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Shorter Duration of TB-Prevention Therapy Including Ethambutol May Be Effective, Study Suggests

A Discussion With Soumya Swaminathan, M.D.

March 3, 2010

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Below is the transcript of a press conference held at CROI 2010 on Feb. 18, featuring Soumya Swaminathan, M.D., of the Tuberculosis Research Center in Chennai, India. She discussed the outcome of a trial comparing a six-month course of tuberculosis (TB) prevention therapy to a three-year course among people with HIV.

Soumya Swaminathan: I presented data that was done at the Tuberculosis Research Center, which is in Chennai in South India. This was a randomized clinical trial to look at the efficacy of two different regimens to prevent tuberculosis [TB] in HIV-infected persons.1 TB is one of the biggest killers of HIV-infected people in India and other TB-endemic countries, so preventive therapy for TB would go a long way in reducing both morbidity and morality. However, though many trials have been done in the past, the issues have always been with programs taking up this as policy. The Indian government felt we needed to generate data in our own country and really look at the optimal duration of drugs that you need to give to prevent TB in a TB-endemic country.

In our study, we looked at a six-month regimen, where we gave two drugs -- ethambutol [EH] and isoniazid [INH] -- daily. The other regimen was three years of isoniazid daily, in lieu of a continuous, or lifelong, regimen. We had a cutoff of three years for this. Patients were initially screened thoroughly for TB, and were only admitted to the study if they did not have active TB. Then they were followed very closely over a period of three years. The outcome measures were the development of TB, as a primary outcome measure, and death. We also looked at the efficacy in those who were skin-test positive, versus those who were skin-test negative for TB, indicating latent infection and a different level of CD4 count.

In short, what we found really was that at the end of three years, the TB rates in both regimens were very low, compared to baseline historical data that we have. (We did not have a placebo arm in our trial, for ethical reasons.) We had a baseline rate of seven per 100 person years in a trial studied earlier on in our center. And in this study, we found rates ranging between 1.5 and 2.5 per 100 person years. So both regimens did well in preventing TB. There was no significant difference between the six-month or the continuous three-year isoniazid. They were both very safe.

We had very low incidence of adverse events. Deaths occurred equally in both arms, and occurred mostly in patients at very low CD4 counts, because this trial was started in an era prior to availability of free antiretroviral treatment [ART]. So for the three or four years of the study, there was no ART available, and patients died. After that, as ART became available, patients were started as they became eligible.

Our results have policy implications for countries like India, that want to implement TB-preventive therapy for HIV-infected persons, because we've shown that six months of two drugs was very safe and was as effective as continuous therapy. Obviously, this is easier to do, would probably have higher acceptability and adherence by patients, and very low levels of adverse events and toxicity. I think the challenges now are to take this from a clinical, randomized trial setting and implement it in a programmatic setting, and do some operational research on that.

Reporter #1: Standard therapy in the U.S. for patients with latent TB infection for prophylaxis is six months of INH. I was wondering why you were studying INH plus ethambutol vs. a 36-month regimen of only INH. Is it a question of resistance? Why were you choosing to look at those more enhanced regimens for prophylaxis?

Soumya Swaminathan: One of the hypotheses was that we're living in a TB-endemic country, so the situation in the U.S. is a little different. You're not exposed to TB in the environment as much as you would in endemic countries. That six months perhaps was not enough, and you might need continuous lifelong prophylaxis -- something like cotrimoxazole -- and maybe you just have to take it forever to have the protections. That's why it was important for us to compare. The three years was really was in lieu of a lifelong regimen. So do people really need to be on it all the time to protect them, or is six months good enough?

The reason we selected ethambutol was that about 15% to 20% of people who developed TB in India have INH resistance at baseline. In many countries, INH resistance varies between 10% and 20%. We thought the second drug might help to deal with those organisms that are resistant to isoniazid. We chose ethambutol because it's quite safe. It's cheap. It's widely available -- and we did not want to use rifampicin for prophylaxis. We wanted to reserve rifampicin for the treatment of patients who actually developed TB. So that was the thinking behind this.

In the same session, there was another paper that was from the CDC [U.S. Centers for Disease Control and Prevention] on the BOTUSA [Botswana-USA] trial that was done in Botswana, where they looked at the same thing, but they looked at six months of INH alone versus 36 months of INH.2 In that population, they actually found that 36 months of INH conferred extra, additional benefit compared to six months. Among patients who were tuberculosis skin-test [TST] positive, the continuous INH arm was 92% more effective than the six-month arm. We did not observe that difference.

We're not exactly sure what the reason is for the different findings in these two trials, which had very similar designs and very similar kinds of followup. Possibly, one aspect is the TB epidemiology and transmission rates in the community. Another difference, of course, is that we used two drugs for six months, while they used just the INH alone, so perhaps that made the difference.

Reporter #2: Dr. Carr, I was wondering if you could comment on the two studies on TB prophylaxis, if there are any implications for treatment in the U.S., a non-endemic country. Have these longer regimens been studied in the U.S. and is it likely to apply?

Andrew Carr: I'm not an infectious disease specialist. My answer would be a little limited by that. My understanding is that the longer regimens haven't been well investigated in a resource-rich setting like the U.S. And with TB not being an endemic disease, most TB in a resource-rich country like the U.S. is a reactivation of TB that the patient already has, rather than recently-acquired TB from the community. So that argues against longer prevention, but that doesn't mean it might not work. I don't believe those studies have been done.

Soumya Swaminathan: I think the longest regimen that's been tried in a resource-rich setting is up to 12 months of isoniazid. It's just marginally better than six months, so that's why the six months is a standard course of treatment.


  1. Swaminathan S, Menon P, Perumal V, et al. Efficacy of a 6-month vs a 36-month regimen for prevention of tuberculosis in HIV-infected persons in India: a randomized clinical trial. In: Program and abstracts of the 17th Conference on Retroviruses and Opportunistic Infections; February 16-19, 2010; San Francisco, Calif. Abstract 103.
  2. Samandari T, Mosimaneotsile B, Agizew T, et al. Randomized, placebo-controlled trial of 6 vs 36 months Isoniazid TB preventive therapy for HIV-infected adults in Botswana. In: Program and abstracts of the 17th Conference on Retroviruses and Opportunistic Infections; February 16-19, 2010; San Francisco, Calif. Abstract 104LB.

