as much. (AbbVie has submitted a new drug application for its “3D” HCV regimen, but has yet to announce a price. Many payers, however, expect it to be nearly as expensive as sofosbuvir.)
So far, nearly all government agencies and private insurers have covered sofosbuvir for all patients with HCV, but many say they may soon limit that coverage to patients who need timely treatment.4 Still, even if that happens, the tendency for HIV to accelerate the progression of HCV may preserve coverage for coinfected patients.
“The costs are enormous, but everyone is working to make sure that people who need treatment get treatment,” said Jürgen Rockstroh, MD, professor of medicine at the University of Bonn, who has run an HIV outpatient clinic since 1995.
“Even among coinfected patients, there are people who can safely wait a bit for treatment to see whether prices fall when new treatments arrive,” added Rockstroh. “But generally speaking, coinfected patients require treatment sooner than people who only have HCV.”
The most recent trial of sofosbuvir and ribavirin tested the 2 drugs in 274 patients with both HIV and HCV. The study population, mirroring the general population of coinfected people, was primarily male (81%) and middle-aged (47 years, on average).
Only 20% of the enrolled patients had developed cirrhosis or received any prior HCV treatment, but all of them used tenofovir and emtricitabine for HIV, and most used antiretrovirals as well. Their mean CD4 cell count was almost 600 cells/mm3.
Each patient received daily treatment with 400 mg of sofosbuvir and a weight-dependent dose of ribavirin that ranged from 1000 mg to 1200 mg. Treatment lasted 12 weeks for 19 previously untreated patients with HCV genotype 2, and 24 weeks for all others.
Sustained virological response rates 12 weeks after the end of treatment (SVR12) were 85% for people with genotype 1, 88% for those with genotype 2, 89% for genotype 3, and 84% for genotype 4. Relapse rates were 13%, 8%, 9%, and 16%, respectively.5
Multivariate analysis found only 1 significant risk factor for diminished response: preexisting cirrhosis. Among cirrhosis, SVR12 was 88% (and 100% for patients with genotype 1b). Among similar patients with cirrhosis, SVR12 was 65% overall (and only 75% for patients with genotype 1b).
Unlike HCV regimens with older protease inhibitors, the sofosbuvir-ribavirin combination did not appear to interact with HIV treatments. Only 4 people experienced intermittent low-level HIV viral load breakthrough, and none of them required any modifications to their antiretroviral regimens. Absolute CD4 cell counts did increase during sofosbuvir treatment, but CD4 percentages held stable.
Side effects, moreover, were mild. Only 6 people suffered severe adverse events, and only 3 quit treatment.
Such findings indicate that the sofosbuvir-ribavirin regimen is significantly better than traditional HCV treatments for coinfected patients in every meaningful way. Still, for patients with HCV genotype 1, that regimen appears greatly inferior to the 3D regimen.
The 3D experimental cocktail combines the protease inhibitor ABT-450, 100 mg of ritonavir, and the NS5A inhibitor ombitasvir in a once-daily fixed-dose coformulation. Patients also take 2 daily doses of the polymerase inhibitor dasabuvir and 1000 mg to 1200 mg of ribavirin per day. Just 12 weeks of such treatment produced an SVR12 rate of 94% among 32 people with both HIV and genotype 1 HCV in one phase 3 trial. An additional 12 weeks boosted the SVR12 rate for another 31 patients, but only by 1 percentage point.6
The 3D regimen achieved these results despite starting with a harder-to-treat population of patients: only 19% had cirrhosis, but 90% had genotype 1a HCV (which is harder to treat than genotype 1b) and one-third had received prior treatment for hepatitis.
None of the patients experienced severe adverse events, and none dropped out of the trial. Five were found with low-level HIV viral load during treatment, but HIV RNA fell back below detectable levels for all patients without any changes to their antiretroviral regimens. There were no significant changes in the CD4 count.
Mark Sulkowski, MD, a professor at Johns Hopkins Medical School who presented the study results at the 20th International AIDS Conference in Melbourne, said that a 12-week treatment would likely provide maximum benefit for most patients, but that 24 weeks of therapy would make sense for patients with cirrhosis and previously treated cases of HCV genotype 1a.
“These new treatments are nothing short of a revolutionary improvement in care,” said Rockstroh, who is also an advisor to the International AIDS Society.
“Just a few years ago, we had 48 to 72 weeks of dual therapy producing SVR in about 30% of those coinfected patients who could endure the treatment,” said Rockstroh. “Now we see well-tolerated, 12-week treatments producing SVR in 95% of patients who have the most common type of hepatitis. It’s just unbelievable to people like me who have been doing this for 20 years.”
The economics, however, are not nearly as clear as the science.
For all the outrage over sofosbuvir’s $1000 per pill price tag, total treatment costs for a 12-week course of the drug are comparable to older (and significantly inferior) HCV regimens.7 A normal course of the most effective medication from the last generation of treatment cost about $70,000 on its own, and such treatment required patients to pay extra for interferon, ribavirin, and multiple trips to the doctor.
The high price of older HCV medications was not a big problem, however, because most patients deferred treatment in hopes that something milder and more effective would arrive before their cases became urgent.
All those deferrals, many of them lasting more than a decade, have created a massive backlog of untreated patients. Estimates are that up to 25% of the approximately 3.2 million people living with HCV have deferred treatment.4
People with HCV genotype 1, the most common strain of the disease, still have reason to delay treatment until the FDA approves the 3D regimen and a 2-drug combination of sofosbuvir and ledipasvir that also produces cure rates above 95%. But those patients won’t be waiting long. At press time, the FDA approved Gilead Sciences’ 2-drug combination of sofosbuvir and ledipasvir for HCV genotype 1, to be marketed as Harvoni.
People with all other types of HCV have no reason to wait for treatment. No medication in advanced trials promises to work any better than the sofosbuvir and ribavirin combination.
Still, estimates about how many people will seek treatment and when they will seek it vary widely.
Gilead Sciences, the company that makes sofosbuvir, expects that about 150,000 Americans will seek treatment next year, when both AbbieVie’s 3D regimen and its 2-drug combo for genotype 1 patients hit the market.8
PricewaterhouseCoopers, however, estimates that nearly 80,000 privately insured Americans will seek treatment next year.9 If that number is right, then the total number receiving treatment next year may be far above Gilead’s estimate because a majority of HCV patients receive their health benefits from Medicaid, Medicare, the Veterans Administration, or a prison system.10
The numbers are already huge. Second- quarter 2014 sales revenues for sofosbuvir were $3.5 billion, and some analysts expect quarterly sales to increase over the next couple years.
PricewaterhouseCoopers estimates that the cost of sofosbuvir alone will increase the total cost of private insurance by half a percentage point next
year. The Kaiser Family Foundation estimates that the cost of sofosbuvir could increase Medicare drug-care premiums up to 8%.11
But the greatest burden will likely fall on state prisons and Medicaid programs, which together provide hepatitis care for 750,000 people. States could face a $55 billion bill if every infected patient in both systems seeks care.12
“If Medicaid programs covered these treatments with no limits, it would both double their total spending on all medication and force dramatic cuts elsewhere, and that would not be right,” said Matt Salo, executive director of the National Association of Medicaid Directors.
“If we cannot get providers to alter the price point, then we are going to have to alter the universe of people who are eligible to receive it,” he added.
Even if payers limit coverage to people who would have sought treatment with older medications, people whose HCV has begun doing real damage, patients will still benefit from the new medications, and coinfected patients will likely benefit more than most.
Their tendency to develop serious liver problems faster and more frequently than patients infected with HCV alone strengthens their claim to treatment. It also strengthens the financial incentives for payers to cover such patients early and save on future costs.
Those future costs are substantial, even for people who only have HCV. Roughly 65% of people who become infected will develop a serious liver problem and up to 20% will develop cirrhosis.13 Indeed, HCV is the leading cause of liver transplants in the United States, a procedure that generally costs well over $300,000.14
That said, widespread early treatment might never pay for itself. One recent study suggests that the average lifetime medical costs associated with 1 new case of HCV are $64,490,15 considerably less than the cost of 1 treatment. What’s more, a study by the Institute for Clinical & Economic Review predicted that the 20-year savings from early cures would only cover 85% of the cost for a single course of sofosbuvir.16
The math only really changes when models assume that an aggressive push combining diagnosis and treatment—one that found more than a million undiagnosed cases and cured nearly every one with the disease—could essentially eradicate HCV.
“Such an effort might eliminate the future medical costs of people who are already infected and prevent millions more from ever becoming infected and ever needing an expensive cure. But at today’s price, it would cost $300 billion, an amount of money that plans, taxpayers, and consumers can’t possibly shoulder,” said Larry McNeely, policy director for the National Coalition on Health Care.
“Many payer budgets are basically fixed, so every $84,000 they spend on Sovaldi for an asymptomatic patient is $84,000 they cannot spend on people who have immediate problems,” said McNeely. “Even if you could eliminate hepatitis C, that trade-off makes no sense.
“That’s not to say payers will simply refuse to cover it,” he added, “but they will have to weigh the costs and benefits. The reality is that many fewer people will get this drug at the current price point than would have gotten it had Gilead chosen a significantly lower price point.”