{"id":27735,"date":"2015-01-29T12:28:43","date_gmt":"2015-01-29T12:28:43","guid":{"rendered":"http:\/\/i-base.info\/htb\/?p=27735"},"modified":"2015-01-30T17:41:46","modified_gmt":"2015-01-30T17:41:46","slug":"good-outcomes-within-the-national-bedaquiline-clinical-access-programme-in-south-africa","status":"publish","type":"post","link":"https:\/\/i-base.info\/htb\/27735","title":{"rendered":"Good outcomes within the National Bedaquiline Clinical Access programme in South Africa"},"content":{"rendered":"

<\/strong>\"45th<\/strong>Polly Clayden, HIV i-Base<\/p>\n

The South African Bedaquiline Clinical Access Programme showed good interim outcomes in people with drug resistant tuberculosis (DR-TB), according to data presented at the 45th Union Conference on Lung Health.<\/strong><\/p>\n

Bedaquiline is a diarylquinoline compound with a novel anti-tuberculosis mechanism of action that inhibits mycobacterial ATP synthase. Janssen Therapeutics manufactures this drug. The FDA approved bedaquiline for the treatment of multi-drug resistant (MDR) TB in December 2012. It was the first new anti-TB drug to be approved by the agency in over forty years.<\/p>\n

In December 2012 the South African Medicine Control Council (MCC) approved a national programme to treat selected DR-TB patients with bedaquiline, which began in March 2013.<\/p>\n

Dr Ndjeka from the National Department of Health presented results on behalf of colleagues from the programme.<\/p>\n

He began the presentation by describing the TB burden in South Africa. He noted that the number of people with TB initiated on treatment was decreasing: between 2009 and 2013 this went from 406, 082 to 332,170, with an 80.9% success rate in 2012. But numbers with MDR-TB initiated on treatment doubled between 2010 and 2013: from 5,313 to 10,719, with a 45% success rate. For extensively drug resistant (XDR) TB treatment success is only between 15% and 20%.<\/p>\n

Laboratory-confirmed pre-XDR and XDR TB patients at five approved South African sites received bedaquiline according to predefined selection criteria: > 18 years of age, susceptible to at least three anti-TB drugs with which to construct the background regimen, negative pregnancy test and using contraception. Pregnant or breastfeeding women and patients with serum creatinine grade >1, lipase grade 2, ALT or AST grade 2 or total bilirubin grade >1 were excluded.<\/p>\n

The cases were presented to a clinical advisory committee, after which the originator company approved bedaquiline with an optimised background regimen of at least three selected second line anti-TB drugs and the MCC approved the prescription on a named-patient basis.<\/p>\n

400 mg bedaquiline was given once daily for two weeks followed by 200 mg three times a week for 22 weeks plus optimised background regimen. The optimised background regimen continued beyond the 22 weeks.<\/p>\n

At base line the 91 participants in the programme, included in the interim analysis, were a median age of 34.1 years (IQR 25.7 \u2013 40.9), 56 (60.5%) were male and 55 (60.5%) were coinfected with HIV. The HIV positive group had a median CD4 count of 249 cells mm3 (IQR 134 \u2013 356), 19 (34.5%) received lopinavir\/ritonavir-based ART regimens and 36 (65.5%) nevirapine-based.<\/p>\n

TB drug resistance patterns were described as: XDR in 33 (36.3%) participants, pre-XDR (fluoroquinalone) in 41 (45.1%) and pre-XDR (injectable) in 17 (18.1%). Optimised background regimens included: clofazimine for 68 (74.5%), linezolid for 64 (70%) and levofloxin for 76 (83.5%).<\/p>\n

At the time of analysis, 60 participants had > 24 weeks of follow up, 2 did not complete bedaquiline (1 died, 1 lost to follow up). Of 58 that completed 24 weeks of bedaquiline, 2 died, 1 transferred and 1 was lost to follow up. Of the remaining 54 on continuation treatment, 15 were culture negative at start, 33 culture-converted and 6 were still culture positive. All the 31 participants with <25 weeks of follow up since treatment start were still on treatment. Of this group, 6 were culture negative at start, 10 culture- converted, and 15 participants had not yet received culture results.<\/p>\n

One participant developed atrial fibrillation on bedaquiline and was withdrawn from treatment. At start of bedaquiline, median QTcF was 408ms (IQR 390-426): there was a median increase of 8 ms (IQR -12 to 31 at 2 months; 14 had increases of >40ms and 2 had QTc >ms (bedaquiline was temporarily withdrawn in 1 and the other resolved in 24 hours).<\/p>\n

Fifteen participants experienced serious adverse events. The general pattern and frequency were considered to be in line with the known safety profile of bedaquiline. There were 3 deaths of which none were related to bedaquiline; 3 QT prolongation probably or possibly related (all resolved); and 3 psychosis\/mood disorder\/delusion, none related to bedaquiline (all 3 were receiving terizidone, prodrug of cycloserine known to cause mood disorder).<\/p>\n

The programme has since been extended to include 12 sites in South Africa.<\/p>\n

In October 2014 the MCC approved bedaquiline and it will be used within the national TB programme under strict control.<\/p>\n

Comment<\/h3>\n

Bedaquiline added to a background regimen was associated with earlier culture conversion and higher cure rates in its registrational trials, but there were unexplained excess deaths in the bedaquiline arms of these studies.<\/strong><\/p>\n

When the FDA approved bedaquiline for treatment of MDR-TB when an effective treatment regimen cannot otherwise be given this included a black box warning about excess deaths and a requirement to complete a phase III trial.<\/strong><\/p>\n

As a result, many programmes, including in South African, were right to approach the drug with caution, and it is reassuring that further safety events were not reported.<\/strong><\/p>\n

The French compassionate use programme has been similarly reassuring. [2] At 6 months, 28\/29 (97%) participants with culture-positive TB achieved culture conversion in a median of 85 days (range 8\u2013235 days). Seven participants (20%) experienced a >60-ms increase in QT interval. This led to bedaquiline discontinuation in 2 (6%) participants. The one death (3%) was not considered related to treatment.<\/strong><\/p>\n

References:<\/p>\n

    \n
  1. Ndjeka N et al. Safe and effective bedaquiline treatment of drug resistant tuberculosis (DR-TB) within the National Bedaquiline Clinical Access Programme in South Africa. 45th Union World Conference on Lung Health, 28 October \u2013 1 November 2014, Barcelona. The Union\/CDC Late breaker session on TB.
    \nhttp:\/\/barcelona.worldlunghealth.org\/programme\/symposia\/body\/Programme-2014-50-sympo-19-p-97.pdf<\/a> (PDF)<\/li>\n
  2. Guglielmetti L et al. Compassionate use of bedaquiline for the treatment of multidrug-resistant and extensively drug-resistant tuberculosis: interim analysis of a French cohort. Clin Infect Dis. (2015) 60 (2): 188-194, first published online October 15, 2014
    \n    http:\/\/cid.oxfordjournals.org\/content\/60\/2\/188.full?sid=d0f4aa8c-28e5-43e2-a5ee-1c263b6dabe5<\/a><\/li>\n<\/ol>\n
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    Polly Clayden, HIV i-Base The South African Bedaquiline Clinical Access Programme showed good interim outcomes in people with drug resistant tuberculosis (DR-TB), according to data presented at the 45th Union Conference on Lung Health. Bedaquiline is a diarylquinoline compound with …<\/p>\n","protected":false},"author":2,"featured_media":0,"comment_status":"open","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[4,37],"tags":[200],"class_list":["post-27735","post","type-post","status-publish","format-standard","hentry","category-conference-reports","category-tb-coinfection","tag-world-conference-on-lung-health-45th-2014"],"_links":{"self":[{"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/posts\/27735","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/users\/2"}],"replies":[{"embeddable":true,"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/comments?post=27735"}],"version-history":[{"count":0,"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/posts\/27735\/revisions"}],"wp:attachment":[{"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/media?parent=27735"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/categories?post=27735"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/tags?post=27735"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}