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No. 2, 2011

INTERNATIONAL RESEARCH AND PROGRAMS BRANCH UPDATE

Behind the Scenes of the Botswana IPT Trial

From her seat on the minibus, Segometse smiled wanly as she saw her village water tower on the horizon. As the minibus lurched from the highway onto an unpaved road, she clutched the bag on her lap; to her horror, the pills in her bag rattled. Her seat-mate heard the sound and raised her eyebrows. Segometse knew the raised eyebrows meant, “Rattling pills tell me that you are infected with HIV.” Everyone knows everything about everybody in a small village, so she plucked up her courage and told her seat-mate, “I am taking pills to prevent TB.” But the reality was that she was infected with HIV and, living in Botswana, she had a high risk of developing TB. That’s why Segometse had enrolled in a CDC study to prevent TB, the IPT Study.

About half of Botswana’s 1.8 million people are infected with TB. A quarter of persons aged 15-49 are also infected with HIV, with women disproportionately affected. As the risk of progressing from latent TB infection to TB disease is very high for HIV-infected persons, there has been a three-fold resurgence of TB in Botswana since its nadir in 1989; rates are now 200 times higher than the rates observed in the United States. Botswana is in the midst of a severe co-epidemic.

In 2001, with the financial support of CDC’s Global AIDS Program, Botswana launched a nationwide TB prevention program of isoniazid preventive therapy, or IPT. Years of research had shown that a 6-month course of IPT reduces the risk of TB disease by 30%-60%. The problem now was that, in places with a lot of TB, the benefit of 6 months of IPT was disappearing after a year or two. In other words, the risk of TB disease in HIV-infected persons living in a TB-prevalent country went back to being very high once they stopped IPT. Could it be that because there was so much TB re-infection in such communities, an HIV-infected person would need to continue IPT without stopping? This question drove a unique CDC study in Botswana between 2004 and 2009.

CDC frequently conducts epidemiologic research in resource-constrained countries, and such projects are rarely easy. However, the Research Team would be conducting a clinical trial, an altogether different kind of undertaking. Clinical trials must be conducted with meticulous care. An external data and safety monitoring committee had to be established; an endpoints committee of experts had to be assembled to agree on whether the cases of TB found were really TB; a U.S.-based auditing company had to be hired; study drugs had to be imported under stringent temperature control after undergoing customs scrutiny in countries where it was not customary to have air conditioned airport warehouses; a data system needed to be set up to record every visit of 2,000 study participants for 3 years. No clinical trial had previously been completed by CDC in Botswana. The entire Team had a steep learning curve before the planned launch of the clinical trial 12 months after being given the green light to begin preparations.

Several challenges faced the study. By 2003, Botswana had rolled out a nationwide program of free antiretroviral therapy (ART), for which all HIV-infected persons were eligible. Since it was well known that ART reduced the risk of TB, many clinicians and public health officials assumed that this would render IPT superfluous. Furthermore, a common concern about IPT among many physicians in Botswana was that the widespread use of IPT would inevitably result in isoniazid resistance. In fact, some doctors were taking their patients off IPT when they started ART.

A key aspect of research involving human subjects in the modern ethical era is to engage the community and the participants as advisors to studies. The members of the two community advisory boards in Botswana included social workers, a university instructor, traditional healers, health workers within the military and police forces, and church pastors. From among the participants in the study itself, two 10-person advisory groups were also assembled. At first most of them seemed reluctant members, quiet and withdrawn. Perhaps they wondered whether their opinions really counted; perhaps they remained suspicious that their HIV status might be exposed and result in embarrassment or shame. However, as they came to see that the TB-HIV Research Team earnestly sought their opinions and candidly presented the successes and challenges of the study, they soon became eager and vocal advocates of the study.

The hiring of new staff resulted in a doubling of the TB-HIV Research Team to 40 persons. Never having conducted a clinical trial, the team desperately needed education. They also needed to receive certification in good clinical practice, or “GCP.” Training in GCP was something that an external, certified organization had to come to Botswana to conduct annually. The senior staff worked hard to quickly prepare numerous standard operating procedures, forms, and appendices. Multiple training sessions were conducted and staff members were repeatedly tested on their knowledge.

The first shipment of drugs arrived a few weeks before the planned launch of the study. The Team fretted over data from the temperature log suggesting that the drugs had overheated in the simmering southern African sun. They breathed a collective sigh of relief when the manufacturer reassured them that brief periods of high temperature exposure did not damage the drugs’ integrity.

Shortly after Thanksgiving Day in 2004, the first participant was enrolled. The Team cheered. Recruitment was deliberately slow at first in order to work out the kinks. It felt as though a lumbering jumbo jet – with thousands of parts and pieces – had finally taken into the air, and the Team prayed that all the nuts and bolts were tied securely. And now that the study had begun, focus had to be maintained, day after day, week after week, for the next 5 years. Continuous quality control became the Team’s mantra: supervisors scrutinized the work of front-line staff, laboratory technicians double-checked results, and data being entered were regularly analyzed and cleaned. An ethic of close collaboration between all cadres of workers was established through weekly meetings. During these meetings, statistics about the trial’s progress were shared and difficulties were aired. No Team member was too low in the hierarchy to be ignored or left unheard; everyone was a critical part of this effort.

In the middle of 2006, after having screened over 4,300 persons, they succeeded in recruiting their target of 2,000 HIV-infected participants. A celebration marked the occasion, yet many challenges remained. Diagnosing TB is notoriously difficult in HIV-infected persons. Whenever a participant became ill, the physician repeatedly tested him or her. About 10 ill persons were carefully assessed for each case of TB that was diagnosed; in a prevention clinical trial it is critical not to miss any TB case.

The Team agonized over every death. Was it caused by TB? Could it have been caused by isoniazid? The deaths were particularly hard to take for the study nurses. They personally knew the difficulties each participant faced in his or her life: unemployment, insufficient food, children who also were infected by HIV, or abusive boyfriends. There were homicides (commonly referred to as “passion killings”) and even suicides among the participants.

Finally, in July of 2009, the study came to a close: the last participant took her last pill. Now the code for this double-blind, placebo-controlled study could be broken. Feverish work by the study’s statistician in Atlanta gradually painted the picture. Some findings were expected and—as is typical in science—there were surprises too.

They discovered that continuous IPT worked: it prevented TB better than the 6-month regimen recommended by the World Health Organization (WHO) and used in Botswana. Upon closer examination, there was an astonishing 92% reduction in TB among participants who were tuberculin skin test (TST) positive. However, the TST-negative participants did not benefit significantly from continuous IPT but suffered a 1%-per-year rate of TB disease. This was a big disappointment since most HIV-infected persons coming for care in resource-constrained settings are TST-negative. Perhaps being TST positive not only indicated infection with TB, but also that the individual’s immunity was sufficiently competent to derive a synergistic benefit from the isoniazid and thus kill the TB bacillus.

A final observation from the IPT study was a source of relief to the Team and TB Program managers in particular: using isoniazid, even for such extended periods of time, did not appear to select for drug-resistant TB.

This study quickly resulted in changes to WHO policy. In January 2010 the results of the study, along with results by other researchers, led to recommendations to provide up to 3 years of IPT where possible and to provide IPT in addition to ART, and a stronger recommendation to administer the TST before initiating IPT. In mid-2010, Botswana’s national program changed its policy to require the TST. Upon hearing the initial report, one health official said, “Finally we can see the impact of what we have been doing all these years.”

The recruiters had appealed to the participants’ higher sense of self when inviting them to join the study: “Help other HIV-infected persons in Botswana and around the world.” The study’s results provide new hope to HIV-infected persons like Segometse. Without the selfless participation of people like her, the study would never have been possible.

—Reported by Taraz Samandari, MD, PhD
DHAP, Epidemiology Branch Chief
Formerly Div of TB Elimination

 

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