[e-drug] Access to treatment for cryptococcal meningitis

["nathan ford" <nathan.ford@london.msf.org>]

E-DRUG: Access to treatment for cryptococcal meningitis
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[Copied as fair use; we apologize for the strange characters in the message due to the conversion to plain text. WB] 

Lancet Infectious Diseases Vol 5, September 2005

Cryptococcal meningitis is a common and often fatal opportunistic infection in patients with late stage HIV infection, especially in Africa and Asia.1â3  US and UK guidelines for treatment recommend a combination of amphotericin B and ïucytosine for the initial 2 weeks,4,5  based on the results of a large randomised trial.6 The superior mycological efïcacy of this combination has recently been conïrmed in Thailand.7 In centres without facilities for blood monitoring, amphotericin B-based therapy cannot be given safely and ïuconazole is the only option. However, ïuconazoleâan essentially fungistatic drugâtakes much longer to sterilise the cerebrospinal ïuid6â8 and has been associated with poorer clinical outcome compared with amphotericin B-based induction therapy.8 Moreover, expanding access to antiretroviral drugs offers patients with HIV-associated cryptococcal meningitis the prospect of a good long-term prognosis, provided they survive the acute cryptococcal infection, supporting an aggressive approach to initial antifungal therapy. Unfortunately, although access to antiretroviral drugs is increasing, access to amphotericin B and ïucytosine in areas with the highest burden of cryptococcal disease has been in decline.

Conventional amphotericin B deoxycholate remains the gold standard for cryptococcal meningitis, but decreasing use of this drug in the treatment of other fungal infections has led to a worldwide reduction in supply from the main manufacturer, Bristol Myers Squibb (BMS). At St Georgeâs Hospital in London, UK, amphotericin B was not available between Sept 2004 and Jan 2005. At Jooste Hospital in Cape Town, South Africa, where 15 cases of cryptococcal meningitis are seen monthly and liposomal amphotericin B is not an alternate option, amphotericin B supplies have been inconsistent over the past 6 months. Furthermore, discrepancies in pricing severely restrict access in some areas.9 In South Africa, where BMS is the only supplier, amphotericin B costs public hospitals more than three times its price in the UK (price per 50 mg vial South African Rand 146 [Â12Â69] vs Â3Â51 in the UK), making a 2-week treatment course unacceptably expensive for a middle-income country with more than 5 million HIV-infected people. Use of the drug has therefore been limited.

Flucytosine is not widely available in Africa and Asia despite being recommended as ïrst-line treatment. It is safe at current doses for 2 weeks in this setting, and is a simple molecule that has been off-patent for many years. Flucytosine was previously marketed by Roche in South Africa, but its registration lapsed in 1996. At that time, in the absence of antiretroviral therapy, the prognosis of patients with HIV-associated cryptococcal meningitis was uniformly fatal. Fortunately, this is no longer the case. Flucytosine is available from Valeant in the USA and Europe, but is also produced by a number of companies in China. Studies are urgently needed to assess the bioavailability of these alternate sources of ïucytosine. However, in many high incidence countries, lengthy regulatory authority approval procedures are required even to import donated Valeant ïucytosine.

In 2000, the lobbying of activists in South Africa and internationally resulted in the launch of Pïzerâs donation of ïuconazole.10 In 2003, the Competition Commission of South Africa found that GlaxoSmithKline and Boehringer Ingelheim had been charging excessive prices for antiretrovirals.11 As a result, the companies agreed to grant licences to a restricted number of generic manufacturers. We are pleased to report that lobbying of BMS to reduce the cost of amphotericin B in South Africa by the Aids Law Project on behalf of the Treatment Action Campaign and the Southern African HIV Clinicians Society has recently been successful in attaining a price reduction to Rand 26 (Â2Â26) per 50 mg vial, effective July 1, 2005, a reduction that will have a large, beneïcial impact on the treatment of cryptococcal meningitis in that country.

However, when the price of essential drugs puts them out of reach of countries with the highest disease burden, a system that relies on philanthropic initiatives by the pharmaceutical industry and the pressure of lobby groups cannot result in sustainable access to medicines. National governments and their drug Antiretroviral roll-out, regulatory authorities should be encouraged to produce or facilitate import of quality cheaper versions of the needed drugs, either brand or generic, as is their right within international trade agreements.12 In the case of cryptococcal meningitis, further efforts to increase access to amphotericin B and ïucytosine are urgently needed and would translate into fewer deaths and less disability from a common HIV-associated opportunistic infection.

Tihana Bicanic, Robin Wood, Linda-Gail Bekker, Marta Darder, Graeme Meintjes, Thomas S Harrison

LGB, TB, and TSH are at the Desmond Tutu HIV Centre, University of Cape Town, Cape Town, South Africa; RW is the Director of the Desmond Tutu HIV Centre, University of Cape Town. MD is the coordinator of the Access to Essential Medicines Campaign, MÃdecins sans FrontiÃres, South Africa. GM is a consultant at the GF Jooste Hospital, Cape Town. TB and TSH are also at St Georgeâs Hospital Medical School, London, UK.

Correspondence to: Dr Tihana Bicanic, Desmond Tutu HIV Centre, Wehner and Beit Building North, Institute of Infectious Diseases and Molecular Medicine, University of Cape Town Faculty of Health Sciences, Anzio Road, Observatory 7925, Cape Town, South Africa. Tel +27 21 6506986; fax +27 21 6506963; tihana.bicanic@hiv-research.org.za

1 Chariyalertsak S, Sirisanthana T, Saengwonloey O, Nelson KE. Clinical presentation and risk behaviours of patients with acquired immunodeïciency syndrome in Thailand, 1994â1998: regional variation and temporal trends. Clin Infect Dis 2001; 32: 955â62.

2 French N, Gray K, Watrea C, et al. Cryptococcal infection in a cohort of HIV-1-infected Ugandan adults. AIDS 2002; 16: 1031â38. 

3 Corbett EL, Churchyard G, Charalambos S, et al. Morbidity and mortality in South African gold miners: impact of untreated disease due to human immunodeïciency virus. Clin Infect Dis 2002; 34: 1251â58.

4 Saag MS, Graybill RJ, Larsen RA, et al. Practice guidelines for the management of cryptococcal disease. Clin Infect Dis 2000; 30: 710â18.

5 Denning DW, Kibbler CC, Barnes RA. British Society for Medical Mycology proposed standards of care for patients with invasive fungal infections. Lancet Infect Dis 2003; 3: 230â40.

6 Van der Horst CM, Saag MS, Cloud GA, et al. Treatment of cryptococcal meningitis associated with the acquired immunodeïciency syndrome. N Engl J Med 1997; 337: 15â21.

7 Brouwer AE, Rajanuwong A, Chierakul W, et al. Combination antifungal therapies for HIV-associated cryptococcal meningitis: a randomised trial. Lancet 2004; 363: 1764â67.

8 Larsen RA, Leal MA, Chan LS. Fluconazole compared with amphotericin B plus ïucytosine for cryptococcal meningitis in AIDS. Ann Intern Med 1990; 113: 183â87.

9 UNICEF/UNAIDS/WHO/MSF. Sources and prices of selected medicines and diagnostics for people living with HIV/AIDS, June 2004. http://www. who.int/medicines/organization/par/ipc/s_pScreen/S_Pscreen.pdf (accessed July 4, 2005).

10 Anon. Diïucan partnership programme. http://www.diïucanpartnership. com (accessed July 4, 2005). 

11 Competition Commission of South Africa. Competition commission decides Tiso Nail transaction was notiïable. http://www.compcom. co.za/resources/Media%20Releases/MediaReleases%202003/Jul/Med% 20Rel%2029%200f%2015%20Oct%202003.asp (accessed July 4, 2005).

12 World Trade Organization. Declaration on the TRIPS agreement and public health, adopted 14 November 2001. http://www.wto.org/ english/thewto_e/minist_e/min01_e/mindecl_trips_e.htm (accessed July 4, 2005).