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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 (Jennifer.Cohn@geneva.msf.org) 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

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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  

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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

(n = 79) IV Ganciclovir (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 thrombophlebitis

- 6%

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 450mg tablet (USD)

Price per patient regimen, 12 weeksa (USD)

Price per patient regimen, 27 weeksb

(USD)

Roche price from IDA Foundation 11.10 2330.42 4660.85

Roche price in India 12.71 2669.17 5339.34 Cipla product for local Indian market 3.73 783.14 1566.28

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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pharmacoeconomic study examined daily and treatment costs from 98 HIV positive CMVr patients from the same national claims database who received treatment with anti-CMV drugs, showed that oral (valganciclovir or ganciclovir) and intraocular therapies incur significantly lower total daily costs ($US69 and $US70) compared with intravenous (ganciclovir, foscarnet or cidofovir) [$US163] or combination ($US215) therapies. Thus oral treatments incurred significantly fewer costs per treatment course as compared to intravenous therapies (-$7185 USD, 95% CI -$3029 - -$11324, P<0.05). Tables below taken from Mahadevia P et al., JAIDS

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 $7185per 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 intraoculartreatment groups were not statistically significant. Becausecombinational treatment represented a small fraction of alltreatment, we do not present cost differences between thisgroup and the others.

DISCUSSIONIn 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 demographicand treatment confounders, the costs for intravenous treatmentstill remained higher. The magnitude of the difference betweenintravenous treatment and the other groups was large. The costdifferences were mainly driven by higher outpatient costs inthe intravenous treatment group. The higher costs for phlebitisfor intravenous treatment were also statistically significantcompared with the other groups.

It has been demonstrated that intravenous ganciclovirand foscarnet are comparable in their efficacy.17 The efficacyof oral valganciclovir, which was approved for the treatment ofCMV retinitis in 2001, is also comparable to that of intrave-nous ganciclovir for induction therapy.4 Nevertheless, our datashow that the proportion of cases treated with intravenoustreatment remained relatively high in 2002 (Fig. 2), at approxi-mately 40%. Switching these patients to oral or intraoculartherapy represents an opportunity for cost savings.

TABLE 2. Unadjusted Total Costs and Cost Per Day By Treatment Type Among 98 CMV Retinitis Patients

Oral Treatment(n = 89 Treatment

Periods Lasting8412 Days)

IntravenousTreatment (n = 102Treatment PeriodsLasting 7974 Days)

IntraocularTreatment (n = 50Treatment PeriodsLasting 5099 Days)

CombinationalTreatment (n = 12Treatment PeriodsLasting 157 Days)

All Treatment Types(n = 253 Treatment

Periods)

Drug treatment costs $351,340 $293,951 $122,257 $10,449 $777,997Adverse event costs $39,621 $53,416 $10,564 $0 $103,601Phlebitis costs $0 $77,401 $0 $0 $77,401Infusion costs $0 $22,001 $0 $0 $22,001Outpatient costs $144,240 $733,616 $200,471 $15,628 $1,093,956Inpatient costs $43,984 $118,761 $25,543 $7,601 $195,889Total costs $579,185 $1,299,147 $358,834 $33,678 $2,270,845Total cost per day $69 $163 $70 $215 $105

FIGURE 2. Proportion of all treatment claims that are oral,intravenous and intraocular treatment among CMV retinitiscases in the post HAART era. IO, Intraocular; IV, intravenous,PO, Oral; Rx, treatment.

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

© 2004 Lippincott Williams & Wilkins 975

If “local” therapy (intravitreous fomivirsen or ganciclo-vir implant) is chosen, concurrent oral ganciclovir is generallyrecommended to reduce the risk of second-eye or visceralCMV disease, and systemic ganciclovir also significantly re-duces the risk of developing Kaposi sarcoma.18 While this ap-proach may be more effective for the general health of a patientthan local therapy alone, it also adds to the cost of therapy andmay expose the patient to more treatment-related adverseevents. Because too few patients were on simultaneous treat-ment, the study was not powered to examine costs differencesamong various dual-treatment combinations.

Prior to HAART therapy, Palella et al2 demonstrated adecline in opportunistic infections among the HIV/AIDSpopulation. Our study showed further, rather dramatic, de-creases in CMV retinitis in a managed-care HIV populationduring the post-HAART era. Our projected rate of CMV reti-nitis decline from 1997 to 1998 may be artificially accentu-ated. We attribute this to a smaller number of managed-careplans that supplied data in 1997 in addition to the low numberof enrolled HIV or AIDS patients in a plan. However, after1997, the incidence rates associated with CMV retinitis in ouranalysis are consistent with HIV Outpatient Study (HOPS)19

database, which demonstrated an approximate incidence of50–300 CMV retinitis cases per 10,000 AIDS patients from1998–2001.

Our study had several limitations. First, because our datasource was claims based, we do not know the specifics of theunderlying clinical indicators that could explain cost differ-ences among the treatment groups. For example, intravenoustreatment may not be the cause of higher costs but a reflectionof worsening disease states, which has higher costs. However,we did adjust for various proxy confounders such as co-existing AIDS-defining illnesses and use of HAART treat-ment, which did not change the large effect size seen in ouranalysis. Secondly, we used strict inclusion criteria, which

may have limited our sample and the generalizability of ourresults. Finally, we cannot be certain that miscoding did notoccur in some of these claims. However, use of claims codes inHIV was found to be very accurate in prior analyses.20,21

In conclusion, we observed that CMV retinitis is lessprevalent and incident among a national managed-care popu-lation during the HAART era of the HIV/AIDS epidemic. Thetotal cost per episode of care, however, remains high. Wefound that oral and intraocular treatment modalities led tolower total costs, suggesting that these agents maybe prefer-able as initial treatment over intravenous therapy.

ACKNOWLEDGMENTSThe authors thank Ms. Kathy Fraeman and Dr. Chris

Barker for their assistance with statistical programming andanalyses.

REFERENCES1. Cunningham WE, Markson LE, Andersen RM, et al. Prevalence and pre-

dictors of highly active antiretroviral therapy use in patients with HIVinfection in the united states. HCSUS Consortium. HIV Cost and ServicesUtilization. J Acquir Immune Defic Syndr. 2000;25:115–123.

2. Palella FJ Jr, Delaney KM, Moorman AC, et al. Declining morbidity andmortality among patients with advanced human immunodeficiency virusinfection. HIV Outpatient Study Investigators. N Engl J Med. 1998;338:853–860.

3. Dunn JP. Cytomegalovirus retinitis in 2003. Hopkins HIV Rep. 2003;15:8–11.

4. Martin DF, Sierra-Madero J, Walmsley S, et al. A controlled trial of val-ganciclovir as induction therapy for cytomegalovirus retinitis. N Engl JMed. 2002;346:1119–1126.

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

Oral vs. IntravenousTreatment Periods

Oral vs. IntraocularTreatment Periods

Intravenous vs. IntraocularTreatment Periods

CostDifference 95% CI

CostDifference 95% CI

CostDifference 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)

Mahadevia et al J Acquir Immune Defic Syndr • Volume 36, Number 4, August 1 2004

976 © 2004 Lippincott Williams & Wilkins

Given the significant benefits from systemic therapy versus intravitreal injections, and the likely costs savings from using oral valganciclovir versus IV therapies (based on the US study above), and the expected decreases in price of valganciclovir based on entry of SRA-approved generic versions into the market, treatment with oral valganciclovir is likely to cost-effective as compared to IV or intravitreal treatments in most contexts. 13. Summary of regulatory status of the medicine (in various countries) Table 5. Regulatory approval status for valganciclovir for indication for CMVr Country Regulatory Status USA, US Food and Drug Administration (36) Approved, 29 March 2001 Australia, Therapeutic Goods Administration (37) Approved, 30 September 2011

11    

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 Agency (40) Approved, 11 April 2014

India, Central Drugs Standards Control Organisation N/A Ukraine, Ukrainian Drug Registration Agency N/A Malta, Medicines Authority (41) Approved, 16 December 2013

Ireland, Health Products Regulatory Authority (42) Approved, 13 September 2002 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)

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