Support for hepatitis C human challenge studies, in The Lancet Gastroenterology & Hepatology

 Here's a call for action, in The Lancet Gastroenterology & Hepatology:

Joint statement in support of hepatitis C human challenge studies by Harvey J Alter, Eleanor Barnes, Mia J Biondi, Andrea L Cox, Jake D Eberts, Jordan J Feld, T Jake Liang, Josh Morrison, Charles M Rice, Naglaa H Shoukry, David L Thomas, Jennifer Van Gennip, Charles Weijer, on behalf of other signatories †, Published:September 20, 2023 DOI:https://doi.org/10.1016/S2468-1253(23)00314-X

"We, the 121 undersigned, believe that human challenge studies among adult volunteers will be critical in the development of hepatitis C vaccines.

...

"Despite the advent of safe and highly effective direct-acting antiviral (DAA) treatments, the ongoing toll of hepatitis C remains high among low-income and middle-income countries and vulnerable populations such as people who inject drugs. Millions of new infections occur annually, outpacing cures in some regions,1 with progress further disrupted by the COVID-19 pandemic. Without a change in strategy and the development of new tools, we will not reach the ambitious goal set out by WHO of elimination of viral hepatitis as a public health threat by 2030. This will require an effective hepatitis C vaccine—“the best insurance for the future”, as highlighted by a recent announcement of the White House national hepatitis C elimination programme.2

...

"Human challenge studies for a hepatitis C vaccine could accelerate vaccine development dramatically. The effort to establish the model and test an initial vaccine candidate could take as little as 3 years. If that candidate fails, subsequent studies to test others could provide evidence of efficacy as quickly as 1 year.

"It is only because of the remarkably effective treatments that we can now consider human challenge studies for hepatitis C. With DAAs, cure rates of people without cirrhosis are reliably over 98%, with highly effective salvage regimens for the few who do not respond to a first course of therapy.5,  6 We are confident that in the era of DAAs, human challenge studies can be done in accordance with the highest ethical and safety standards. Healthy volunteers providing fully informed consent would be infected for at most 6 months before treatment and would be free to go about their lives with the right to request treatment and withdrawal from a study at any time. Acute infection causes no or few symptoms in most, and unlike in most challenge studies, where the risk of transmission necessitates quarantine of participants, the risk of passing hepatitis C to others is very low in day-to-day life.

"The impact of a vaccine would be enormous: reducing transmission, preventing cirrhosis, and most importantly, markedly reducing the rate of liver cancer, the world's second-most deadly cancer in terms of total fatalities.7 The global success of hepatitis B vaccine in achieving these goals exemplifies the importance of an effective hepatitis C vaccine. With the prospect of such a significant advance, we have confidence that people will volunteer to participate in hepatitis C challenge studies, and with such a strong team of experts worldwide, we are confident this approach will lead to the development of a successful hepatitis C vaccine."

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† Here's the full list of 121 signers of the letter

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1Day Sooner has a related web page with some background: https://www.1daysooner.org/hepatitis-c-open-letter

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Earlier related posts:

Monday, May 15, 2023

Eliminating Hepatitis C, now that there's a cure (even though it's expensive)

Saturday, August 26, 2023

Challenge trials for a Hepatitis C vaccine

Sunday, November 1, 2020

What do we know about the effects of payments to participants in challenge trials for vaccines, and other public spirited activities?

Challenge trials for a Hepatitis C vaccine

 The Journal Clinical Infectious Diseases has a special supplement on challenge trials (human infection trials) of a Hep C vaccine (now that Hep C is a curable disease):

Volume 77, Issue Supplement_3, 15 August 2023

Controlled Human Infection Model for HCV Vaccine Development

SUPPLEMENT ARTICLES

Controlled Human Infection Model for Hepatitis C Virus Vaccine Development: Is It Time to Be Real? 

T Jake Liang and others

Clinical Infectious Diseases, Volume 77, Issue Supplement_3, 15 August 2023, Page S215, https://doi.org/10.1093/cid/ciad343

• Hepatitis C virus (HCV) elimination has been a goal of the public health and scientific communities since its identification in 1989. Despite the advance and availability of highly effective antiviral regimens to treat HCV infection, it is unlikely that global HCV elimination can be achieved without an effective preventive vaccine. Because of the lack of appropriate animal models for preclinical testing and the perception that highly effective treatments would suffice in addressing the global burden of HCV, HCV vaccine development has not been a high priority. To accelerate vaccine development, the concept of a controlled human infection model (CHIM) for HCV has been proposed, in which healthy human volunteers would be deliberately infected with HCV for the purpose of testing the efficacy of candidate vaccines. This concept of challenge studies is not new and has been applied to more than 25 infectious agents, including the cholera vaccine, for which all efficacy data that served as the basis for regulatory approval were obtained from CHIM studies. Without a CHIM strategy, HCV vaccine development may not be feasible. In a recent phase 2 randomized controlled trial, over 900 people who inject drugs were screened to enroll 548 individuals to receive a T-cell–based HCV vaccine candidate or placebo. After a monumental effort that took over 6 years to complete, the trial documented 75 incident HCV infections overall, with only 45 included in the final analysis, and showed no protection against initial infection or progression to chronicity with the vaccine. While this study demonstrated that vaccine testing in the at-risk population can be done, future testing of additional HCV vaccine candidates using a similar pathway may be impractical in light of the duration and cost. With the ability to cure those who do not clear the virus, HCV CHIM is now a conceivable approach that could be a critically important, if not necessary, intermediate stage of vaccine development. HCV CHIM could de-risk vaccine candidates, accelerate development, reduce cost, and allow the selection of more promising candidates for further testing in larger clinical trials. CHIM may conceivably be used for larger phase 2/3 efficacy trials as a basis for clinical approval. In developing such a model, many challenges and questions must be addressed. In this Supplement issue, we, the editors of this Supplement commissioned various articles written by respective subject matter experts who provide their perspectives and opinions on these challenges and questions, ranging from the source of viral inoculum and the safety of transient HCV infection to the perspective of potential volunteers and the ethics of CHIM. While we strive to be data-driven and evidence-based, some of the opinions represent the views of the authors of each article and may be controversial. Ultimately, we hope these perspectives will enable fulsome discussion about the feasibility of HCV CHIM and lead to the development of well-designed clinical protocols.

  Supplement sponsorship. This article appears as part of the supplement “Controlled Human Infection Model for HCV Vaccine Development,” sponsored by Toronto General Research Institute, United States National Institutes of Health, Johns Hopkins University, the Canadian Institutes of Health Research (CIHR), and the Canadian Network on Hepatitis C (CanHepC). CanHepC is funded by a joint initiative of CIHR (HPC-178912) and the Public Health Agency of Canada.

• View article

Ethics of Controlled Human Infection Studies With Hepatitis C Virus 

Annette Rid and others

Clinical Infectious Diseases, Volume 77, Issue Supplement_3, 15 August 2023, Pages S216–S223, https://doi.org/10.1093/cid/ciad382

• Global elimination of hepatitis C virus (HCV) will be difficult to attain without an effective HCV vaccine. Controlled human infection (CHI) studies with HCV were not considered until recently, when highly effective treatment became available. However, now that successful treatment of a deliberate HCV infection is feasible, it is imperative to evaluate the ethics of establishing a program of HCV CHI research. Here, we evaluate the ethics of studies to develop an HCV CHI model in light of 10 ethical considerations: sufficient social value, reasonable risk–benefit profile, suitable site selection, fair participant selection, robust informed consent, proportionate compensation or payment, context-specific stakeholder engagement, fair and open collaboration, independent review and oversight, and integrated ethics research. We conclude that it can be ethically acceptable to develop an HCV CHI model. Indeed, when done appropriately, developing a model should be a priority on the path toward global elimination of HCV.

• View article 
• Supplementary data

Volunteering for Infection: Participant Perspectives on a Hepatitis C Virus Controlled Human Infection Model 

Jake D Eberts and others

Clinical Infectious Diseases, Volume 77, Issue Supplement_3, 15 August 2023, Pages S224–S230, https://doi.org/10.1093/cid/ciad350

The perspectives of former challenge study participants and a survey of other potential volunteers can inform the design of hepatitis C virus controlled human infection models, including on topics such as transparency, volunteer safety and risk, and compensation.

• Ethical human subjects research requires participants to be treated safely and respectfully, yet much bioethical debate takes place without participants. We aim to address this gap in the context of controlled human infection model (CHIM) research. Based upon our own experience as study participants, and bolstered by a survey of 117 potential hepatitis C virus CHIM participants, we present ideas to inform efficient, ethical, and scientifically useful study design. We advocate for full protocol transparency, higher compensation, commitment to the rapid dissemination of study results, and proactive efforts to detail risk-minimization efforts as early as possible in the recruitment process, among other measures. We encourage researchers to proactively partner with volunteer advocacy organizations that promote collective representation of volunteers to maximize their agency, and guard against ethical issues arising from healthy human subjects research.

• View article 
• Supplementary data

First Do No Harm? Modeling Risks and Benefits of Challenge Trials for Hepatitis C Vaccine DevelopmentGet access

Alyssa Bilinski and others

Clinical Infectious Diseases, Volume 77, Issue Supplement_3, 15 August 2023, Pages S231–S237, https://doi.org/10.1093/cid/ciad379

• Background

  In 2019, about 58 million individuals were chronically infected with hepatitis C virus. Some experts have proposed challenge trials for hepatitis C virus vaccine development.

  Methods

  We modeled incremental infections averted through a challenge approach, under varying assumptions regarding trial duration, number of candidates, and vaccine uptake. We computed the benefit-risk ratio of incremental benefits to risks for challenge versus traditional approaches. We also benchmarked against monetary costs of achieving incremental benefits through treatment.

  Results

  Our base case assumes 3 vaccine candidates, each with an 11% chance of success, corresponding to a 30% probability of successfully developing a vaccine. Given this probability, and assuming a 5-year difference in duration between challenge and traditional trials, a challenge approach would avert an expected 185 000 incremental infections with 20% steady-state uptake compared to a traditional approach and 832 000 with 90% uptake (quality-adjusted life-year benefit-risk ratio, 72 000 & 323 000). It would cost at least $92 million and $416 million, respectively, to obtain equivalent benefits through treatment. BRRs vary considerably across scenarios, depending on input assumptions.

  Conclusions

  Benefits of a challenge approach increase with more vaccine candidates, faster challenge trials, and greater uptake.

• View article 
• Supplementary data
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  Earlier:

  Monday, May 15, 2023

  Eliminating Hepatitis C, now that there's a cure (even though it's expensive

  and here are my posts on challenge trials (and Covid vaccines).

Eliminating Hepatitis C, now that there's a cure (even though it's expensive)

 There's growing discussion about eliminating Hep C in the U.S., doing appropriate deals with the two drug companies whose patents still run for another six years.

Fleurence RL, Collins FS. A National Hepatitis C Elimination Program in the United States: A Historic Opportunity. JAMA. 2023;329(15):1251–1252. doi:10.1001/jama.2023.3692

"One of the most dramatic scientific achievements of the last few decades has been the development of direct-acting antivirals (DAAs) that can cure hepatitis C in more than 95% of people infected. But 9 years after the first such treatment was approved in the United States, the simple 8- to 12-week oral cure is not reaching a significant fraction of the more than 2.4 million US residents chronically infected with hepatitis C.1 More than 15 000 US residents die of hepatitis C every year unnecessarily. In its fiscal year 2024 budget proposal, the Biden-Harris administration has put forward a bold 5-year program to put the nation on course to eliminate hepatitis C in the United States.

"The consequences of untreated hepatitis C can be severe: cirrhosis, liver failure, hepatocellular cancer, and death. Curative treatment stops transmission, prevents liver cancer and liver failure, and saves lives. It is even likely to be cost-saving, by avoiding expensive medical treatments for liver failure and liver cancer. So why is this not a public health success story? One major reason is that many people with hepatitis C have poor access to health care and experience other chronic health and social inequities. Hepatitis C disproportionately affects individuals without insurance, American Indian and Alaska Native persons, non-Hispanic Black persons, justice-involved populations, and people who use illicit drugs.2

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"Among those diagnosed, hepatitis C treatment coverage is far below what is needed to achieve elimination goals. Only about one-third of people diagnosed with hepatitis C who have private insurance, Medicare, or Medicaid get treated, and the proportion is probably even lower for those without insurance.4 This is in part due to current restrictions, such as requirements for patient sobriety, requirements to document evidence of liver fibrosis, and the restriction of access to treatment only to those seen by specialists, that have been put in place by public and private insurers in reaction to the high cost of DAAs ($90 000 per patient initially, still around $20 000). Low rates of treatment may also reflect the complexity of traversing the full cascade of care in our health care delivery system.

"Addressing this missed opportunity can save both lives and money. A national effort can build on lessons from programs launched by jurisdictions such as the states of Louisiana and Washington, the Cherokee Nation, the Veterans Health Administration, and the Federal Bureau of Prisons. For example, the Veterans Health Administration has treated more than 92 000 veterans with hepatitis C virus since 2014, with cure rates exceeding 90%.5 A key lesson from these initiatives is that success requires both managing the cost of the medications and developing a comprehensive public health effort to identify persons with hepatitis C and link them to care.

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"the program aims to provide broad access to curative hepatitis C medications. A key element will be a national subscription model to purchase DAAs for those who are particularly underserved today: Medicaid beneficiaries, justice-involved populations, people without insurance, and American Indian and Alaska Native individuals who are treated through the Indian Health Service. With this approach to drug purchasing pioneered in Louisiana,7 the federal government will negotiate with manufacturers to purchase as much treatment as needed for all individuals in the designated groups. The pharmaceutical industry can expect more revenue for DAAs for these populations than it is receiving today, but at a much lower per-patient cost. That’s a win-win. Beyond the subscription model, the program will seek to provide additional co-pay assistance to Medicare beneficiaries. Private insurers will also be strongly encouraged to increase coverage for hepatitis C testing and treatment and limit out-of-pocket costs where possible."

Transplanting kidneys that are infected with hepatitis C (to uninfected patients) or HIV (to already infected patients) to ease the organ shortage

Two stories, one on Hep C kidneys to uninfected patients, another on HIV kidneys to patients already infected with HIV.

Here's the first story, on transplanting Hep C infected kidneys to patients who don't have the disease: http://www.statnews.com/2016/03/18/kidney-transplant-hepatitis-c/

"Transplant surgeons at two US hospitals are about to do something long considered taboo: put kidneys from donors with hepatitis C into recipients without the infection.

In first-in-the-world clinical trials scheduled to launch later this spring, independent teams from the University of Pennsylvania and Johns Hopkins University will take kidneys from deceased carriers of the hep C virus, put them into patients with renal failure, and then give them a 12-week course of an antiviral therapy in the hopes that they will emerge infection-free.

If successful, the trials could enable hundreds of transplants each year for patients who might otherwise die waiting for a kidney.
...
"The idea behind the two upcoming trials is to take older patients who have long waits ahead and don’t have living donors, and allow them to jump the queue — if they’re willing to take on a bit more risk.

The risk of hep C infection is deemed manageable, and ethically acceptable, thanks to the latest wave of hep C medications, which offer cure rates of 95 percent and higher.

“For a 60-year-old diabetic who doesn’t have a living donor, who hasn’t been on the wait list very long, they’re miserable on dialysis, their mortality rate is high — that person might roll the dice on this and say, ‘You know what? These drugs work, and it’s worth it to me to get off dialysis sooner,’” said Dr. Heather Morris, a nephrologist at the Columbia University Medical Center.

“Initially, we’re targeting the population that has the highest mortality risk while waiting for a transplant,” explained Dr. Christine Durand, a transplant infectious disease specialist at Johns Hopkins. But if the technique proves safe and effective, she added, organs from hep C patients might one day join the regular organ pool.

“If it was me who needed a kidney,” Durand said, “I would sign up for this.”
...
"Both the Penn and Hopkins studies are backed by Merck, the drug company that makes Zepatier, the latest hep C agent to hit the market. The company is supplying its $54,500-per-patient medicine for free and providing additional financial support for staff and lab tests.
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Here's the story about HIV kidneys:

Hahnemann to begin transplanting organs from HIV-positive donors

"The organs would be given only to patients who also are HIV-positive and have agreed to accept them. The transplants will be part of research that will carefully monitor both the transplant and the potentially deadly disease.

Johns Hopkins Hospital in Baltimore announced last month that it would be the first to offer HIV-positive organs to HIV-positive patients on its waiting list. The advantage of such transplants is that they might reduce waiting times for HIV-positive patients and also free up other organs for patients who don't have the immune-weakening virus.

The new approach was made possible by the HIV Organ Policy Equity (HOPE) Act of 2013. Before that, it was illegal to transplant organs from people with HIV. The ban was enacted when the blood-borne virus was considered a death sentence, but now that it is so much more manageable, people who are infected often die of something else.

The Philadelphia hospital has now received permission from the United Network for Organ Sharing (UNOS) to begin what are called HIV-positive to HIV-positive liver and kidney transplants. Doctors expect that most of the transplanted organs will be kidneys and that the first case will occur this year. The hospital currently has 45 HIV-positive patients either on its waiting list for kidneys or being evaluated for transplants."

Good news about a dangerous disease (hepatitis), at a high price

The good news is that there's a cure. The bad news is that it isn't cheap. Here's the NY Times headline on what is proving to be a blockbuster drug:
$1,000 Hepatitis Pill Shows Why Fixing Health Costs Is So Hard--Critics Raise Concerns About Sovaldi

"A new drug for the liver disease hepatitis C is scaring people. Not because the drug is dangerous — it’s generally heralded as a genuine medical breakthrough — but because it costs $1,000 a pill and about $84,000 for a typical person’s total treatment."

The story raises a number of interesting points.  Here's one:

"Until now, doctors would mostly treat hepatitis C patients’ symptoms. Some drugs attacked the virus itself, but they did not work very well. And most had side effects, including fever, depression and anemia, that about half the patients were not healthy enough to tolerate.

Those drugs were also expensive — the most effective drug cocktail before Sovaldi cost about $70,000 — but because few patients chose them, the price tag did not cause a big reaction. Sovaldi is different. Patients want this drug, with its high success rate and smaller list of side effects. That means a big financial shock to the health care system all at once."