TB treatment: four month continuation phase better than six months

World Health Organization (WHO) guidelines on directly observed tuberculosis (TB) treatment should be updated as soon as possible, say treatment advocates, following the publication of an international study showing that six months of continuation phase treatment with isoniazid and ethambutol results in higher rates of relapse after treatment when compared to a four month continuation phase using isoniazid and rifampicin.

The study also found that directly observed induction phase treatment given three times a week is inferior to daily treatment.

Current WHO and national TB programme guidelines for TB treatment recommend two months of intensive, directly observed treatment with four drugs - isoniazid, rifampicin, ethambutol and pyrazinamide. Treatment then continues with either four months of rifampicin and isoniazid, or six months of isoniazid and ethambutol. However, the two continuation phase regimens have never been compared in a randomised study.

The International Union Against Tuberculosis and Lung Disease and the United Kingdom Medical Research Council designed a study to answer two questions:

• Does three times a week directly observed therapy during the two month induction period produce equivalent culture negative rates to daily directly observed therapy?
• Does a rifampicin-containing two drug regimen lasting four months result in equivalent outcomes to the six month regimen currently recommended for continuation of TB treatment by WHO?

The study recruited 1355 patients with two TB smear positive samples in China, Nepal, Benin, Guinea, Tanzania and Mozambique. Patients with extrapulmonary tuberculosis or severe illness were excluded, and all patients were required to have a firm home address in order to permit follow-up. HIV testing was carried out and patients were informed of their HIV status if they wished to know. Twelve percent of patients were HIV-positive, all but one in African treatment centres.

Study design

Participants were randomised to one of the following regimens:

• Daily four drug treatment according to WHO directly observed treatment short course (DOTS) guidelines, followed by six months of isoniazid and ethambutol (456 patients).
• Four drug treatment directly observed three times a week, followed by six months of isoniazid and ethambutol (466 patients).
• Daily four drug treatment according to WHO DOTS guidelines, followed by four months of isoniazid and ethambutol (433 patients).

All patients were automatically moved from four drug therapy to two drug continuation therapy after two months, regardless of their TB culture status at this point. Normal practice is to continue the intensive treatment phase until a negative smear result.

Sputum samples were collected before treatment, after two months of treatment, at the end of treatment and three, six and twelve months after the end of treatment, and 24 and 30 months after the start of TB treatment.

Treatment failure was defined as a positive sputum culture at the end of treatment or a relapse after the end of treatment (defined as a culture of 20 or more colonies or initiation of treatment for relapse). Patients with one culture of 20 to 100 colonies followed by a negative culture and no new treatment were not defined as cases of relapse.

Results

At the end of the two month intensive treatment phase sputum samples were available for 93% of patients who had provided samples within two weeks of the due date. Negative cultures were significantly fewer in the three times weekly treatment group: 77% of the three times weekly group had negative cultures, compared to 85% of patients who received daily treatment (p = 0.001).

At the end of chemotherapy there was no significant difference in the proportions of patients with negative smear results between the three treatment groups, but twelve months after the completion of treatment patients with baseline sensitivity to isoniazid and rifampicin who had received an eight month regimen were significantly more likely to have an unfavourable outcome, with an adjusted odds ratio of 2.86.

A Kaplan-Meier analysis of time to unfavourable outcome showed that as time went on, the risk of an unfavourable outcome among patients who received an eight month treatment regimen grew. Two and a half years after the beginning of treatment 5% of the six month treatment group had experienced an unfavourable outcome, compared to 10% of the eight month / daily induction treatment group and 15% of the eight month / three times weekly induction treatment group. Almost all unfavourable outcomes in the six month treatment group occurred during the first 18 months after treatment began, but continued to accumulate throughout the follow-up period in the eight month treatment groups.

In 68 HIV-positive patients available for assessment twelve months after the completion of chemotherapy, one patient receiving the six month treatment regimen had an unfavourable outcome, compared to 13 of the eight month group (5% vs 27%, p = 0.09). The authors note that although not statistically significant, this trend is suggestive.

Loss to follow up was highest in African centres with higher HIV prevalence. Twelve months after the end of treatment 42 patients had died (of whom 27 died during treatment) but a total of 311 out of 1355 randomised patients were unavailable for assessment, representing a loss to follow up of 23%.

Baseline resistance to isoniazid did not compromise outcomes in the six month treatment group, but did compromise outcomes in the eight month treatment groups, where 31% of those with reduced isoniazid sensitivity had unfavourable outcomes compared to 7% of those with isoniazid sensitivity.

Implications for treatment guidelines

The authors note that while their findings provide evidence that may influence future treatment guidelines, other factors will need to be taken into consideration before any decision is taken. They stress that their study could not take into account the potential effect of poor quality services on the emergence of rifampicin resistance during the continuation phase. If patients experience relapse of TB after the induction phase while receiving isoniazid and ethambutol, they can receive a rifampicin-containing induction regimen again. If continuation phase treatment with rifampicin fails and patients develop resistance to rifampicin, they will require more complex treatment for multi-drug resistant TB.

In a letter to WHO and the Stop TB Partnership issued this week, treatment advocates urged WHO to move forward with new recommendations on TB treatment following the results of the trial.

“Switching continuation phase regimens from isoniazid/ethambutol to isoniazid/rifampicin should be priority, especially in areas – such as the former Soviet states – with high rates of baseline resistance to isoniazid – and in others with high rates of TB/HIV coinfection.”

They say that the Strategic and Technical Advisory Group for Tuberculosis recommended that WHO release updated TB guidelines incorporating the new findings. The treatment advocates, who attended the 4th Global Stop TB Partnership TB/HIV Working Group in Addis Ababa in September, claim that some country TB programmes are resisting the change due to `programme inertia` and reluctance to implement a further four months of directly observed rifampicin-based therapy.

However isoniazid and rifampicin are the two most potent drugs in the TB arsenal. Many fear that if these two drug are given for four months without direct observed therapy, there is a danger that a patient will be poorly adherent, and develop multi-drug resistant TB, which is both very difficult and expensive to treat. The key reason for preferring the six month continuation phase with INH and ethambutol is that it is felt that the treatment can be given to the patient on a monthly out-patient basis, without directly observed therapy (which taxes already overburdened health care infrastructures). In other words, they fear that directly observed therapy for 6 months, rather than DOTS (2 months) would triple the direct observation workload for already struggling programmes.

In its 2003 recommendations on TB treatment (Guidelines for national programmes. WHO, 2003. p. 34), WHO noted that six month continuation phase was ”particularly appropriate for countries with limited public health care access and unable to organize a system of direct observation through health facilities, community health workers or volunteers.”

Treatment advocates argue that antiretroviral therapy has provided other models that seem highly effective at encouraging adherence, and that national programmes could step up community-based adherence support for TB treatment if they invest in community-based treatment literacy programmes and building a cadre of community TB treatment supporters.

Some countries have already adopted different treatment protocols based on treatment with isoniazid and rifampicin in the continuation phase which are designed to limit the human resource burden of directly observed treatment. In South Africa's National TB Control Programme, for example, some treatment centres carry out TB treatment using a five month continuation phase in which isoniazid and rifampicin are given three times a week. Other centres give rifampicin and isoniazid five times a week during the four month continuation phase, and also give the induction regimen for five days out of seven during the first two months.

HIV & AIDS Treatment in Practice Editor Theo Smart contributed to this report.