Malaria: bold decisions needed
Authors: Zoë Mullan
Journal: The Lancet Global Health (2015)

As we went to press this month, the annual meeting of the American Society of Tropical Medicine and Hygiene (ASTMH) was just wrapping up in Philadelphia. The sessions were, as usual, rather malaria-heavy, but this year the disease's predominance was perhaps forgivable in light of two key issues. First was the release, just days before the meeting began, of the recommendations of the WHO Strategic Advisory Group of Experts on Immunization (SAGE) and the Malaria Policy Advisory Committee (MPAC) on use of the RTS,S/AS01 malaria vaccine. The groups advised that, despite the vaccine having shown partial efficacy in a large phase 3 trial published in The Lancet in April, further real-world demonstration studies should be done before wider roll-out. This small bombshell was doubtless on many minds at ASTMH as four sets of malaria modelling groups presented the results of a major collaborative project on the potential public health impact and cost-effectiveness of the vaccine. The study, also published in The Lancet, set out to answer questions that the phase 3 trial was not well positioned to address—ie, on mortality, since few deaths were observed in the trial because of the uncharacteristically high level of care provided; long-term impact; and in what settings the vaccine might be expected to have most benefit. The models used empirical data on vaccine efficacy from the phase 3 trial and historical data relating clinical and severe incidence to mortality. Over a 15-year follow-up period, with 72% coverage of four doses, and at a parasite prevalence in 2–10 year olds (ie, transmission intensity) of 10–65%, the models predicted that the vaccine could prevent a median of 116 480 clinical cases (range across models 31 450–160 410) and 484 deaths (189–859) per 100 000 fully vaccinated children. The incremental cost-effectiveness ratio under these assumptions and at a vaccine cost of US$5 per dose was estimated to be $87 ($48–$244) per disability-adjusted life-year averted, making the vaccine highly cost effective under the WHO threshold of less than gross domestic product per capita. When the inevitable question from the floor about the SAGE/MPAC advice came, WHO's Vasee Moorthy was quick to stress that the organisation had not yet stated its formal position on the matter. Peter Smith, chair of one of the technical expert groups reporting into MPAC, added that the modelling study had shaped the group's thinking, but that uncertainties remained regarding implementation practicality and safety (the phase 3 trial showed a higher number of cases of meningitis and cerebral malaria in the vaccine group). Immunisation, particularly with a partly effective vaccine, is of course only one component of any malaria control strategy. Treatment is also fundamental, and worrying signs from western Cambodia were the second key issue on the agenda at ASTMH. The region is the epicentre of resistance to artemisinins and the situation is becoming more and more desperate. With the artemisinin combination therapy (ACT) dihydroartemisinin–piperaquine “massively failing”, resistance spreading into higher transmission areas, and new antimalarials more than 4 years away from registration, new strategies are urgently needed. One such strategy is explored in another modelling study published in the journal this month. Multiple first-line therapies (MFT) is a strategy in which several ACTs are simultaneously prescribed to individual patients in a random manner. The authors' individual-based microsimulation, which accounted for several key features not included in previous models, compared simultaneous distribution of artemether–lumefantrine, artesunate–amodiaquine, and dihydroartemisinin–piperaquine against strategies in which these ACTs were cycled or used sequentially. The model tracked 1 million individuals for 20 years, and MFT was found to be significantly better at delaying emergence of resistance to both artemisinins and their partner drugs. The authors suggest adjusting national guidelines accordingly. Triple therapies (ie, an artemisinin plus two partner drugs) are also being considered, and the ongoing TRAC II study is exploring the efficacy of dihydroartemisinin–piperaquine–mefloquine and artemether–lumefantrine–amodiaquine against ACTs in eight countries. Results are expected at next year's ASTMH meeting. WHO now has some monumental decisions to make regarding its guidance on both roll-out of the RTS,S vaccine and on optimal population-level ACT use. In an era in which many talk of elimination, will WHO take the bold steps necessary to make this happen?