tag@treatmentactiongroup.org
CROI 2020 TB Round Up

Contact: Lindsay McKenna, Mike Frick

March 16, 2020 – Treatment Action Group welcomes the flurry of tuberculosis (TB) data reported at the 2020 Conference on Retroviruses and Opportunistic Infections (CROI). A summary of major findings, TAG’s take on them, and a more detailed overview of key findings are below.

Major Findings

  • WHIP3TB demonstrated that among people living with HIV in high TB transmission settings, a single course of 3HP was as effective as two periodic courses of 3HP (p3HP) in preventing TB disease;
  • IMPAACT 2001 determined that pregnant and postpartum adults with and without HIV can receive the same dose of rifapentine as part of the 3HP regimen for TB prevention as non-pregnant adults;
  • IMPAACT 1078 secondary analyses found that initiating IPT during pregnancy is associated with increased risk of adverse pregnancy outcomes even after adjusting for known risk factors, adding further context to the risk/benefit ratio for initiating IPT during pregnancy in women living with HIV, and reinforcing the importance of conducting randomized clinical trials in pregnant and postpartum women; and
  • ODYSSEY determined that, in children 6 < 18 years old living with HIV, twice daily dolutegravir dosing was safe and sufficient to overcome the effects of rifampicin on dolutegravir exposures.


TAG Analysis

“Advocates working on TB prevention often ask us whether a single course of the 3HP short-course regimen is enough to protect a person living with HIV from developing TB. Results from the WHIP3TB trial presented at CROI 2020 suggest that the answer is yes. WHIP3TB compared the effectiveness and safety of 3HP given once versus 3HP given once a year for two years (an approach called periodic 3HP, or p3HP) among people living with HIV (PLHIV) ages 2 years and older in South Africa, Ethiopia, and Mozambique.  TB incidence was similar among participants taking 3HP and those receiving p3HP over 24 months. 3HP and p3HP were both safe, and flu-like reactions of the type seen in a small percentage of people in previous 3HP studies were rare. TAG congratulates the Aurum Institute, trial sponsor KNCV, and funder USAID on completing this highly relevant study. Evidence that a single course of 3HP protects PLHIV in areas with high TB transmission should make it easier and less expensive to scale-up 3HP globally. We hope this result encourages country programs and donors to move quickly to make 3HP available to PLHIV everywhere.”— Mike Frick, TB project co-director, TAG

“Treatment Action Group welcomes the P2001 data presented by the IMPAACT network at CROI 2020. P2001 determined that people who are pregnant do not need to take a different amount of rifapentine, a core component of the three-month, once-weekly 3HP regimen for TB prevention. The P2001 investigators did not observe any drug-related serious adverse events or active TB in the women and infants enrolled in the study. These findings bring us closer to unlocking a new, potentially safer TB preventive therapy option for pregnant women, a population especially vulnerable to TB. Still, the study was not powered for safety. To fully inform women deciding whether to take rifapentine during pregnancy, a randomized clinical trial powered to determine optimal timing and safety of 3HP and other rifapentine-containing TB prevention regimens during pregnancy is necessary and should be initiated with urgency. Such a study should be a priority for the IMPAACT network to carry forward. Furthermore, we urgently need prospective registries to be able to capture certain safety signals, such as rare birth defects.” — Lindsay McKenna, TB project co-director, TAG

“We learned the importance of conducting randomized clinical trials in pregnant and postpartum women from P1078, a phase IV trial to evaluate the safety of immediate (antepartum) versus deferred (postpartum) isoniazid preventive therapy (IPT) in HIV-positive women. The investigators found that IPT was associated with a 1.6-fold increase in risk of adverse pregnancy outcome when initiated during pregnancy compared to postpartum. The secondary analyses from this study presented at CROI 2020 found that even after adjusting for known risk factors, initiating IPT during pregnancy is associated with increased risk of adverse pregnancy outcomes. Trials designed and powered to answer questions about the optimal timing and safety of TB preventive therapy regimens in pregnant women are critical to informing policy as well as individual provider and patient discussions and decisions about how best to protect pregnant women and their infants from TB, and should remain a priority area of work for the IMPAACT network.”— Lindsay McKenna, TB project co-director, TAG

 


More Details on the Studies

WHIP3TB: phase IV comparative effectiveness and safety of 3HP given annually versus once in PLHIV living in high TB transmission settings.

Abstract available from: http://www.croiconference.org/sessions/effectiveness-3hp-annually-vs-once-hiv-positive-people-whip3tb-trial.

  • This two-part study enrolled people living with HIV 2 years or older and on ART for 3 or more months from South Africa, Ethiopia, and Mozambique.
  • Part A of the study was an observational, randomized comparison of 3HP versus six months of daily isoniazid (6H). The primary objective of part A compared treatment completion rates among people taking 3HP versus 6H. A significantly greater percentage of people taking 3HP completed therapy (90.4%) compared to people taking 6H (50.5%). 
  • Secondary objectives of Part A compared 6H and 3HP with respect to TB incidence and all-cause mortality. TB incidence and mortality were each non-significantly higher among participants taking 3HP, but this could have been due to the small number of people enrolled in the 6H arm (participants were randomized to 3HP, p3HP, 6H in 9:9:2 ratio).
  • Part B of the study was a randomized controlled trial of 3HP given once versus 3HP given once a year for two years (an approach called periodic 3HP, or p3HP). The primary objective of Part B compared TB incidence among participants taking p3HP versus 3HP. There was no statistically significant difference in TB incidence between people taking 3HP versus p3HP over 24 months.
  • Secondary objectives of Part B looked at all-cause mortality, TB incidence in months 12–24, serious adverse events, and incidence of rifampicin-resistant TB. There were no significant differences between 3HP and p3HP by any of these measures.
  • Among people living with HIV in high TB transmission settings, a single course of 3HP was as effective as two periodic courses of 3HP (p3HP) in preventing TB disease.
  • 3HP and p3HP were safe, with the most common severe adverse event being hepatitis. Hypersensitivity and flu-like reactions of the type seen in a small percentage of people taking 3HP in previous studies in clinical practice were rare. No deaths were attributed to study medication.


IMPAACT 2001: phase I/II pharmacokinetics (PK) and safety of 3 months of once-weekly rifapentine + isoniazid (3HP) for TB prevention in pregnant and postpartum women with and without HIV.

Abstract available from: http://www.croiconference.org/sessions/rifapentine-pharmacokinetics-and-safety-pregnant-women-and-without-hiv-3hp.

  • Enrolled pregnant women with and without HIV in 2nd or 3rd trimester (N = 50) from Haiti, Kenya, Malawi, Thailand, and Zimbabwe to determine the impact of pregnancy on rifapentine pharmacokinetics compared to historical non-pregnant controls and by trimester and HIV status.
  • Rifapentine blood levels were in the therapeutic range known to be effective in preventing TB. This means that people who are pregnant do not need to take a different amount of rifapentine compared to people who are not pregnant. 
  • Additionally, there were no drug-related serious adverse events and no cases of active TB in the women and infants enrolled in the study.
  • It’s important to note that P2001 was not powered for safety and that all of the HIV-positive pregnant women enrolled into the study were on efavirenz-based regimens.
  • Pharmacokinetic studies to evaluate rifapentine administered with other ARVs (e.g., dolutegravir) during pregnancy and the postpartum period, and a larger clinical trial powered to more definitively evaluate the safety of rifapentine use during pregnancy and the postpartum period are necessary.

 

IMPAACT P1078 (TB APPRISE): adjusted analyses from phase IV trial to evaluate the safety of immediate (antepartum) versus deferred (postpartum) IPT in HIV-positive women in high-TB burden settings.

Abstract available from: http://www.croiconference.org/sessions/adjusted-analysis-effect-ipt-adverse-pregnancy-outcomes-women-hiv.

  • Previously unadjusted analyses of P1078/ TB APPRISE, which enrolled 956 mother-infant pairs from 8 countries, showed that IPT during pregnancy in PLHIV significantly increased odds of a composite outcome of fetal demise, preterm delivery (PTD), low birth weight (LBW) or congenital anomaly, but not of any individual outcomes when evaluated alone.
  • Secondary analysis, which adjusted for important covariates (maternal age, ARV regimen, timing of ARV initiation, CD4 count, IGRA status, mid-upper arm circumference, non-infectious pregnant complications, twin pregnancy), determined mid-upper arm circumference, non-infectious pregnant complications, and twin pregnancy were important risk factors in at least one of the pregnancy outcomes studied.
  • The adjusted odds of fetal demise, PTD, LBW, or congenital anomaly (composite outcome 1) were 1.68 times higher among women on immediate IPT compared to deferred (1.19–2.38, P = 0.003)
  • The adjusted odds of fetal demise, PTD, LBW, or neonatal death (composite outcome 2) were 1.59 times higher among women on immediate IPT compared to deferred (1.12–2.26, P = 0.009)
  • The adjusted odds of early neonatal death, fetal demise, PTD, or LBW (composite outcome 3) were 1.70 times higher among women on immediate IPT compared to deferred (1.20–2.42, P = 0.003)
  • The adjusted odds of LBW was 1.68 times higher among women on immediate IPT compared to deferred (1.10–2.59, P = 0.018); there was no evidence that immediate IPT had a significant effect on PTD, perinatal or neonatal mortality alone
  • Initiating IPT during pregnancy is associated with increased risk of adverse pregnancy outcomes even after adjusting for known risk factors, adding further context to the risk/benefit ratio for initiating IPT during pregnancy in women living with HIV.

 

ODYSSEY: phase I/II pharmacokinetic substudy to estimate the impact of rifampicin on dolutegravir in children and the safety of doubling dolutegravir dosing in children.

Abstract available from: http://www.croiconference.org/sessions/adequate-dolutegravir-exposure-dosed-bid-rifampicin-children-6.

  • Enrolled (N=31 for safety and N=13 for PK) children 6 < 18 years old to receive 25 mg dolutegravir once a day vs. twice a day with rifampicin and 50 mg dolutegravir once a day vs. twice a day with rifampicin.
  • In children 6 < 18 years old living with HIV, twice daily dolutegravir dosing was safe and sufficient to overcome the effects of rifampicin on dolutegravir exposures. 
  • There are currently no data to inform dolutegravir dosing and safety when co-administered with rifampicin to children less than 6 years old or weighing less than 25 kg.

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