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). 1 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