Rifapentine and isoniazid for TB prevention in patients with HIV
Although tuberculosis is relatively uncommon in the United States, it remains a potent killer in less developed regions. In South Africa, TB is the number one cause of death and there is a disproportionate share of HIV-associated tuberculosis. People with HIV are more likely to progress from latent tuberculosis to active tuberculosis disease, making prevention of tuberculosis transmission a priority.
In 2018, the World Health Organization (WHO) recommended a
12-week regimen of 900 grams of rifapentine and 900 grams of
isoniazid, taken once weekly, to prevent latent tuberculosis
infection from turning into tuberculosis disease. Previously, 6
to 9 months of isoniazid was the norm, but research concluded
that not enough patients were finishing the full medication
course.
While adding rifapentine promised to increase adherence rates
and effectively prevent tuberculosis disease, scientists were
wary about prescribing the combination, known as 3HP, for people
taking dolutegravir, which WHO recommended as the first-line HIV
treatment for people initiating antiretroviral therapy (ART).
“[B]ased on a study conducted among healthy HIV-negative
volunteers, there were concerns that 3HP [rifapentine/isoniazid]
and dolutegravir were not tolerable when given together,”
Kelly Dooley, MD, PhD, associate professor of medicine,
pharmacology & molecular sciences at Johns Hopkins
University School of Medicine’s Center for Tuberculosis
Research, told Contagion®.
“Moreover, since rifapentine is a strong inducer of
metabolizing enzymes, we were not sure if 3HP would reduce
dolutegravir concentrations significantly enough that we would
need to adjust the dolutegravir dose.”
Dooley, along with colleagues at the University of California
San Francisco and South Africa, launched a study designed to
examine rifapentine and isoniazid’s safety and efficacy in
an HIV-positive population taking dolutegravir. The study, which
was published in
The Lancet HIV, enrolled 60 South African adults with HIV who had been taking
efavirenz and were virally suppressed. The participants then
transitioned to a dolutegravir-based ART regimen; after 8 weeks
on the new regimen they began taking weekly doses of rifapentine
and isoniazid, which they continued for 12 weeks, after which
they continued taking ART for 4 weeks until the study’s
conclusion (with the option to continue ART after the study).
Bloodwork was done at baseline and every few weeks throughout
the study period.
During the study, there were 3 grade 3 adverse events, including
2 episodes of elevated creatinine possibly associated with ART
and 1 episode of hypertension deemed unlikely to be caused by
ART.
The participants’ mean trough concentrations of
dolutegravir were sufficient throughout the study, and they
stayed virally suppressed, leading the investigators to declare
rifapentine and isoniazid safe and effective for the prevention
of tuberculosis disease in HIV-positive people who take the
standard 50 mg daily dose of dolutegravir.
The authors noted that in a prior study in which rifapentine and
isoniazid were given to HIV-negative subjects, 2 out of 4
subjects experienced adverse events such as fever, elevated
liver enzymes, and had high C-reactive protein and other
cytokine levels.
In the more recent study, by contrast, C-reactive protein rates
went down over time. The authors theorize that higher levels of
inflammation in people living with HIV may tamp down immune
responses such that rifapentine and isoniazid pose less of a
threat than they do to those with more reactive immune systems;
however, the reasons are not fully known.
Next up for the investigative team is a scaled-up study
enrolling people living with HIV who have not yet begun ART.
“We will explore the effects of 3HP on HIV treatment
outcomes to confirm that 3HP and ART can be started
simultaneously and that doing so is safe and effective,”
Dooley told Contagion®.
“More importantly, our trial provided the safety and
dosing information that was needed to support rollout of 3HP
among [people living with HIV] taking [dolutegravir].”
Source:
Contagion
