Treating multidrug-resistant tuberculosis (MDR TB) with regimens that include a greater number of drugs may improve outcomes, and baseline drug susceptibility testing (DST) could identify drugs with the greatest likelihood of success, according to a research paper. The prospective cohort study, conducted by Peter Cegielski of the Centres for Disease Control, Atlanta, Georgia, and colleagues, used information on regimen composition, baseline DST, and time to sputum conversion from 1,137 adults with MDR TB, from nine countries.
The World Health Organisation (WHO) guidelines for the treatment of multidrug-resistant tuberculosis (MDR TB) recommend a regimen consisting of at least five potentially effective drugs. However, the researchers found that receiving an average of at least six potentially effective drugs per day was associated with a 36% (adjusted hazard ratio (aHR) 1.36, 95% CI 1.09-1.69) greater likelihood of responding to treatment (defined by time to initial sputum culture conversion) than receiving an average of at least five but fewer than six potentially effective drugs per day. Inclusion of more drugs to which baseline drug susceptibility testing (DST) results indicated susceptibility was associated with a 65% higher likelihood of sputum culture conversion per drug (aHR 1.65, 95% CI 1.48-1.84, per drug), and inclusion of pyrazinamide was associated with a doubling of the likelihood of sputum culture conversion (aHR 2.00, 95% CI 1.65-2.41).
Surprisingly, including an additional drug to which baseline DST results indicated resistance was associated with a 33% higher likelihood of sputum culture conversion per drug (aHR 1.33, 95% CI 1.18-1.51, per drug). Inclusion of more drugs for which DST had not been performed was beneficial only if the regimen already contained a minimum of three likely effective drugs.
The authors caution that this is an observational study and cannot prove that increasing the number of drugs in treatment regimens or basing drug choice on DST results improves outcomes. Patients who received a particular treatment may have another shared characteristic that affected the disease outcome, other than those that the authors were able to adjust for in their analysis. The study is also limited by the use of initial sputum conversion and does not provide any information on risk of relapse, and that they were not able to assess the effects of individual drugs.
However, these results suggest changes to the current WHO guidelines for the treatment of MDR TB might be beneficial. The authors say: “… our analysis suggests that MDR TB regimens including more potentially effective drugs than the minimum of five currently recommended by WHO may encourage improved response to treatment in patients with MDR TB. In addition, rapid access to high quality DST results could facilitate the design of more effective individualised regimens.”
For treating multidrug-resistant tuberculosis (MDR TB), the World Health Organization (WHO) recommends a regimen of at least four second-line drugs that are likely to be effective as well as pyrazinamide. WHO guidelines indicate only marginal benefit for regimens based directly on drug susceptibility testing (DST) results. Recent evidence from isolated cohorts suggests that regimens containing more drugs may be beneficial, and that DST results are predictive of regimen effectiveness. The objective of our study was to gain insight into how regimen design affects treatment response by analyzing the association between time to sputum culture conversion and both the number of potentially effective drugs included in a regimen and the DST results of the drugs in the regimen.
Methods and Findings
We analyzed data from the Preserving Effective Tuberculosis Treatment Study (PETTS), a prospective observational study of 1,659 adults treated for MDR TB during 2005–2010 in nine countries: Estonia, Latvia, Peru, Philippines, Russian Federation, South Africa, South Korea, Thailand, and Taiwan. For all patients, monthly sputum samples were collected, and DST was performed on baseline isolates at the US Centers for Disease Control and Prevention. We included 1,137 patients in our analysis based on their having known baseline DST results for at least fluoroquinolones and second-line injectable drugs, and not having extensively drug-resistant TB. These patients were followed for a median of 20 mo (interquartile range 16–23 mo) after MDR TB treatment initiation. The primary outcome of interest was initial sputum culture conversion. We used Cox proportional hazards regression, stratifying by country to control for setting-associated confounders, and adjusting for the number of drugs to which patients’ baseline isolates were resistant, baseline resistance pattern, previous treatment history, sputum smear result, and extent of disease on chest radiograph.
In multivariable analysis, receiving an average of at least six potentially effective drugs (defined as drugs without a DST result indicating resistance) per day was associated with a 36% greater likelihood of sputum culture conversion than receiving an average of at least five but fewer than six potentially effective drugs per day (adjusted hazard ratio [aHR] 1.36, 95% CI 1.09–1.69). Inclusion of pyrazinamide (aHR 2.00, 95% CI 1.65–2.41) or more drugs to which baseline DST indicated susceptibility (aHR 1.65, 95% CI 1.48–1.84, per drug) in regimens was associated with greater increases in the likelihood of sputum culture conversion than including more drugs to which baseline DST indicated resistance (aHR 1.33, 95% CI 1.18–1.51, per drug). Including in the regimen more drugs for which DST was not performed was beneficial only if a minimum of three effective drugs was present in the regimen (aHR 1.39, 95% CI 1.09–1.76, per drug when three effective drugs present in regimen).
The main limitation of this analysis is that it is based on observational data, not a randomized trial, and drug regimens varied across sites. However, PETTS was a uniquely large and rigorous observational study in terms of both the number of patients enrolled and the standardization of laboratory testing. Other limitations include the assumption of equivalent efficacy across drugs in a category, incomplete data on adherence, and the fact that the analysis considers only initial sputum culture conversion, not reversion or long-term relapse.
MDR TB regimens including more potentially effective drugs than the minimum of five currently recommended by WHO may encourage improved response to treatment in patients with MDR TB. Rapid access to high-quality DST results could facilitate the design of more effective individualized regimens. Randomized controlled trials are necessary to confirm whether individualized regimens with more than five drugs can indeed achieve better cure rates than current recommended regimens.
All-cause 8-week mortality is reduced by rapid point-of-care urine-based testing for tuberculosis (TB), using a test for detection of mycobacterial lipoarabinomannan (LAM) to guide rapid treatment initiation in hospitalised HIV-positive people with signs and symptoms of TB, according to a late-breaker study presented by Dr Jonny Peter of the University of Cape Town, and colleagues, at the 46th Union World Conference on Lung Health.
Those who received LAM testing in addition to standard of care diagnostics were 18% less likely to die at 8 weeks (aHR = 0.82; 95% CI: 0.70-0.96, p = 0.015).
The LAM strip test measures for the presence of lipoarabinomannan in urine. The test has shown variable sensitivity and specificity in different populations, and has performed best in studies of hospitalised patients with HIV infection and advanced immunosuppression (CD4 count below 150 cells/mm3). The test is not considered suitable for outpatient screening. (Lawn 2012)
Speeding up diagnosis by using a point-of-care test in addition to laboratory diagnostic tests such as TB culture or Xpert MTB/RIF has the potential to speed up the initiation of treatment and to increase the number of people receiving treatment.
The randomised controlled trial studied whether the LAM strip test, in combination with current available TB diagnostics, would improve TB-related mortality, morbidity and length of hospital stay in HIV-positive people. TB mortality is high, especially in people living with HIV with extensive immune damage, where a TB diagnosis is already difficult.
The study was conducted in South Africa, Tanzania, Zambia and Zimbabwe.
Of the 8,728 patients with presumed HIV/TB co-infection from secondary and tertiary hospitals 2,659 were randomised to be included in the study, made up of 1,336 people in the LAM arm and 1323 in the non-LAM arm. Patients in the LAM arm were allocated LAM in addition to routine TB diagnostics (minimum of two sputum smear specimens and culture and one Xpert MTB/RIF, if available).
A total of 1,257 patients were included in the modified intention to treat analysis and 59 were lost to follow-up.1,198 patients were analysed per protocol analysis, after 70 did not receive the LAM test, 47 did not meet the inclusion criteria and nine were excluded from the analysis due to withdrawing consent and missing hard copy documents.
A total of 1,323 people were allocated to the non-LAM arm where routine TB diagnostics were used to detect TB. 1,271 patients were included in the modified intention to treat analysis after 38 did not receive diagnostic tests, 23 did not meet the inclusion criteria and 14 were excluded from the analysis. An additional 58 people were lost to follow-up resulting in 1,213 patients being included in the per protocol analysis.
Of the 2,528 people included in the study, the median age was 37 (IQR: 30-44) and 51% (n = 1300) were women. 27 % (n = 682) had previously had TB. The median CD4 count was 84 cells/mm3 (IQR: 26 – 208 cells/mm3), with 2% (n = 59) at WHO clinical Stage 1, 27%(n = 671) at Stage 2, 53% (n = 1331) at Stage 3 and 17 % (n = 438) at Stage 4. Almost half (48%, n = 1224) were on ART at study entry and 73% (n = 615/848) of eligible patients were initiated on ART at 8-week follow up.
Of the total number of people started on anti-TB treatment, 52% (n = 648) of people who were diagnosed using LAM compared to 48% (598) in the non-LAM arm (p = 0.024). The time-to-treatment analysis showed significant differences in the cumulative proportion of people receiving TB treatment and the number of deaths for patients who started treatment by the end of Day 1 (55.1 % vs 40.3%); end of Day 2 (71.1% vs 60.5%); end of Day 3 (79.2% vs 69.1%) and the end of Day 4 (84.0 % vs 75.6%) between the LAM and non-LAM arm respectively (p < 0.001 for all of these).
The study also showed that there was no significant difference between the two groups in the hospital length of stay from enrolment or change in TB morbidity as measured by Karnofsky score in patients on TB treatment.
Despite overall suboptimal test sensitivity even for people with low CD4 counts, as shown in a study published in July this year by the same group, the ability of LAM to identify patients at high risk of death or lost-to-follow-up offers important prognostic value.
Sensitivity measures the percentage of results that will be (correctly) positive when a disease is actually present. Lower rates of sensitivity will produce more false negative results.
This previous study of outpatients with HIV showed that among 583 participants with signs and symptoms of TB that had HIV or refused testing, the overall LAM sensitivity was 22.7 % (95% CI: 16.6 – 28.7; n = 41/181) and 30.4 % (95% CI: 17.1 – 43.7; n = 14/46) in the CD4 ≤ 100 cells/mm3 sub-group. Among culture-positive TB cases, adjunctive LAM testing did not improve the sensitivity of either sputum Xpert-MTB/RIF [78.2 % (95% CI: 69.8 – 86.7) versus 76.1 % (95% CI: 67.4-84.8, p = 0.7] or smear-microscopy [56.2 % (95% CI: 45.9 – 66.5) versus 43.8 % (95% CI: 33.5 – 54.1, p = 0.1).
The commercially available urine LAM strip test, a point-of-care tuberculosis (TB) assay, requires evaluation in a primary care setting where it is most needed. There is currently inadequate data to guide implementation in TB and HIV-endemic settings.
Adult HIV-infected outpatients with suspected pulmonary TB able to self-expectorate sputum from four primary clinics in South Africa, Zambia and Tanzania underwent diagnostic evaluation [sputum smear microscopy, Xpert-MTB/RIF, and culture (reference standard)] as part of a prospective parent study. Urine LAM testing (grade-2 cut-point) was performed on archived samples. Performance characteristics of LAM alone or in combination with sputum—based diagnostics were evaluated. Potential impact on 2 and 6-month morbidity (TBscore), patient dropout rates, and prognosis (death/ loss to follow-up) were evaluated.
Among 583 participants with suspected TB that were HIV-infected or refused testing, the overall LAM sensitivity (95 % CI; n/N) and in the CD4 ≤ 100 cells/mm3 sub-group was 22.7 % (16.6-28.7; 41/181) and 30.4 % (17.1-43.7; 14/46), respectively. Overall specificity was 93.0 % (90.5-95.6; 361/388). Amongst culture-positive TB cases, adjunctive LAM testing did not improve the sensitivity of either sputum Xpert-MTB/RIF [78.2 % (69.8-86.7; 72/92) versus 76.1 % (67.4-84.8; 70/92), p = 0.7] or smear-microscopy [56.2 % (45.9-66.5; 50/89) versus 43.8 % (33.5-54.1; 39/89), p = 0.1). Clinic-based LAM, as an adjunct to either smear microscopy or Xpert MTB/RIF same-day testing, would neither have decreased patient dropout, nor increased same-day treatment initiation in this clinical setting where same-day chest radiography was available. LAM positivity was associated with 6-month lost-to-follow-up/death (AOR 4.4; p = 0.002) but not TBscore (at baseline or change in TBscore 2-months post-treatment) (p = 0.17).
In African HIV-TB co-infected outpatients able to self-expectorate sputum LAM had limited sensitivity even at low CD4 counts, and offered no significant incremental diagnostic yield over Xpert-MTB/RIF or smear microscopy. In primary care clinics with chest radiography and where empiric TB treatment is common, LAM seems unlikely to improve rates of same-day treatment initiation and patient dropout, however, the ability of LAM to identify patients at high risk of death or lost-to-follow-up may offer important prognostic value.