Fluoroquinolones and isoniazid-resistant tuberculosis: implications for the 2018 WHO guidance

Discussion

In this analysis of Hr TB patients notified by London hospitals between 2009 and 2013, 16.4% of individuals had a negative outcome. (H)RfZE and (H)RfZE-Fq/M regimens were taken by 92.6% of individuals without additional drug resistance (apart from to S) and with both regimen and regimen-specific outcome data. Among these patients, we found no discernible difference in the odds of a negative regimen-specific outcome between (H)RfZE and (H)RfZE-Fq/M regimens. Examining individuals with a positive treatment outcome, the overall duration of treatment was generally 12 months, with Z durations of 2 months in the initiation phase. After adjustment for Hr genotype, the likelihood of a negative outcome was found to be lower among individuals treated with (H)RfZE-Fq/M, but this analysis was underpowered.

Our findings sit in the context of preceding work on the relative efficacy and effectiveness of different regimens for Hr TB, including four meta-analyses [17–20]. Fregonese et al.'s [17] individual-level patient meta-analysis, the foundation of the 2018 WHO guidelines, showed a value for including a Fq in continuous (H)RZE regimens, and suggested equivalence between 6 and 8–9 months of (H)RZE. The WHO acknowledges that overall treatment length findings may be subject to confounding by indication, due to patients with more complex sites of disease receiving longer regimens [5].

Notably, global RCT evidence for the effectiveness of Fqs in non-MDR-TB derive solely from the Rifaquin trial, as ReMox did not demonstrate non-inferiority when H was replaced with M for non-MDR TB [21, 22]. When considering the choice of Fq, although the WHO recommends the use of Lfx, M was generally used in our study. Within Fregonese et al. [17], roughly equal numbers of studies used these two drugs, which were not directly compared. However, comparative data are available from a MDR-TB trial (no difference in treatment outcomes when comparing the two drugs; fewer adverse events for M) [23], and rabbit and mouse models (M broadly superior over Lfx) [24, 25]. Lfx doses in such studies may have been too low [26, 27]. Further RCTs are required.

The above meta-analyses were unable to thoroughly consider the role of Hr genotype and phenotype in treatment decisions; the evidence from previous observational studies is unclear [1, 28]. Where adjustment for genotype in observational studies has been undertaken, it was largely for inhA and katG. In our cohort, with a very high prevalence of fabG1 in addition to katG mutations, we find an indication that the Hr genotype is influential. fabG1 is part of the inhA operon and is involved in fatty acid synthesis; SNPs within the gene are known to confer Hr [29, 30].

The evidence currently underpinning global treatment guidelines for Hr TB is limited. Our study adds to this discussion, including consideration of the effect of resistance phenotype and genotype on the regimen–outcomes relationship. Importantly, in our core analysis, 192 patients received a Fq in addition to (H)RfZE, which provides substantial new evidence to that presented by Fregonese et al. [17], whose analysis of treatment success included 251 patients receiving a Fq. Our findings did not differ when site of disease was adjusted for as a confounder (including meningeal TB or other central nervous system involvement; data not shown) and when patients with additional drug resistance were included.

Within this study, actual rather than intended treatment durations were captured, which prevented us from undertaking analyses of the impact of overall or drug-specific durations. Importantly, however, when considering 9 versus 12 months of treatment, the majority of negative outcomes occurred before 9 months and the number of relapses was small, with two of the three occurring after >15 months of treatment. Thus our data may indicate the potential to shorten treatment to 9 months in our setting. Some patient notes could not be accessed as patients had died. This was unlikely to have been of a magnitude sufficient to bias our findings. We did not differentiate between recurrence due to relapse versus reinfection, and thus may have overestimated the number of negative outcomes (nondifferential misclassification). Gaps in phenotypic data arose due to 1) missing records within NMRS from a specific period and reference laboratory; and 2) incomplete data entry into NMRS from the reference laboratory (cross-tabulations against patient characteristics did not indicate that this particularly affected any specific patient groups). The phenotypic and genotypic Hr patterns documented summarise that of the overall bacterial population; the presence of minor strains will not have been captured. Our findings about thrice-weekly dosing may represent the use of such a dosing pattern specifically among patients where directed observation of treatment was deemed necessary. HIV status, a potential confounder, was not obtainable during data collection.

Despite these limitations, there are important ramifications for our findings both nationally and internationally. We document a drug combination that differs from that recommended (with very low certainty) by the WHO [5], which may be as effective. We note that, if the overall duration of treatment is long enough (12 months), a Fq may not be necessary in certain settings, even with relatively short durations (median 2 months in the initiation phase) of Z. Notably, in settings where DST occurs via phenotyping from cultures, the WHO regimen ≥6[H]RZE-6Lfx is likely to have total duration of 7.5–9 months, when time to result is considered. This also affects the longer regimen in their 6- versus 8–9-month duration comparison; the latter translates to 9.5–12 months. By comparison, in settings undertaking rapid genotyping directly from patient samples, the WHO regimen duration would be 6 months and the average duration documented here ∼10 months.

Global regimen choices will depend upon the trade-off between patient desire for regimens of minimal length, adherence concerns, adverse events, ease of administration and cost. Costs are raised if fixed dose combination pills cannot be used and Fqs are added in. When it comes to comparing the likelihood of adverse events, the trade-off would be between a longer duration of E, but shorter duration of Z in our predominantly used regimen, versus continued Z and the addition of LfX, as per the WHO recommendations. Each of these drugs has its own distinct adverse event profile [23, 31].

Fq DST results are important when deciding on Fq use within a Hr regimen. Only 48 individuals in the London cohort had their baseline samples tested for resistance to M. In 2018, PHE rolled-out prospective WGS to provide routine resistance predictions and mutation identification, thus improving the rapidity of DST and coverage of second-line testing. New molecular Hr tests can also aid rapidity, as the use of WGS still depends on culture [32].

Within the limitations of an observational study, where the use of Fqs was not randomised, we find in a high-income setting with comprehensive patient management, a 12-month (H)RfZE regimen with a short Z duration to be similarly effective for Hr TB, with or without a Fq. Hr genotype may influence these findings. In the absence of Fqs and long durations of Z, this regimen may have fewer adverse events than the WHO recommended ≥6[H]RZE-6Lfx. RCTs should be undertaken to provide stronger global recommendations.