Cryptococcal meningitis is a leading cause of death in HIV-infected individuals in Africa. The current recommended treatment is a drug called amphotericin B deoxycholate. Treatment with amphotericin B requires 14 days of intravenous infusions given in hospital, making it difficult and costly to administer. It also causes many side effects, including kidney failure and low blood count, making close laboratory monitoring essential. The combination of the costs associated with prolonged hospital admissions, the difficulties in administration and the need for laboratory monitoring make amphotericin B treatment difficult in much of Africa. The only alternative currently available treatment is called fluconazole. Treatment with fluconazole is inadequate, and is associated with death rates of approximately 60%. A modified form of amphotericin B is available called liposomal amphotericin B (Ambisome). This is considerably less toxic than standard amphotericin B, and is known to be efficacious in treatment of cryptococcal meningitis. Its use has been limited by the high cost of therapy, but recent data suggest that much shorter courses of Ambisome may be effective in the treatment of cryptococcal meningitis. Due to its lower toxicity, higher doses of Ambisome can be given safely, and it also persists for a long time in the tissues, raising the possibility of delivering highly effective induction therapy with very few (1, 2, or 3) doses. A large reduction in the number of doses and duration of hospitalisation, together with reduced pricing of Ambisome, may result in cryptococcal meningitis treatment costs that are not more than those with 2 weeks of conventional amphotericin B, and provide a convenient, safe and efficacious alternative to conventional amphotericin B therapy. This study aims to define the most effective and most cost-effective schedules for Ambisome use in the treatment of cryptococcal meningitis. A currently ongoing study is testing the safety and effect on rate of clearance of cryptococcal infection of one, two or three dose Ambisome treatment regimens compared to the standard 14-day course. The shortest of these Ambisome regimens that is found to be safe and effective will be utilized in this proposed large clinical trial to determine whether or not it is as effective as the standard 14-day amphotericin B deoxycholate treatment in terms of preventing deaths from cryptococcal meningitis. If short-course Ambisome treatment regimens were shown to be of comparable effectiveness in the treatment of HIV-associated cryptococcal meningitis, the results of this study would lead to changes in international treatment guidelines, and provide an effective and practical treatment option for HIV-associated cryptococcal meningitis with the potential to prevent many thousands of deaths.

Context of the research Each year over 30 million pregnancies occur in malaria endemic areas of sub-Saharan Africa. Malaria in pregnancy (MiP) has devastating consequences for the mother and unborn child. The control of malaria in pregnancy in parts of East and southern Africa is under threat. Pregnant women are often infected with malaria without showing any outward signs or symptoms which, if left undetected and untreated, can cause anaemia and interfere with the development of the foetus leading to loss of the pregnancy, or premature birth and low birth weight, which in turn increases the risk of early infant death. The World Health Organisation (WHO) therefore recommends a preventive strategy called 'intermittent preventive treatment in pregnancy' (IPTp) in which mothers receive a single dose of 3 tablets of medication called sulphadoxine-pyrimethamine (SP) at each scheduled antenatal visit starting in the 2nd and 3rd trimester. However, the effectiveness of this strategy is being compromised due to high levels of resistance to SP in the malaria parasite population. The recent search for safe, effective and well-tolerated alternatives drugs has proven elusive because most of the new candidates tested were not tolerated well enough to be used for preventive purposes. Other trials evaluating test and treat strategies have also proven disappointing. All hopes are now pinned on an antimalarial called dihydroartemisinin-piperaquine (DP), which is known to be safe in the 2nd and 3rd trimester of pregnancy and highly effective for treatment of clinical malaria. The high profile journals Lancet and the New England Journal of Medicine recently published the results of two exploratory trials, completed in 2015 (including one by this research team in Kenya). These showed that DP, when taken as IPT by pregnant women, was well tolerated and much more effective than SP in preventing malaria. However these two trials were not big enough to be able to evaluate the impact on the pregnancy outcome and the health of the newborn. WHO reviewed the evidence in July 2015 and concluded that DP is indeed a promising alternative to SP and recommended that a larger, confirmatory, trial is needed, before it can consider whether to recommend this drug as an alternative to SP in areas of high resistance. Study aims and objectives This multi-centre trial will enrol about 3,000 pregnant women in six hospitals in Kenya and Malawi and compare the safety, tolerance and beneficial effects of IPTp with DP to the current strategy with sulphadoxine-pyrimethamine in reducing pregnancy loss, low birthweight, preterm birth and small-for-gestational-age babies, and early infant deaths. The trial will include sub-studies on health economics to determine the cost of the strategy in relation to its benefits, the acceptability of the intervention among pregnant women and health providers, paying particular attention to adherence to the 3-day regimen, and the operational feasibility of implementing the intervention in the routine health system. Potential applications and benefits After a decade of intensive multi-centre trials to find new prevention strategies for malaria in pregnancy, DP has been shortlisted as the only potential alternative to SP for IPTp, but evidence of its benefits on infant outcomes is needed. As an experienced network, specialised in malaria prevention trials in pregnancy, we are in a unique position to address these gaps in an expedited manner. The findings of this new trial will provide the definitive evidence for whether or not this drug should be recommended to replace SP in areas with high levels of resistance by the parasite to SP. A positive result may lead to a direct policy change by the WHO in countries experiencing these levels of parasite resistance, including most countries in East and southern Africa, benefiting women at risk of malaria in these regions resulting in healthier pregnancies and healthier newborns.