Project Details
Layman's description
Treatment of rifampicin-resistant tuberculosis(RR-TB, resistance to the most potent anti TB drug) is very challenging. Fortunately, new drugs (bedaquiline (BDQ, B), delamanid, and pretomanid (Pa)), repurposed drugs like linezolid (LZD, L) and shorter regimens (reduction from 18 to 6 months) improved treatment outcomes. The shortest option is the novel 6-month regimen, including at least BDQ, Pa and LZD. Moxifloxacin (MFX; M) is added when resistance to fluoroquinolone (FQ) is excluded.
The BPaL-M regimen for FQ susceptible RR-TB showed 90% treatment success in one trial. More evidence from its implementation in National TB Programmes (NTP) is required to assess effectiveness in routine care. In addition, there are still concerns about the safety of this regimen. BPaL-M includes 2 QT prolonging drugs (BDQ and MFX), thus increasing the risk of cardiotoxicity. Whether levofloxacin (LFX; Lf), a FQ with significantly less QT prolonging effect, can replace MFX in this standardized RR-TB regimen has not yet been studied. In Vietnam, I will therefore conduct a pragmatic randomized clinical trial to compare BPaL-M with BPaL-Lf in terms of safety (QT prolonging effect) and clinical effectiveness (treatment success versus death, treatment failure or relapse) (objective 1).
Pre-extensively drug-resistant TB (pre-XDR-TB; RR-TB also resistant to FQ) until recently had a very poor prognosis. BPaL (BDQ, Pa and LZD) as pre-XDR TB regimen, with 1200 mg LZD, showed 90% success in a trial setting. LZD at 1200 mg was poorly tolerated. Based on recently published findings, the same regimen but with 600mg LZD has been recommended by WHO, while also recommending research on the generalizability of trial findings. In Vietnam, in an already ongoing prospective observational cohort study that I coordinate, I will study outcomes and safety of BPaL regimen, with a special focus on the tolerability of LZD, for which the dose is adapted from 1200 to 600 mg during the course of study implementation (objective 2).
As LZD is increasingly used in short all-oral RR-TB treatment regimens, its tolerability is of concern. Previous studies on LZD toxicity during short treatment were conducted in relatively small cohorts. To study the association between the dose of LZD over body weight and LZD related toxicity, I will study a large study population with data from patients treated with either BPaL, BPaL-M or BPaL-Lf (objective 3).
Moreover, reviews of LZD’s effect and toxicity have been conducted but none covers the most recent period, during which it was studied more profoundly, at different dosages, and for a shorter duration. I will therefore conduct a systematic review to summarize published data on the toxicity of LZD for different dosages in short 6-9 -month regimens, while also summarizing the treatment outcomes of these novel short regimens.
Together my findings will directly inform short RR-TB treatment guidelines in Vietnam, a country with a high RR-TB burden. Considering that WHO continuously adapts recommendations to operational research findings, our results will also very likely inform international RR-TB treatment guidelines, to come to a standardised short regimen that is optimized in terms of both effectiveness and safety.
The BPaL-M regimen for FQ susceptible RR-TB showed 90% treatment success in one trial. More evidence from its implementation in National TB Programmes (NTP) is required to assess effectiveness in routine care. In addition, there are still concerns about the safety of this regimen. BPaL-M includes 2 QT prolonging drugs (BDQ and MFX), thus increasing the risk of cardiotoxicity. Whether levofloxacin (LFX; Lf), a FQ with significantly less QT prolonging effect, can replace MFX in this standardized RR-TB regimen has not yet been studied. In Vietnam, I will therefore conduct a pragmatic randomized clinical trial to compare BPaL-M with BPaL-Lf in terms of safety (QT prolonging effect) and clinical effectiveness (treatment success versus death, treatment failure or relapse) (objective 1).
Pre-extensively drug-resistant TB (pre-XDR-TB; RR-TB also resistant to FQ) until recently had a very poor prognosis. BPaL (BDQ, Pa and LZD) as pre-XDR TB regimen, with 1200 mg LZD, showed 90% success in a trial setting. LZD at 1200 mg was poorly tolerated. Based on recently published findings, the same regimen but with 600mg LZD has been recommended by WHO, while also recommending research on the generalizability of trial findings. In Vietnam, in an already ongoing prospective observational cohort study that I coordinate, I will study outcomes and safety of BPaL regimen, with a special focus on the tolerability of LZD, for which the dose is adapted from 1200 to 600 mg during the course of study implementation (objective 2).
As LZD is increasingly used in short all-oral RR-TB treatment regimens, its tolerability is of concern. Previous studies on LZD toxicity during short treatment were conducted in relatively small cohorts. To study the association between the dose of LZD over body weight and LZD related toxicity, I will study a large study population with data from patients treated with either BPaL, BPaL-M or BPaL-Lf (objective 3).
Moreover, reviews of LZD’s effect and toxicity have been conducted but none covers the most recent period, during which it was studied more profoundly, at different dosages, and for a shorter duration. I will therefore conduct a systematic review to summarize published data on the toxicity of LZD for different dosages in short 6-9 -month regimens, while also summarizing the treatment outcomes of these novel short regimens.
Together my findings will directly inform short RR-TB treatment guidelines in Vietnam, a country with a high RR-TB burden. Considering that WHO continuously adapts recommendations to operational research findings, our results will also very likely inform international RR-TB treatment guidelines, to come to a standardised short regimen that is optimized in terms of both effectiveness and safety.
| Status | Active |
|---|---|
| Effective start/end date | 1/01/23 → … |
IWETO expertise domain
- B780-tropical-medicine
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