Three-drug regimen beats XDR-TB in first trial

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A regimen of three oral drugs given for six months was enough to clear extensively drug-resistant tuberculosis (XDR-TB) in 29 of the first 31 people to have completed the treatment course, Dr Francesca Conradie of Sizwe Tropical Disease Hospital, Johannesburg, told the 2017 Conference on Retroviruses and Opportunistic Infections (CROI).

If the results are replicated in a larger population, the findings could revolutionise the prospects for treating not just XDR-TB, but also the more severe cases of MDR-TB (multidrug-resistant tuberculosis).

Abstract 1
Patients with Extensively Drug Resistant (XDR) tuberculosis (TB) have had limited options for treatment and high mortality. Nix-TB is an ongoing open label study in South Africa of bedaquiline (400 mg qd for 2 weeks followed by 200 mg tiw), pretomanid (200 mg qd) and linezolid (1200 mg qd) given orally for 6 months.
Participants are required to have documented XDR-TB, or MDR TB treatment intolerance or failure (TI or Fr). The primary endpoint is bacteriologic failure, relapse or clinical failure at 6 months after treatment. Participants who are culture positive at 4 mos treatment may extend treatment for 3 mos. Clinical, laboratory and sputum liquid culture evaluations are performed at baseline and wks 1, 2, 4, 6, 8 and then every 4-6 wks through treatment. Eye examinations with slit lamp are made 3 times. Participants who complete treatment are followed for 24 mos after treatment end with repeat clinical assessments and sputum cultures.
Since April 2015, 61 participants have been enrolled as of 15 December 2016 at 2 sites. 49% of the participants are HIV positive, 79% have XDR-TB and 21% have MDR TI or Fr to prior therapy. 34 have completed the 6 months of therapy with the drug regimen and 20 have been followed to the primary endpoint at 6 months after treatment. All surviving patients were culture negative by 4 mos, with 74% negative at 8 wks. 4 participants died within the first 8 wks of therapy; 3 had multi-organ TB on autopsy and 1 had a GI bleed due to erosive esophagitis. 27% had serious adverse events (AE). No surviving participants have withdrawn from the study due to any clinical AE or lab abnormalities. The expected linezolid toxicities of peripheral neuropathy (PN) and myelosuppression (MSPN) were common but manageable. 71%, of participants had at least one linezolid dose interruption (22% of all participants due to MSPN and 28% due to PN), during the 6 mos of treatment. One had peak ALT and AST > 3 X ULN and total bili > 2X ULN, but these improved and treatment restarted without a recurrence. There were 7 cases of grade 3 or 4 transaminitis and all resolved and allowed the study regimen to be continued. There were no cases of optic neuritis. As of 15 December, 2016, there has been 1 microbiological relapse.
Current results of this greatly simplified and shortened all-oral regimen for drug resistant TB are encouraging in terms of both efficacy and safety.

Francesca Conradie, Andreas H Diacon, Daniel Everitt, Carl Mendel, Christo van Niekerk, Pauline Howell, Kyla Comins, Mel Spigelman


Although XDR-TB may be a consequence of failure of previous treatment for MDR-TB, research in South Africa has shown that transmission between people, often outside the household, is the primary driver of the country’s growing XDR-TB crisis. Furthermore, research presented this week at CROI shows that migration and travel plays a big part in the spread of XDR-TB in South Africa’s most severely affected province, KwaZulu-Natal.

Kristin Nelson of Emory University, Atlanta, shared results of a study which sought to identify the geographical locations of individuals with genetically-linked XDR-TB infections. The study was designed to determine whether particular locations were strongly implicated in the spread of XDR-TB.

Surprisingly, the researchers found that the median distance between the homes of people in these genetically-linked pairs was 111km and 83% of people in genetically-linked pairs lived in different districts of the province. A very high level of mobility for work, for health care-seeking and for family reasons appears to be contributing to the spread of XDR-TB. Household transmission, traditionally considered to be the most important arena of TB transmission and the focus of contact tracing and case-finding efforts, appears to be less important than previously assumed.

Abstract 2
Transmission of drug-resistant tuberculosis (TB) is a major threat to TB control, especially in high HIV prevalence settings. We have previously shown that nearly 70% of extensively drug-resistant (XDR) TB cases in KwaZulu-Natal province, South Africa are due to transmission, rather than unsuccessful TB treatment. We identified epidemiologic links through close contacts or hospital admission for 30% of cases, but found no epidemiologic link for the remaining 70%. We hypothesize that genomically-linked cases live or seek healthcare near one another and may have unrecognized epidemiologic links. We compared geospatial distances between homes and health facilities for participants with ≤ 5 single nucleotide polymorphism (SNP) differences to determine geographic proximity.
We enrolled culture-confirmed XDR TB cases in KwaZulu-Natal from 2011-2014. We collected clinical and demographic characteristics, GPS coordinates of homes and XDR TB diagnosis facility, and performed whole genome sequencing (WGS) of TB isolates. We defined a SNP difference of ≤ 5 as genomic evidence of transmission between two cases ('case-pair'). We calculated spatial distances using Haversine's formula and defined geographic proximity as
We enrolled 296 participants with WGS results, from all 11 districts in KwaZulu-Natal. Among these, 179 (66%) participants formed 671 case-pairs with ≤ 5 SNPs. The median distance between home residences of case-pairs was 115 km (IQR 63-154) (Figure 1); the median distance between diagnosing facilities was 93 km (IQR 44-131). Only 116 (17%) case-pairs lived or were diagnosed within 20 km of each other. Median distance did not vary significantly when the SNP threshold was reduced to 3 and 1 SNP (p=0.27 for homes, p=0.56 for diagnosing facilities). There was no significant difference in geographic distances for case-pairs based on whether both were HIV-positive, HIV-negative or had discordant HIV status (p=0.87 for homes, p=0.20 for diagnosing facilities).
Although two-thirds of XDR TB participants from KwaZulu-Natal, South Africa were genomically-linked, only 17% lived or were diagnosed at a health facility within 20 km of their case-pair. Further research examining migratory patterns, particularly between rural and urban areas, is needed to determine their role in TB transmission and the spread of drug resistance.

Kristin N Nelson, Neel R Gandhi, Sara C Auld, James C Brust, Barun Mathema, Nazir Ismail, Pravi Moodley, Angela Campbell, Salim Allana, N Sarita Shah

Aidsmap material Abstract 1 (80LB) Abstract 2 (77)

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