MINMON Study Details: What and Where
Terri Wilder: Thanks for speaking with me today.
Sunil Solomon: Thank you for the opportunity.
Wilder: First, tell me about the MINMON Study and its objective.
Solomon: The MINMON Study was designed to see if we could deliver hepatitis C treatment therapy to people living with hepatitis C globally in a very simple and safe manner that had minimal in-person contact and minimal monitoring.
“MINMON” actually stands for “minimal monitoring.” Could we use such an approach and still deliver care in a very efficacious and safe manner to people living with hepatitis C globally, across the world?
Wilder: Talk to me about the study design and the setting.
Solomon: This study was conducted as part of the AIDS Clinical Trials Group, which is funded by the Division of AIDS from the National Institute of Virology and Infectious Diseases, from the NIH [National Institutes of Health]. Gilead Sciences provided the study drug. They also provided some additional funding.
The different sites and the setting was all across the world, where the AIDS Clinical Trials Groups operate. There are 12 countries where the ACTG currently operates, all of which were eligible to participate in the trial. And all the study sites were the Division of AIDS-certified clinical research sites that were affiliated with the AIDS Clinical Trials Group network globally.
The study design itself: It was a single-arm trial. It was open label and a Phase 4. All study participants across the whole world got the exact same medications: a 12-week course of sofosbuvir/velpatasvir, which is a fixed-dose compound genotypic combination.
The MINMON Approach: Minimizing Contact While Improving Care
Wilder: Tell me about the MINMON approach.
Solomon: The MINMON approach really was designed to minimize face-to-face contact with the participants. All of us look at medical care and say, “If I was infected with hepatitis C, how would I want to be treated? Would I want to go to a doctor every week?” It was also borrowing from different diseases and also the advances in hepatitis C therapy—that really was the essence of the MINMON. The essence really was simplicity.
A couple of things have happened with hepatitis C therapy over the years, especially over the past decade. In 2016 we started seeing a lot of pan-genotypic regimens with extremely high efficacy. Sofosbuvir and velpatasvir was the first pan-genotypic, one-tablet, once-a-day regimen with extremely high efficacy rates that was approved. That really prompted us to ask the question: If it’s going to work equally across different genotypes, do we need to actually have a genotype at baseline?
We decided it wasn’t necessary. So the first element was to completely eliminate that need for pretreatment genotyping. This is very important because, in most low- and middle-income country settings, they don’t have access to genotyping. Waiting for patients to get a genotype means that people can’t get treated, despite the fact that you did have pan-genotypics around. So this was the first thing we eliminated.
The second thing that happened with hepatitis C treatment over the years is the treatments had become extremely safe.
Previously, we were treating people with interferons and ribavirin—multiple drugs which are very toxic and were not very efficacious. So, we would do something called response-guided therapy. We would look at what your response to therapy was, like, 4 weeks, or 8 weeks, or 12 weeks into therapy. If you weren’t responding favorably, then we would stop your treatment, because we didn’t think it made sense to expose you to treatments that were toxic, especially if you were not going to respond.
What’s happened with direct-acting antiretrovirals, ever since sofosbuvir and velpatasvir and the different regimens that have been available globally, is they’ve been extremely safe. So there was no reason for discontinuation. There was no response-guided therapy. There really was no reason to do any of those interim labs at weeks 4, 8, or 12. We said, “OK. There’s no need.”
There was also no need to come and see a physician just to get a refill, and so, we said, “OK. The second step is going to be, let’s eliminate all on-treatment monitoring.”
The third component was borrowing from HIV, where multi-months’ dispensation of antiretrovirals has pretty much become the norm. In some countries, we deploy six months’ worth of refills at a time. Yet, for HIV, I think most programs in the U.S. and globally would require people to come in at least every four weeks; and in some programs, globally, they want people to come in every two weeks for refills.
This is challenging on multiple levels, because if you had to come in for a refill, you had to see a doctor, and then you had to take time off from work, you had to take public transport or your own private transport. It really is a lot of inconvenience, and it’s something that I wouldn’t want to do.
We know from HIV that people can be given three months’ or six months’ worth of medications, and they’re completely fine, and they’re adhering, and they’re virologically suppressed. Why can’t we just give them all the 84 tablets at baseline? That was the third component of the MINMON.
The last thing that we did in the MINMON approach was, while we did give them the 84 tablets and told them, “We don’t need to see you on treatment. We don’t need any genotyping at baseline,” we did have two remote touchpoints. One was at Week 4, where we instructed the different sites, “You can do whatever you want to contact the participants. Just don’t make them come in. You can call them. You can email them. WhatsApp. Text message.” Different countries use their own protocols locally — whatever was convenient to the participant.
They would touch base with the participant on Week 4, which was more like a check-in. It would be like, “Are you taking your medications? Is everything going well?” For people who said they were taking their medications; sites would say, “Great. Keep it up. You’re one-third of the way through.” For people who report that they were not a hundred percent adherent, they would tell them, “Remember, hepatitis C treatment works, but it only works if you’re a hundred percent adherent.” So, that was the contact at Week 4.
The contact at Week 22 essentially was to tell them, “OK. You’re ready to come in for a visit to check whether you have responded to therapy or not.”
Those were the four components: There’s no pretreatment genotyping; we give them all the 84 tablets at baseline; we had no scheduled on-treatment clinic visits or laboratory visits; and we had these two remote touchpoints, one at Week 4 and one at Week 22.
Wilder: How would this approach work for a patient with more advanced liver disease, like cirrhosis? Is that a concern?
Solomon: Absolutely. I think that actually, in the trial, we did exclude people with decompensated cirrhosis.
Cirrhosis essentially means that your liver is scarred. There’s some scar tissue on your liver. But even among cirrhotics, there are two different groups. You have the compensated cirrhotics who were the ones who had some scar tissue on the liver, but the liver is still able to perform its daily functions. Then you have the decompensated cirrhotics who have a lot of scarring in their liver tissue, and their liver is not able to function normally.
For the decompensated cirrhotics, there is enough data to show that just this one drug does not work; this combination of sofosbuvir and velpatasvir does not work as well in this group as it does in compensated cirrhotics. So, this group was excluded from the trial because they do need a lot more intensive monitoring, especially from hepatologists, to make sure that whatever the liver functions that have been affected are being monitored closely.
This MINMON approach is not something that we would advocate for in decompensated cirrhotics because they do have critical liver disease that needs to be managed by experienced hepatologists.
But we did include people who were compensated cirrhotics, because the evidence available at that point in time, in 2016 when we designed the study, showed that even in compensated cirrhotics, 12 weeks of sofosbuvir and velpatasvir did get extremely high cure rates.
But what we did as part of the trial was, we did have a lot of counseling built in, related to their cirrhosis. At baseline, they received that cirrhosis counseling. Then when they came in for their SVR [sustained virologic response] assessment, we told them, “Well, you have been cured of your hepatitis C, but you do have some scar tissue on your liver. So don’t forget to keep following up for your liver disease to make sure that the progression is not bad, and your cirrhosis is taken care of.”
It’s almost looking at it as two separate things. You can use the MINMON approach for compensated cirrhotics to cure them of their hepatitis C. But you still need to follow them up with specialist care, and manage their cirrhosis, to monitor it on regular intervals to make sure that it doesn’t get worse.
MINMON Study: Profile of Participants
Wilder: Can you go into more detail about who was eligible to be included in the study?
Solomon: We kept our eligibility criteria really broad. The one thing that we did require was that you had to have some evidence of active hepatitis C infection. That’s HCV RNA with at least 1,000 IU/mL. You had to have detectable HCV virus in your blood. We also required you to be hepatitis C treatment-naïve, meaning that you had never been treated before with any of these direct-acting antiretrovirals, any other treatment for hepatitis C.
Obviously, all participants had to provide written informed consent, and they were willing to be contacted remotely, because that was part of our approach.
We did allow cirrhotics, as I told you, to take part in the trial, but we only allowed compensated cirrhotics. That enrollment was capped at 20%. We didn’t allow people with advanced liver disease to be enrolled in the trial.
We also allowed people with HIV coinfection to be a part of the trial, because there is a large proportion of HIV-infected people globally who also are living with hepatitis C virus. We capped their enrollment at 50%, so no more than 200 participants could be coinfected. Those were our key inclusion criteria.
In terms of exclusion, we excluded people who had decompensated cirrhosis, as I’ve already mentioned. We also excluded women who were pregnant, because there is not enough data on the use of sofosbuvir and velpatasvir in pregnant women.
The last group we excluded were people with chronic hepatitis B infection. There is limited information on what happens to hepatitis B, and there have been some reports of flaring of hepatitis B-associated liver disease when you treat people for hepatitis C.
When I say evidence of hepatitis B, for purposes of this trial we only excluded people who had hepatitis B surface antigen positive. There was some mixed information available in 2016 suggesting that isolated core may be associated with liver flares as well. But the evidence wasn’t concrete and, at that point, we decided that we would only exclude people who were surface antigen positive. If you were hepatitis B isolated core positive, we would still include you in the trial.
The trial itself never really tested people for these different other markers of hepatitis B. They only tested people for surface antigen. If they were positive, they were excluded; if they were negative, they were included—regardless of what their other hepatitis B markers looked like.
Wilder: And you said the sample size was 400? Is that right?
Solomon: Yes. The overall sample size was 400.
Wilder: Can you talk about the breakdown of participants by gender and race?
Solomon: In gender, 35% of the samples, or 139 participants, reported female sex at birth. We had 6%, which was 22 participants, who reported being on the transgender spectrum. So that was sex and gender identity.
In terms of race, 42% of the sample was white, 18% were Black, and 28% were Asian. The one thing to note is that we did capture race and ethnicity separately. About 25% of the population self-identified as Hispanic. And because we had 131 participants from Brazil, we also had a lot of mixed-race identification, in both the race and the ethnicity.
We did end up with a reasonably good mix of the population, where the majority were not white.
Wilder: There weren’t many study participants enrolled from Uganda and South Africa. Is that because those countries don’t have high rates of hepatitis C? Or were there issues with the recruitment?
Solomon: For Uganda, they recruited very quickly for 13 participants, but it took them a long time to get their approvals in place. They opened up much later, when there were far fewer slots left to enroll in the trial.
For the international sites, we didn’t actually have quotas for each of these different countries—there were 268 slots across all the countries. The countries that did better could enroll faster. So, for Uganda, there may be more infections. But overall for the number of either hepatitis C monoinfected or HIV/hep C-coinfected participants, I believe there are significantly more in Brazil and Thailand compared to the sites in Uganda and South Africa.
That’s probably for two reasons. One is probably they opened later. And then they also probably had fewer participants, compared to Brazil and Thailand.
Wilder: It also looks like around a third of the individuals were either former or current injection drug users. Obviously that’s a very important cohort to include. What can you tell me about these participants?
Solomon: We did not exclude people who injected drugs, but we also said that in the judgment of the clinical investigators of the site, as long as they felt that they were stable, and they could participate in the protocol, they could be included in the trial. Like you said, I think people who inject drugs are an extremely important population when it comes to elimination of hepatitis C. We’re never going to be able to eliminate hepatitis C without the inclusion of this population.
Again, we recruited participants from the AIDS Clinical Trials Group research sites globally. The overall mix of people who inject drugs in these sites is not that high. I’m hoping that when we get the primary manuscript out, we will have a lot more detailed information about how this approach worked in people with a history of active drug use.
Wilder: Can you say more about the participants that were living with HIV and hepatitis C coinfection?
Solomon: Sure. Because this was the AIDS Clinical Trials Group, and most of these sites are geared towards recruiting HIV participants for trials, we did see a large proportion of participants who were coinfected with HIV and hepatitis C.
We enrolled 166 participants out of the 400—42% of the population—who had both HIV and hepatitis C coinfection. The only criterion we had for coinfected persons was they could not be on any efavirenz-containing regimen, because there’s a drug-drug interaction between efavirenz and the sofosbuvir/velpatasvir combination.
They also had to satisfy either one of two other [HIV-related] criteria. If they were on antiretroviral therapy, then their HIV RNA had to be less than 400 copies/mL. Essentially, if you were on treatment, we wanted you to be suppressed. The reason we wanted that was because we were trying to do a protocol where there’s no interim clinical visits at all. We didn’t want someone who was unsuppressed, who had to go into the clinic multiple times for their HIV care.
The other group that we did allow were people who had a CD4 count greater than 350, but not on antiretroviral therapy—and, at least at enrollment, reported that they did not want to get on treatment for at least the next six months. This was the same reason: We didn’t want people having interim visits.
That being said, 164 out of the 166 coinfected people whom we recruited were on suppressive antiretroviral therapy.
MINMON Study Construction: Evaluating Safety and Efficacy
Wilder: What methods did you use to evaluate safety and efficacy in the study?
Solomon: The efficacy of the study was evaluated using the sustained virologic response, which was essentially having the HCV RNA less than the lower limit of quantification at least 22 weeks from the time you started treatment. That’s the standard measure they’ve been using across all clinical trials or population-based studies around hepatitis C.
In terms of safety, these drugs have been through a lot of safety trials before, in terms of Phase 1, Phase 2, Phase 3 trials. The safety outcomes we looked at were adverse events and serious adverse events that were reported during the course of the treatment period—from the time they started until 28 weeks were completed.
When I told you that there were no scheduled on-treatment clinical visits or labs, [but] participants could come in at any point in time. They were more than welcome to have unplanned clinical visits. And we recorded all these unplanned visits and the reasons why these unplanned visits happened.
Study Results: MINMON Comparable to Routine Clinical Care
Wilder: What were the results of the study?
Solomon: Overall, out of the 399 participants who initiated treatment—I believe 400 participants were enrolled in the trial, out of which one participant didn’t initiate treatment—379 achieved sustained virologic response. The overall sustained virologic response rate was 95%.
That is pretty comparable to what we would see in routine clinical care, having people come in every four weeks or every eight weeks, and then doing more laboratory monitoring while they were in care, dispensing medications every four weeks. And we would still achieve somewhere between 95% and 96%. So, we felt that this was definitely comparable to what we are currently seeing in clinical care.
Wilder: Can we talk a bit more about SVR by subgroups? What accounts for those who were not able to achieve SVR?
Solomon: We looked at country, sex at birth, cirrhosis status, HIV infection, and other criteria. I think the only group where the confidence intervals of the SVR did not overlap at 95, which was the overall confidence interval, was the age group of 20 to 29.
A couple of things to note there: This population has been shown to have poor adherence to multiple things. Even in HIV, younger populations, especially adolescents, we generally have to have much more interventions in terms of adherence to improve virologic outcomes.
The same has also been seen with hepatitis C in extremely young age groups—the young 20s. Their adherence may not be the best. But we only had 33 participants in this group. It’s very hard to make any decisive conclusions about this group from the study.
Across the other groups, the confidence intervals did overlap with the overall estimate of the study. So, it did seem to perform well.
We didn’t perform any formal hypothesis testing across these different groups. And it’s very hard for me to say right now that these 20-to-29 year olds did worse [on MINMON] because I don’t know what proportion were also cirrhotic, or what proportion were active drug users. That is something we will dig into in a lot more detail as we go forward.
In terms of the non-responders, out of the 20 people who didn’t respond, we lost two participants after baseline. Essentially, they started treatments and we never heard from them again for the duration of the study.
There was one participant who showed up for their follow-up visit two days before the SVR visit window opened, and that sample could not be used. That person also did not achieve SVR.
One thing that was interesting in these groups was: About two-thirds of the participants on whom we had follow-up information, even though they failed treatment, they reported a higher percent adherence. Similarly, about 13 of the people who failed treatment also reported that they completed their treatment within an acceptable time frame of 77 to 91 days, which is about 10% plus-or-minus the 84, which is what we would estimate as good adherence. There were quite a few people here.
But the challenge we have here in this particular study design: Because we had no samples while they were on treatment, we don’t know if they were actually cured of the virus and then got reinfected between the time treatment ended and the time they came in for their SVR assessment.
We are looking at the sequences of the samples from the time they failed to what the sequences looked like at baseline. And by comparing these two sequences, we will be able to try and identify if this was a case of relapse or if this was a case of reinfection. I think that would be something important going forward.
It’s a very limited amount of information we have on the non-responders because, by design, we did not have any on-treatment visits. We don’t have any samples stored from while they were on treatment, to try and check drug levels or to try and check for viral load. In that way, that is one of the limitations of the trial design itself.
Wilder: Were there any serious adverse events that were recorded?
Solomon: There were a total of 14 participants who reported serious adverse events throughout the course of the trial. But only five of these serious adverse events happened while they were on study medication, and none of these adverse events were associated with the study drug.
They included suicidal ideation and depression. There was one case of myocardial infarction. There was some hypertension, respiratory failure, anemia, and a person who was ultimately diagnosed with preexisting pernicious anemia. Those were the serious adverse events, but none of them were associated with the study product.
There were 28 adverse events, in which we had five adverse events that were attributable to the study product. Those included two episodes of diarrhea, one case of headache, one report of fatigue, and there was one episode of abdominal distension that resulted in the treatment discontinuation.
Overall, in terms of relation to the study product, we had no serious adverse events at all, and we only had five adverse events that were related to the study product.
Wilder: In terms of implementation of the MINMON strategy, you had three participants that lost their study medication and two that reported premature discontinuation. What do you do when that happens?
Solomon: At the study entry, everyone had little boxes, they had numbers, and they also had specific instructions saying, “If you lose your study medications, call the study site immediately.” As part of the trial, we were going to give them one free refill if they lost study medications, as long as they did not interrupt for more than 40 days, in which case you would need to start the entire course again from zero.
Out of the three participants who lost the study medications, two people contacted the study site, within four or five days from the time they lost their study medications, and we replaced the study medications for those two participants.
There was one participant who reported losing the study medication and did not report to the site for more than 14 days. I think he lost the study medication on Day 6 and we found out about it on Day 28, when we had that remote contact. For that participant, we could not replace study medications as part of the trial.
In terms of the premature discontinuation, one of them was the loss of study medications that wasn’t reported to us. Another participant had abdominal distention, which the study clinician felt was associated with sofosbuvir and velpatasvir.
Otherwise, as far as we know, all of the other participants completed their course of study medications. Some of them obviously took longer to finish it. But all parties eventually finished their study medications.
One thing that was critical to us was, if a lot of patients had reported losing their study medications, then the MINMON approach really doesn’t seem like an effective or a good approach. Ideally you don’t want to be replacing medications for too many people, because in some countries these medications are very expensive.
Wilder: Besides having limited information on non-responders, were there any other limitations to the study?
Solomon: Because, by design, it was a one-off trial, we don’t know whether, if we had the standard procedures in place, could the SVR have been significantly higher? If you four-weekly contact with the participants, dispensation every four weeks, and we tested for your viral load more frequently? That’s the question we can’t answer.
With relevance to HIV and hep C coinfected participants, the limitation for us is because almost all the participants were on HIV treatment and virologically suppressed, by default we selected for people who were more likely to be adherent. So it’s unclear if this 94.6% SVR that we saw among HIV/hep C coinfected people could be generalized to all HIV-infected people, even the ones who are fully adherent to antiretrovirals.
The other limitation: Ideally, we would have loved to have run this trial through a primary health care center or something with minimal infrastructure. Through sheer elimination, we really had to decentralize care and take it down all the way to the grassroots level. But because by design, because it’s an AIDS Clinical Trials Group trial, it was out of ACTG sites globally.
But the important thing to note was, we literally had no clinical visits required. All the investigations that we have used, with the exception of the hepatitis C viral load, would be available in any primary health care center. We were using complete blood panels, liver panels, and adrenal function tests—tests that were routinely available in most clinical settings.
Looking Ahead: MINMOM and the Future of HCV Treatment
Wilder: Most of these studies are conducted to help improve the care of patients. Do you think the results from this study could inform clinical practice going forward?
Solomon: In terms of clinical practice, especially given the new normal that we’re living in—where we are trying to minimize face-to-face contact and we’re moving to strategies such as telemedicine and virtual consultations—this is something that fits in perfectly.
It does have a huge role to play with the hepatitis C elimination agenda because, by eliminating tests like genotyping and multiple frequent tests, you’re really bringing down the costs associated with delivering treatment. To deliver treatment in a resource-limited setting—or even in the U.S.—it’s not just the cost of medication, but it’s also the cost of all the different monitoring tests and the different pre-treatment tests, and everything that we would require. That whole thing is one package.
We literally cut so many tests off from that package that it’s going to be a minimal addition to what the actual cost of therapy itself is in the U.S. And in non-U.S. settings, it greatly improves access, because genotyping is something that didn’t exist. The WHO has been advocating for pan-genotypic regimens and eliminating the requirement for genotyping, and I think this study provides enough evidence that you don’t need that pre-treatment genotype.
So, it does show that you could manage this with really limited resources and in settings with minimal in-person, face-to-face contacts. If you could work out some way of doing laboratory tests remotely, you could treat like 90% of the patients who are probably non-cirrhotic but living with hepatitis C, without ever having to come into a physical space. That’s where medicine is also growing going forward, and where we’re trying to make things and cater to the next generation.
Even in the U.S., I feel that we’re switching more and more to where things come to us—with Amazon and the other big players, everything comes to you. The same thing is happening globally: In India, people want things to come to them; they don’t want to go to places.
This is a strategy where, with telemedicine and having remote blood draws—either blood collections happening at home or going to a remote lab and getting a blood draw, and getting that essential basic analysis done—we could probably cure your hep C remotely.