Study in southern Mexico reports that DOTS programme can reduce the prevalence of drug resistant TB

A pilot tuberculosis (TB) control programme in southern Mexico achieved a high cure rate, and reduced the incidence and transmission of drug resistant TB, according to a study published in the April 2^nd edition of the Lancet. The success of the programme, based on the World Health Organization’s DOTS (Directly Observed Therapy—Short-course) strategy, was particularly notable because it occurred in a health district where more than a third of the cases were resistant to at least one TB drug when the study began.

However, claims that: “the strategy [was] effective against drug resistant tuberculosis” — especially multidrug resistant tuberculosis (MDR-TB) as an editorial associated with the piece is titled — could be somewhat misleading. DOTS with a standard first-line regimen works well as a prevention and control strategy, but in this study resulted in an unacceptable rate of treatment failure and mortality in patients with MDR-TB.

DOTS

The purpose of DOTS as a public health strategy is to reduce the transmission of TB, as well as, the likelihood of poor treatment adherence that might lead to drug resistant tuberculosis. The strategy consists of several components besides treatment.

One pillar of DOTS involves diagnosing infectious pulmonary TB with a test known as sputum-smear microscopy. Even though this technique is not foolproof, it should capture those TB cases that are infectious.

“Smear-positive” cases are then treated with a combination of (usually) four first-line anti-TB drugs, administered by direct observed therapy for two months, which should clear the infection. The patient is then given four month or six course of two-drug maintenance therapy to mop up any residual TB.

To work well, the DOTS strategy requires that the government establish systems to maintain a consistent supply of the anti-TB drugs, as well as systems for monitoring, recording and reporting patient outcomes.

Where done right, DOTS has dramatically reduced the incidence and spread of TB in most settings. However, in areas where resistance has become common to drugs in the first-line regimen, due to inadequate TB control programmes in the past, there are fears that using the same standardised regimen might lead to frequent treatment failures and might even lead to increasing transmission of drug resistance — especially MDR TB.

TB in Mexico

In the 1990’s, drug resistant TB was becoming an increasing problem in southern Mexico. Even though the country had a national TB programme, a programme review by the WHO identified inadequate technical policies and management deficiencies (one of which was an excessive emphasis on case detection). To bring the programme in line with the WHO-recommended DOTS strategy, changes were initiated in 1996 in pilot areas including the Orizaba Health Jurisdiction of Veracruz State, to be gradually extended nationwide.

The study

The pilot programme in Orizaba provided researchers with an opportunity to study the effects of DOTS in a challenging setting. With a total population in 1995 of 292,221, Orizaba had stable TB rates more twice as high as the rest of the country (during the three year period before the study, there were 42.6 cases per year per a population of 100,000).

Furthermore, drug resistant TB was not uncommon. About a third of all cases (new and retreated) showed some signs of resistance. 20.7% of new (previously untreated) cases were resistant to at least one anti-TB drug and 3.3% were MDR TB (which, in 1995, translated to 5 cases for the whole jurisdiction).

Starting in 1995 (before the pilot programme was actually implemented) and over the next five years, the researchers prospectively measured the incidence rate of pulmonary TB, the amount of TB transmission — as evidenced by clustered cases (where molecular evidence can demonstrate that one individual has transmitted TB to a cluster of others), and the rate of primary resistance to at least one first-line drug. 436 patients out of 490 diagnosed with TB in Orizaba consented to be a part of the study.

The researchers report that over the course of the study, the incidence rate of pulmonary tuberculosis fell by 54.4% between 1995 and 2000; the percentage of clustered pulmonary tuberculosis cases decreased by 62.6% from 22% to 8%; and the rate of primary drug resistance decreased by 84% from 9.4 to 1.5 per 100 000 people per year. Rates of multidrug-resistant (MDR) tuberculosis were also reported to have decreased.

Caveats and cautions

While we do not wish to detract from the basic message of this study — that a well-implement DOTS programme using a standardised first-line regimen can be successful even in settings with moderate levels of drug resistant, the data from this study could nonetheless bear some closer inspection.

The changes that power the study’s statistical calculations appear to have occurred primary between the first (before the new DOTS programme started) and the second year and to a lesser extent between the fourth and final year. During the second year, in which the new programme actually began, one would not expect to see much of an effect in the reported surveillance results. And indeed, there is no change in the number of new cases diagnosed until the third year.

However, by the year the programme started, there was already an immediate and dramatic drop in the clustered TB cases and in the number of cases reporting any resistance (new cases and retreated cases with any resistance or MDR-TB). After the second year, the resistance figures vary little and in some cases increase (retreated cases with MDR-TB for example).

Given that one of the problems with Mexico’s old TB control programme was an undue emphasis on case detection, one has to wonder whether this skewed the study's early results. How much do these figures represent an actual decline in the number of TB cases, or are they just the result of a decreased emphasis on case detection? How does one actually determine a baseline for this sort of analysis?

Another potential problem with the number crunching are the patients not included in the analysis. Fifty-four patients with TB did not consent to participate in the study. Of those who did, resistance data are not available for 28% of the patients. These missing data were predominantly from patients from an indigenous ethnic group or with a history of incarceration.

Did a constant percentage of patients diagnosed with TB enter the study each year? Or was enrolment greater when the study started? While no study can achieve perfect participation, such variables may matter when dealing with small differences.

It is interesting to note that there was a protocol change during the fourth year. Up to that point, the TB regimen only consisted of three drugs, while four were recommended internationally. According to the authors, “In 1998, when the preliminary data from our study showed high rates of drug resistance, the local health jurisdiction adopted the WHO standard regimen of initiating therapy with four drugs for newly diagnosed patients and five drugs for previously treated patients.”

The next year, the figures are noticeably better. There was almost half the number of new cases of TB, which is a little odd because most incidence of TB is reactivation disease from infections acquired years earlier in life — unless there is coinfection with HIV, which increases the risk of rapid reactivation and progression. (But HIV seroprevalence in this study was only around 2%). However, there could be environmental factors to explain a more rapid activation of TB in this poor population, which in turn could possibly explain a more rapid effect of curative treatment on transmission.

The fate of those with MDR-TB

It stands to reason that successful treatment of TB will reduce the number of cases that become drug resistant, and thus reduce transmission of drug resistant TB from one patient to another. However, this study’s findings should not be used to argue that using a fixed regimen of first-line drug is an adequate solution to control MDR-TB where it is firmly established (such as Eastern Europe) or where there is a very high burden of TB and a high rate of HIV co-infection (in settings such as Africa).

The standard treatment with first-line drugs was clearly inadequate for patients with MDR-TB in this study — only succeeding in 14% of the patients with retreatment MDR-TB.

During this study, “treatment with second-line drugs was not locally available, and treatment could not be modified by the local health centre on the basis of the results of drug-susceptibility testing. Patients with MDR tuberculosis were referred to the national tuberculosis control programme.”

The fact that there were no new (incident) cases of MDR-TB recorded in this study was likely due to the removal of these cases from the community, either to pursue treatment elsewhere, or to die.