IMPROVE-2 Trial

Chief Investigating Officer:    Prof Feiko ter Kuile

Trial Manager:                         Dr Hellen Barsosio (Kenya)

Co-Investigators:                    Dr Simon Kariuki (Kenya), Dr Mwayi Madanitsa (Malawi)

Sub-Study Investigators:        Dr Eva Maria Hodel, Dr Jenny Hill,  Prof Kara Hanson, Silke Fernandes


Study Title:

Intermittant preventative treatment with dihydroartemisinine-piperaquine and single-course azithromycin for malaria, sexually transmitted and reproductive tract infections in HIV-infected pregnant women in Kenya and Malawi: a multi-centre 3-arm placebo-controlled trial

Short Title: IMproving PRegnancy Outcomes with intermittant preVEntative treatment in Africa (IMPROVE-2)

Context of the research:

In malaria-endemic Africa, co-infection with HIV and malaria conspire to increases the risk of pregnancy loss, preterm delivery, and growth retardation resulting in small babies. HIV uninfected women in these areas receive intermittent preventive therapy in pregnancy (IPTp) with the antimalarial sulphadoxine-pyrimethamine (SP) to mitigate these effects. HIV infected women receive daily prevention with cotrimoxazole (CTX), an antibiotic which also has broad antimalarial activity. However, the malaria parasite is increasingly resistant to SP and CTX.

Recent trials with IPTp with mefloquine when provided in addition to daily CTX suggested that chemoprevention with an effective antimalarial markedly improves the protection against malaria in HIV-infected women compared to daily CTX alone. However, mefloquine was not well tolerated and other antimalarials are needed. The long-acting antimalarial combination of dihydroartemisinin–piperaquine (DP) is well tolerated and has shown great promise in trials in HIV-negative women in Uganda and Kenya. Chemoprevention with monthly DP has also been explored in a small study (N=200) of HIV-infected women on daily CTX in Uganda. Unfortunately, the study was inconclusive because malaria transmission was low. It also showed a drug interaction with the anti-retroviral efavirenz, which markedly reduced the protective drug levels of DP.

WHO recommends replacing efavirenz-based antiretroviral therapy (ART) with dolutegravir-based ARTs in the general population. However, for women of child-bearing age, WHO recommends efavirenz-based ARTs because the safety of dolutegravir in first trimester pregnancy remains to be established. Pharmacological models suggest that in HIV-infected women on efavirenz-based ARTs, weekly prophylaxis with DP, using one-third of the monthly dose, will result in better drug levels and is likely to be better tolerated than increasing the monthly DP dose.

We will therefore assess the safety and efficacy of malaria chemoprevention with weekly DP in women on daily CTX and efavirenz-based ARTs.

Other causes of poor birth outcomes are sexually transmitted and reproductive tract infections (STI/RTI), which are highly prevalent in East/Southern Africa especially in HIV-infected women. Like malaria, they remain mostly asymptomatic, and are undetected and untreated. These infections cannot be treated with DP or CTX. Azithromycin (AZ) is an antibiotic that is very effective against a wide range of these infections and can safely be given during pregnancy. We will determine whether adding a single course of AZ at enrolment to DP can further improve birth outcomes.

Aim:

To determine whether weekly prophylaxis with DP, alone or combined with AZ, in HIV-infected pregnant women on ARTs and daily CTX improves current policies to control malaria and STIs/RTIs in areas with high resistance, prevalence of STIs/RTIs and malaria in East & Southern Africa.

Trial Design

This is a 3-arm multi-centre trial involving 927 pregnant women in 8 hospitals in Kenya and Malawi comparing daily CTX alone, versus CTX + DP alone, and CTX + DP + AZ. CTX will be given daily, DP will be given weekly and AZ will be given once at enrolment. The primary outcome is the incidence of malaria infection. This study is conducted alongside a sister trial among HIV-negative women (IMPROVE trial, NCT03208179) that evaluates monthly IPTp-DP, alone or combined with AZ.

Potential applications and benefits:

A definitive result may influence policy change by WHO in countries experiencing high levels of parasite resistance, and potentially paving the way for integrated strategies to combat malaria and curable co-infections hopefully resulting in healthier pregnancies and newborns.