HIV Infections Clinical Trial
Official title:
A Clinical Trial to Establish The Effectiveness of Daily Co-trimoxazole Prophylaxis For Prevention of Malaria in Pregnancy
Malaria is a major contributor of disease burden in Sub-Saharan Africa: 90% of global cases
occur there, and pregnant women and children under 5 years are the most vulnerable. Malaria
in pregnancy increases risks of abortion, stillbirth, prematurity, intrauterine growth
retardation and maternal anemia, and is associated with higher risk of low birth weight and
perinatal, neonatal and infant mortality. For prevention and control of malaria in
pregnancy, the WHO recommends Intermittent Preventive Treatment (IPT) with antimalarial
drugs, insecticide treated nets (ITNs) and effective treatment of malaria and anemia.
HIV in pregnancy increases the risks of malaria, and it seems that the efficacy of IPT with
the drug sulphadoxine-pyrimethamine (SP) is decreased in HIV+ pregnant women.
Malaria prevention in pregnancy in Zambia relies on ITNs and IPT with SP. Daily prophylaxis
with cotrimoxazole (CTX) effectively reduces mortality and morbidity in HIV+ individuals,
and antibiotic therapy during pregnancy might help to decrease adverse pregnancy outcomes.
CTX prophylaxis improves birth outcomes in HIV+ women with CD4<200/µl: a study concluded
that antenatal provision of CTX was beneficial for HIV+ pregnant women with low CD4 but not
in women with ≥200/µl (however, this study was carried out in an area with very low risk of
malaria , and CTX may have a different effect depending on endemic conditions). The WHO
recommends daily CTX in addition to ARVs, to prevent opportunistic infections in all HIV+
patients.
Concurrent administration of SP and CTX may increase the incidence of severe adverse
reactions in HIV+ patients, so WHO has promoted CTX prophylaxis as an alternative to SP for
the IPT in immuno-compromised pregnant women. Unfortunately, there is insufficient
information on the effectiveness of daily CTX for preventing malaria infection in pregnancy:
so, SP is still the only antimalarial recommended by WHO for this purpose. With the increase
in SP resistance and with the newer antimalarials still being studied for safety and
efficacy in pregnancy, CTX could be an alternative for SP in reducing malaria and
malaria-related morbidity and mortality in pregnancy.
This study will try to to see if in HIV- and HIV+ pregnant women, CTX is not inferior to SP
in reducing placental parasitaemia. Such information is needed to issue updated, effective
guidelines on malaria prevention in pregnancy
Malaria is a major contributor of the disease burden in Sub-Saharan Africa: some 90% of
global cases occur in Sub-Saharan Africa, with pregnant women and children < 5 representing
the most vulnerable population. P.falciparum infection in pregnancy leads to parasite
sequestration in the maternal placental vascular space, causing increased risks of abortion,
stillbirth, prematurity, intrauterine growth retardation and maternal anaemia; it is also
associated with increased risk of low birth weight (LBW) and perinatal, neonatal and infant
mortality.In low transmission areas, malaria can be severe with a high risk of maternal and
perinatal mortality (up to 60-70%). In highly endemic areas, malaria is still associated
with maternal anaemia, LBW and stillbirth. For prevention and control of malaria in
pregnancy, the WHO recommends Intermittent Preventive Treatment (IPT), insecticide treated
nets (ITNs) and effective case management for malaria and anaemia.
HIV-1 infection in pregnancy increases the risks of malaria. In HIV+ pregnant women, in
addition, the efficacy of IPT with sulphadoxine-pyrimethamine (SP) appears decreased.
In Zambia, the malaria incidence rate increased from 121.5/1000 in 1976 to 482.0/1000 in
2003. The high rates were predominantly evident among pregnant women and children <five.
Malaria prevention in pregnancy in Zambia relies on ITNs and IPT with SP.
Several studies in Zambia and Uganda demonstrated that daily cotrimoxazole (CTX) prophylaxis
is effective in reducing mortality and morbidity in HIV+ individuals and that antibiotic
therapy during pregnancy might impact positively to the reduction of adverse pregnancy
outcomes. CTX prophylaxis significantly improves birth outcomes in HIV+ women with
CD4<200/µl. A recent study in Zambia concluded that antenatal provision of CTX was
beneficial for HIV+ pregnant women with low CD4 but not in women with ≥200/µl. However, this
study was carried out in an area with an extremely low risk of malaria infection; CTX may
have had a different impact if malaria transmission was either holo or hyperendemic. Today,
WHO recommends daily CTX in addition to ARVs, to prevent opportunistic infections in HIV+,
regardless of the background prevalence of CTX microbial resistance.
Concurrent administration of SP and CTX has been associated with increased incidence of
severe adverse reactions in HIV+ patients. Therefore, WHO has promoted CTX prophylaxis as an
alternative to SP for the IPT in immuno-compromised (CD4 < 350/µl)pregnant women.
Unfortunately, there is insufficient information on the effectiveness of daily CTX for
preventing malaria infection (placental parasitaemia) and its consequences (maternal anaemia
and low birth weight) in pregnancy: so, presently, SP is the only antimalarial treatment for
which data on efficacy and safety for IPT is available, and the WHO recommends that at least
2 doses of SP are given after the first trimester. With the documented increase in SP
resistance and with the newer antimalarials still being studied for safety and efficacy in
pregnancy, CTX could be an alternative for SP in reducing malaria and malaria related
morbidity and mortality in pregnancy.
The focus of this study is the malaria related outcome in pregnancy: we will target both HIV
negative and HIV positive pregnant women, assuming that CTX is not inferior to SP in
reducing placental parasitaemia. Such information is urgently needed in order to issue
updated, effective guidelines on intermittent preventive treatment in pregnant women.
An open label clinical trial is the best design to assess the research question and its
consequences on the offspring, both in HIV negative pregnant women and in HIV positive
pregnant women with CD4 count ≥350/µl. The parallel design was chosen evaluate to each group
separately, as HIV might interact with CTX efficacy. Offsets for efficacy were based on
literature review.
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Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Prevention
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