So in 2007, the study in Khayelitsha was initiated
to determine whether IPT further reduces the risk of TB in HIV-positive people
concurrently receiving ART
– and furthermore, whether it is safe to take IPT
with ART. (IPT and ART have overlapping toxicities including peripheral
neuropathy, severe rashes, raised ALT and clinical hepatitis, raising the
possibility of elevated rates of these treatment-limiting toxicities.)
Khayelitsha is a township of Cape Town, South
Africa, with a total population of at least 600,000 and a TB case notification
rate of 1600/100,000 population per annum. The HIV prevalence, drawn from test
results at the antenatal clinic, is 33.3%. At the Ubuntu Clinic, where the
study was performed, the HIV prevalence found among new cases of TB in adults
is at least 70%.
The study was a pragmatic (where the rest of
treatment occurs as in the real world) randomised placebo-controlled trial. The
patient, doctor and local pharmacy were all blinded as to whether the patients
were taking IPT or a matching placebo, which was self-administered for 12
months, and dispensed with their ART.
The primary endpoint was all TB (definite, probable
or possible). The secondary endpoints included drug adverse events; or death.
The main exclusion criterion was active TB (based on a TB symptom screen plus
smear and/or culture.
The study enrolled 1369 volunteers. The study period was four years, with screening
beginning in 2007 and a minimum follow-up of 12 months. The last patient was
randomised in October 2010, and the study closed in September 2011. Only participants who completed
the TB screening process were randomised; and they were stratified by whether
they were new or established ART patients.
skin tests were not required to participate in the study. There is an ongoing
debate in South Africa about how long IPT should be given. The BOTUSA and
Thibela studies both showed that the effect of IPT began to decline rapidly
after discontinuation of IPT in people living with HIV who had a positive
tuberculin skin test (TST), leading some researchers to advocate for continuous
IPT to be given in these high-burden settings to people living with HIV. The
response from the community has been somewhat muted however, with some
activists noting that since the benefit of IPT was only seen in TST-positive
patients, continuous lifelong IPT might pose a risk to those who were TST-negative.
The researchers, however, have stressed that the logistical challenges of
performing a TST, which requires cold chain storage for tuberculin and skin
test reading two to three days after it is administered, constitute a barrier
to providing IPT if a tuberculin skin test is a requirement to receive it.
During the intervention
period, follow-up was monthly to 2-monthly in line with their regular ART
appointments; liver function tests (ALT) were checked monthly for the first
three months then every three months, and
patients were monitored for adverse events (side-effects) and adherence for ART and study drug.
Follow-up continued until they developed TB, a serious adverse event or study
closure, and at each visit they were screened for TB with a symptom screen and went
through TB diagnosis if necessary.