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Indication: Treatment of adults with post-transplant cytomegalovirus infection/disease who are refractory (with or without genotypic resistance) to 1 or more prior antiviral therapies
CADTH recommends that Livtencity should be reimbursed by public drug plans for the treatment of adults with post-transplant cytomegalovirus (CMV) infection/disease who are refractory (with or without genotypic resistance) to 1 or more prior antiviral therapies if certain conditions are met.
Livtencity should only be covered to treat adult patients with CMV infections that are refractory (with or without resistance) to 1 or more of the following antiviral drugs: valganciclovir, ganciclovir, foscarnet, or cidofovir.
Livtencity should only be reimbursed if prescribed by clinicians with experience and expertise in transplant medicine, transplant infectious disease, or infectious diseases, and if the cost of Livtencity is reduced.
CMV infection is a common infection caused by a type of herpes virus. Most people do not experience symptoms; however, it can cause serious complications in patients with weakened immune systems, such as transplant recipients. Serious complications include disease of the infected organ (e.g., liver, lung, digestive tract) or rejection of the transplanted organ. The prevalence of post-transplant CMV infection in Canada is unknown. Estimates of refractory CMV infection in Europe and the US are between 19% and 21% for recipients of solid organ transplant (SOC) and 9% and 47% for recipients of hematopoietic stem cell transplant (HSCT).
Currently available antiviral treatments are often associated with severe side effects, and there are limited options when treatments are ineffective (i.e., refractory infection) or the infection becomes resistant to available antiviral drugs.
Treatment with Livtencity is expected to cost approximately $58,128 per patient per 7.5-week course of treatment.
The CADTH Canadian Drug Expert Committee (CDEC) recommends that maribavir be reimbursed for the treatment of adults with post-transplant CMV infection/disease who are refractory (with or without genotypic resistance) to 1 or more prior antiviral therapies only if the conditions listed in Table 1 are met.
One open-label, randomized, double-arm, phase III trial (SOLSTICE, N = 352) demonstrated that treatment with maribavir resulted in greater achievement of CMV viremia clearance, as well as maintenance of viremia clearance and symptom control compared to investigator-assigned anti-CMV treatment (IAT) in recipients of SOT or HSCT who had refractory CMV infection with or without resistance. Evidence from the SOLSTICE trial demonstrated that, compared with IAT (monotherapy or dual-combination of IV ganciclovir, oral valganciclovir, IV foscarnet, or IV cidofovir), 8 weeks of treatment with maribavir was associated with statistically significant and clinically meaningful improvement in confirmed CMV viremia clearance at the end of week 8 (55.7% versus 23.9%; 32.8% adjusted difference; 95% confidence interval [CI], 22.80 to 42.74; P < 0.001). Treatment with maribavir, compared to IAT, was also associated with greater confirmed CMV viremia clearance and symptom control at the end of week 8 and maintained through week 16 (8 weeks beyond the treatment phase; 18.7% versus 10.3%; 9.5% adjusted difference; 95% CI, 2.02% to 16.88%; P = 0.013).
Patients identified the need for effective treatments that improve outcomes, reduce mortality, relieve symptoms, have fewer or less severe side effects, improve health-related quality of life (HRQoL), and eliminate admission to the hospital. CDEC concluded that treatment with maribavir meets some of these needs as numerically fewer patients treated with maribavir in the SOLSTICE study discontinued treatment due to adverse events (AEs) compared to IAT. Furthermore, lower rates of hematologic and renal toxicities observed with maribavir treatment may fill a gap in the treatment landscape whereby other drugs have known toxicities that limit their use; however, the potential comparative safety benefit of maribavir is not known. Patients identified a need for more treatment options that are easy to administer; the oral formulation of maribavir meets this need.
Using the sponsor-submitted price for maribavir and publicly listed prices for all other drug costs, the incremental cost-effectiveness ratio for maribavir was $403,089 per quality-adjusted life-year (QALY) compared with IAT (combined comparator of ganciclovir, valganciclovir, foscarnet, and cidofovir). At this the incremental cost-effectiveness ratio, maribavir is not cost-effective at a $50,000 per QALY willingness-to-pay threshold for adult recipients of SOT or HSCT who have CMV infection/disease that is refractory (with or without genotypic resistance) to 1 or more prior antiviral therapies. A price reduction is required for maribavir to be considered cost-effective at a $50,000 per QALY threshold.
Reimbursement Conditions and Reasons.
Maribavir (Livtencity) is an oral tablet indicated for the treatment of adults with post-transplant CMV infection/disease who are refractory (with or without genotypic resistance) to 1 or more prior antiviral therapies. The Health Canada–recommended dose is 400 mg (two 200 mg tablets) twice daily, resulting in a daily dose of 800 mg.
The number of patients undergoing transplants in Canada has been rising over the past decades. The Canadian Institute for Health Information reported that the number of SOT procedures in Canada (excluding Quebec) increased from 1,036 in 2011 to 2,594 in 2020. Similarly, the Canadian Institute for Health Information reported that the number of autologous and allogeneic HSCT procedures in Canada increased steadily from 1,236 in 2010 to 1,605 in 2014. Despite the limited data on refractory and resistant CMV infections in the Canadian context, the sponsor-submitted systematic review found that between 19% and 21% of those receiving SOT and 9% and 47% of those receiving HSCT experienced refractory CMV infection in Europe and the US. The majority of studies (4 studies) identified in the sponsor’s systematic review reported resistant CMV infection in 1% to 8% of recipients of SOT, with 1 study from the Netherlands reporting that as many as 37% of recipients of SOT had mutations conferring CMV resistance. In patients receiving HSCT, 2% to 3% had resistant infection.
CMV is a beta-herpes virus that remains dormant in the human body for life after primary infection. Patients with compromised immune systems, immune suppression in preparation for transplant, and post-transplant maintenance immunosuppression are at significantly increased risk of CMV infection, which can manifest into clinical complications, including CMV disease. CMV infection may be asymptomatic and only detectable by viral replication; however, when symptoms are present (i.e., in the case of CMV infection manifesting into CMV disease or CMV syndrome) patients may experience fever, low white blood cell counts (leukopenia), muscle weakness, fatigue, shortness of breath, blurry vision or loss of vision, abdominal pain, blood in stools, nausea, vomiting, or diarrhea. The possible complications of CMV in patients who received transplant include transplant failure, liver and digestive disease (e.g., hepatitis or colitis) and infections in different organs (e.g., pneumonia, pancreatitis, meningitis, myocarditis) or the blood.
The most widely used antivirals for first-line preemptive therapy are IV ganciclovir, oral valganciclovir, and IV foscarnet. When patients are resistant to available treatment, subsequent therapy options are limited. No treatments are currently approved by Health Canada for patients with refractory or resistant CMV.
To make its recommendation, the committee considered the following information:
A total of 9 patient advocacy groups provided input on maribavir for the treatment of adults with post-transplant CMV infection/disease that is refractory and/or resistant to 1 or more prior antiviral therapies. The groups conducted a total of 3 surveys to capture input. The patients were predominantly those with myeloma and/or autologous HSCT, noted by clinical experts to be a group for which CMV infection is not a concern, rather than patients who are recipients of allogenic HSCT and are at risk for CMV infection. Patients reported on the negative impact of staying in the hospital and away from home for weeks to months for treatment. CMV infection also affected patients’ ability to work and perform in school, mental health (i.e., stress and anxiety), ability to care for and spend time with families and friends, sexual life (i.e., intimacy concerns due to spreading CMV to their partners), and finances. Patients value effective medications with fewer side effects (e.g., taste disturbances, nausea, vomiting, feeling weak or tired, urinary changes), no contraindications and interactions with immunosuppressants, that are simple to administer, and that are covered by the drug plans. Patients also value an improvement to their quality of life, relieving CMV infection, eliminating overnight stays at a hospital, and reducing the severity of side effects (most commonly anxiety; weight loss; pain in the back, joints, or muscles; and diarrhea) caused by currently available treatments. Availability of maribavir may allow patients to be treated closer to home and potentially have an impact on improving equity or access to treatment.
The clinical experts consulted by CADTH identified that, based on the limitations of existing therapies, the goals of anti-CMV treatment are to control the virus and its symptoms until a patient’s immune system is strong enough to fight the virus (rather than eradicating it). As such, the goals of existing treatments are to improve symptoms (if the patient has end-organ disease), reduce mortality, improve graft function and/or reduce graft loss, minimize adverse effects, and improve quality of life.
The clinical experts indicated that challenges with existing treatments include high rates of hospitalizations for treatment administration and toxic side effects. The clinical experts also described concerns around patients becoming resistant to current treatment options, though they likely expect patients using maribavir to develop resistance, as well. The clinical experts stressed the importance of treating patients with the least toxic and most effective drug early, citing that some of the outcomes from delayed treatment are irreversible (e.g., graft loss due to ganciclovir or valganciclovir that causes myelosuppression that cannot be reversed).
According to the clinical experts, definitions of resistance and refractory are important to identify patients most suitable for treatment with maribavir. Patients most likely to respond to maribavir include those who have intolerances or life-threatening side effects to other drugs, those who can have their immunosuppression reduced, and/or those who can have their immune function improve.
In routine clinical practice, the clinical experts indicated that anti-CMV treatment is given until CMV is either negative or “low level”; however, the definition of “low level” is unclear and treatment duration must be individualized based on multiple patient characteristics; for example, graft-versus-host disease (GVHD) or toxicity.
Per the clinical experts, complete response to maribavir would be defined as resolution of symptoms of end-organ disease and eradication of CMV viremia.
CADTH received input from 1 clinician group, CTTC.
The input provided by CTTC generally aligned with the input provided by the clinical experts consulted by CADTH. Pertaining to the patient population, the clinician group added that patients who are post-transplant often struggle with a lack of appetite and/or poor oral intake; therefore, the patients with eating difficulties might be less suitable for maribavir, which is associated with dysgeusia/ However, the clinician group emphasized that the toxicity profile of conventional salvage therapies is much more concerning. Furthermore, the group emphasized that it is particularly challenging to treat CMV infection in patients with GVHD because GVHD therapies are immunosuppressive (i.e., increase the risk of CMV infection), myelosuppressive (i.e., exacerbate the toxicities caused by valganciclovir), and nephrotoxic (i.e., exacerbate the toxicities caused by foscarnet).
Input was obtained from the drug programs that participate in the CADTH reimbursement review process. The clinical experts consulted by CADTH provided advice on the potential implementation issues raised by the drug programs.
Responses to Questions From the Drug Programs.
One open-label, randomized (2:1), double-arm, phase III trial (SOLSTICE, N = 352) was included in the CADTH systematic review. The primary objective of the SOLSTICE study was to compare the efficacy and safety of maribavir versus IAT for treatment of refractory and/or resistant CMV infection in recipients of SOT and HSCT. The trial included adult patients with documented CMV infection that is refractory to the most recent treatment or resistant to it (only if patients also met refractory criteria). Patients received 400 mg oral maribavir twice daily or another IAT (i.e., foscarnet, ganciclovir, valganciclovir, or cidofovir) for up to 8 weeks. The primary end point was confirmed CMV viremia clearance at the end of week 8 (regardless of premature treatment discontinuation). The key secondary end point was a composite of confirmed CMV viremia clearance and symptom control at the end of week 8, maintained through week 16 (8 weeks beyond the treatment phase) after receiving exclusively study-assigned treatment. Other secondary end points included recurrence, all-cause mortality, resistance to maribavir or IAT, health care resource utilization, and HRQoL. Harms outcomes were also examined. In the SOLSTICE study, both treatment groups were generally balanced but notable differences were observed in characteristics such as age, type of preparative conditioning regimen, presence of CMV resistance-associated amino acid substitutions, and CMV serostatus for the donor-recipient pairs of HSCT, CMV DNA level, and net immunosuppression use changed before initiation of study treatment.
The mean age of enrolled patients was 53.0 years (standard deviation = 13.22 years). Most patients were White (75.6%) and male (60.5%). Most patients underwent an SOT (59.9%), with the kidney (50.2% of patients who received SOT), lung (29.4% of patients who received SOT), and heart (10.9% of patients who received SOT) being the most transplanted solid organs. Patients who underwent HSCT predominantly underwent allogenic transplant procedures (99.3%). ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Most patients did not have confirmed acute or chronic GVHD (91.2% and 96.9%, respectively), and did not use antilymphocyte treatment (57.7%). The majority of patients had some renal impairment (32.1% with mild and 23.3% with moderate), but no hepatic impairment (92.3%).
The primary end point was confirmed CMV viremia clearance at the end of week 8 (regardless of premature treatment discontinuation) as measured by CMV DNA levels. The adjusted difference in proportion of responders between maribavir and IAT was 32.8% (95% CI, 22.80 to 42.74; P < 0.001) in favour of maribavir (55.7% versus 23.9%).
The key secondary end point was a composite of confirmed CMV viremia clearance and symptom control at the end of week 8, maintained through week 16. The adjusted difference in proportion of responders between maribavir and IAT was 9.5% (95% CI, 2.02% to 16.88%; P = 0.013) in favour of maribavir (18.7% versus 10.3%).
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| The Kaplan-Meier estimate for median days to CMV viremia clearance was 22.0 days (95% CI, 21.0 days to 23.0 days) for the maribavir group and 29.0 days (95% CI, 22.0 days to 35.0 days) for the IAT group.
Of patients who responded to treatment, 33 (17.9%) in the maribavir group and 8 (12.3%) in the IAT group had CMV viremia recurrence during the first 8 weeks of the study. Comparative recurrence data cannot be interpreted because clearance is a prerequisite for recurrence.
The number of patients who died in the maribavir group was 27 (11.5%) and 13 (11.1%) in the IAT group. The median observed event time for those who died was 55.0 days (minimum = 3.0 days; maximum = 182.0 days) in the maribavir group and 73.0 days (minimum = 13.0 days; maximum = 186.0 days) in the IAT group. The hazard ratio was 1.14 (95% CI, 0.549 to 2.357). Conclusions for all-cause mortality could not be drawn because the 95% CI around the hazard ratio was wide, including the possibility of both appreciable benefit and harm for maribavir compared with IAT.
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The adjusted difference in rates ratio of hospital admissions between the maribavir and IAT groups during the on-treatment phase was 0.65 (95% CI, 0.45 to 0.94), favouring maribavir. The adjusted difference in incidence rate ratio of length of stay between the maribavir and IAT groups during the on-treatment phase was 0.46 (95% CI, 0.23 to 0.92), favouring maribavir.
Although HRQoL data were collected, it was only reported descriptively. Generally, patients reported an improvement in HRQoL scores (i.e., EQ-5D utility score and 36-Item Short Form Health Survey) over time and across both treatment groups. No definitive conclusions can be made between the treatment groups due to a lack of statistical testing and missing data.
Overall, 228 (97.4%) patients in the maribavir group and 106 (91.4%) patients in the IAT group experienced 1 or more treatment-emergent AEs. Ninety (38.5%) patients in the maribavir group and 43 (37.1%) patients in the IAT group experienced 1 or more severe AEs. Thirty-one (13.2%) patients in the maribavir group and 37 (31.9%) patients in the IAT group permanently discontinued treatment with study drugs due to AEs.
There are limited concerns for internal validity. SOLSTICE was an open-label study. Stratified randomization was conducted using interactive response technology , suggesting allocation concealment. For the primary end point and multiple secondary end points, a central laboratory and an end point adjudication committee were appropriately used to reduce the risk of detection bias. The study population in the SOLSTICE trial was adequately defined and the clinical experts consulted by CADTH indicated that the eligibility criteria were overall appropriate. Both treatment groups were relatively balanced, with some notable differences in characteristics such as age, type of preparative conditioning regimen, presence of CMV resistance-associated amino acid substitutions and CMV serostatus for the donor-recipient pairs of HSCT, CMV DNA level, and net immunosuppression use changed before initiation of study treatment. The analysis populations used in the SOLSTICE trial were appropriate for measuring the effect of the assignment to the interventions and all analyses were pre-specified. The comparators used were identified by the clinical experts as appropriate. Statistical testing was performed for the primary and key secondary outcome. However, the open-label design can increase the risk of performance and detection bias, particularly for outcomes that are subjective in measurement and interpretation (e.g., CMV symptom controls, subjective AEs). There were some outcomes in the study for which results may be biased due missing outcome data (notably, HRQoL).
There are some implications of the trial on external validity. One stark difference between how the treatment was administered in the SOLSTICE trial and what would be expected in routine clinical practice was the 8-week fixed duration. As identified by the clinical experts consulted by CADTH for this review, clinicians treat patients until CMV DNA levels are low enough or negative, not for a fixed duration. The clinical experts indicated that the baseline characteristics of patients enrolled in the SOLSTICE trial were generally representative of the post-transplant CMV population in Canada, although they noted that patients in the SOLSTICE study would represent the most fit patients in this population, which is common in clinical trials. Furthermore, the clinical experts noted that although the comparators (i.e., IAT) used are reflective of routine clinical practice, the distribution of each IAT in the SOLSTICE trial is not reflective of Canadian clinical practice. It may be difficult to design a trial with IAT distributions that reflect the diversity of Canadian clinical practice. As a result, generalizability of results to the Canadian setting is uncertain. Moreover, conclusions on comparative efficacy for each antiviral cannot be drawn.
The sponsor provided a series of additional exploratory analyses of individual patient data from the SOLSTICE trial. The results of the individual patient data analyses were used as direct inputs into the base case and scenarios of the cost-effectiveness model.
Cost and Cost-Effectiveness.
CADTH identified several limitations with the sponsor’s analysis: the anticipated market uptake for maribavir in patients receiving HSCT was likely overestimated, the budget impact estimate is uncertain as treatment duration is highly variable and a key driver of analyses, and the proportion of patients eligible for public coverage is uncertain and may underestimate the budget impact if inaccurate. Lastly, the estimated target population is uncertain: the incidence of CMV viremia in patients receiving SOT and the proportion of SOT recipients who have refractory and/or resistant infections was likely underestimated, and the proportion of HSCT recipients who have refractory and/or resistant infections was likely overestimated. A CADTH reanalysis decreased the market shares for maribavir in patients receiving HSCT and adjusted the target population parameters to reflect clinical expert opinion. In the CADTH reanalysis, the estimated budget impact for maribavir was $7,811,026 in year 1, $10,073,188 in year 2, and $12,108,445 in year 3, for a 3-year total of $29,992,660. CADTH found the budget impact of maribavir to be sensitive to treatment duration, incidence of CMV viremia and proportion of those with refractory and/or resistant CMV, and proportion of patients eligible for public coverage.
Dr. James Silvius (Chair), Dr. Sally Bean, Mr. Dan Dunsky, Dr. Alun Edwards, Mr. Bob Gagne, Dr. Ran Goldman, Dr. Allan Grill, Dr. Christine Leong, Dr. Kerry Mansell, Dr. Alicia McCallum, Dr. Srinivas Murthy, Ms. Heather Neville, Dr. Danyaal Raza, Dr. Emily Reynen, and Dr. Peter Zed.
Meeting date: August 24, 2022
Regrets: Two expert committee members did not attend.
Conflicts of interest: None
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Indication: Treatment of adults with post-transplant cytomegalovirus infection/disease who are refractory (with or without genotypic resistance) to 1 or more prior antiviral therapies.
Sponsor: Takeda Canada Inc.
Final recommendation: Reimburse with conditions
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