Charting the Course: Antivirals for Refractory CMV Infections

Dr Atul Humar (Ajmera Transplant Center): So we're going to take a deeper dive into antivirals, the mechanism of action, when to use them and the data supporting it.

[00:34:27]

GCV: Mechanism of Action

So let's start with ganciclovir. Of course the backbone of what we use either valganciclovir, which is a prodrug of ganciclovir or ganciclovir, requires mono phosphorylation. And this is done by the viral protein kinase encoded by UL97, and then triphosphorylated by cellular enzymes, and then binds to the dNTP binding site on UL54, which encodes the viral DNA polymerase.

[00:34:55]

Ganciclovir and Valganciclovir: CMV Clearance Kinetics

And as we heard, ganciclovir or valganciclovir are the initial mainstays of therapy. And this trial, the VICTOR study, done now 15 years ago or so, showed that both were really equivalent in the vast majority of patients. And you can see on this graph on the y-axis is the viral load. Back then we’re using copies per mL, and an x-axis is time. And you can see oral valganciclovir vs IV ganciclovir were similar in terms of viral clearance kinetics.

Both are highly potent drugs. The most common limiting toxicity is cytopenia. As mentioned before, a really important point, and that was shown in the VICTOR study, is that viral load may actually increase within the first week of treatment. And this is just a dead virus spilling out from the tissue into the plasma or whole blood. And be very careful about interpreting small changes in viral load. Remember, it should be interpreted in a logarithmic scale.

[00:35:59]

Considerations for Renal Function Monitoring With Ganciclovir and Valganciclovir

So monitoring of renal function is very important with ganciclovir and assessing renal function. And that's primarily because you have to dose adjust. It's not because—you know, a lot of people will say ganciclovir is nephrotoxic, but it's actually not nephrotoxic in the vast majority of patients. So you have to monitor to dose adjust.

And importantly, in the VICTOR study, the creatinine clearance or the renal function was estimated using the Cockcroft-Gault formula, not eGFR. And if you go to most hospital settings now eGFR is more commonly used. But really there hasn't been the evidence that you can use eGFR to calculate ganciclovir dose. So you just need to be cognizant of the differences in these measurements.

[00:36:46]

Patient Case #1: CMV Treatment

So we'll do a case to start with. So 55-year-old women, 4 months after kidney-pancreas transplant. D– CMV D+/R+ ATG induction and is on standard immunosuppression with Tac, MMF and prednisone. So she receives 3 months of valganciclovir prophylaxis. A month later, she presents with fever, fatigue, mild diarrhea, myalgias, temperature is 38.2. Creatinine is 1.97 mg/dL or 174 mmol/L. And you can see the white count and platelet and hemoglobin are all low. The CMV viral load is 14,000 IU per mL.

[00:37:33]

CMV Treatment Recommendations

Now, the treatment recommendation in her would be to start either oral or IV ganciclovir. So we would typically choose oral valganciclovir for her, unless we were really concerned about absorption with the diarrhea that she's having. Monitor the viral load weakly, monitor CBC, creatinine and treat as - as Dr Kotton pointed out, treat until you reach a certain threshold. So it doesn't necessarily have to be negative as undetectable, it has to be below your center specific threshold that you define.

And then after treatment, you can monitor patients or you can give secondary prophylaxis if you believe they're at high risk for recurrence.

[00:38:14]

Patient Case #1: 2 Wk Later

So let's say this patient receives, you know, valganciclovir or ganciclovir for 2 weeks, but she remains clinically unwell. And now the viral load has gone from 14,000 to 44,000. So you send for resistance testing, you reduce the immunosuppression.

[00:38:33]

Poll 4

And the question is what do you do next? So the - so answer this question. So

1. You could increase the ganciclovir dose to up to a maximum of 10 milligrams per kilogram BID, adjusted for her renal function. So this would be double dose ganciclovir;
2. You could change to IV foscarnet; or
3. You could change to oral maribavir.

Okay. Two of them. First. Yeah. Okay. So that’s interesting. So the majority of people would actually double the dose, ganciclovir adjusted for renal function. This - we'll discuss this in more detail. There's not necessarily a right or wrong answer to this question.

[00:39:29]

Antiviral Drugs for CMV: Mechanism of Action

So let's go through the mechanism of action of the alternative antivirals, starting with—we already discussed ganciclovir, and that's shown in the blue here, binding to the dNTP binding site.

Cidofovir does not require that initial phosphorylation step. So it just requires a triphosphorylation by cellular enzymes. And then it also binds to the dNTP binding site on the UL54.

Foscarnet on the other hand does not require any phosphorylation, it directly binds to UL54 at an alternative site called the pyrophosphate binding site. So you can see how the resistance can arise for each of these drugs. For ganciclovir, it’s a mutation in UL97 so that it no longer phosphorylates ganciclovir, or a mutation in UL54 so that it no longer binds ganciclovir.

And cidofovir, you require a UL54 mutation. And foscarnet, you require a UL54 mutation for resistance.

[00:40:29]

Foscarnet and Cidofovir for CMV Treatment

So what about foscarnet and cidofovir? Well, historically, foscarnet has been the primary alternative therapy for refractory/resistant CMV. And it's interesting because, you know, people have a lot of experience with foscarnet, but there's no actual large randomized controlled trial of foscarnet in solid organ transplant recipients. And there's a number of case series. This is 1 of the larger ones that looked at 22 solid organ transplant patients receiving foscarnet and they had a high rate of toxicity.

The actual inhibition of viral replication was quite good. It's a very potent drug. But there's a very high rate, especially in solid organ transplant patients of nephrotoxicity. Other adverse events might include electrolyte abnormalities, GI disturbance, and cytopenias.

Cidofovir, there's actually even less data in solid organ transplant patients. And I think most of us would very, very uncommonly or rarely use cidofovir. But this is 1 of the larger studies. It's 16 patients of whom 10 were solid organ transplant patients. The rate of nephrotoxicity was very high, 37%. And there was also a high rate of ocular toxicity, so uveitis. And 50% actually had failure to clear DNAemia.

[00:41:56]

Maribavir for CMV Treatment

Now the other more recently licensed drug for treatment of refractory/resistant CMV is maribavir. It's an oral drug only, so there's no IV maribavir. And the way this drug works is actually inhibits the viral protein kinase UL97. So this is also the protein that phosphorylates ganciclovir. But in the virus it seems to have another function. It seems to be involved in nuclear egress of the virus. So when the viral particle is made in the nucleus, it has to egress out of the nucleus into the cytoplasm of the cell, and blocking UL97 seems to prevent that process.

Maribavir does not affect the UL54 polymerase. The good thing about maribavir is it's not myelosuppressive or nephrotoxic. The main side effect is a taste disturbance or dysgeusia. So you actually have to warn patients about that before starting the drug so that they're aware that that might happen.

[00:42:56]

SOLSTICE: Maribavir vs Investigator-Assigned Therapy for Resistant or Refractory CMV

This is the phase III trial that led to approval of maribavir for this indication. So it's called the SOLSTICE study, and it included both stem cell and solid organ transplant patients with a viral load or DNAemia above 910 IU per ml, and they were deemed to be refractory/resistant by the investigator.

Patients were randomized to 400 milligrams PO BID of maribavir for 8 weeks or what was called investigator-assigned therapy, which meant that it was the choice of the investigator what drug to give. And if we look at what drug those patients got, most of them got either ganciclovir, valganciclovir often at a higher dose, or foscarnet were the 2 most common options.

In that arm, they were allowed to also rescue with maribavir if the investigator felt they were failing or intolerant of the IAT. The primary endpoint was clearance of CMV at Week 8. I want to emphasize that the bottom line here, if you look at the viral loads in those patients, they’re actually quite low. So the median viral load was 3377 and 70% of patients had CMV DNAemia levels of less than 10,000 IU per mL.

[00:44:18]

SOLSTICE: Symptom Control and Confirmed CMV Viremia Clearance

This is the results of the study. So the maribavir was superior to the IAT. And we can see at Week 8. So remember it's 8 weeks of therapy. The clearance was 55% in the maribavir arm vs 23.9% in the IAT arm. After patients stopped therapy there was recurrence of DNAemia. And you can see by Week 12 it's 22%—22.6 and 10.3%. And by Week 20, it's 18.3% and 9.4%.

There were a lot more patients in the IAT arm who did not complete their therapy, so they had to stop typically due to neutropenia or leukopenia in the ganciclovir patients or due to nephrotoxicity in the foscarnet patients.

[00:45:09]

Maribavir Resistance Maps to UL97

Now, 1 of the main concerns with maribavir is the development of resistance. And there was this study looked in detail at all those patients enrolled in the SOLSTICE study. And what they found was that maribavir resistance developed in 26% of those patients. So this is emergent resistance means it's developing after initiation of the maribavir.

And where does maribavir resistance map to? It maps also to UL97, just like ganciclovir resistance does. But the resistance mutation sites tend to be different for the most part. The 3 most common maribavir resistance mutations here are shown in blue, and only 1 of those has an overlapping ganciclovir resistance, which is the C480F mutation.

In the SOLSTICE study, the median time to development of maribavir resistance was about 56 days after starting treatment.

Now the clinical clue how do you suspect maribavir resistance is, if you have a patient on maribavir and the viral load starts to go down, and then while they're still on the drug, the viral load starts to go up. About 86% of those patients will have maribavir resistance.

[00:46:26]

Pearls From the International CMV Guidelines

So here's the pearls from the international guidelines. So what we said is refractory CMV without detected resistance should be managed by monitoring patients’ current treatment or switching to another therapy depending on viral load trajectory, clinical conditions, AEs, availability and cost.

We said maribavir is the principal alternative therapy for treating patients with CMV that is resistant to ganciclovir or foscarnet, and that was a strong recommendation. And then we said foscarnet is the initial therapy for clinically unwell patients with high viral loads. And this was a weak recommendation. But based on a lot of discussion and a lot of opinion from the group, we put out a cutoff of approximately 50,000 IU in plasma based on expert opinion.

[00:47:23]

Algorithm for the Treatment of R/R CMV Disease

There's a very nice algorithm within the guidelines which Camille will present. This is a simplified version of the algorithm. But you can see if you have inadequate response to treatment, check drug dose, reduce immunosuppression, send for resistance testing.

If you have a refractory/resistant CMV, at that point, you look at what the viral load is. Is it low to moderate or is it high? If it's low to moderate, you can give maribavir. If it's high, you start with foscarnet, especially if the patient is clinically unwell.

And then you can step down to maribavir once you have good viral control. If you have CNS disease or retinitis, you should avoid maribavir in that setting because the absorption concerns and it hasn't been well studied.

If you have a proven resistance, then you choose the antiviral based on the resistance profile, whether that could be maribavir or foscarnet.

[00:48:25]

Costs of Maribavir vs Investigator-Assigned Therapy for Refractory CMV Post Transplant

Now 1 of the issues with maribavir is that it is very costly. And this was a follow up study to the SOLSTICE that looked at the cost analysis of patients enrolled in that study. So the first column is maribavir. The second column is investigator-assigned therapy. So they looked at treatment costs. They looked at costs with retreatment, so patients who relapsed. They looked at hospitalization costs. They looked at costs due to adverse events. And they looked at total organ graft dysfunction and loss and the costs related to that.

And in the end, the 2 costs are actually pretty similar, with maribavir being just slightly cheaper than the investigator-assigned therapy when you take all those costs into account.

[00:49:14]

Guideline Recommendations: Additional Therapies for Resistant/Refractory CMV

So here are some additional kind of pearls from the guidelines. We had a lot of discussion on the use of adjunctive IVIg or CMV IgG. It's not routinely recommended but might be considered for refractory/resistant CMV and very severe CMV.

T-cell therapy, there's a big section on T-cell therapy in the guidelines, and it does seem to work in a subset of patients, but the trials are very small. Many of the products out there are typically third party T-cell products are not routinely available in many jurisdictions, but there are other trials going on, and this is an option for selected patients.

Several drugs used for other purposes, including mTOR inhibitors like sirolimus and everolimus, leflunomide and artesunate are reported to have anti-CMV effects. But really, we didn't feel that there was sufficient evidence to recommend any of these drugs for treatment of resistant CMV infection. And that really, if you're using an unapproved or experimental therapy, the evidence is weak and limited to anecdotal reports, and it should be done in the context of a clinical trial.

[00:50:28]

Can I Use Letermovir for CMV Treatment?

Now 1 common question that we get is can we use letermovir for treatment? And I think this was especially before maribavir became widely available. This was actually commonly being done in practice. And so how does letermovir work? Well, when the virus is replicating, it produces these concatemeric strands of DNA which are adjoining strands of DNA. And those require cleavage prior to packaging. And that cleavage is done by the terminase complex, which is a set of proteins that combines together.

And 1 of those proteins is encoded by UL56, which is inhibited by letermovir.

[00:51:12]

Letermovir for CMV in Transplant Recipients

So what's the data on using letermovir for treatment? There's not a lot of data. Most of its case series. This is 1 of the larger case series. There was 47 transplant patients including both stem cell and solid organ transplant patients. 37 of those had a viral load of less than 1000 and 10 had a viral load of greater than 1000.

What the authors saw in this study was that those with a viral load less than a 1000 seemed to have a reasonable response, although we don't know how many of those would have cleared viremia on their own.

But those were the viral load greater than 10,000 had really kind of mixed outcomes, with a lot of failures and development of letermovir resistance. So in the guidelines, what we recommend is against the routine use of letermovir for treatment due to potential for resistance emergence, especially if the viral load is reasonably moderately higher or very high.

[00:52:09]

What About Combination Therapy?

Now the other question that arises a lot is combination therapy. And really this is a data free zone. It's a clinical anecdotes only, case reports. And data are needed on the use of combination therapy, although many experts might use it in selected situations. Kind of the cost of these and the access to them can become significant issues.

Now here are some of the theoretical combinations that could be considered. In the past, many people used to use ganciclovir plus foscarnet to try to spare the foscarnet doses, but there is minimum evidence to support this and it's not really recommended anymore.

You could add letermovir to either ganciclovir or to foscarnet or to maribavir. There is a theoretical benefit to targeting 2 different viral enzymes, targeting both the UL54 and the UL56. But again, there is no data yet to support doing this.

You could add foscarnet to maribavir, but what you should not do is add ganciclovir and maribavir. And the reason for this is the 2 appear to be antagonistic. And that makes sense because the maribavir will inhibit UL97 and so it won't phosphorylate ganciclovir anymore.

You can add CMV immune globulin, and many experts reported adding either CMV-IG or IV-IG for severe disease or refractory/resistant CMV.

Many in the room, at the time we did, the expert panel preferred using CMV-IG in that setting. There are other agents being investigated, but these are best done through clinical trials.

[00:53:56]