Valganciclovir.Pdf

Application for the inclusion of valganciclovir in the WHO Model List of Essential Medicines

1. Summary statement of the proposal for inclusion, change or deletion

Inclusion of the adult oral formulation of valganciclovir hydrochloride is proposed for the treatment of cytomegalovirus retinitis (CMV), an AIDS associated opportunistic infection (OI).

The principal reasons for requesting this inclusion are as follows: 1. There remains a significant burden of HIV-related cytomegalovirus retinitis in adults living in middle and low-income countries. 2. Valganciclovir, an oral medication, provides equivalent systemic treatment to intravenous ganciclovir, the gold standard for treatment of CMV retinitis. Since at least three months of treatment is required, oral valganciclovir provides cost savings, reduced logistic burden on the health care system, and higher efficacy than other treatment options. 3. Valganciclovir will reduce mortality in patients with HIV-related CMV retinitis. High mortality is associated with HIV-related CMV retinitis in resource-limited settings, where only local therapy (intraocular injection) is available. Systemic anti-CMV treatment (valganciclovir) is the standard of care in high-income countries, and the only realistic option to offer appropriate standard of care is by making oral valganciclovir available. 4. Valganciclovir will reduce the incidence of HIV-related blindness by providing an oral, systemic therapy that will offer prophylaxis for second eye involvement, and by providing a form of treatment that will be far more effective at reaching all patients in need. Current treatment for CMV retinitis in resource-limited settings is generally not available, and where available, consists of weekly intraocular injections that place a high social and financial burden on the patient and care givers, and exclude from therapy those patients who live at a distance from centers with clinicians are specially trained in the ophthalmic procedure of intraocular injection.

Name of the focal point in WHO submitting or supporting the application (where relevant)

Nathan Ford

3. Name of the organization(s) consulted and/or supporting the application

MSF/Médecins Sans Frontières - Access Campaign Rue de Lausanne 78 P.O Box 116 1211 Geneva, Switzerland Contact: Jennifer Cohn, Medical Coordinator ([email protected])

4. International Nonproprietary Name (INN, generic name) of the medicine

Valganciclovir hydrochloride (HCl)

5. Formulation proposed for inclusion; including adult and paediatric (if appropriate)

Valganciclovir HCl (Valcyte®, Hoffmann-la Roche) 450mg as oral administration (tablet).

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VALCYTE, valganciclovir, oral formulation contains 496.4mg of valganciclovir HCl (approximate molecular weight is 390.83). Its chemical name is: L-valine, 2-[(2-amino-1, 6-dihydro-6-oxo-9H- purin-9yl)methoxy]-3-hydroxypropyl ester, monohydrocholoride. Valganciclovir HCl is a polar hydrophilic compound. Valganciclovir is the L-valyl ester of, and prodrug for, ganciclovir. (1) The Valcyte® formulation is an improved formulation of Cymevene (ganciclovir), also marketed by Hoffmann-la Roche (“Roche”), an injectable formulation for the treatment of cytomegalovirus retinitis.

The tablet formulation of valganciclovir includes: 496.3mg of valganciclovir HCl, microcrystalline cellulose, povidone K-30, crospovidone and stearic acid with a film-coat containing Opadry Pink®. (2)

6. International availability - sources, of possible manufacturers and trade names

Valganciclovir HCl 450 mg tablet (Trade name: Valcyte®; Manufacturer: Hoffmann-la Roche), US FDA approved on March 29th 2001, NDA # 021304

Valganciclovir HCl, 450 mg tablet, manufactured by Dr Reddys in India, US FDA approved on November 4th 2014, ANDA # 200790

Valganciclovir HCl, 450 mg tablet, manufactured by Endo Pharmaceuticals in India, US FDA approved on November 4th 2014, ANDA # 203511

7. Whether listing is requested as an individual medicine or as an example of a therapeutic group

The request for inclusion is for the single medicine valganciclovir HCl.

8. Information supporting the public health relevance (epidemiological information on disease burden, assessment of current use, target population)

8.1 Epidemiological information, cytomegalovirus retinitis

Globally, more than 35 million people are living with HIV, 90% of these individuals live in developing countries. (3,4) Cytomegalovirus retinitis (CMVr) is a preventable late-stage opportunistic infection (OI) in people living with HIV/AIDS (PLWHAs), and among the most common OIs affecting this population. (5) The average age of those with CMVr is quite young, with most studies revealing a mean age in the 30s. Thus CMVr seems to strike during prime productive years of life. (6) It is particularly prevalent in South, Southeast and East Asia. (6)

CMV retinitis is part of a systemic infection, although in HIV/AIDS patients in low- and middle- income countries, the eye is the only end-organ where the presence of clinical infection is easy to establish. Evidence from both before and after the introduction of HAART in resource rich and resource poor countries have shown that CMV viremia predicts mortality, and in most reports is the most powerful predictor of mortality. (7–11) A recent retrospective study in South Africa demonstrated significantly lower mortality for HIV positive patients with CMV viremia >5100 copies/mL who were treated with ganciclovir as compared to those who did not (58% versus 100%). (12) Although this study has limitations, including its retrospective design and small sample size, it suggests that treating HIV patients with CMV viremia provides a significant mortality benefit. As CMVr is strongly correlated with CMV viremia, a mortality benefit may also

2 be enjoyed by patients with CMVr who are treated with valganciclovir, even in the absence of the diagnostic ability to detect CMV viremia.

If left untreated, CMVr can lead to permanent loss of vision. (13) It is the leading cause of blindness in PLWHAs. (14) Vision loss can emerge from damage to the optic nerve or macula, retinal detachment (which can present itself even years after CMVr has been treated), or the development of immune recovery uveitis (IRU) (occurs in approximately 20 percent of CMVr cases). (13) CMVr is characterized on fundoscopic examination by dense retinal whitening (that tends to follow vessels) and irregular border with small white satellite lesions. (13) Complete retinal destruction occurs within three to six months in AIDS patients. (13) Early diagnosis is crucial in preventing vision loss in AIDS patients, and given it is initially often asymptomatic, fundoscopic screening should not be limited to only those who have symptoms. (13) Early diagnosis and treatment also significantly reduces the risk of CMVr spreading to the contralateral eye; this occurs in approximately 50 to 61 percent of untreated CMVr cases within six months of infection. (14) In a study by Kampen et al., the risk of acquiring second-eye CMVr (within six months) reduced to 19.6 percent in AIDS patients on anti-CMVr treatment. (14)

The disease burden of CMVr may be underestimated due to factors such as lack of diagnosis and awareness around one’s risk of CMVr. Prohibitive treatment prices fail to provide incentives for screening by clinicians of patients at risk. In addition, highest CMVr burden is found in resource-limited settings where quality care and ART availability may be limited. CMVr mostly develops during late-stage HIV infection when a patient’s immune system is severely compromised (i.e. CD4 count <100 cells/µL) and is facing a multitude of additional health complications.

Prevalence of CMVr in developed countries has dramatically reduced over the years with the introduction and scale-up of highly active antiretroviral therapy (HAART): in 1995, approximately one-third of those infected with HIV also had CMVr and even today, areas of lower ART accessibility have similar rates of CMVr. (6,13) However, high ART accessibility does not completely correlate with reduced risk of CMV. CMV risk still remains if ART initiation is late; if ART failed; and if care and monitoring are limited. (6) For example, Asia (specifically Southeast Asia) presents the highest rates of CMV, in part because one in five patients have a CD4 count of <100 cells/µL upon ART initiation. (6) In fact, patients can present with CMVr after ART initiation, particularly as patients may present with immune reconstitution inflammatory syndrome to CMVr and in Thailand is the second most frequent OI to emerge after initiation of ART. (6)

A meta-analysis study by Ford et al. found that CMVr prevalence in resource-limited settings range from <5% in Southern Africa to over 30% in Southeast Asia. (6) Regional prevalence rates were 14% in Asia, 2.2% in Africa, and 12% in Latin America. (6) Thailand, Myanmar, China and India all had prevalence rates higher than 5%. (6) Studies show that prevalence rates are 2-20% in India and 19.8% in Thailand among those receiving HAART. (4) Another study by Tun et al. in Myanmar found a CMVr prevalence of 24% in patients screened (211 out of 891), all of whom needed urgent intervention to prevent blindness. (15) Incidence of CMVr ranges from 0-19.6% in Sub-Saharan Africa. (4)

8.2 Assessment of current use

Accessibility and use of valganciclovir for CMVr in low and middle-income countries (L&MICs) is currently very low given previous prohibitive prices. This may change with growing generic availability and negotiated prices. Refer to section 12.1 for pricing information.

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In January 2014, the WHO Prequalification program included valgancicovir in the Invitation to manufacturers and suppliers of medicinal products for HIV infection and related diseases to submit Expressions of Interest for WHO Prequalification. It was included as an anti-viral agent under “Medicines to treat HIV/AIDS related conditions for adults, adolescents and children.”

8.3 Target population

The target population is adults with HIV-associated CMVr.

9. Treatment details (dosage regimen, duration; reference to existing WHO and other clinical guidelines; need for special diagnostics, treatment or monitoring facilities and skills)

9.1 Reference to existing WHO and other clinical guidelines

Non-WHO clinical guidelines first recommend that patients at-risk for, or recently diagnosed with, CMVr be ensured access to HAART as it slows down progression of CMVr. (4) Treatment options for CMVr include: intravenous (IV) therapy with ganciclovir, foscarnet, or cidofovir; ganciclovir implant; intravitreal injections of ganciclovir, foscarnet, cidofovir or fomivirsen; and oral valganciclovir or ganciclovir. (19)

In the past, treatment for CMVr typically involved intravenous ganciclovir, as this has proven to have the highest efficacy in decreasing progression of the disease. However, the side effects and risks of IV implants are high and costly for patients. IV ganciclovir and foscarnet involve indwelling catheters, which are costly, inconvenient, and expose patients to risk of secondary sepsis. (4) In addition, they require that patients receive daily infusions of an hour or more (one hour for ganciclovir, two hours for foscarnet), (4) a difficult feat in resource-limited settings. Intravenous cidofovir has a high-risk of nephrotoxicity (up to 50% of cases) and uveitis (10% of cases). (4) The ganciclovir implants (which are no longer available) required an operating room and full surgical support, were costly, carried surgical risks (eg endophthalmitis, retinal detachment, intraocular hemorrhage, migration of the device), and were only recommended in conjunction with a systemic treatment (such as oral valganciclovir). (4) Finally, intravitreal injections require ophthalmic specialization or an investment in training primary care providers to administer the treatment. (15) Furthermore, patients must return weekly for the injections during therapy. (15)

Oral valganciclovir is most recommended because of its lower overall cost, lower risk of adverse reactions, high efficacy, easy administration, and ability to be used for both induction and maintenance therapy. (4) Oral valganciclovir does not require the training and specialization needed for other therapy regimens (e.g., intravitreal injections, etc.), a benefit given that resource-limited settings often lack access to trained ophthalmic providers. (4) Treatment with oral valganciclovir is the standard of care in western countries and has shown to reduce CMVr- related mortality even in patients failing HAART. (15)

The Guidelines for the Prevention and Treatment in Opportunistic Infections in HIV-infected Adults and Adolescents1 recommends the following for effective treatment of CMVr (along with ART): [1] oral valganciclovir; [2] IV ganciclovir; [3] IV ganciclovir followed by oral valganciclovir; [4] IV foscarnet; and [5] IV cidofovir. All but IV cidofovir were rated as A1 level

1 Comprises of recommendations from the Center for Disease Control (CDC), National Institutes of Health (NIH) and the HIV Medicine Association of the Infectious Diseases Society of America

4 recommendations. (20) The treatment regimen should be tailored to each case given severity and location of disease, immune suppression, adherence ability, and potential drug interactions. These guidelines are for the United States and are comprised of recommendations from the Center for Disease Control (CDC), National Institutes of Health (NIH) and the HIV Medicine Association of the Infectious Diseases Society of America. The European AIDS Clinical Society guidelines are very similar. (21)

The Canadian Infectious Disease Society guidelines for the management of CMVr in HIV/AIDS recommend the use of valganciclovir during treatment. (22) Guideline consensus was made in October 2002 by ten members of the Canadian CMV Disease in HIV/AIDS Consensus Group which consisted of: infectious disease specialists, one primary care physician and a ophthalmologist with expertise in HIV and CMV infection.

The WHO currently does not have guidelines for the treatment of cytomegalovirus, but there are expectations that they will exist within the next couple of years.

9.2 dosage regimen (23)

Dosing recommendations for treatment of cytomegalovirus retinitis in adults with HIV/AIDS: Induction therapy: 900mg (two 450mg tablets), twice a day with food for 21 days Maintenance therapy (per MSF recommendations): 900mg (two 450mg tablets), once a day with food until the following three criteria are met: 1) the retinitis has become inactive on retinal exam; 2) the person has been on ART for at least 3 months; and 3) the CD4 count is above 100.

Table 1. Dosing recommendations for patients with renal impairment CrCl (mL/min)a Induction dose Maintenance/prevention dose ≥60 900mg twice daily 900mg once daily 40-59 450mg twice daily 450mg once daily 25-39 450mg twice daily 450mg every 2 days 10-24 450mg every 2 days 450mg twice weekly <10 (on hemodialysis) Not recommended Not recommended a CrCl = creatinine clearance

10. Summary of comparative effectiveness in a variety of clinical settings:

10.1 Identification of clinical evidence (search strategy, systematic reviews identified, reasons for selection/exclusion of particular data)

Pubmed, Medline and Embase databases were searched using the keywords CMV, CMVr, cytomegalovirus retinitis, cytomegalovirus, cytomegalovirus infections and valganciclovir, Valcyte and HIV, HIV-1, HIV-2, HIV infection, human immunodeficiency virus, AIDS, opportunistic infections. No date or language restrictions were included. All clinical trials (including randomized clinical trials, observational data, case series and case reports) and reviews were included. The search revealed a total of 122 articles of which 33 were selected for full text review and 14 included. Of the 14 included, 8 were review articles. Articles were primarily excluded during the title and abstract screen due to incorrect population (e.g. solid organ transplant population) and during the full text review for wrong population [3], for use of valganciclovir in as prophylaxis rather than treatment [6], or for not including data on valganciclovir safety and/or effectiveness [10].

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Initial dose ranging studies demonstrated excellent bioavailability of valganciclovir. Brown et al. enrolled 39 adult patients (all male) who were both HIV- (CD4 count >100 cells/µL) and CMV- seropositive in an open-label, dose-ranging pharmacokinetic study. (24) Subjects were randomized into a fasted group and fed group. Both groups received 450mg, 875mg, 1750mg (two 875mg tablets), and 2625mg (three 875mg tablets) of oral valganciclovir for three days in random order with a four-day period in between each dosage period. The fasted group received dosages after an overnight fast and before a standardized breakfast. The fed group received dosages after the standardized breakfast. Results confirmed valganciclovir’s higher bioavailability as compared to ganciclovir and reflected the concentration-time profiles of IV ganciclovir. Food increased this bioavailability by 124-156% in the fed group. A 900mg dose of valganciclovir reflected a target mean AUC24 value of 26mg/L h, comparable to IV ganciclovir dosage of 5mg/kg.

Registrational studies demonstrated that valganciclovir had acceptable safety and efficacy in treating CMVr as compared to standard of care, IV ganciclovir. Study WV 15376 was a phase II/III study, randomized non-blinded study that compared valganciclovir to IV ganciclovir for induction therapy for CMVr, with the primary endpoint of CMVr progression 4 weeks after therapy initiation. This was a non-inferiority study. This study enrolled 160 HIV-seropositive patients on HAART with newly acquired CMVr. (25) The study was carried out in 42 sites: 22 in the United States, 11 in Europe, 3 in Mexico, 3 in Canada, 2 in Australia, and 1 in Brasil. Eighty patients received three weeks of induction therapy (5mg/kg twice daily) and one week of maintenance therapy (5mg/kg once daily) with IV ganciclovir. The remaining 80 patients received three weeks of induction therapy (900mg twice daily) and one week of maintenance therapy (900mg once daily) with oral valganciclovir. After four weeks, all patients received maintenance therapy with valganciclovir (900mg/day). Mean baseline CD4 count in the IV ganciclovir group was 54 cells/mm3, 58 cells/mm3 in the valganciclovir group. After 4 weeks, 10% of patients in the IV ganciclovir group and 9.9% of patients in the valganciclovir group showed progression of retinitis after four weeks. Time to progression was also similar between the two groups. This study showed that valganciclovir is non-inferior to IV ganciclovir as induction therapy for HIV-associated CMVr.

Study WV 15705 was a single-arm study which enrolled 212 HIV-seropositive patients who had already received treatment for CMVr (for a minimum of four weeks) with oral valganciclovir (for a mean of 779 days) to provide a safety profile for the drug. However, this study also provides some efficacy outcomes. (26) The study was carried out in 43 sites in 10 countries. Patients were given maintenance therapy for CMVr of 900mg/day of oral valganciclovir; those with active CMVr began with induction therapy for CMVr (900mg twice daily). The subjects were mostly male (91%) and white (79%) with a baseline mean CD4 count of 140 cells/µL; 91 percent were receiving HAART. (26) Results showed that 36 patients (17%) presented progression of retinitis and that patients with a CD4 count of >200 cells/µL were less likely to progress. (26) Six percent of those who entered the study with unilateral CMVr (6%) developed contralateral retinitis and fifty patients (24%) experienced deterioration of visual activity but experienced no change in functional vision. (26) Fifteen patients (7%) experienced retinal detachment. (26)

Similarly, oral ganciclovir was shown to have equivalent efficacy to valganciclovir in treating CMVr. In a prospective cohort of 250 patients living in the US with CMVr and treated with anti- CMV therapy included 75 treated with either oral ganciclovir or valganciclovir therapy. Comparing these groups showed that the adjusted hazard ratios (HRs) for valganciclovir versus oral ganciclovir were non-significant for mortality (0.6, 95% CI 0.3-1.1), visceral CMV (0.5, 95% CI 0.04-6.4) and CMVr progression (0.9, CI 0.3-2.7). (27)

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Systemic CMVr therapy with either ganciclovir or valganciclovir has also been compared to local therapy with intra-vitreal injections of ganciclovir. Evaluation of the same cohort of 250 described above showed a significant advantage to systemic therapy of either valganciclovir or ganciclovir over intravitreal ganciclovir injections or implants. Systemic therapy compared to local (intravitreal injections or implants) was associated with 50% less mortality (adjusted hazard ratio [aHR], 0.5; 95% CI 0.3–0.7; P=0.006), 90% less new visceral CMV disease, such as CMV colities (aHR, 0.1; 95% CI, 0.04–0.4; P=0.004), and among those with unilateral CMV retinitis at presentation, 80% less occurance of CMVr in the contralateral eye (aHR, 0.2; 95% CI, 0.1– 0.5; P=0.0005). Retinitis progression was also significantly less common in those who received systemic treatment only versus regimens containing intravitreal injections (aHR, 3.4; P =0.004) and significantly greater visual field loss (aHR 5.5, P<0.01).

Valganciclovir has also been shown to be effective in treating immune recovery uveitis (IRU) with macular edema, the pathophysiology of which is suspected to be due to immune reconstitution to CMV disease. A case series described 5 patients with IRU and macular edema who were treated for 3 months with valganciclovir. Compared to baseline visual tests, after 3 months of valganciclovir treatment, vision improved by a mean of 11 letters (P=0.05) suggesting valganciclovir may be useful in treating IRU as well. (28)

Many CMVr studies located in resource-limited settings treat their subjects with IV ganciclovir because of the lack of access to valganciclovir in these nations. They call for the scale-up of valganciclovir in developing countries due to its high efficacy, the possibility for an all-oral regimen and easy administration. (13,15,29)

10.2 Summary of available data (appraisal of quality, outcome measures, summary of results) and estimates of effectiveness

Based on high quality evidence, valganciclovir is a safe, effective drug for the treatment of CMVr and CMVr-related vision loss in patients with HIV/AIDS. It has been shown to be non-inferior to IV ganciclovir for treatment of CMVr and as a systemic therapy has significant benefits (including mortality benefits) over local therapy such as ganciclovir intravitreal injection. Its oral formulation improves quality of life for patients with HIV as it removes the need for indwelling catheterization and chronic intravenous therapy. (30)

Based on this systematic review of the evidence, there is high quality evidence to recommend oral valganciclovir as treatment for CMVr. Please refer to summary and GRADE tables in separate document.

11. Summary of comparative evidence on safety:

11.1 Estimate of total patient exposure to date

In 2008, total annual market sales for Valcyte® was US $239 million. (16) Roche’s total global sales from January to December 2013 for Valcyte® and Cymevene (ganciclovir) were $778 million. (17) Roche’s total global sales form January to December 2012 were $698 million. (18) It is important to note that these sales represent the market for all uses of both valganciclovir and ganciclovir, including CMV prevention and/or treatment in the solid organ transplant and bone marrow transplant population.

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11.2 Description of the adverse effects/reactions and estimates of their frequency

Valganciclovir is a relatively safe drug. Dose ranging studies showed that valganciclovir is well- tolerated with little adverse reactions (and no relationship between dosage and incidence of adverse events) and drug exposure comparable to IV ganciclovir. (24) In study 15705, the most common adverse reactions reported were: diarrhea (35%), nausea (23%), fever (18%), neutropenia (18%), and oral candidiasis (17%). (26) Adverse reactions were more frequent in patients who entered the study with a CD4 count of <50 cells/µL.(26) Table 2 and 3 (below) present adverse reaction results from Study WV 15705 and WV 15376, respectively. Both study WV 15705 and WV 15376 concluded that adverse reactions to valganciclovir were similar to those of IV ganciclovir, with the exception that catheter-related infections were more common in the IV ganciclovir group.

Table 2. Adverse reactions in study 15705 (30) Adverse event Valganciclovir IV Ganciclovir (n = 79) (n = 79) Diarrhea 16% 10% Nausea 8% 14% Neutropenia (ANC <500/ul) 11% 13% Headache 9% 5% Anemia (Hgb <8g/dL) 8% 8% Catheter-related infection 3% 11%

Table 3. Percent of patients with selected adverse events occurring during Study WV 15376 (refer to section 10.1): Adverse event Valganciclovir arm (n = 79) IV ganciclovir arm (n = 79) Diarrhea 19% 10% Oral candidiasis 14% 6% Headache 9% 5% Fatigue 8% 5% Nausea 9% 14% Venous phlebitis and - 6% thrombophlebitis Pyrexia 14% 13% Neurotropenia 14% 13%

A randomized, open-label study by Jung and Dorr enrolled 18 subjects in the US who were both HIV- and CMV-seropositive and treated each with a single-dose of valganciclovir (360mg), oral ganciclovir (1000mg), and IV ganciclovir (5mg/kg for one hour) in random order. (31) The 18 subjects (15 males, 3 females) did not have AIDS-defining illness (all had a CD4 count of ≥100 cells/µL) or CMV disease but were seropositive for both. Results demonstrated that valganciclovir was better tolerated than both ganciclovir regimens and serum concentration of ganciclovir were detected earlier and at higher levels than the oral or IV ganciclovir, demonstrating approximately 10 fold higher bioavailability in oral valganciclovir than oral ganciclovir.

The product label states that valganciclovir is contraindicated in patients with hypersensitivity to valganciclovir or ganciclovir. Warnings include risk of cytopenias and thus, suggest not to administer valganciclovir if absolute neutrophil count is < 500 cells/µL, platelet count is <

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25,000/µL, or hemoglobin is < 8 g/dL. Similar to ganciclovir, animal studies suggest that valganciclovir may cause temporary or permanent inhibition of spermatogenesis and is a teratogen and mutogen. Thus, it is Pregnancy Category C and women of childbearing age should use contraception while using valganciclovir. (2)

These data show that valganciclovir has comparable or less severe adverse drug reactions than ganciclvori and less renal toxicity than foscarnet and cidofovir. Oral administration reduces the risks of IV catheter or injections necessitated by the other anti-CMVr drugs.

With regards to drug-drug interactions, valganciclovir is rapidly converted to ganciclovir and thus, valganciclovir’s drug–drug interactions will be very similar to ganciclovir. (32)

12. Summary of available data on comparative cost and cost-effectiveness within the pharmacological class or therapeutic group:

12.1 Range of costs of the proposed medicine

Upon its introduction in 2001, Valcyte® in the US, was priced at US $23.98 (AWP) per 450mg tablet: US $95.92 per day during induction phase and US $47.96 per day during maintenance phase. (33)

Roche and the Medicines Patent Pool (MPP) signed an agreement on 5 August 2013 to reduce the price of Valcyte® to approximately US $275 for 60 tablets for 138 developing countries. (34)

Brief survey below done by MSF in 2012 on Valganciclovir pricing

Table 4. Valganciclovir prices (based on MSF internal survey of manufacturers) Price per patient Price per patient Price per 450mg regimen, 12 weeksa regimen, 27 weeksb tablet (USD) (USD) (USD) Roche price from IDA 11.10 2330.42 4660.85 Foundation Roche price in India 12.71 2669.17 5339.34 Cipla product for local 3.73 783.14 1566.28 Indian market Roche price for MPP 4.32 907.20 1814.40 a. Scenario 1. 3 weeks of induction therapy, followed by 9 weeks of maintenance therapy (210 tablets) b. Scenario 2. 3 weeks of induction therapy, followed by 24 weeks of maintenance therapy (420 tablets)

With the introduction of generics into the market as is happening now, the cost of valganciclovir is expected to drop significantly. However, the other stringent regulatory agency approved generics have not been able to provide us with prices at the time of submission.

12.2 Resource use and comparative cost-effectiveness presented as range of cost per routine outcome

No cost-effectiveness analysis exists that compares use of IV ganciclcovir and oral valganciclovir for treatment of CMVr in resource limited settings. However, one study looked at the costs of oral, intravenous and intravitreal therapies for CMVr. (35) This US

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J Acquir Immune Defic Syndr • Volume 36, Number 4, August 1 2004 Cytomegalovirus Retinitis

costs per day were $69 for oral therapy, $163 for intravenous, and $70 for intraocular. We adjusted for differences in the proportion of patient- time on HAART treatment, proportion of time with co- existing AIDS-defining illness, duration of treatment periods, and other demographics (Table 3). Oral treatment saved $7185 per treatment period as compared with intravenous treatment (95% CI, −$11,342, −$3029). Intravenous treatment costs $6,866 (95% CI, $2161, $11,570) more than intraocular treat- ment. The total cost differences between oral and intraocular treatment groups were not statistically significant. Because combinational treatment represented a small fraction of all treatment, we do not present cost differences between this group and the others.

DISCUSSION In this study, we found that total costs of treatment were lower for oral and intraocular therapy as compared with intra- venous therapy. After adjustment for potential demographic and treatment confounders, the costs for intravenous treatment still remained higher. The magnitude of the difference between intravenous treatment and the other groups was large. The cost differences were mainly driven by higher outpatient costs in the intravenous treatment group. The higher costs for phlebitis for intravenous treatment were also statistically significant compared with the other groups. It has been demonstrated that intravenous ganciclovir and foscarnet are comparable in their efficacy.17 The efficacy pharmacoeconomic study examined daily and treatmentof oral valganciclovir, costs from which 98 HIV was approvedpositive for CMVr the treatment of patients from the same national claims database whoCMV received retinitis in 2001,treatment is also comparablewith anti-CMV to that drugs, of intrave- showed that oral (valganciclovir or ganciclovir) andnous intraocular ganciclovir therapies for induction incur therapy. significantly4 Nevertheless, ourlower data totalFIGURE daily 2. Proportion costs ($US69 of all treatment and $US70) claims that compa are oral,red withshow intravenous that the proportion (ganciclovir, of cases treatedfoscarnet with intravenousor cidofovir)intravenous and[$US163] intraocular or treatmentcombination among ($US215) CMV retinitis therapies.treatment Thus remained oral relatively treatments high in 2002incurred (Fig. 2), at approxi- cases in the post HAART era. IO, Intraocular; IV, intravenous, mately 40%. Switching these patients to oral or intraocular significantlyPO, Oral; Rx, treatment. fewer costs per treatment course as compared to intravenous therapies (-$7185 USD, 95% CI -$3029 - -$11324, P<0.05). therapy represents an opportunity for cost savings.

Tables below taken from Mahadevia P et al., JAIDS TABLE 2. Unadjusted Total Costs and Cost Per Day By Treatment Type Among 98 CMV Retinitis Patients

Oral Treatment Intravenous Intraocular Combinational (n = 89 Treatment Treatment (n = 102 Treatment (n = 50 Treatment (n = 12 All Treatment Types Periods Lasting Treatment Periods Treatment Periods Treatment Periods (n = 253 Treatment 8412 Days) Lasting 7974 Days) Lasting 5099 Days) Lasting 157 Days) Periods) Drug treatment costs $351,340 $293,951 $122,257 $10,449 $777,997 Adverse event costs $39,621 $53,416 $10,564 $0 $103,601 Phlebitis costs $0 $77,401 $0 $0 $77,401 Infusion costs $0 $22,001 $0 $0 $22,001 Outpatient costs $144,240 $733,616 $200,471 $15,628 $1,093,956 Inpatient costs $43,984 $118,761 $25,543 $7,601 $195,889 MahadeviaTotal costs et al $579,185 $1,299,147J Acquir Immune $358,834 Defic Syndr • Volume $33,678 36, Number 4, $2,270,845 August 1 2004 Total cost per day $69 $163 $70 $215 $105

© 2004 Lippincott Williams & Wilkins 975 TABLE 3. Bootstrap Predicted Linear Regression Results for Incremental Cost Differences Among Oral, Intravenous, and Intraocular Treatment Periods Adjusting for Age, Gender, Insurance Status, Duration of Treatment, Geographic Region, Coexisting AIDS Defining Illness, HAART Use, and Intrapatient Correlation

Oral vs. Intravenous Oral vs. Intraocular Intravenous vs. Intraocular Treatment Periods Treatment Periods Treatment Periods

Cost Cost Cost Difference 95% CI Difference 95% CI Difference 95% CI Drug treatment costs 596 (−552, 1743) 1551 (429, 2672) 955 (−399, 2309) Adverse event costs −78 (−913, 757) 215 (−561, 991) 293 (−215, 801) Phlebitis costs −798 (−1372, −224) −132 (−326, 62) 666 (138, 1194) Infusion costs −205 (−469, 58) 10 (−70, 90) 215 (−58, 488) Outpatient costs −6144 (−9268, −3021) −2031 (−4508, 445) 4113 (432, 7794) Inpatient costs −555 (−1443, 333) 68 (−903, 1039) 623 (−316, 1562) Total costs −7185 (−11342, −3029) −320 (−3512, 2872) 6866 (2161, 11570)

Given the significant benefits from systemic therapy versus intravitreal injections, and the likely costsIf savings“local” therapy from (intravitreous using oral fomivirsen valganciclovir or ganciclo- versusmay IV havetherapies limited our(based sample on and the the US generalizability study above), of our andvir implant) the expected is chosen, concurrentdecreases oral ganciclovirin price of is valganciclovir generally results. based Finally, on we entry cannot of be SRA certain-approved that miscoding generic did not versionsrecommended into to the reduce market, the risk treatment of second-eye with or oral visceral valgancicloviroccur in some is oflikely these to claims. cost However,-effective use ofas claims compared codes in toCMV IV disease,or intravitreal and systemic treatments ganciclovir in also most significantly contexts. re- HIV was found to be very accurate in prior analyses.20,21 duces the risk of developing Kaposi sarcoma.18 While this ap- In conclusion, we observed that CMV retinitis is less proach may be more effective for the general health of a patient prevalent and incident among a national managed-care popu- 1than3. localSummary therapy alone,of regulatory it also adds to status the cost ofof therapy the medicine and lation (in during various the HAART countries) era of the HIV/AIDS epidemic. The may expose the patient to more treatment-related adverse total cost per episode of care, however, remains high. We events. Because too few patients were on simultaneous treat- found that oral and intraocular treatment modalities led to Tablement, the 5. study Regulatory was not powered approval to examine status costs for differences valganciclovirlower for total indication costs, suggesting for CMVr that these agents maybe prefer- Countryamong various dual-treatment combinations. able as initialRegulatory treatment over intravenousStatus therapy. Prior to HAART therapy, Palella et al2 demonstrated a USA,decline US in opportunisticFood and Drug infections Administration among the HIV/AIDS (36) Approved,ACKNOWLEDGMENTS 29 March 2001 Australia,population. OurTherapeutic study showed Goods further, Administration rather dramatic,de- (37) The authorsApproved, thank Ms. 30 Kathy September Fraeman and2011 Dr. Chris creases in CMV retinitis in a managed-care HIV population Barker for their assistance with statistical programming and during the post-HAART era. Our projected rate of CMV reti- analyses. nitis decline from 1997 to 1998 may be artificially accentu- 10 ated. We attribute this to a smaller number of managed-care REFERENCES plans that supplied data in 1997 in addition to the low number 1. Cunningham WE, Markson LE, Andersen RM, et al. Prevalence and pre- of enrolled HIV or AIDS patients in a plan. However, after dictors of highly active antiretroviral therapy use in patients with HIV 1997, the incidence rates associated with CMV retinitis in our infection in the united states. HCSUS Consortium. HIV Cost and Services 19 Utilization. J Acquir Immune Defic Syndr. 2000;25:115–123. analysis are consistent with HIV Outpatient Study (HOPS) 2. Palella FJ Jr, Delaney KM, Moorman AC, et al. Declining morbidity and database, which demonstrated an approximate incidence of mortality among patients with advanced human immunodeficiency virus 50–300 CMV retinitis cases per 10,000 AIDS patients from infection. HIV Outpatient Study Investigators. N Engl J Med. 1998;338: 853–860. 1998–2001. 3. Dunn JP. Cytomegalovirus retinitis in 2003. Hopkins HIV Rep. 2003;15: Our study had several limitations. First, because our data 8–11. source was claims based, we do not know the specifics of the 4. Martin DF, Sierra-Madero J, Walmsley S, et al. A controlled trial of val- ganciclovir as induction therapy for cytomegalovirus retinitis. N Engl J underlying clinical indicators that could explain cost differ- Med. 2002;346:1119–1126. ences among the treatment groups. For example, intravenous 5. Martin DF, Dunn JP, Davis JL, et al. Use of the ganciclovir implant for the treatment may not be the cause of higher costs but a reflection treatment of cytomegalovirus retinitis in the era of potent antiretroviral therapy: recommendations of the International AIDS Society-USA panel. of worsening disease states, which has higher costs. However, Am J Ophthalmol. 1999;127:329–339. we did adjust for various proxy confounders such as co- 6. Piascik P. Fomiversen sodium approved to treat CMV retinitis. JAm existing AIDS-defining illnesses and use of HAART treat- Pharm Assoc. 1999;39:84–85. 7. MacDougall DS. Update on cidofovir for CMV retinitis. J Int Assoc Phy- ment, which did not change the large effect size seen in our sicians AIDS Care. 1997;3:18–24. analysis. Secondly, we used strict inclusion criteria, which 8. Davies L, Maynard A. An economic exploration of oral and intravenous

976 © 2004 Lippincott Williams & Wilkins Netherlands, Dutch Medicines Evaluation (38) Approved, October 2001 European Union, European Medicines Agency (39) Approved, 10 Aug 2013 Japan, Ministry of Health, Labour and Welfare N/A UK Medicines and Healthcare products Regulatory Approved, 11 April 2014 Agency (40) India, Central Drugs Standards Control Organisation N/A Ukraine, Ukrainian Drug Registration Agency N/A Malta, Medicines Authority (41) Approved, 16 December 2013 Approved, 13 September 2002 Ireland, Health Products Regulatory Authority (42) Renewed, 4 November 2013

14. Availability of pharmacopoeial standards (British Pharmacopoeia, International Pharmacopoeia, United States Pharmacopoeia, European Pharmacopeia)

Pharmacopoeial standards only exist for the United States Pharmacopoeia and National Formulary:

Valganciclovir HCl (USP1707839) UoM: 500mg CAS No.:175865-59-5 Mol For.: C14 H22 N6 O5 . Cl H Mol Wt.: 390.82

15. Proposed (new/adapted) text that could be included in a revised WHO Model Formulary

Treatment of HIV-related cytomegalovirus retinitis

Valganciclovir oral administration (450mg tablet)

11

Sources

1. Sugawara M, Huang W, Fei YJ, Leibach FH, Ganapathy V, Ganapathy ME. Transport of valganciclovir, a ganciclovir prodrug, via peptide transporters PEPT1 and PEPT2. J Pharm Sci. 2000 Jun;89(6):781–9.

2. Valcyte. Valcyte Tablet Formulation [Internet]. Valcyte: valganciclovir HCl tablets. 2013 [cited 2014 Nov 21]. Available from: http://www.valcyte.com/hcp/about/aids- patients/formulation-and-dosing

3. WHO. HIV/AIDS [Internet]. World Health Organization. [cited 2014 Nov 21]. Available from: http://www.who.int/hiv/en/

4. Stewart MW. Optimal management of cytomegalovirus retinitis in patients with AIDS. Clin Ophthalmol Auckl NZ. 2010;4:285–99.

5. Sugar EA, Jabs DA, Ahuja A, Thorne JE, Danis RP, Meinert CL, et al. Incidence of cytomegalovirus retinitis in the era of highly active antiretroviral therapy. Am J Ophthalmol. 2012 Jun;153(6):1016–24.e5.

6. Ford N, Shubber Z, Saranchuk P, Pathai S, Durier N, O’Brien DP, et al. Burden of HIV-related cytomegalovirus retinitis in resource-limited settings: a systematic review. Clin Infect Dis Off Publ Infect Dis Soc Am. 2013 Nov;57(9):1351–61.

7. Wohl DA, Zeng D, Stewart P, Glomb N, Alcorn T, Jones S, et al. Cytomegalovirus viremia, mortality, and end-organ disease among patients with AIDS receiving potent antiretroviral therapies. J Acquir Immune Defic Syndr 1999. 2005 Apr 15;38(5):538–44.

8. Deayton JR, Prof Sabin CA, Johnson MA, Emery VC, Wilson P, Griffiths PD. Importance of cytomegalovirus viraemia in risk of disease progression and death in HIV-infected patients receiving highly active antiretroviral therapy. Lancet. 2004 Jun 26;363(9427):2116–21.

9. Micol R, Buchy P, Guerrier G, Duong V, Ferradini L, Dousset J-P, et al. Prevalence, risk factors, and impact on outcome of cytomegalovirus replication in serum of Cambodian HIV-infected patients (2004-2007). J Acquir Immune Defic Syndr 1999. 2009 Aug 1;51(4):486–91.

10. Durier N, Ananworanich J, Apornpong T, Ubolyam S, Kerr SJ, Mahanontharit A, et al. Cytomegalovirus viremia in Thai HIV-infected patients on antiretroviral therapy: prevalence and associated mortality. Clin Infect Dis Off Publ Infect Dis Soc Am. 2013 Jul;57(1):147–55.

11. Fielding K, Koba A, Grant AD, Charalambous S, Day J, Spak C, et al. Cytomegalovirus viremia as a risk factor for mortality prior to antiretroviral therapy among HIV-infected gold miners in South Africa. PloS One. 2011;6(10):e25571.

12

12. Mayaphi SH, Brauer M, Morobadi DM, Mazanderani AH, Mafuyeka RT, Olorunju SAS, et al. Cytomegalovirus viral load kinetics in patients with HIV/AIDS admitted to a medical intensive care unit: a case for pre-emptive therapy. PloS One. 2014;9(4):e93702.

13. Heiden D, Ford N, Wilson D, Rodriguez WR, Margolis T, Janssens B, et al. Cytomegalovirus retinitis: the neglected disease of the AIDS pandemic. PLoS Med. 2007 Dec;4(12):e334.

14. Kempen JH, Jabs DA, Wilson LA, Dunn JP, West SK. Incidence of cytomegalovirus (CMV) retinitis in second eyes of patients with the acquired immune deficiency syndrome and unilateral CMV retinitis. Am J Ophthalmol. 2005 Jun;139(6):1028–34.

15. Tun N, London N, Kyaw MK, Smithuis F, Ford N, Margolis T, et al. CMV retinitis screening and treatment in a resource-poor setting: three-year experience from a primary care HIV/AIDS programme in Myanmar. J Int AIDS Soc. 2011;14:41.

16. Ranbaxy Laboratories Ltd. Ranbaxy gains tentative approval to manufacture and market Valganciclovir Hydrochloride tablets- [Internet]. RANBAXY. 2008 [cited 2014 Nov 21]. Available from: http://www.ranbaxy.com/us/ranbaxy-gains-tentative- approval-to-manufacture-and-market-valganciclovir-hydrochloride-tablets/

17. Roche. Roche delivers strong 2013 results (media release). Basel; 2014 [cited 2014 Nov 21]. Available from: http://www.roche.com/med-cor-2014-01-30-e.pdf

18. Roche. Roche Media Release: Full-year 2012 results – Appendix (media release). 2002 [cited 2014 Nov 21]. Available from: http://www.roche.com/mrar12ane.pdf

19. Kempen JH, Frick KD, Jabs DA. Incremental Cost Effectiveness of Prophylaxis for Cytomegalovirus Disease in Patients with AIDS. PharmacoEconomics. 2001 Dec 1;19(12):1199–208.

20. The Guidelines for the prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from the Centers for Disease Control and Prevention, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. [cited 2014 Nov 21]. Available from: http://aidsinfo.nih.gov/contentfiles/lvguidelines/adult_oi.pdf

21. European AIDS Clinical Society. Guidelines Version 7.02 [Internet]. 2014 Jun [cited 2014 Nov 21]. Available from: http://www.eacsociety.org/Portals/0/140601_EACS%20EN7.02.pdf

22. Lalonde RG, Boivin G, Deschênes J, Hodge WG, Hopkins JJ, Klein AH, et al. Canadian consensus guidelines for the management of cytomegalovirus disease in HIV/AIDS. Can J Infect Dis Med Microbiol J Can Mal Infect Microbiol Médicale AMMI Can. 2004 Nov;15(6):327–35.

13

23. Valcyte. Valcyte for Acquired Immunodeficiency Syndrome (AIDS) Patients [Internet]. Valcyte: valganciclovir HCl tablets. 2013 [cited 2014 Nov 21]. Available from: http://www.valcyte.com/hcp/about/aids-patients

24. Brown F, Banken L, Saywell K, Arum I. Pharmacokinetics of valganciclovir and ganciclovir following multiple oral dosages of valganciclovir in HIV- and CMV- seropositive volunteers. Clin Pharmacokinet. 1999 Aug;37(2):167–76.

25. Martin DF, Sierra-Madero J, Walmsley S, Wolitz RA, Macey K, Georgiou P, et al. A Controlled Trial of Valganciclovir as Induction Therapy for Cytomegalovirus Retinitis. N Engl J Med. 2002 Apr 11;346(15):1119–26.

26. Lalezari J, Lindley J, Walmsley S, Kuppermann B, Fisher M, Friedberg D, et al. A safety study of oral valganciclovir maintenance treatment of cytomegalovirus retinitis. J Acquir Immune Defic Syndr 1999. 2002 Aug 1;30(4):392–400.

27. Jabs DA, Ahuja A, Van Natta M, Dunn JP, Yeh S, Studies of the Ocular Complications of AIDS Research Group. Comparison of treatment regimens for cytomegalovirus retinitis in patients with AIDS in the era of highly active antiretroviral therapy. Ophthalmology. 2013 Jun;120(6):1262–70.

28. Kosobucki BR, Goldberg DE, Bessho K, Koh HJ, Rodanant N, Labree L, et al. Valganciclovir therapy for immune recovery uveitis complicated by macular edema. Am J Ophthalmol. 2004 Apr;137(4):636–8.

29. Laher F, Ashford G, Cescon A, Cullen C, Lazarus E, Puren A, et al. Held to Ransom: CMV Treatment in South Africa. South Afr J HIV Med. 2010 Apr 30;11(1):31.

30. Patil AJ, Sharma A, Kenney MC, Kuppermann BD. Valganciclovir in the treatment of cytomegalovirus retinitis in HIV-infected patients. Clin Ophthalmol Auckl NZ. 2010;4:111–9.

31. Jung D, Dorr A. Single-dose pharmacokinetics of valganciclovir in HIV- and CMV-seropositive subjects. J Clin Pharmacol. 1999 Aug;39(8):800–4.

32. Cvetković RS, Wellington K. Valganciclovir: a review of its use in the management of CMV infection and disease in immunocompromised patients. Drugs. 2005;65(6):859–78.

33. Pham P. Valganciclovir (Valcyte®). Infect Dis Clin Pract. 2001;10(5):281–2.

34. Medicines Patent Pool. Hoffman-la Roche agreement for valganciclovir [Internet]. 2013 Aug [cited 2014 Nov 21]. Available from: http://www.medicinespatentpool.org/wp-content/uploads/MPP-Roche-Agreement-5- August-20133.pdf

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35. Mahadevia PJ, Gebo KA, Pettit K, Dunn JP, Covington MT. The epidemiology, treatment patterns, and costs of cytomegalovirus retinitis in the post-haart era among a national managed-care population. J Acquir Immune Defic Syndr 1999. 2004 Aug 1;36(4):972–7.

36. FDA. U.S. Food and Drug Administration Approved Drug Products profile, Valcyte [Internet]. FDA/Center for Drug Evaluation and Research - Office of Communications; [cited 2014 Nov 21]. Available from: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search .Overview&DrugName=VALCYTE&CFID=851342&CFTOKEN=71a2451fcd9299c6- 3358076A-923F-127B-BCD11871FB08020C

37. Roche. Safety Data Sheet: VALCYTE Powder for Oral Solution [Internet]. Dee Why, Australia; 2013 Nov [cited 2014 Nov 21]. Available from: http://www.roche- australia.com/content/dam/internet/corporate/roche/en_AU/files/SDS/VALCYTE_sds .pdf

38. Roche. Valcyte receives Dutch regulatory approval for treatment of AIDS-related CMV retinitis [Internet]. I-Base HIV Treatment Bulletin. 2001 [cited 2014 Nov 21]. Available from: http://i-base.info/htb/4817

39. European Medicines Agency. EMEA-000726-PIP01-09-M02: Valcyte [Internet]. [cited 2014 Nov 21]. Report No.: P/0220/2013. Available from: http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/pips/EMEA- 000726-PIP01-09-M02/pip_000699.jsp&mid=WC0b01ac058001d129

40. Medicines and Healthcare Products Regulatory Agency. Public Assessment Report Valganciclovir 450mg Film-coated Tablets [Internet]. Teva UK Limited; 2014 Jul [cited 2014 Nov 21]. Report No.: UK/H/5484/001/DC. Available from: http://www.mhra.gov.uk/home/groups/par/documents/websiteresources/con433870. pdf

41. Medicines Authority, Malta Medicines List [Internet]. [cited 2014 Nov 21]. Available from: http://www.medicinesauthority.gov.mt/file.aspx?f=766

42. VALCYTE [Internet]. Health Products Regulatory Authority. [cited 2014 Nov 21]. Available from: http://www.hpra.ie/homepage/medicines/medicines-information/find- a-medicine/results/item?pano=PA0050/150/001&t=VALCYTE#

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