MSF: Open letter

April 12 2012

To:

Ms. M Hela, Registrar of Medicines. By e-mail: helam@health.gov.za.

Professor PFK Eagles, Medicines Control Council, Chairperson. By e-mail: peagles@uwc.ac.za.

Dr. NE Khomo, Medicines Control Council, Vice-Chair. By e-mail: nekhomo@gmail.com.

Ms. P Nkambule, MCC Clinical Evaluation & Trials, Clinical Trials Committee. By e-mail: nkambp@health.gov.za.

Dr S Munbodh, MCC Clinical Evaluation & Trials, Section 21. By e-mail: munbods@health.gov.za.

CC:

The Hon. Dr. Aaron Motsoaledi, Minister Of Health. By fax: 012 395 9165, 021 465 1575.

Regarding: Compassionate use of bedaquiline for drug-resistant tuberculosis in South Africa

Dear Registrar Hela, Professor Eagles, Dr. Khomo, Ms. Nkambule, Dr. Munbodh and Honourable Minister Motsoaledi

South Africa has a serious epidemic of drug resistant tuberculosis. Every year approximately 10,000 people are diagnosed with multidrug-resistant TB (MDR-TB), with a substantial proportion of these suffering from extensively drug resistant tuberculosis (XDR-TB) (1). Unfortunately, treatment with currently available drugs is only successful for around 60% of MDR-TB patients and 44% of XDR-TB patients, even under the best of circumstances (2, 3).

Many patients who are not successfully treated succumb to the disease quite rapidly, particularly those who are HIV infected. However, for the proportion of patients who remain alive, current treatment options are ineffective, thereby leading to treatment failure. Many of these patients were infected directly, through transmission of an already drug resistant TB strain, and have been highly compliant with treatment. This contradicts the misguided belief that these patients mainly developed drug resistant TB through delinquency or non-compliance with treatment.

Encouragingly, there are some new medications with demonstrated good efficacy in the treatment of drug resistant TB in clinical trials. However, completion of all clinical trials required for full registration of new drugs is extremely lengthy, and many patients with few effective treatment options are ineligible for such trials. The concept of ‘compassionate use’ has been developed to allow earlier access to promising new pharmaceuticals for patients, such as those in whom existing treatment for drug resistant tuberculosis is likely to be ineffective or has already failed. Many countries have now established the legal and regulatory framework to enable select groups of patients to access drugs through ‘compassionate use’, and the World Health Organization has recently called for countries to strengthen existing regulatory frameworks to enable access to new drugs, while preventing misuse of these drugs (4).

TMC-207 (bedaquiline) is a drug that represents the first new class of TB drugs to be developed in 60 years. A phase II clinical trial demonstrated that addition of bedaquiline to a standard MDR regimen for patients with drug resistant tuberculosis reduced the time to conversion to a negative sputum culture and increased the proportion of patients with conversion of sputum culture (5). In mid-2011, Tibotec, the pharmaceutical company that developed bedaquiline, made the drug available, free of charge, under ‘compassionate use’ criteria.

Based on this availability, a number of sites across South Africa, where drug resistant tuberculosis is being treated through the provision of high quality care, applied for access to the drug via an application to the Medicines Control Council (MCC) in terms of Section 21 of the Medicines and Related Substances Act 101 of 1965. The MCC granted approval to the Khayelitsha Drug Resistant TB Programme in Cape Town (6), in August 2011 (see appendix 1 for approval letter). Despite this approval, Tibotec has been unwilling to supply us with bedaquiline. The reason seems to be that the MCC made a verbal communication to Janssen, Pharmaceutical Companies of Johnson and Johnson, (formerly Tibotec) that it was withdrawing approval; Médecins Sans Frontières (MSF) in Khayelitsha has not received any communication to this effect, nor any rationale for such a decision.

In the meantime, a number of patients who would have benefited from inclusion of bedaquiline in a ‘last-chance’ treatment regimen have been denied this opportunity. Some patients in Khayelitsha, a few of whom are described below, could have been treated with a multidrug regimen that, with the inclusion of bedaquiline, offered the potential chance of cure, while simultaneously ‘protecting’ bedaquiline from the development of resistance. In addition to strict patient eligibility criteria established by Tibotec, the use of bedaquiline in Khayelitsha would have the oversight of an existing clinical committee (consisting of local clinical practitioners and other specialists) that would decide on the most appropriate regimen for each individual patient and whether inclusion of bedaquiline is appropriate. All patients treated in the Khayelitsha DR-TB programme are supported by a team of trained and dedicated health care workers and counselors, and therefore any patients commencing a tailored regimen including bedaquiline would be closely monitored. 

We therefore urge the MCC to reverse this apparent decision, and confirm that approval for compassionate use of bedaquiline through Section 21 of the Medicines and Related Substances Act 101 of 1965 will continue.

If the MCC has indeed withdrawn its approval for compassionate use of bedaquiline, and refuses to reconsider its decision, we then call on the MCC to provide written justification for its actions which have denied potentially life-saving treatment to these patients.

Phumeza* is a 21 year old college student. She is HIV negative and has not had tuberculosis previously. She was diagnosed with pulmonary TB based on clinical grounds and started the “normal” TB treatment regimen. The TB diagnosis was subsequently confirmed with a sputum culture, but resistance to both rifampicin and isoniazid was demonstrated (MDR-TB). Standard MDR-TB treatment was commenced and continued for 2 months until the laboratory reported that the original sample also displayed resistance to amikacin, indicating that Phumeza was infected with pre-XDR-TB. The treatment regimen was then changed to the standard XDR-TB regimen, excluding capreomycin due to renal toxicity at that time. Phumeza’s sputum cultures became negative for TB and remained negative for 8 months during treatment. Despite excellent adherence to treatment, cultures became positive again and resistance to ofloxacin was demonstrated at this point (indicating that she had XDR-TB), implying that her treatment regimen was failing. Had bedaquiline been available at this point, it would have been possible to tailor a regimen with drugs thought to still be effective based on her treatment history and molecular genotype testing, and therefore provide a reasonable chance of cure, without necessarily compromising bedaquiline. This regimen might have included: bedaquiline, capreomycin, levofloxacin, linezolid, clofazimine and PAS. *Phumeza has given permission to use her name and photograph and is the author of an online blog describing her experiences: http://blogs.msf.org/tb/author/phumeza/ .

Andiswa* is a 30 year old mother of three. She is HIV positive and has been on antiretroviral treatment for five years, with a suppressed viral load for the past year. She was successfully treated for tuberculosis 2 years before a second pulmonary TB diagnosis. She was diagnosed with MDR-TB after failing to respond to the first-line treatment regimen she was receiving, and thus commenced standard MDR-TB treatment. Her sputum cultures converted to negative after 3 months of this regimen and treatment was continued. Despite good adherence and no demonstrated second-line resistance, her cultures became positive again at month 9 on treatment; this was 3 months after completion of the standard six-month injectable phase which includes the drug kanamycin. Standard XDR-TB treatment, including high dose isoniazid, was instituted at this point due to failure of standard MDR-TB treatment. However, despite continued good adherence, sputum cultures remained positive throughout 11 months of this revised treatment regimen and resistance to amikacin and ofloxacin was subsequently demonstrated (XDR-TB). Although Andiswa has received substantial second-line treatment and further treatment options are limited, it would have been possible to include bedaquiline into a regimen containing at least 3 other ‘clean’ drugs when treatment failure was first identified at 9 months of treatment. *Name has been changed for reasons of confidentiality.

Aviwe is a 19 year old engineering undergraduate. He is HIV negative. He was diagnosed with pulmonary TB and shown to be rifampicin resistant using the XpertMTB/Rif test (i.e. GeneXpert), which  is now available to patients in Khayelitsha. He was started on the standard MDR-TB treatment regimen but, while adherent to treatment, he continued to lose weight over the following 2 months. Further drug susceptibility testing on his original diagnostic specimen showed resistance to amikacin and ethionamide (pre-XDR-TB). The standard regimen was modified with the addition of capreomycin and PAS, and ethionamide was withdrawn due to probable resistance and the severe nausea and vomiting that he suffered due to the well-known side effects of this medication. Shortly after this, results from subsequent sputa showed further resistance to ofloxacin (XDR-TB). This is the point at which treatment could have been optimized, with the strongest regimen available, due to extensive and ongoing development of resistance and possible compromise of the only 2 effective second line drugs, moxifloxacin and teridizone, in the original standard regimen (before the full DST results were available). With the availability of at least 4 ‘clean drugs’: capreomycin, PAS, linezolid and clofazimine, an effective regimen could have been tailored to support the addition of bedaquiline and offer a better chance of cure. *Aviwe has given permission to use his name and photograph.

Please confirm receipt of this letter as soon as it reaches your offices.

We further urge the approval of compassionate use of bedaquiline be confirmed by 25^th April 2012, failing which a written response indicating the MCC’s plan to approve compassionate use is released by the same date. 

Sincerely,

Dr Gilles Van Cutsem, Médecins Sans Frontières/Doctors Without Borders (MSF)

Dr Jennifer Hughes, Médecins Sans Frontières/Doctors Without Borders

Dr Helen Cox, Médecins Sans Frontières/Doctors Without Borders

Dr Eric Goemaere, Médecins Sans Frontières/Doctors Without Borders

Dr Peter Saranchuk, Médecins Sans Frontières/Doctors Without Borders

Dr Daniela Garone, Médecins Sans Frontières/Doctors Without Borders

Dr Vivian Cox, Médecins Sans Frontières/Doctors Without Borders

Dr Indira Govender, Médecins Sans Frontières/Doctors Without Borders

Dr Virginia De Azevedo, City of Cape Town Department of Health

Dr Simiso Sokhela, City of Cape Town

Dr Lincoln Stoffels, City of Cape Town

Dr Vuyokazi Ntlantsana, City of Cape Town

Dr Eve Mendel, City of Cape Town

Dr Janet Giddy, Provincial Government Western Cape (PGWC)

Dr Florian Batstone, PGWC

Dr Elizabeth Augustine, PGWC

Dr Rosie Burton, GF Jooste Hospital, Cape Town

Dr Janet Scott, DP Marais TB Hospital, Western Cape

Dr Roland Croxford, DP Marais TB Hospital, Western Cape

Dr Cedric J. Werely, Stellenbosch University

Prof Rob Warren, Stellenbosch University

Dr Tom Boyles, University of Cape Town

Prof Mark Nicol, University of Cape Town

Prof Graeme Meintjes, University of Cape Town

Prof Gary Maartens, University of Cape Town

Prof Helen McIlleron, University of Cape Town

Dr Hanif Esmail, University of Cape Town

Prof Leslie London, University of Cape Town

Ms Morna Cornell, University of Cape Town

Dr John Simpson, National Health Laboratory Service, Cape Town

Dr Joanna Bielowski, Right to Care

Prof Francois Venter, RHRU, University of the Witwatersrand

Dr Francesca Conradie, President of the Southern African HIV Clinicians Society

Dr Nesri Padayatchi, Deputy Director, CAPRISA

Prof Yunus S. Moosa, University of Kwa-Zulu Natal

Prof Gavin Churchyard, Executive Director, The Aurum Institute

Dr Paul David, Chairman of the Board, The Aurum Institute

Dr Dave Clark, The Aurum Institute

Dr Liesl Page-Shipp, The Aurum Institute

Dr Kerrigan McCarthy, The Aurum Institute

Dr Salome Charalambous, The Aurum Institute

Dr Varanna Gharbaharan, WRHI TB Program Advisor

Dr Andrew Black, WRHI Technical Head TB

Dr Mary-Ann Davies, University of Cape Town

The Southern African HIV Clinicians Society

Médecins Sans Frontières

References

1.            World Health Organization. Global Tuberculosis Control 2011. Geneva: World Health Organization2011 Contract No.: WHO/HTM/TB/2011.16.

2.            Orenstein EW, Basu S, Shah NS, Andrews JR, Friedland GH, Moll AP, et al. Treatment outcomes among patients with multidrug-resistant tuberculosis: systematic review and meta-analysis. Lancet Infect Dis. 2009 Mar;9(3):153-61.

3.            Jacobson KR, Tierney DB, Jeon CY, Mitnick CD, Murray MB. Treatment outcomes among patients with extensively drug-resistant tuberculosis: systematic review and meta-analysis. Clin Infect Dis. 2010 Jul 1;51(1):6-14.

4.            World Health Organization. More evidence and better diagnostics needed before redefining severe forms of drug-resistant TB says WHO.  2012 [cited 2012 28/3/2012]; Available from: http://www.who.int/mediacentre/news/notes/2012/mdr_tb_20120323/en/#.

5.            Diacon AH, Pym A, Grobusch M, Patientia R, Rustomjee R, Page-Shipp L, et al. The diarylquinoline TMC207 for multidrug-resistant tuberculosis. N Engl J Med. 2009 Jun 4;360(23):2397-405.

6.            Médecins Sans Frontiéres. Scaling up diagnosis and treatment of drug-resistant tuberculosis in Khayelitsha, South Africa.  Cape Town2011; Available from: http://www.msf.org.za/publication/scaling-diagnosis-and-treatment-drug-resistant-tuberculosis-khayelitsha-south-africa.