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Managing HCV infection and organ donation
Medication selection, patient education among skills driving better outcomes
SPs Help Make HCV+ Organ Transplantation Safer
Organ transplants from hepatitis C virus (HCV)-positive donors to HCV-negative recipients will continue to increase in frequency as more transplant centers develop protocols for their management, said experts from major transplant programs in a session at the ASHP 2020 Midyear Clinical Meeting and Exposition.
Integrated specialty pharmacies have responded to this trend by playing a key role in assisting with the selection of medication, management of drug interactions, procuring medication (including insurance approval and financial assistance) and patient education.
These are timely efforts, given that the number of transplant centers using HCV-infected kidneys jumped from 11 in 2015 to 39 through the first three months of 2019 (J Am Soc Nephrol 2019;30[10]:1939-1951).
Although direct-acting antiviral (DAA) drugs have had virtually universal success in clearing the virus from these patients in multiple clinical trials over the past several years (Rev Recent Clin Trials 2019;14[3]:173-182), management of these cases can be complex. “Integrated specialty pharmacy programs can provide the resources necessary to allow these patients to gain access to and remain adherent to DAA therapy,” said Alicia Carver, PharmD, BCPS, a specialty pharmacist in the Digestive Disease Center at Vanderbilt University, in Nashville, Tenn.
More than 110,000 patients were on the waitlist for solid-organ transplants as of late 2020, and more than 5,000 people died while on the waitlist in 2019. Meanwhile, the opioid epidemic has led to an increase in overdoses as well as an increased number of potential organ donors who are HCV-positive.
Beginning with a pioneering clinical trial launched by researchers at Penn Medicine in 2016, a series of trials have demonstrated the safety and efficacy of positive-to-negative transplants for solid organs—including kidney, liver, heart, lung and pancreas—with high rates of sustained virologic response (SVR), low rates of adverse effects and decreased costs, while reducing waitlist time and increasing life expectancy (N Engl J Med 2017;376[24]:2394-2395; Ann Intern Med 2017;166[2]:109-117; Am J Kidney Dis 2020;75[6]:857-867; N Engl J Med 2019;380[17]:1606-1617; Lancet 2019;4[10]:771-780).
Preemptive Versus Reactive DAA Treatment
There are two primary approaches to treatment initiation for patients receiving an HCV-positive organ: preemptive (beginning prior to the transplant) and reactive (after the transplant), each with its own advantages and disadvantages. “The preemptive strategy allows for a shorter DAA course, which patients and providers both may find attractive,” said Kristin Beeker, PharmD, MBA, a clinical pharmacy specialist in the specialty pharmacy at the Medical University of South Carolina (MUSC), in Charleston, which began transplanting HCV-positive kidneys to HCV-negative recipients in 2018 and expanded the program to heart, liver, pancreas and lung recipients in 2019.
“We also can potentially prevent HCV infection from occurring, decrease HCVrelated complications and eliminate the need for genotyping. However, there is an increased risk of clinical instability since the patient is receiving a new
organ and we aren’t sure how they will respond to that transplant. That adds another potentially complicating factor i in the early post-transplant recovery period when the patient may not yet be fully stable. There is also an increased risk of drug interactions.
“You also have to have a backup plan if the patient’s insurance doesn’t approve the therapy, since preemptive treatment is not FDA approved,” she said. “That involves either partnering with the manufacturer to obtain medication through a study, or moving to reactive therapy post-transplant.”
Reactive therapy has the advantages of clinical stability in the patient as well as a known decrease in drug–drug interactions, treatment failures and resistance. “Every patient responds differently to transplantation, so it is nice to understand how the patient responds before introducing a new medication with known drug interactions and side effects to potentially complicate the patient’s clinical course,” Beeker said. “But reactive treatment can mean an increased time to DAA initiation, an increased risk for hepatitis C–related complications, and genotyping may or may not be required.”
Studies have demonstrated successful outcomes with both strategies (N Engl J Med 2019;380[17]:1606-1617; Lancet 2019;4[10]:771-780; Am J Transplant
—Alicia Carver, PharmD
[2]:109-117; Am 57-867; N Engl 6-1617; Lancet
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ary nt y A and ttracPharmD, y specialist in at the Medical ( ) m to heart, liver, pancreas and lung pients in 2019.
y Insurance and Financial Advocacy
Getting insurance coverage for direct-acting antiviral (DAA) therapy in transplant patients, particularly in a preemptive situation, can be complex. The involvement of a skilled specialty pharmacy team is essential.
In a report presented at the American Transplant Congress in May 2020, Vanderbilt University specialty pharmacists reported on a series of 91 transplant patients who received DAA therapy. “All of them were able to access coverage,” said Alicia Carver, PharmD, BCPS, a specialty pharmacist in the Digestive Disease Center at Vanderbilt University, in Nashville, Tenn. “Of the 91 patients, 97% were insured; the 3% who were uninsured or underinsured went on to get medications through the manufacturer. For those with insurance, 65% were approved through the prior authorization process, and 35% were approved on appeal. We did not have to move forward with a second level of appeal for any patient.”
The most common reasons for denial were lack of chronicity of the hepatitis C virus diagnosis and a request for more than eight weeks of therapy. The median time to approval was six days, and to first dose, eight days. “To improve your chances for success, be sure to provide all the requested information, including genotype, if it is at all possible to get it,” Carver said. “Most of the insurance providers do require it at this point.”
Other tips to improve the chances of getting a course of DAA therapy approved: • Use a formulary agent if possible. • Ensure appropriate duration of therapy. Ledipasvir + sofosbuvir (Harvoni,
Gilead) and glecaprevir + pibrentasvir (Mavyret,
AbbVie) may be only approved for eight weeks; if that is insufficient, consider appeal prior to treatment start. • If denied, cite appropriate studies and clinical documentation. • Consider a peer-to-peer option if necessary.
Financial assistance options for DAA therapy also can be pursued, including manufacturer copay cards for those patients with commercial insurance. All of the recommended regimens have cards available that reduce patient out-ofpocket costs to $5 and reduce the overall cost of care. Foundations including the Patient Assistance Network Foundation, the Patient Advocate Foundation, Healthwell Foundation, The Assistance Fund and the Good Days Foundation have income-based assistance that can range from $6,000 per year to maximums of $15,000-$30,000, but funds open and close throughout the year depending on available resources.
For patients who are underinsured or uninsured, manufacturers have their own support programs: Gilead’s SupportPath and AbbVie’s MyAbbVie Assist are income-based, and may also assist patients after multiple insurance denials or if insurance coverage is lost while on treatment, Carver said. plan appr treat said. with i
2019;19[11]:3046-3057; JAMA Cardiol 2020;5[2]:167-174; Hepatology 2020;72[1]: 32-41). The current joint guidelines of the American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America (IDSA) recommend early reactive treatment for liver transplant patients, employing a pangenotypic DAA regimen beginning when the patient is clinically stable—with “early” meaning within the first month
after transplant, but preferably within the first week. For nonliver solid organs, the AASLD/IDSA guidelines state that treatment can occur either immediately pretransplant or within the first week posttransplant. “The goal is to undertake DAA therapy as early as clinically possible to avoid the development of acute hepatitis and other complications of HCV infection,” they noted.
Regimen Selection
In programs such as Vanderbilt’s and MUSC’s, integrated specialty pharmacists have been effective and involved members of the care team, helping to ensure rapid access to DAA therapy.
One of their main sources of information and guidance on therapy are the AASLD/IDSA guidelines. Whether therapy is initiated preemptively or reactively, the guidelines recommend two options for DAA therapy for recipients of HCV-positive organs: glecaprevir-pibrentasvir (Mavyret, AbbVie) or sofosbuvir-velpatasvir (Epclusa, Gilead). Treatment is typically 12 weeks. “While the guidelines recommend an eightweek regimen of glecaprevir-pibrentasvir for preemptive therapy in liver transplant recipients, in real-world settings the eight-week duration is not widely practiced at present, because there is not a lot of literature to support the use of only eight weeks of medication in these patient populations,” Beeker said.
Other regimens that have also been successfully used in clinical trials include 12 to 24 weeks of ledipasvirsofosbuvir (Harvoni, Gilead), elbasvir-grazoprevir (Zepatier, Merck) and sofosbuvir-velpatasvir-voxilaprevir (Vosevi, Gilead), although the latter is typically only used in patients who have already been exposed to another DAA regimen and so not common in transplant patients, Carver said.
Selection of the appropriate DAA treatment is a slightly different process for organ transplant recipients than for traditional chronic HCV patients, Beeker explained. “Factors that we typically would consider for the chronic hepatitis C patient include genotype, cirrhosis status, treatment history, timing of treatment initiation, comorbidities and drug–drug interactions,” she said. “But for patients who are not established with chronic hepatitis C, cirrhosis and treatment history are not a factor and genotype may not be readily available. So the things we really consider in this population are the timing of treatment initiation, comorbidities and interactions with other drugs [see below] that may negatively impact the outcome of treatment with the DAA regimen.”
What are some of the most common considerations in selecting the appropriate DAA regimen? First, Carver said, absorption concerns are important in these patients, so regimens that can be given either with or without food can be an attractive choice. According to the drug’s prescribing information, ledipasvirsofosbuvir, sofosbuvir-velpatasvir and elbasvir-grazoprevir can be given without regard to food, whereas glecaprevirpibrentasvir and sofosbuvir-velpatasvirvoxilaprevir should be taken with food in order to ensure optimal uptake.
Another issue is alteration of the dosage form. “Many of these patients may be on enteral feeding, which can require crushing of the medication to swallow or deliver via gastrostomy or PEG [percutaneous endoscopic gastrostomy] tubes,” Carver said. “Ledipasvir-sofosbuvir and sofosbuvir-velpatasvir both have a very bitter taste, which can be a deterrent to the patient if they are crushed for swallowing.” She highlighted several studies on crushing and swallowing or delivery via enteral tube, PEG tube and gastrostomy button; although there were varying increases or decreases in absorption, all patients achieved SVR at 12 weeks (J Viral Hepat 2018;25[2]:214-215; Ther Drug Monit 2020;42[2]:163-164; A J Heath Syst Pharm 2020;77[6]:417-148).
“A phase 4 crossover bioequivalence study comparing crushed sofosbuvir-velpatasvir versus the whole tablet, CRUSADE-1, is ongoing,” she said.
Because all DAAs require gastricdependent absorption, and stress ulcer prophylaxis is common after transplant, acid-suppressing drug management is a key concern with these therapies, given that acid suppression could potentially decrease DAA absorption and compromise SVR. “The use of proton pump inhibitors [PPIs] is notrecommended with sofosbuvir-velpatasvir,” Carver said. “If you absolutely must coadminister them, take the DAA with food and wait four hours before dosing the PPI. Absorption is decreased with the other acid-suppressing agents, but it is not thought to affect SVR.” H2 blockers can be taken simultaneously with ledipasvir-sofosbuvir or sofosbuvir-velpatasvir, or 12 hours apart; there is no guidance on their administration with glecaprevir-pibrentasvir. For antacids, dosing is recommended to be separated from DAA administration by four hours.
Another common drug–drug interaction for DAAs is amiodarone. “Postmarketing studies revealed serious symptomatic bradycardia when administered with sofosbuvir, which was increased with concomitant beta-blockers, cardiac comorbidities and/or advanced liver disease,” Carver said (N Engl J Med 2015;373[19]:1886-1888; also see “warning and precautions” in prescribing information). “Coadministration of these drugs is not recommended; if they must be used together, it requires inpatient cardiac monitoring for 48 hours followed by two weeks of outpatient monitoring.”
Although glecaprevir-pibrentasvir also causes increased amiodarone concentration, “no bradycardia has been reported and only outpatient monitoring is recommended, so that would be a preferred option for these patients,” Carver said. Even if a transplant patient’s current drug list does not include amiodarone, if their comorbidities suggest that they may have been on the drug in the past, “the specialty pharmacist should investigate further, as the drug has a long half-life,” she added.
Immunosuppressants also can interact with DAAs, causing, for example, increased tacrolimus levels. “Anticonvulsants and antimycobacterials are not commonly used in these patients but it’s important to know that there are serious interactions producing decreased DAA concentrations, and they should not be used together,” Carver said. “It’s important to look at each agent and regimen for common drug–drug interactions and consider therapeutic alterations. Should we choose another DAA or should we change the drug that interacts with it?”
Communication Is Key
Because a transplant patient’s medication list may change, regular ongoing communication about their most current medications is important. “In our program, the inpatient transplant pharmacist provides medication administration teaching upon discharge, with a detailed medication action plan [MAP],” Carver said. “The specialty pharmacist reinforces the MAP during detailed DAA education.” One useful tool for this process: the University of Liverpool HEP Drug Interactions Checker (www.hep-druginteractions.org/checker).
Although patients typically tolerate DAA regimens well with few side effects, the specialty pharmacist plays an important role in ensuring that the observed side effects—typically fatigue, headaches, nausea and vomiting, diarrhea and insomnia—do not interfere with adherence. “Mitigation strategies could include changing the timing of the DAAs to minimize these symptoms. For example, if the patient is experiencing headaches an hour or two after taking their medication, it may be beneficial to move dosing to right before bedtime so that the side effect isn’t noticed as much,” she said.
Acetaminophen also can be used for headaches, she added, noting that nonsteroidal anti-inflammatory drugs are not recommended in a transplant population because they can interact with antirejection medications. Additionally, “antiemetics can be taken prophylactically for nausea, melatonin and diphenhydramine for insomnia, and it’s important to ensure that patients stay hydrated.”
“An integrated specialty pharmacy approach helps optimize treatment outcomes in hepatitis C–negative transplant patients receiving hepatitis C–positive organs,” Beeker said. “We are able to improve drug–drug interaction management while improving patient satisfaction, achieving decreased time to treatment and insurance approval, and, at the same time, increasing revenue and margin.” —Gina Shaw
—Kristin Beeker, PharmD, MBA
