Hepatitis C pipeline: BONANZA! The gold rush is under way

19 July 2014. Related: Pipeline report, Hepatitis coinfection.

By Tracy Swan

The direct-acting antiviral (DAA) era officially began in late 2013, with approval of the first all-oral treatment for hepatitis C virus (HCV) genotypes 2 and 3.

A hefty pipeline will increase HCV treatment options, especially for people with genotype 1, by mid-to-late 2014. Cure rates above 95 percent—after only 12 weeks of treatment—have become commonplace in HCV clinical trials.* DAAs have been miraculous for people with cirrhosis, HIV/HCV coinfection, and before and after liver transplantation.

But the outrage about sky-high DAA prices is quickly overtaking excitement about these wonder drugs. Advocates and clinicians are forced to fight for access to outrageously expensive drugs for people who cannot wait for affordable options—or watch people die from a curable infection.

Gilead’s nucleotide polymerase inhibitor, sofosbuvir—the backbone of most DAA regimens—is US$1,000 per tablet. Such a price limits access to this lifesaving drug, even in high-income countries, where the market for DAAs is projected to reach over US$100 billion by 2023. [1]

*A sustained virologic response (SVR)—meaning that hepatitis C virus becomes undetectable during treatment and remains undetectable for at least 12 weeks after treatment is finished—is equivalent to a cure.

DAAs Offer a Tantalizing Possibility: Global HCV Eradication

At least 185 million people have been infected with hepatitis C virus. [4] HCV is most prevalent in low- and middle-income countries (LMICs). [4] Egypt has the highest hepatitis C prevalence (14%) followed by Cameroon (13.8%), Uganda (6.6%), Uzbekistan (6.5%), the Democratic Republic of Congo (6.4%), and Pakistan (5.9%). [5, 6, 7] In populous LMICs such as China and India, HCV prevalence is lower, but the sheer number of people with HCV—almost 30 million in China and over 18 million in India—is staggering. [5, 6, 7]

Less toxic, more effective, and more convenient HCV treatment is a global boon for individual and public health. In April of 2014, the World Health Organization (WHO) issued Guidelines for the Screening, Care and Treatment of Persons with Hepatitis C. [8] The Guidelines are essential for informing decision makers and health care workers, but high-priced diagnostics and drugs will impede their implementation. “I hope these guidelines will help to promote a reduction in price and thereby an increase in access,” said Stefan Wiktor, Team Lead of the WHO Global Hepatitis Programme. [9]

Global eradication of HCV is possible, if pharmaceutical companies will allow generic DAA production in LMICs. “Competition and generic production really are the keys to reductions in prices,” says Dr. Wiktor. [10] DAAs can be produced inexpensively, according to an analysis from the University of Liverpool (using molecular weight, chemical structure, complexity, dose, and cost of comparable HIV antiretroviral agents). The actual production cost for 12 weeks of a single DAA ranges from US$10 to US$270, assuming an annual volume of 1–5 million treatment courses (see table 1). [5]

The Médecins Sans Frontières (MSF) Access Campaign has set a target price for the complete package of HCV diagnostics, care, and DAA treatment in LMICs: less than US$500. [11]

* Weight-based dosing

Choosing the Best First-Line DAA Regimen

I have the simplest tastes. I am always satisfied with the best.

—Oscar Wilde

Global progress against HCV has been hobbled by complex diagnostics and monitoring requirements, and suboptimal, expensive, and difficult-to-tolerate treatment. DAAs can radically simplify HCV treatment and reduce diagnostic and monitoring requirements. In the United States, the demand for HCV treatment is likely to outstrip the capacity of specialists to deliver it. Simple DAA regimens will make it easier for nonspecialist providers to begin treating HCV in people with less advanced liver disease.

The characteristics of optimal HCV regimens for resource-limited settings—simplicity, convenience, and manageability—are also relevant for high-income countries. Desirable characteristics for DAA regimens (assuming affordability, safety, and tolerability) include:

• Highly effective—cure rate of >80%—regardless of host and viral factors, especially in populations most likely to be prioritized for treatment (e.g., people with cirrhosis or HIV/HCV);
• Pangenotypic, potent regimens with a high barrier to drug resistance;
• Simple regimens that obviate a battery of pretreatment testing (IL-28B genotyping, viral subtyping, and drug resistance), and do not require extensive monitoring for safety, efficacy, and treatment outcome;
• Manageable drug-drug interactions, allowing coadministration with commonly used medications (treatment for HIV and tuberculosis, methadone, buprenorphine, statins, hormonal contraception, and psychotropic medications);
• Safety during pregnancy and nursing;
• Safety and efficacy in pediatrics;
• Fixed treatment duration (preferably ≤12 weeks);
• No food requirement;
• No cold storage needed;
• Once-daily dosing; and
• Low pill burden.

*Child–Pugh class A cirrhosis only

There are no data on these regimens in people who inject drugs, during pregnancy and nursing, or in pediatrics (ribavirin is contraindicated in pregnancy, during nursing and in children under three years old). There are virtually no data on DAA safety, efficacy, and tolerability in people with common comorbidities.

Sofosbuvir, simeprevir, and ribavirin can be stored at room temperature (below 84°F or 28°C); sofosbuvir can be taken with or without food; ribavirin and simeprevir should be taken with food. Data on food and storage requirements for experimental DAAs are not available. All regimens have a low pill burden and require limited monitoring during treatment.

HCV Treatment Landscape

Note: Comprehensive information on DAA regimens is available online, at http://www.pipelinereport.org/2014/hcv/update.

Genotype 1: There Is No Balm in Gilead

Despite the remarkably rapid progress against HCV, patients with genotype 1 and cirrhosis—who urgently need treatment to avert transplantation, liver cancer, and death—are still waiting for DAAs, since peginterferon may be too dangerous, too toxic, or ineffective. Yet there is an effective DAA regimen for genotype 1—even in null responders with compensated cirrhosis.

In COSMOS, a phase II trial, Janssen’s simeprevir and Gilead’s sofosbuvir were highly effective and safe for people with HCV genotype 1 and compensated cirrhosis, regardless of treatment history; cure rates over 90 percent were reported after 12 weeks of treatment. [22, 23] Despite the need for, and promise, of this regimen, Gilead declined to continue codevelopment with Janssen.

Simeprevir and sofosbuvir have been approved separately. The combination was not approved by regulatory agencies, but treatment guidelines in the United States and the European Union recommend off-label use for people with HCV genotype 1 who are ineligible for interferon-based treatment. [24, 25] Gilead’s monopolistic approach has limited awareness of off-label HCV treatment options among physicians; according to a Decision Resources report, “a notable share” of gastroenterologists and infectious disease specialists continue to prescribe suboptimal boceprevir- and telaprevir-based treatment to genotype 1 patients (these regimens are no longer recommended by the American Association for the Study of Liver Diseases, the Infectious Diseases Society of America, or the European Association for the Study of the Liver). [26]

Collaboration between sponsors facilitates development of potentially lifesaving regimens. Unfortunately, commercial interests have trumped medical need—it is unacceptable that Gilead’s desire to dominate the HCV market has delayed or complicated access to the best possible treatment.

Climb Every Mountain: Curing Genotype 3

Despite a gushing pipeline, there are still critical gaps in HCV treatment—especially in genotype 3, which has global distribution. An interferon-free cure-all for genotype 3—especially for people with cirrhosis—remains elusive, although there are DAA regimens in clinical trials. BMS is sponsoring ALLY-3, a 150-person phase III trial of daclatasvir and sofosbuvir in genotype 3 (treatment-naive and treatment-experienced). Merck is launching a phase IIb trial of sofosbuvir with a fixed-dose combination of MK-5172 (protease inhibitor) and MK-8742 (NS5A inhibitor) for 8 or 12 weeks.

There are three strategies for increasing efficacy of sofosbuvir-based treatment in genotype 3: adding peginterferon to a 12-week regimen of sofosbuvir and ribavirin; combining sofosbuvir with another DAA (daclatasvir, ledipasvir, or GS-5816); or extending the duration of treatment with sofosbuvir and ribavirin to 16 or 24 weeks. Each strategy has limitations. Peginterferon is unappealing to, or contraindicated for, many people; daclatasvir, ledipasvir, and GS-5816 are not yet approved (limiting access to people who are eligible for clinical trials, or early access and named-patient programs), and the cost of a 24-week regimen (US$168,000 for sofosbuvir) is likely to make payers balk.

High drug prices—not the basic human right to health care—are the bedrock of cost per cure.* Other factors, such as a country’s disease burden, and the resources it has for hepatitis C are not considered. Cost per cure attempts to transform unaffordable medicines into bargains, by reducing health care costs in the future (for example, HCV cost per cure is less expensive than liver transplantation).

* “Cost per cure” is calculated by dividing a standard cost reference by the sustained virologic response (or cure) rate in a specific population, then multiplying it by 100.

*Data from www.goodrx.com (Accessed on May 2, 2014).

**Daclatasvir price is based on the cost to France’s ATU program, which is €35,000 (US$47,974.52) per patient, regardless of dose (Source: www.seronet.info/article/traiter-lhepatite-c-sans-interferon-des-atu-pour-le-simeprevir-et-le-daclatasvir-66334; accessed on May 3, 2014).

HIV: Not Special, Anymore

People with HIV and hepatitis C (especially genotype 1) are less likely to be cured by peginterferon and ribavirin treatment. In the DAA era, HIV is no longer a poor prognostic factor for response to HCV treatment. Adding a protease inhibitor to PEG-IFN and RBV has produced similar SVR rates, regardless of HIV status. [33, 34, 35, 36]

Now, proof of concept has been established for efficacy of peginterferon-free regimens in people with HIV and HCV (see table 4). In fact, cure rates from some of the clinical trials in HIV/HCV have been higher than those in HCV monoinfection, probably due to experience with, and support for, adherence to antiretroviral therapy.

The only consideration for treating people coinfected with HIV and HCV is avoiding—or managing—drug-drug interactions between DAAs and antiretrovirals (ARVs). To date, the only pangenotypic DAA-based regimen that can be used without restrictions with ARVs (except AZT and ddI which are contraindicated with ribavirin) is 12 weeks of sofosbuvir, peginterferon, and ribavirin.

As of mid-2014, several trials are open or planned in people with HIV/HCV.

Source: www.clinicaltrials.gov.

Hepatitis C Trials: Not Just for Middle-Aged, Non-Cirrhotic White Males?

A majority of the participants in HCV clinical trials are middle-aged white males. Enrollment of people from other racial and ethnic groups is shamefully inadequate. There are no data on participation in, or outcomes from, HCV clinical trials among Native Americans and Alaska Natives, although they share the highest incidence of, and mortality from, HCV in the United States. [39]

African Americans

Information about how DAAs perform in the people most likely to use them is critical, yet it often is unavailable until postmarketing studies have been completed. African Americans are underrepresented in clinical trials, despite high HCV prevalence (22% of cases in the U.S.). [40] Enrollment of African Americans hovers below 20 percent in all but one industry-sponsored trial, Gilead’s PHOTON.

Hepatitis C infection is more likely to become chronic, and peginterferon-based treatment is less effective for people with the IL28B TT genotype and other genetic polymorphisms found more frequently among African Americans than people of other races and ethnicities. [41] African Americans with HCV have poor posttransplant survival rates, and significantly higher incidence of, and mortality from liver cancer than their white counterparts. [42, 43]

Hispanics

Hispanics are twice as likely to die from viral hepatitis than non-Hispanic Whites. [44] HCV progresses more rapidly in Hispanics than African Americans or Whites, and they are more likely to develop cirrhosis. [45] Type 2 diabetes (which is associated with poor response to peginterferon) is prevalent among Hispanics, underscoring the need for more effective HCV treatment, yet they are often underrepresented in clinical trials.

Women

Although HCV trials enroll a substantial proportion of women, sponsors fail to break out race and ethnicity data by gender, obscuring possible differences in efficacy. Sex- and age-specific side effects are not well characterized in HCV clinical trials, leaving women without adequate information to inform their HCV treatment decisions.

Adverse Events

The expression “generally well tolerated” is used to describe virtually any adverse event (AE) that doesn’t kill participants in HCV clinical trials. AE reports from DAA trials tend to be overshadowed by the astonishing cure rates and ever-shorter treatment durations. Years of looking at long, long lists of AEs and high discontinuation rates from trials of peginterferon and ribavirin-based regimens have numbed conference attendees (who are also not the ones experiencing them). But these adverse events are likely to be worse in the real world, given that people in clinical trials are usually healthier, monitored more closely, and cared for by more experienced clinicians.

In phase II and phase III trials of DAAs, at least five percent of study participants experienced an adverse event (see table 7). Adverse events are not always reported in terms of severity and duration, and it is unclear how many people are bedeviled by multiple AEs.

Ribavirin the Terrible

Although peginterferon is quickly becoming a therapeutic relic, ribavirin is still in the mix. It may be more toxic than anyone realized. Some of the AEs associated with peginterferon (irritability, anxiety, depression, insomnia, nausea, muscle and joint pain) have now been reported in ribavirin-containing arms of peginterferon-free trials.

Even without ribavirin, it is difficult to identify which drug or drugs are the culprits, since DAAs are not used alone.

People Who Inject Drugs

In the developed world, 80 percent of new HCV infections occur in people who inject drugs (PWID), due to lack of access to sterile injection equipment. [68] Worldwide, 10 to 15 million PWID have been infected with hepatitis C virus. [69] Yet only two to four percent of PWID have been treated, due to a range of structural, socioeconomic, cultural, legal, and other barriers. [70] Concerns about poor adherence lead some physicians to withhold treatment from PWID, regardless of evidence that adherence and

From TasP to CasP

I don’t want to be called a transmitter—that’s electricity.

—Jude Byrne, Senior Project Officer, National Hepatitis C and Other BBVs/STIs Program, Australian Injecting & Illicit Drug Users League (AIVL)

Research on HIV treatment as prevention (TasP) has inspired modelers to look at the impact of HCV treatment on prevalence among people who inject drugs. Unlike HIV, hepatitis C can be cured; only a few months of oral drugs are needed to accomplish this. Mathematical models indicate that treating a small proportion of PWID will significantly reduce HCV prevalence, given the high SVR rates seen in DAA clinical trials. [72]

HCV cure as prevention (CasP) is an advocacy platform for ramping up access to both HCV prevention and treatment for PWID. But barriers such as criminalization and discrimination will stymie efforts to implement CasP among PWID. It is critical that people who inject drugs be involved in the design, implementation, and oversight of CasP programs, and that these programs be linked to larger social justice movements.

Pregnancy and Pediatrics

Each year, 60,000 infants are born with HCV infection. In HCV-monoinfected women, the rate of vertical transmission is three to five percent; HIV coinfection doubles the risk. [73, 74] It may be possible to prevent vertical transmission with ribavirin-free DAA regimens, but there have not been any trials so far.

The standard of care for children from 3 to 17 years of age is peginterferon and ribavirin, which has many side effects and may inhibit growth. [75] Earlier HCV regimens were not ideal for use in pediatrics (or adults). Newer DAA regimens should be studied in pediatrics.

Conclusion

Although the HIV experience is valuable for tackling HCV, there are significant differences between these viruses and responses to them. HIV activists have mobilized worldwide using a human rights–based framework, wielding evidence from global research networks to fight for programs that prevent, diagnose, and treat HIV. In contrast, the dialogue about HCV has been primarily focused on cost-effectiveness, due to high prices and flaccid responses from governments and donors.

The hard work—transforming the HCV treatment cascade from scarcely a dribble into a waterfall—is just beginning. Access to affordable HCV viral-load testing and treatment can become a reality, so long as people are willing to fight for them.

The lessons learned from AIDS treatment activism and scale-up are relevant to hepatitis C: drugs cannot stop an epidemic by themselves, no matter how good they are. Activists, donors, governments, implementers, and clinicians must work together to make sure that HCV treatment reaches all who need it.

Recommendations

Research

1. Support public-private research partnerships for HCV diagnostics and treatment; leaving drug development solely to the pharmaceutical industry does not serve public health, and may be hazardous.
2. Focus on development of HCV diagnostics for resource-limited settings, using the WHO ASSURED criteria; pilot HCV treatment projects are opportunities to simultaneously validate innovative HCV diagnostics.
3. Identify and study the best DAAs for preventing vertical transmission.
4. Launch pediatric trials in HCV and HIV/HCV coinfection (with the most suitable candidates).
5. Study DAA regimens in people with HCV genotypes 5 and 6.
6. Develop DAAs in different formulations (long-acting, single-injection) to facilitate HCV treatment scale-up.
7. Enroll representative populations in HCV clinical trials, especially people with advanced liver disease from high-prevalence populations.

Policy and Implementation

1. Governments must not continue to ignore HCV; it is time for national plans to address the epidemic. People with HCV and their allies, people who inject drugs, epidemiologists, medical providers, researchers, and policy makers need to participate in development and implementation of their national plans.
2. Donors need to support and coordinate efforts to increase global access to HCV prevention, diagnostics, care, and treatment in LMICs.
3. Pharmaceutical companies must allow generic competition, since they have ample opportunity to recoup investment in, and amply profit from their DAAs.
4. Implementers must gear up; it is time to initiate widespread capacity building so that nonspecialist providers, community health care workers, and peers can deliver HCV education, screening, care, and treatment.
5. People who inject drugs must have the opportunity to participate in the design, implementation, and oversight of HCV prevention, testing, and treatment programs intended for them.

Endnotes

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