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AIDS:
doi: 10.1097/01.aids.0000202652.49020.94
Correspondence

Ritonavir/saquinavir safety concerns curtail antiretroviral therapy options for tuberculosis–HIV-co-infected patients in resource-constrained settings

Gray, Andya,b; Karim, Salim S Abdoolb,c; Gengiah, Tanuja Nb

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aDepartment of Therapeutics and Medicines Management

bCentre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu-Natal, Durban, South Africa

cDepartment of Epidemiology, Columbia University, New York, USA.

Received 17 March, 2005

Accepted 15 April, 2005

Tuberculosis is the most common serious opportunistic infection associated with HIV infection in sub-Saharan Africa, and a strong case has been made for integrating tuberculosis and HIV care [1]. In those settings where the tuberculosis and HIV epidemics converge, existing tuberculosis programmes provide an opportunity for efficiently identifying those HIV-infected patients who are eligible for antiretroviral therapy (ART), as well as for initiating this therapy in order to utilize the existing tuberculosis directly observed therapy infrastructure. This approach is, however, dependent on the availability of effective, safe and affordable antiretroviral regimens that are compatible with the standard treatments for tuberculosis, including rifampicin. As a result of cost considerations, the widespread use of alternative rifamycins, such as rifapentine or rifabutin, is not feasible in resource-constrained settings.

Current guidelines, such as those from the US Department of Health and Human Services, suggest that regimens based on the non-nucleoside reverse transcriptase inhibitor efavirenz be used as first-line choices in patients receiving concomitant rifampicin [2]. Therapy choices become far more difficult in the face of treatment-limiting toxicities, virological failure or pregnancy. In these cases, a protease inhibitor-based regimen is needed as nevirapine may not be an appropriate option because of its interaction with rifampicin and additive hepatic toxicity. The guidelines suggested the use of ritonavir-boosted saquinavir [2]. Although the ability of ritonavir to boost plasma concentrations of saquinavir is well described, there is only limited evidence that this combination is adequate to counteract the enzyme induction caused by rifampicin and is clinically effective [3,4]. The issue of a ‘Dear Health Care Provider' letter by Roche Pharmaceuticals on 7 February 2005 has now caused considerable additional uncertainty [5]. The manufacturers have informed the US Food and Drug Administration of problems experienced in a phase I, randomized, open-label, multiple-dose clinical pharmacology study in healthy volunteers. Of 28 patients given rifampicin 600 mg once a day together with ritonavir 100 mg and saquinavir 1000 mg twice a day, 11 (39.3%) had developed significant hepatocellular toxicity during the 28-day study period. In the light of this evidence, the continued use of this combination cannot be supported. As a consequence, the US Food and Drug Administration Advisory has now removed the only protease inhibitor-containing regimen recommended for use concurrently with rifampicin containing tuberculosis treatment, and has thereby reduced the therapeutic options available for those requiring ART beyond standard first-line therapy options. In the absence of direct advice to the contrary, two options are being explored that we feel to be questionable. Some have argued that the exact doses of ritonavir and saquinavir used in the pharmacokinetic study (100 mg and 1000 mg, respectively) were different from those used in practice (400 mg and 400 mg, given twice a day), thus justifying thte continued use of this combination. Others have argued that adding additional ritonavir to co-formulated lopinavir–ritonavir would be sufficient to overcome the hepatic enzyme induction caused by concomitant rifampicin. However, in an open-label, randomized trial of two such dosing regimens in health volunteers, 12 out of 32 subjects withdrew from the study [6]. For nine of these, the co-administration of lopinavir–ritonavir and rifampicin was associated with elevations in liver enzyme levels. The similarity to the outcome of the saquinavir–ritonavir pharmacokinetic study cannot be ignored. The remaining options are, thus, either to switch to a triple nucleoside regimen or to cease further antiretroviral therapy until the completion of the rifampicin-containing tuberculosis treatment.

Until recently, the multitude of studies on alternative treatment regimens has focused on the needs of the developed world where ART has been widely available and switching options are increasingly important. The Global Fund Against AIDS, TB and Malaria, the WHO's 3-by-5 programme, the US President's Emergency Program For AIDS Relief (PEPFAR) and local efforts are slowly increasing access to ART in resource-constrained regions such as sub-Saharan Africa. The newly described toxicity of the rifampin, saquinavir, ritonavir regimen thus vividly highlights the great need for research, particularly pharmacokinetic studies, also to address the ART options appropriate for resource-limited settings, and in particular, in this instance, for co-administration with rifampicin-containing tuberculosis treatment.

Sponsorship: The START trial is supported as part of CAPRISA by the National Institute of Allergy and Infectious Diseases, National Institutes of Health, US Department of Health and Human Services (grant no. U19AI51794).

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References

1. Abdool Karim SS, Abdool Karim Q, Friedland G, Lalloo U, El Sadr WM, on behalf of the START project. Implementing antiretroviral therapy in resource constrained settings: opportunities and challenges in integrating HIV and TB care. AIDS 2004; 18:1–5.

2. US Department of Health and Human Services. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. 23 March 2004.

3. Veldkamp AI, Hoetelmans RMW, Beijnen JH, Mulder JW, Meenhorst PL. Ritonavir enables combined therapy with rifampin and saquinavir. Clin Infect Dis 1999; 29:1586.

4. Lourta L, Toibaro J, Garcia Messina O, Duran A, Saenz C, Gonzalez C, Losso M. Retrospective comparison of 3 antiretroviral treatment options in patients with HIV infection and tuberculosis receiving rifampin. In: 11th Conference on Retroviruses and Opportunistic Infections. San Francisco, 8–11 February 2004 [Abstract no. 762].

5. Dear Health Care Provider letter. Roche Pharmaceuticals, 7 February 2005. http://www.fda.gov/medwatch/SAFETY/2005/safety05.htm#Invirase. Accessed: 11 February 2005.

6. La Porte CJL, Colbers EPH, Bertz R, Voncken DS, Wikstrom K, Boeree MJ, et al. Pharmacokinetics of adjusted-dose lopinavir–ritonavir combined with rifampicin in healthy volunteers. Antimicrob Agents Chemother 2004; 48:1553–1560.

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Appendix

The Starting Tuberculosis and Anti-Retroviral Therapy (START) project team includes: Salim Abdool Karim, Quarraisha Abdool Karim, Susan Brobst, Gavin Churchyard, Wafaa El-Sadr, Gerald Friedland, Clive Gray, Andy Gray, Rene Gonin, Richard Hafner, Scott Hammer, Rodney Hoff, Munira Khan, Mark Lurie, Terence Moodley, Marita Muurman, Kogieleum Naidoo, Gonasagrie Nair, Nesri Padayatchi, Diane Pizzano, Moussa Sarr, Aarthi Singh and Douglas Wilson.

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