Every year, Treatment Action Group (TAG) publishes its Pipeline Report —an overview of research and development in the diagnosis, prevention, treatment, and potential future cure of HIV, hepatitis C, and tuberculosis.
The 2020 report was released earlier this summer; we previously explored what's new in HIV treatment and prevention with Richard Jeffreys, who authored the HIV sections.
To discuss the latest developments in hepatitis C diagnostics and treatment, Terri Wilder spoke with Annette Gaudino and Bryn Gay, who authored those sections of the Pipeline Report.
Gaudino is TAG’s state and local policy director, working across hepatitis C, HIV, and tuberculosis programs to advance elimination efforts in the United States jurisdictions, with special attention to the needs and human rights of people who use drugs. She provides strategic guidance and training to state and local partners and contributes to TAG’s policy work on prescription drug pricing and health systems equity.
Gay is TAG's hepatitis C virus project director; she focuses on global advocacy related to hepatitis C, access to affordable medicines, and harm reduction, particularly in the Global South.
Terri Wilder: I appreciate both of you being with me today. This is a great document. I learned a lot as I was reviewing it. Bryn, I want to start with you. At the beginning of the hepatitis C diagnostics section of the Pipeline Report, you start out writing that even before the COVID-19 pandemic, there were 400,000 deaths [every year] from liver disease and cancers related to hepatitis C, and that deaths from overdoses were increasing.
I wanted to ask you if you think that there’s a possibility that COVID-19 could worsen these death tolls.
Bryn Gay: Yes, Terri. So, as you’ve been seeing, COVID-19 has been obliterating our already fragile safety nets for vulnerable groups, including people who use drugs and people from key affected communities. This includes hepatitis C and HIV. And so, since COVID-19, we’ve been seeing increases in overdose deaths reported in 35 states. Meanwhile, we’re seeing a lot of states in the United States slashing budgets and facing austerity. This includes putting hepatitis C, tuberculosis, syringe and naloxone programs, and other harm reduction and health services on the chopping block.
People who have been living with hepatitis C, people who use drugs; they may be more isolated. People may be using drugs alone. They may be missing medical appointments and other essential services. They may be lacking support systems.
One of the biggest challenges is ensuring that people continue to have the access to the care and the support that they need. And I just wanted to mention that one of the biggest challenges in the hepatitis C care cascade is losing patients to follow-up—between confirming their diagnosis and starting people on DAAs [direct-acting antivirals]. So, people who are living with hepatitis C may be at risk of losing their employer-based health insurance or Medicaid, they may be facing eviction or housing instability, and they may have had experience with COVID-19.
So, they’re facing a number of different crises. This has just destabilized them from being able to address chronic diseases, such as hepatitis C.
TW: I know that the COVID-19 pandemic has interrupted screening and testing programs for hepatitis C. I’ve talked to some of the programs. And I’m wondering, Bryn, if you can talk about ways that countries could really strengthen lab and diagnostic capacity, or if there’s innovative methods to expand testing via health departments during this time.
Gay: Yes. The United States and a number of other countries have been really hit hard by COVID-19. And so, they’re putting together a lot of different relief packages. And this could include funding, the scaling up of testing (for hepatitis C, as well), and strengthening some of the resources that they’re going to require for both epidemics. This could include investing in multi-disease diagnostics platforms that can run the different tests at the same time, to diversify and improve supply chains, and to develop their health care workforce, and also to expand community outreach and awareness raising.
Something that I found really interesting in doing the work for the Pipeline Report: Some of the countries that have initially been hit really hard, especially in Southeast Asia, with COVID-19; they were able to get a handle on it through early testing and contact tracing. And then they integrated the COVID-19 testing in their HIV and hep C outreach and screening. So, this was basically building it into the different programs that were already trying to engage people from key populations into getting them tested and linked to treatment and care.
I also wanted to mention that there’s ways that countries can leverage the global funding and procurement, so that while they’re ordering their COVID-19 tests, they can also include hep C, TB, hep B, HIV—all of these—into volume-based deals. And this approach would align with all the different advocacy that we’ve been saying to simplify, decentralize, and integrate diagnostics into existing health infrastructure.
TW: Bryn, you also mention some studies that are underway that I thought were really interesting, such as SELFIE and ICECREAM—which are such interesting names for studies—and that they evaluate the impact and feasibility of hepatitis C RNA self-testing among men who have sex with men on reducing the time to diagnosis, starting treatment for reinfections, and preventing onward transmission. I wonder if you can tell me a little bit more about those studies.
Gay: Yeah. So, there are pretty limited studies that we’ve seen, in terms of hepatitis C prevention and transmission among MSM. There’s a few that are sort of longitudinal studies in Amsterdam and in the Swiss cohort that have been reported on for PrEP and a lot of different HIV research. But these two studies are currently recruiting patient participants. They’re basically trying to understand how home-based self-tests for hepatitis C could decrease the time to getting reinfections diagnosed, and then allowing the participants to inform their partners and to get started again on DAAs.
Basically, the two studies are looking at similar questions to understand what would be the impact on transmission. The ICECREAM study, I thought, was interesting because it uses self-sampled RNA blood tests, dry blood spot tests, as well as has an online behavioral assessment to understand what the risk factors are for reinfection. So this is, I think, something that we want to follow to understand: How are we going to adapt some of the prevention methods for reinfection among MSM?
TW: You also, again, talk about how the research and development in diagnostic and validation studies for hepatitis C self-tests experienced delays because a lot of the companies were rushing to prove and market diagnostics for COVID-19. Prior to this, in July of 2019, the hepatitis C diagnostics expanded, and several tests were approved for WHO prequalification.
Can you talk about that? So much of the work that, I think, everybody’s doing, is being impacted by COVID-19.
Gay: With the self-test, it’s more the interruption to the studies that were underway, so they couldn’t necessarily continue to run the tests. So those are on pause for the moment. But they’re being investigated: how hepatitis C self-testing would work, how it would be accepted in the community and resource-limited settings.
It’s under investigation. And it should be, I think, evaluated, and we should have some results from that probably by the end of this year.
But, yeah. I think since July 2019, there have been a lot of tests that are already currently used in the field, but that went through the WHO pre-qualification process, which is basically a global regulatory approval process that’s been independently evaluating the performance of these tests.
And so, various tests that I think people are very familiar with—the RealTime Abbott viral load test; ARCHITECT core antigen test, which is used in huge hospital laboratories—these are all some that we’re very familiar with. And it’s basically just that they were able to get through a more fast-track procedure and get it PQed. Probably since December ’19, we’re seeing the list expand. I think it’s exciting because we have more options out there for confirmatory tests, for RNA prick tests, as well as the ARCHITECT core antigen test.
And then I did want to mention there’s two portable hep C PCR tests, or platforms, that have been approved; and at least one that’s underway. So, Molbio, which is an Indian company, has submitted for WHO PQ. And so, it’s a little bit less expensive. You have fast turnaround results for within, like, 40 minutes, to get a confirmatory test.
Basically, the Genedrive and the Molbio have the potential of bringing testing, that confirmatory testing, closer to where patients are. And the other interesting piece with this is that there’s a number of trainings that are available with these platforms to shift tasks from laboratory technicians and doctors to shifting those tasks to physicians’ assistants and potentially nurses who could then run these tests in the community. This actually gets patients more ready for treatment and reduces the time to getting confirmed.
So, I think that these were two tests that I think we’re really excited about; that we finally have more portable testing platforms that could be potentially rolled out in the field.
TW: When I think about hepatitis C, particularly in the United States, I think about the enormous amount of money that it costs to treat. But before that, you have to be diagnosed. Prior to that, you have to be screened and tested. You talk about these test-and-treat programs and cost- effectiveness when using a simplified diagnostic pathway. And you also mention the WHO collaborative registration procedure as a way to save costs. Can you share what all that means, and how it contributes to getting people screened and tested; but also, mechanisms for saving money?
Gay: Yeah. It’s really exciting to see that we do have good guidance now to try to reduce the number of steps needed to get someone diagnosed, and then potentially starting them earlier on treatment. We also have this really incredibly good and effective cure that can treat all genotypes.
So, I think that the emphasis here is that there should be no longer an excuse for governments to not start their testing and treatment programs. So, while we’re sort of in this pause, and while we have a number of interruptions to health programs, we could be making the administrative and legal fixes necessary to get some of the other work done for hepatitis C. That means changing national testing guidelines, so that we have reduced the number of steps.
I think that there’s a couple of interesting case studies that show how this simplified diagnostics pathway—which is, you’re having one antibody test, reflex testing for an RNA and core antigen confirmatory test, some kind of a liver function test, and to start patients on pan-genotypic DAAs—this can cost somewhere around $80 per patient. And this also could potentially have a reduced cost of about $376 per patient, as seen in Cambodia—which is massive savings in the health budgets of countries. Basically, this can result in better treatment outcomes, compared to long-term costs associated with undiagnosed and untreated patients. Did you want me to go into the WHO CRP [collaborative registration procedure]?
TW: Yeah. That would be great if you could.
Gay: Along those same lines, this is basically just a way of harmonizing registration of these diagnostics. And this has been done in HIV; and there is a piloted process in five African countries. And so this basically helps fast-track access for diagnostics by simplifying the national registration steps, by looking at what those bottlenecks are, and coming up with ways to understand the product sameness of those WHO prequalified products. And so, this basically fast-tracks the process and can ultimately save costs, because you’re using less bureaucratic, administrative time to get those tests registered in a country.
TW: And I’m wondering, because the world is on pause and we’re all trying to figure out how to work and achieve goals related to health in this chaotic time; I’m just curious. What do you think are some of the key advocacy focuses for the remainder of 2020 related to diagnostics?
Gay: I think they’re the same as before COVID-19, in that we need companies to disclose the pricing; the cost of goods. So, we need to understand what the ex works price of these diagnostics are so that we can actually negotiate better. And at the country level, the government level, we need to be simplifying the diagnostics algorithm, prioritizing point-of-care tests, and using sampling methods such as dried blood spot tests, which basically would shorten the time for people to get started onto treatment.
I think we need to just normalize, decentralize, and integrate hep C testing, like we do for HIV and pregnancy tests, so that we make these kinds of tests available at different settings. And I think I mentioned this, that these can be made available in pharmacies, in vending machines, in mobile clinics. Let’s just normalize that people get tested.
TW: Great. So, Annette, you were the author of the hep C treatment section of the Pipeline Report. And in it, you state—and I quote—“For all intents and purposes, the hepatitis C treatment pipeline is closed, and no novel oral DAA combinations are expected for the global market.” Can you tell me more about that, and why that is?
Annette Gaudino: We’re facing a little bit of a paradox, in that we have the incredible success of the science that’s brought us highly effective treatments, but the ongoing marginalization and stigmatization of the communities most impacted and with the heaviest burden of viral hepatitis C—mainly, people who inject and use drugs. So, on the one hand, there’s no strong financial incentive to continue to develop novel combinations, DAA combinations, for the world, when we have so many that work so well (even though not enough patients can access them). And, on the other hand, we lack the political will to do really concerted efforts to make sure that those treatments are accessible, as Bryn described, to make sure that testing is easily accessible, normalized, and integrated into health systems, and, in fact, expanded into those communities that may be somewhat removed and have challenges, in terms of accessing the normal public and private health systems in their countries.
TW: You know, much like my interest in your writing around the connection between hep C and men who have sex with men that I talked with Bryn about, you mention in your section that short-course treatment for acute hepatitis C infection among men who have sex with men is essential, given the relatively high rates of hepatitis C among men using PrEP for HIV prevention.
I’m just curious: Why do you think this is happening, and what kind of educational messaging is being geared towards men who have sex with men, or should be? I don’t really recall seeing much messaging around high rates of hepatitis C infection among men who have sex with men using PrEP. Maybe I’m just looking in the wrong place. I’m clearly not that target audience. But I’m just kind of curious about your thoughts about that.
Gaudino: I think if you ask the average person, they wouldn’t be able to tell you that viral hepatitis C and hepatitis B are sexually transmitted diseases. We just don’t think of them in that way. But, in fact, they are. And that’s especially true for men who have sex with men.
So, when you already start off with thinking about viral hepatitis as being a separate category, away from, distinct from, sexually transmitted infections, then you have that initial barrier. So once you do that education, now you have to look at your health care system.
Men who are using PrEP should be getting regular health checkups to make sure that their drug levels are appropriate to protect them; but also to monitor them for sexually transmitted infections. And that has tended to focus on the bacterial infections, like syphilis and gonorrhea.
If you don’t have it integrated into your health care system and into your primary care settings—where these men are seeking care—to also be testing for hepatitis C and hepatitis B, you’re going to see ongoing transmission. You’re missing opportunities to treat people.
So, add that to the challenges of health care systems in resource-limited settings—you know, low- and middle-income countries—or just pretty much any community health setting right now in the COVID era, due to the challenges of the pandemic, but also what we anticipate are going to be the yearslong knock-on effects of the economic devastation brought on by the COVID pandemic; well, we’re going to see significant cutbacks to public health and subsidies that allow low-income or no-income people to readily access primary health care. There are some real challenges there.
And I also just want to clarify some of the nuances of it. We also need to do a better job of surveillance among men who have sex with men, with regards to the hepatitis C incidence and prevalence. But also, we do see relatively higher rates of reinfection among these cohorts, especially men who are using PrEP—again, because their sexual practices are changing, so they may be more vulnerable to other sexually transmitted diseases, including viral hepatitis.
The community of people who inject drugs is still much more heavily burdened. So, in some communities, 70% to 80% of people in a community who inject drugs may have at least been exposed to viral hepatitis, if not actually have active chronic infection. So the numbers are less than that among men who have sex with men, but because of ongoing risk behaviors, you’re going to see more reinfection. So you may have to retreat people who were initially cured for a viral hepatitis C infection again. Regular monitoring and integration of viral hep testing into the range of sexual health services and ongoing testing that men who have sex with men should be receiving is really, really important. And we haven’t seen it comprehensively implemented.
TW: I have some questions to continue this train of thought on thinking about certain communities or certain populations. And I read in your report about some difficult-to-treat subtypes of hepatitis C that are prevalent in Sub-Saharan Africa. And I wonder if you can talk about that. Why is that unique to that area? And are there any medications that are helping at all?
Gaudino: Thanks for asking about that. So, I think it’s important for everyone to understand that we all came—meaning, human beings—all came from the African continent. So, the genetic diversity along the different ethnicities and the different populations on the African continent, specifically the Sub-Saharan African region, is just the greatest in the world. Unfortunately, we don’t value people of African origin and people on the continent as much as we should.
And so, in the case of the development of the DAAs to treat viral hepatitis C, we did not do sufficient clinical trials among people from the continent, or from the African diaspora. So we did not find out until later that there are some genotypes, subtypes, prevalent in these communities and in immigrant communities of the diaspora that are more difficult to treat.
Historically, we have seen that genotype 3—so, the genotypes of viral hepatitis are just the main different genetic variations of the virus. There are six major types, and also a seventh type that’s somewhat rare. And genotype 3, which is very prevalent in South Asia and East Asia, had been more difficult to treat. Even now, some of the very potent pan-genotypic treatments that we have; you have to take them for a little bit longer in order to successfully treat a genotype 3 infection, especially if you’re doing a retreatment or you have cirrhosis.
But these other subtypes; we didn’t have enough patients in our clinical trial pools for it to surface. Now that some Sub-Saharan African countries, specifically Rwanda, are starting to scale up hepatitis C test-and-treat programs, we’re starting to see failures. You know, we expect greater than 90% cure rates. And in some communities, we were seeing—you know, in some programs—we were seeing 70% cure rates. This was also found among African immigrants in a London clinic, in a paper that was presented last year at the International Liver Congress.
So, we do have some preliminary data and also just some educated guesses that we can make, based on the treatment resistance profiles of these subtypes—looking and doing some DNA sequencing—for the virus that these folks are infected with, and that is causing the treatment to fail.
Based on those resistance profiles and some of this initial data, we can say with some confidence (although we obviously need more research) that pan-genotypic combinations, such as sofosbuvir/velpatasvir (SOF/VEL), also known by the brand name Epclusa, and the generic combination of sofosbuvir/daclatasvir should do well in these patients. We may need to treat them a little bit longer. But also, we have reason to believe, based on an in vitro study that is included in the Pipeline chapter, that glecaprevir/pibrentasvir (G/P), also known by the brand name Mavyret, has shown some good activity against some of these subtypes.
So, we do have treatments, pan-genotypic treatments, that should be able to improve the outcomes for patients with these difficult-to-treat subtypes. We need to do more research to fine-tune the algorithms, the treatment algorithms, for them. And we also need to acknowledge that these subtypes are also found among people in South Asia, the South Asian region. So it’s not just Sub-Saharan Africa; it’s basically some very populous regions with high burdens of viral hepatitis C that were simply not included in the clinical regulatory approval trials for the DAAs.
TW: I want to talk about children under the age of 18 with hepatitis C. What is happening in terms of treatment for this particular population?
Gaudino: In the last year or so, we have fortunately seen some approvals of effective drugs for these patients. Sofosbuvir/ledipasvir, known as Harvoni, has been approved by the FDA for treatment in patients 3 years of age and older—weight-based treatments. Treatments do need to be modified for children and for adolescents based on their weight to avoid more challenging side effects, and making sure that they’re able to stay adherent because they’re not having side effects.
Unfortunately, Harvoni is not pan-genotypic. So this approval is only for genotypes 1, 4, 5, and 6. Genotypes 2 and 3, which, while they are less prevalent in Europe and North America; 2 and 3 are prevalent in Asia, South and East Asia, and other parts of the world. So, there’s still some work to be done there.
In the case of Mavyret (a.k.a. G/P), we received FDA approval for the use of that DAA in patients ages 12 to 17—again, weight-based treatments. You really do need to have some form of experienced provider in order to administer these treatments to these patients. According to the American Liver Foundation, in the U.S. alone, we have anywhere from 23,000 to 46,000 children—that means people younger than 18—living with hepatitis C, chronic hepatitis C, infection. This is not an insignificant number of children, in the U.S. and around the world, who need treatment. Sorry, but Epclusa can also be used for children over 6 years.
TW: Great. I guess I just had a question about children. And this might sound like a stupid question. But how are children—and I guess I’m not thinking about, like, 15 to 18—but how are children getting hepatitis C?
Gaudino: Most children with hepatitis [got the virus as] a result of parent-to-child transmission. The chances of a person who is pregnant, who has chronic hepatitis C infection, passing infection on to their child is one in 20—so, about 5% to 6%—based on some studies. We definitely need more data. The study that I’m particularly thinking of was in Kentucky, which had seen an incredible increase in the absolute numbers of children being born infected, or at least antibody positive, for viral hepatitis C—you know, born to mothers with known infection. So that’s one of the huge drivers.
Obviously, there are some older adolescents who may be injecting drugs and are not able to access, or are not accessing, harm reduction services for clean syringes and other ways to protect themselves from transmission. So, it’s both those things. But parent-to-child transmission, I would say, is probably the primary driver.
TW: Thanks for bringing that piece up. I did want to ask you about hepatitis C treatment for pregnant people. Is the safety and efficacy of DAAs still pending for that population?
Gaudino: We don’t have any reason to believe that these drugs will not be safe in pregnant people, but we are still collecting data required in order to do regulatory approvals. We can’t go by small studies; we really need to have sufficiently powered studies and make sure that we recruit diverse patient populations for these clinical trials—and monitor them for a while afterwards to make sure that they don’t relapse, and that there aren’t any side effects that affect either the parent or the child during the course of treatment.
So, regulatory approvals are still pending. But we’re very optimistic that DAA treatments will be proven safe and effective in pregnant people who do have chronic hepatitis C infection and that we’ll be able to soon recommend and prescribe those patients, so that individuals who are seeking prenatal care, if they’re diagnosed, that they can be treated and cured and then hopefully eliminate parent-to-child transmission, which would also be hugely important for children, and all those living with chronic hepatitis.
TW: Are there any updates on hepatitis C vaccines?
Gaudino: Of course, as always happens, there was a paper that was published, shortly after we went to press, in South Korea that showed some initial promising results of a vaccine candidate, which is now entering phase 1 trials in South Korea. It’s really encouraging to see that this research is ongoing, and that we’re starting to have results.
I also want to highlight that in the most recent House Appropriations bill, TAG was successful in advocating for the inclusion of some earmarked targeted funding for research and development of a hepatitis C vaccine, and that $8 million has been appropriated for that purpose. There’s still a lot of work to be done on the budgets, and any continuing resolutions this year. But getting that line item in there was a significant victory, and something that perhaps hadn’t been on the radar of appropriators before. TAG worked really hard to make sure it is on the radar.
There is a group at Oxford that is working on a vaccine candidate that had previously reported being stalled in their work because of lack of commercial interest and public funding. We’re hoping that these investments will catalyze more development on that candidate and other candidates, and start to bring that work forward.
We, unfortunately, did get some negative results from a previous candidate that was tested in a cohort of people actively injecting drugs. It showed no protective effect. But perhaps there’s more to be learned about that candidate. And it’s possible that changes to that candidate or its use in combination may prove more effective, or it may have some therapeutic values that we’re not aware of right now.
So, the work is ongoing. But, again, I’m very encouraged to see that labs globally haven’t given up thinking about a vaccine and effective preventatives, prophylactic vaccine, for hepatitis C virus.
TW: At the end of the chapter, you mention that this would be the final hepatitis C treatment chapter in the TAG Pipeline Report. And I was curious: Why is that?
Gaudino: Well, there’s a lot of advocacy to be done, but there’s not a lot—as we’ve been saying—of science that’s coming down the way, with regard to new classes of drugs. However, there’s still a lot to be learned about how to best use these drugs in current patient populations. For example, looking again at short-course treatments. How low can we go? How short can we go? Is six weeks as short as we can go? What about reducing time courses for other DAA combinations?
There are still some combinations that we are awaiting results on—for example, sofosbuvir/ravidasvir, which is a novel combination that was developed by Presidio and manufactured by Pharco in Egypt, that we’re hoping to get some results, with regards to patients having genotype 5 and 6, so that we can show some pan-genotypic activity for that combination.
China has developed a novel combination using ravidasvir with danoprevir, which is a pre-existing DAA that kind of fell by the wayside earlier in the DAA story. But they’ve recently approved that for genotype 1 patients. However, that is only for the Chinese market.
We’re looking ahead to things like long-acting injectables. You know, what is the potential to have a DAA formulation that can be given in one or two injections that could lead to cure? How would that work? Would it be acceptable to patients? What are the pros and cons of that, versus an oral once-a-day regimen in people that lasts six weeks or eight weeks?
So, there are still things to be determined, in terms of how best to get DAAs into people that need them. But most of that work is implementation science and delivery methods. And it is the advocacy that needs to happen. So we’re really going to be focusing on trying to get drugs into bodies, as ACT UP used to say; and not so much updating on the latest research. Because it’s just really, really slowed to a trickle right now.
TW: Bryn or Annette, is there anything that you think would be important to talk about in closing that I didn’t already ask you about?
Gaudino: I would say that COVID has revealed many things. But these are things that people living under oppressive systems and in marginalized communities already knew—about the fragility of our so-called safety net, about the lack of political will to care for certain communities, based on their criminalized behavior or just their status in society, and that the status quo ante before COVID was not working for a lot of people.
So, there’s a lot of work to be done—not just to recover, hopefully in the near future, from the devastating impacts of the global COVID-19 pandemic—but to really fix the problems that were preexisting it that have been, you know, again, sort of revealed and highlighted by the pandemic.
Everything that’s been happening in the last six months really begs the question: As we’re seeing policy ideas that have been considered too radical and too disruptive to even consider—things like Medicare for All, things like viewing essential medicines as public goods—those things were beyond the pale. And now you have governments and policy makers scrambling to apply those concepts for when it comes to COVID, for one infectious disease.
If it’s a good idea for COVID-19, why isn’t it a good idea when it applies to hepatitis C virus? So, I think we all have a lot of work to do. But the environment that we’re working in; the terrain has shifted radically under everybody’s feet. And let’s see what we do with that.