[Ip-health] Letter in Lancet GH urges WHO to act on treatment of HIV related cytomegalovirus diseases
Ellen 't Hoen
ellenthoen.ip at gmail.com
Fri Jan 24 05:18:33 PST 2014
We urge WHO to act on cytomegalovirus retinitis
David Heiden a, Peter Saranchuk b, NiNi Tun c, Bertrand Audoin d, Jen Cohn e, Nicolas Durier f, Gary Holland g, W Lawrence Drew h, Ellen ‘t Hoen i
On Nov 11, 2013, The Lancet Global Health published an analysis of the causes of vision loss 1990—2010.1 This analysis does not mention the risk of vision loss as a result of untreated cytomegalovirus retinitis in people with HIV, despite the infection's continued prevalence in low-income and middle-income countries. Cytomegalovirus disease was one of three unusual infections in the report by the US Centers for Disease Control and Prevention2 that marked the official start of the AIDS epidemic on June 5, 1981. Before the availability of antiretroviral therapy, cytomegalovirus retinitis, the most common manifestation of AIDS-related cytomegalovirus infection, affected a third of patients with AIDS and accounted for more than 90% of AIDS-related blindness.
Sadly, cytomegalovirus retinitis remains the neglected disease of the AIDS pandemic,3 and there is an increasing group of young patients in low-income and middle-income countries made healthy by successful treatment of underlying HIV, yet left permanently blind from undiagnosed or inadequately treated cytomegalovirus retinitis. Cytomegalovirus retinitis was second only to cataract as a cause of bilateral blindness in the Chiang Mai region of Thailand,4 and findings of a recent systematic review confirmed a substantial burden of disease, particularly in southeast Asia, with no apparent reduction in prevalence noted in the past decade.5
On Oct 12, 2013, The Lancet editors6 cited the “bold but attainable goal” of reducing the global prevalence of avoidable blindness. Cytomegalovirus retinitis is covered in every set of guidelines from the US Centers for Disease Control and Prevention, and now there is a unique opportunity for both the WHO Department of Blindness and WHO Department of AIDS to give full attention to this problem. Roche and the Geneva-based UNITAID-supported Medicines Patent Pool have signed an agreement that provides a unique opportunity to reduce blindness and mortality in patients who present with late-stage HIV infection and cytomegalovirus retinitis or extraocular cytomegalovirus disease.7 The agreement immediately makes valganciclovir available to treatment programmes at a price reduction of up to 90% in 138 low-income and middle-income countries. Additionally, increased use of valganciclovir might incentivise generic drug entry into the market, promising even deeper and more sustainable price reductions than at present.
Treatment with a simple pill, valganciclovir, is realistic in every setting, whereas the standard of care in low-income and middle-income countries—a weekly intraocular injection of ganciclovir8—is inadequate for several reasons and even intraocular injection is unavailable in most settings.3 However, a simple pill will not entirely solve the problem, and appropriate measures for crucial early detection of cytomegalovirus retinitis in the well-defined vulnerable group of newly diagnosed patients with AIDS (those with CD4 cell counts below 100 cells per μL), are urgently needed. Unfortunately, with no mention of cytomegalovirus retinitis by WHO and no WHO guidelines on cytomegalovirus treatment, there has been little attention to treatment in national programmes, and systematic early screening is done in only one country, Myanmar (Burma), by enterprising non-governmental organisations.9 Strong action by WHO and others now offers opportunity to break the vicious cycle of underdiagnosis of cytomegalovirus retinitis and a lack of available, affordable treatment.
Valganciclovir and systemic (rather than local) treatment are the standard of care in high-income countries.10 Furthermore, there is compelling evidence that cytomegalovirus retinitis11 and systemic cytomegalovirus infection12 are linked to mortality rates, and reasonable evidence that systemic treatment of cytomegalovirus retinitis will reduce mortality.13 How should valganciclovir be given to newly diagnosed patients with AIDS and cytomegalovirus retinitis? A common-sense starting point (based on both standards of care in high-income countries and extensive direct personal clinical experience) would be to provide valganciclovir 900 mg twice a day for 2 weeks and then valganciclovir 900 mg once a day until three conditions are met: a minimum of 3 months has elapsed, active cytomegalovirus retinitis has completely resolved, and a good response to antiretroviral therapy has been achieved. The current practice of intraocular ganciclovir injection should be continued for the first 2 weeks to provide local induction. The blood cell count should be monitored for leucopenia. It is important to preserve techniques of intraocular injection for patients who become cytopenic and for patients who might not be able to take oral drugs (comatose state, severe dysphagia, etc), or in whom the retinitis does not seem to respond promptly (including because of the development of resistant strains).
Well designed operational research is needed to refine this starting point. Research is also needed to find out whether prophylactic valganciclovir treatment in high-risk patients might reduce AIDS mortality as well as blindness, as substantial data suggest.14, 15WHO leadership is needed to provide cytomegalovirus diagnosis and treatment guidelines, support countries' efforts to scale up diagnosis, and explore the possibility of integration of routine eye screening with indirect ophthalmoscopy into routine care for all patients first presenting with advanced HIV, as has been done in Myanmar.9
WHO needs to take action against cytomegalovirus retinitis for treatment programmes to move towards elimination of preventable blindness and meet their targets for universal eye health.
E'tH is a regular consultant to the Medicines Patent Pool and WHO. All other authors declare that they have no conflicts of interest.
1 Bourne R, Stevens GA, White RA, et al. Causes of vision loss worldwide, 1990—2010: a systematic analysis. Lancet Global Health2013; 1: e339-e349. PubMed
2 CDC. Pneumocystis pneumonia—Los Angeles. MMWR Morb Mortal Wkly Rep 1981; 30: 250-252. PubMed
3 Heiden D, Ford N, Wilson D, et al. Cytomegalovirus retinitis: the neglected disease of the AIDS pandemic. PLoS Med 2007; 4:e334. CrossRef | PubMed
4 Pathanapitoon K, Ausayakhun S, Kunavisarut P, et al. Blindness and low vision in a tertiary ophthalmologic center in Thailand: the importance of cytomegalovirus retinitis. Retina 2007; 27: 635-640. CrossRef | PubMed
5 Ford N, Shubber Z, Saranchuk P, et al. Burden of HIV-related CMV retinitis in resource-limited settings: a systematic review. Clin Infect Dis 2013; 57: 1351-1361. CrossRef | PubMed
6 The Lancet. Opening eyes to prevent blindness. Lancet 2013; 382: 1226. Full Text | PDF(351KB) | CrossRef | PubMed
7 Medicines Patent Pool. Access more affordable valganciclovir through the Medicines Patent Pool/Roche agreement.http://www.medicinespatentpool.org/licensing/current-licences/access-more-affordable-valganciclovir-through-the-medicines-patent-pool-roche-agreement/. (accessed Jan 6, 2014).
8 Ausayakhun S, Yuvaves P, Ngamtiphakorn S, Prasitsilp J. Treatment of cytomegalovirus retinitis in AIDS patients with intravitreal ganciclovir. J Med Assoc Thai 2005; 88: S15-S20. PubMed
9 Tun N, London N, Kyaw MK, 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. PubMed
10 Drew WL, Ehrlich KS. Management of virus infections (cytomegalovirus, herpes simpex virus, varicella-zooster virus). In:Volberding P, Sande M, Lange J, Greene W, Gallant J, eds. Global HIV/AIDS medicine. New York: Elsevier, 2007: 437-461.
11 Hoover DR, Peng Y, Saah A, et al. Occurrence of cytomegalovirus retinitis after human immunodeficiency virus immunosuppression. Arch Ophthalmol 1996; 114: 821-827. CrossRef | PubMed
12 Deayton JR, Sabin CA, Johnson MA, et al. Importance of cytomegalovirus viraemia in risk of disease progression and death in HIV-infected patients receiving highly active antiretroviral therapy. Lancet 2004; 363: 2116-2121. Summary | Full Text |PDF(89KB) | CrossRef | PubMed
13 Kempen JH, Jabs DA, Wilson LA, et al. Mortality risk for patients with cytomegalovirus retinitis and acquired immune deficiency syndrome. Clin Infect Dis 2003; 37: 1365-1373. CrossRef | PubMed
14 Spector SA, McKinley GF, Lalezari JP, et alfor the Roche Cooperative Oral Ganciclovir Study Group. Oral ganciclovir for the prevention of cytomegalovirus disease in persons with AIDS. N Engl J Med 1996; 334: 1491-1497. CrossRef | PubMed
15 Hodson EM, Jones CA, Webster AC, et al. Antiviral medications to prevent cytomegalovirus disease and early death in recipients of solid-organ transplants: a systematic review of randomised controlled trials. Lancet 2005; 365: 2105-2115. Summary | Full Text | PDF(122KB) | CrossRef | PubMed
a Seva Foundation and California Pacific Medical Center, Pacific Eye Associates, San Francisco, CA 94115, USA
b Southern Africa Medical Unit, Médecins Sans Frontières, Cape Town, South Africa
c Medical Action Myanmar, Yangon, Myanmar
d International AIDS Society, Geneva, Switzerland
e Médecins Sans Frontières Access Campaign, Geneva, Switzerland
f TREAT Asia, amfAR (The Foundation for AIDS Research), Bangkok, Thailand
g Department of Ophthamology, Jules Stein Eye Institute, University of California Los Angeles, Los Angeles, CA, USA
h Clinical Virology Laboratory, San Francisco, CA, USA
i Medicines Law and Policy, Paris, France
Ellen 't Hoen, LLM
Medicines Law & Policy
e-mail: ellenthoen.ip at gmail.com
Ellen 't Hoen, LLM
e-mail: ellenthoen.ip at gmail.com
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