March 20, 2015

Delay HCV Tx and Watch Patients Die

by Michael Smith
North American Correspondent, MedPage Today

Meeting Coverage 03.01.2015

-- Even successful treatment carries risk if it is delayed, model suggests.

SEATTLE -- Delaying hepatitis C (HCV) treatment in patients who also have HIV increases the risk of liver complications and death even if the therapy is successful, a researcher said.

In a computer modeling study, treating a patient in METAVIR stage F3 disease instead of stage F2 increased the risk of liver-related death from 5% to 10%, according to Cindy Zahnd, a research assistant at the University of Bern in Switzerland.

And if successful HCV treatment was delayed until stage F4, the risk of liver-related death rose to 25%, compared with therapy at stage F2, Zahnd said here at the 2015 Conference on Retroviruses and Opportunistic Infections.

That's because "people who are living with HIV have many other risk factors that maintain them at a certain risk even after HCV clearance," Zahnd said.

It might seem obvious that delayed treatment increases the risk of complications or death, Zahnd told MedPage Today, but there is little long-term follow-up of actual patients that quantifies that danger.

"The point of this exercise was to project the long-term risk," she said.

The issue is important, especially in the U.S. where there is "push-back" against paying for some of the new and expensive anti-HCV agents early in the disease course, commented David Thomas, MD, of Johns Hopkins University School of Medicine, who moderated a media conference at which the data was discussed.

"Sometimes drugs aren't paid for in patients in a lower stage of disease," he said, because of a "mental model that someone would have to go to F4 before they get into trouble."

So insurers and other payers are often content to wait, he said, especially since some newer agents have been controversial because of their costs.

What the study shows, he added, is that "this approach has consequences."

The researchers used data from the Swiss Hepatitis C Study for the period before the newer agents were available to obtain estimates of the risk of progression in coinfected patients, Zahnd said.

In those days, treatment was with pegylated interferon and ribavirin, only about 60% of patients attempted the treatment, and only about 40% were able to clear HCV, she noted.

Those data suggested, however, that successful treatment would reduce the risk of liver fibrosis progression by a factor of 10, the risk of decompensated cirrhosis by the same factor, and the risk of hepatocellular carcinoma by a factor of 2.6.

Their model assumed that uptake of treatment with newer agents would be 100% and that cure rates would be about 90%, Zahnd said.

In that scenario, if treatment is provided soon after diagnosis -- between a month and a year later -- less than 3% of patients would die of liver complications, the model showed.

On the other hand, if treatment was delayed until METAVIR stage F2 or higher, the risks gradually increased, reaching 25% in those treated at stage F4, Zahnd said.

The investigators were "a bit surprised" to find that the proportion of liver-related deaths was so high despite successful treatment in most patients, Zahnd said, and concluded that some of the events would have taken place after the HCV was cleared.

Indeed, at the higher stages, most liver-related deaths would occur after the patient had cleared HCV, she said. In some patients, she reported, fibrosis progression would be maintained through persistent risk factors, such as drug toxicity, coinfections, or metabolic liver disease.

One implication of the analysis, Zahnd said, is that delaying treatment -- aside from the individual risks -- also increases the risk of transmitting HCV to others.

Indeed, she said, delaying treatment until METAVIR stage F4 would quadruple the infectious period.

She cautioned that the study had heterogeneous data sources, and also explained that it modeled a closed cohort with no transmission so the analysis probably under-estimates the positive impact of early HCV treatment.

And the model did not include the possibility of re-treatment, Zahnd said, which might have led to an over-estimate of the number of people experiencing liver-related complications.

The analysis was part of the Swiss HIV and the Swiss Hepatitis C Cohort studies. Zahnd did not disclose any relevant relationships.

Thomas disclosed no relevant relationships.

Reviewed by F. Perry Wilson, MD, MSCE Assistant Professor, Section of Nephrology, Yale School of Medicine and Dorothy Caputo, MA, BSN, RN, Nurse Planner

last updated 03.02.2015

Primary Source

Conference on Retroviruses and Opportunistic Infections

Source Reference: Zahnd C, et al "Impact of deferring HCV treatment on liver-related events in HIV+ patients" CROI 2015; Abstract 150.

Source

Annals of Internal Medicine

17 March 2015, Vol 162, No. 6>

Original Research | 17 March 2015

Jagpreet Chhatwal, PhD; Fasiha Kanwal, MD, MSHS; Mark S. Roberts, MD, MPP; and Michael A. Dunn, MD

[+-] Article and Author Information

Ann Intern Med. 2015;162(6):397-406. doi:10.7326/M14-1336

Background: Sofosbuvir and ledipasvir, which have recently been approved for treatment of chronic hepatitis C virus (HCV) infection, are more efficacious and safer than the old standard of care (oSOC) but are substantially more expensive. Whether and in which patients their improved efficacy justifies their increased cost is unclear.

Objective: To evaluate the cost-effectiveness and budget impact of sofosbuvir and ledipasvir.

Design: Microsimulation model of the natural history of HCV infection.

Data Sources: Published literature.

Target Population: Treatment-naive and treatment-experienced HCV population defined on the basis of HCV genotype, age, and fibrosis distribution in the United States.

Time Horizon: Lifetime.

Perspective: Third-party payer.

Intervention: Simulation of sofosbuvir–ledipasvir compared with the oSOC (interferon-based therapies).

Outcome Measures: Quality-adjusted life-years (QALYs), incremental cost-effectiveness ratios (ICERs), and 5-year spending on antiviral drugs.

Results of Base-Case Analysis: Sofosbuvir-based therapies added 0.56 QALY relative to the oSOC at an ICER of $55 400 per additional QALY. The ICERs ranged from $9700 to $284 300 per QALY depending on the patient's status with respect to treatment history, HCV genotype, and presence of cirrhosis. At a willingness-to-pay threshold of $100 000 per QALY, sofosbuvir-based therapies were cost-effective in 83% of treatment-naive and 81% of treatment-experienced patients. Compared with the oSOC, treating eligible HCV-infected persons in the United States with the new drugs would cost an additional $65 billion in the next 5 years, whereas the resulting cost offsets would be $16 billion.

Results of Sensitivity Analysis: Results were sensitive to drug price, drug efficacy, and quality of life after successful treatment.

Limitation: Data on real-world effectiveness of new antivirals are lacking.

Conclusion: Treatment of HCV is cost-effective in most patients, but additional resources and value-based patient prioritization are needed to manage patients with HCV.

Primary Funding Source: National Institutes of Health.

Source

Annals of Internal Medicine

17 March 2015, Vol 162, No. 6>

Original Research | 17 March 2015

Mehdi Najafzadeh, PhD; Karin Andersson, MD; William H. Shrank, MD, MSHS; Alexis A. Krumme, MS; Olga S. Matlin, PhD; Troyen Brennan, MD, JD, MPH; Jerry Avorn, MD; and Niteesh K. Choudhry, MD, PhD

[+-] Article and Author Information

Ann Intern Med. 2015;162(6):407-419. doi:10.7326/M14-1152

Background: New regimens for hepatitis C virus (HCV) have shorter treatment durations and increased rates of sustained virologic response compared with existing therapies but are extremely expensive.

Objective: To evaluate the cost-effectiveness of these treatments under different assumptions about their price and efficacy.

Design: Discrete-event simulation.

Data Sources: Published literature.

Target Population: Treatment-naive patients infected with chronic HCV genotype 1, 2, or 3.

Time Horizon: Lifetime.

Perspective: Societal.

Intervention: Usual care (boceprevir–ribavirin–pegylated interferon [PEG]) was compared with sofosbuvir–ribavirin–PEG and 3 PEG-free regimens: sofosbuvir–simeprevir, sofosbuvir–daclatasvir, and sofosbuvir–ledipasvir. For genotypes 2 and 3, usual care (ribavirin–PEG) was compared with sofosbuvir–ribavirin, sofosbuvir–daclatasvir, and sofosbuvir–ledipasvir–ribavirin (genotype 3 only).

Outcome Measures: Discounted costs (in 2014 U.S. dollars), quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios.

Results of Base-Case Analysis: Assuming sofosbuvir, simeprevir, daclatasvir, and ledipasvir cost $7000, $5500, $5500, and $875 per week, respectively, sofosbuvir–ledipasvir was cost-effective for genotype 1 and cost $12 825 more per QALY than usual care. For genotype 2, sofosbuvir–ribavirin and sofosbuvir–daclatasvir cost $110 000 and $691 000 per QALY, respectively. For genotype 3, sofosbuvir–ledipasvir–ribavirin cost $73 000 per QALY, sofosbuvir–ribavirin was more costly and less effective than usual care, and sofosbuvir–daclatasvir cost more than $396 000 per QALY at assumed prices.

Results of Sensitivity Analysis: Sofosbuvir–ledipasvir was the optimal strategy in most simulations for genotype 1 and would be cost-saving if sofosbuvir cost less than $5500. For genotype 2, sofosbuvir–ribavirin–PEG would be cost-saving if sofosbuvir cost less than $2250 per week. For genotype 3, sofosbuvir–ledipasvir–ribavirin would be cost-saving if sofosbuvir cost less than $1500 per week.

Limitation: Data are lacking on real-world effectiveness of new treatments and some prices.

Conclusion: From a societal perspective, novel treatments for HCV are cost-effective compared with usual care for genotype 1 and probably genotype 3 but not for genotype 2.

Primary Funding Source: CVS Health.

Source

Charity attacks Gilead over hepatitis C drug restrictions

Wed Mar 18, 2015 4:18pm EDT

(Reuters) - Charity Medecins Sans Frontieres has accused U.S. drugmaker Gilead Sciences Inc GILD.O of restricting access to its breakthrough hepatitis C drug Sovaldi in developing countries as it tries to protect profit margin in wealthier nations.

MSF, also known as Doctors Without Borders, said Gilead's restrictions aimed to stop discounted supplies of Sovaldi being diverted to patients from rich countries, but that the effort had resulted in "multiple restrictions and demands" on people receiving treatment in poor countries.

It said Gilead was excluding people without national identity documents, a move that hurts migrants, refugees and marginalized patients.

"We're seeing Gilead trying everything it can to squeeze every last drop of profit out of some middle-income and (high-income) countries, and millions of people with hepatitis C will have to pay the price," said Rohit Malpani, Director of Policy and Analysis at MSF's Access Campaign.

Gilead said in developing countries it operates a system of tiered pricing and voluntary generic licensing to help enable access to its hepatitis C medicines.

"As part of these efforts, the company works to ensure that the medicines reach their intended recipients with patient access our primary goal," a Gilead spokesman said.

Sovaldi, which is far more effective and better-tolerated than older treatments, has come under fire for its $1,000-a-pill price tag in the United States. It racked up $10.3 billion in sales for Gilead in its first year on the market.

Gilead said it is in discussions with 11 generic drugmakers to identify strategies for supplying 91 developing nations. But activists have said such deals would not ensure access to several middle-income countries where health authorities will struggle to provide treatment to patients.

"We will continue to seek input on all areas of our access program as it evolves, and make any improvements as needed," Gilead said.

In a statement on Wednesday ahead of a meeting between Gilead and the generics producers, MSF urged the companies to reject a program under which it says the U.S. drugmaker keeps people in developed and some middle-income countries, where Sovaldi's cost is "exorbitant," from accessing cheaper copies.

"MSF is greatly concerned that this program will establish an ugly precedent and will be introduced in all countries where the company and its generic licensees sell the drug," the charity said.

About 150 million people in the world live with chronic hepatitis C, most of them in low- and middle-income countries.

(Reporting by Zeba Siddiqui in Mumbai and Bill Berkrot in New York; Editing by Marguerita Choy)

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Hepatitis C: only a step away from elimination?

The Lancet

Editorial

Volume 385, No. 9973, p1045, 21 March 2015

Globally, an estimated 185 million people are infected with hepatitis C virus (HCV). Acute HCV infections are usually asymptomatic. However, about 75% of patients develop chronic infection, which can lead to liver cirrhosis and hepatocellular carcinoma. 700 000 deaths worldwide could be attributed to HCV in 2013. While most people affected live in low-income and middle-income countries in Asia, Africa, and the Middle East, in the UK an estimated 200 000 individuals are infected with HCV, and annual deaths from HCV have quadrupled since 1996. These figures are appalling, surely. But the extraordinary recent developments in treatment for hepatitis C offer substantial grounds for optimism. A series of new drugs—more effective in viral clearance with fewer side-effects—are changing the landscape for hepatitis C.

Today's Lancet gives a sense of the remarkable past few years it has been for hepatitis C. As described in Paul Webster and colleagues' comprehensive Seminar, until recently interferon in combination with ribavirin was the main treatment for hepatitis C, but eligibility, safety, tolerability, and effectiveness were limited. The development of direct-acting antiviral drugs towards NS3/4A protease, NS5B polymerase, and NS5A replication complex has progressed tremendously and now allows for interferon-free therapies. Four clinical trials with new regimens are published in today's issue. The C-WORTHY trial assessed a single-tablet once-daily regimen of grazoprevir (protease inhibitor) and elbasivir (NS5A inhibitor) with or without ribavirin for patients with HCV genotype 1. Eric Lawitz and colleagues report a sustained virological response (SVR) at 12 weeks, irrespective of ribavirin and duration of treatment. Similarly, Mark Sulkowski and colleagues report very encouraging results (SVR at 12 weeks: 87–97%) in patients co-infected with HIV. With about 25% of individuals infected with HIV being co-infected with HCV, inclusion of this group of patients in trials is also of utmost importance. In the PHOTON-2 trial, Jean-Michel Molina and colleagues specifically assessed the recently approved regimen sofosbuvir (NS5B inhibitor) plus ribavirin in patients infected with HCV genotypes 1–4 co-infected with HIV. They confirm the pan-genotypic potential of sofosbuvir (SVR 12 weeks: 84–89%), offering HIV co-infected patients a useful interferon-free option. The fourth trial published in today's issue goes a step further and assesses whether the addition of a third direct-acting antiviral drug to an interferon-free, ribavirin-free combination (sofosbuvir and ledipasvir) would allow shorter treatment duration—an important factor for a patient population in which treatment compliance and adherence can be an issue.

These trials are important because they offer new effective treatment options for HCV infection. “An opportunity now exists to almost eliminate this infection from the UK”, wrote Roger Williams and colleagues in The Lancet Commission on Addressing liver disease in the UK. Highly effective new antiviral drugs not only can cure those treated but also can reduce transmission of HCV and therefore its prevalence. The Commission estimated that with these new antiviral drugs we could contemplate the “eradication of infections from chronic hepatitis C virus in the UK by 2030”. Indeed, modelling studies for England showed that increasing diagnostic and number of people treated by 27 times would result in a 95% reduction in the prevalence of HCV infection, an 80% reduction in hepatocellular carcinoma, and avert 5200 deaths by 2030.

While new drugs offer new opportunities, new challenges also arise. Scaling-up treatment—in any country—will face important cost issues. But the high costs of these new medicines, which should be robustly scrutinised and, where appropriate, challenged, must not inhibit a careful and comprehensive analysis of the broader benefits they might bring. For example, as Melanie Calvert and colleagues argue this week, patient-reported outcomes offer the opportunity to have the patient's voice more forcefully heard in health policy decision making. The self-reported benefits to patients from these new anti-HCV regimens might prove to be substantial. And the financial returns from reduced health-care costs and higher economic activity might easily outweigh the expense of the medicines themselves. This kind of broader cost-effectiveness work needs to be urgently completed.

Next month, The Lancet Infectious Diseases is hosting its inaugural Viral Hepatitis Summit in Shanghai (April 10–12). We look forward to this meeting addressing the increasingly urgent need for a global plan to eliminate hepatitis C. With no vaccine in sight, if we are truly to contemplate elimination of hepatitis C by 2030, ensuring that treatments reach marginalised groups and are accessible to all those living with HCV will be crucial.

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