Political clout will help fight the killer disease Malaria will resurge if countries do not commit to funding Page 3 FT SPECIAL REPORT www.ft.com/reports | @ftreports Tuesday April 17 2018 Inside Urgent need to find new treatments Scientists fear a catastrophic surge in resistance Page 2 HIV co-infection can create a lethal cocktail Pregnant women are particularly at risk Page 3 Zambia’s ambitious goal is set for 2021 The president writes of his country’s suffering and determination Page 4 Bold southern African target is still in reach But Elimination8 countries struggle with continued outbreaks Page 6 A s fear over the Ebola out- break took hold across Sierra Leone during 2014, doctors began to fret about how to deal with an unex- pected side effect. Rather than a surge in consultations as the deadly fever spread, patient attendance at clinics was dropping sharply. Ebola was sparking international con- cern and ultimately levied a heavy death toll in Sierra Leone, claiming nearly 4,000 lives. However, officials soon realised Ebola was leaving a still greater body-count in its wake from an underlying epidemic more neglected than usual as a result of the panic: malaria. The disease shares some symptoms with Ebola and some patients stayed at home rather than risk infection or misdiagnosis with Ebola. This meant they could not receive life- saving malaria treatment. In response, public health experts hatched a radical plan that drew on an approach first deployed 80 years ago: large-scale mass drug administration (MDA) of anti-malarial medicines to local communities. Rather than focus laboriously on try- ing to diagnose and treat those with the parasite, they distributed antimalarial drugs to 2.7m people regardless of whether they were infected. The result was to reduce the number of suspected and confirmed cases of malaria by between two-fifths and half, and to cut the number of false alerts over Ebola infections by 30 per cent. Pedro Alonso, head of the Global Malaria Programme at the World Health Organization, who has argued in recent years for wider use of MDA, says: “We have tools that can significantly reduce mortality. We should be using them where required.” MDA as a technique to fight malaria was first deployed as early as the 1930s in Italy and Liberia. The premise was that it could both reach those in need of treatment more effectively and wipe out the parasite in others who were infected but had no symptoms or significant ill effects. The aim was to eliminate malaria by breaking the cycle of trans- mission of parasites between infected people via mosquitoes. The use of MDA took off sharply in the postwar era, when synthetic drugs led by chloroquine made it far easier and cheaper to mass-produce treatments. It was applied from the late 1940s in Africa, and then in Latin America, China, and central, south and south-east Asia. From the 1950s, in an effort to ensure it was taken up more widely, “indirect” MDA programmes were devised, mix- ing chloroquine with cooking salt for free distribution, notably in Brazil and in south-east Asia. In 1957, at a meeting in Brazzaville, Republic of the Congo, the World Health Organization officially endorsed MDA. Yet as signs of malaria’s resistance to drugs grew — notably in regions where MDA had been applied — there was soon a counter-movement to halt the prac- tice. Specialists argued that it risked triggering the preferential selection of Continued on page 2 Officials place renewed hope in mass drug administration Strategy saves lives, but there are concerns it could spur resistance and backfire, says Andrew Jack Heavy toll: Ebola meant malaria sufferers did not seek treatment — AFP/Getty Images ‘We have tools that can reduce mortality. We should be using them’ FT Health Combating Malaria
Transcript
Political clout will helpfight the killer diseaseMalaria will resurge ifcountries do not committo fundingPage 3
FT SPECIAL REPORT
www.ft.com/reports | @ftreportsTuesday April 17 2018
InsideUrgent need to findnew treatmentsScientists fear acatastrophic surge inresistancePage 2
HIV co-infection cancreate a lethal cocktailPregnant women areparticularly at riskPage 3
Zambia’s ambitiousgoal is set for 2021The presidentwrites of hiscountry’ssuffering anddeterminationPage 4
Bold southern Africantarget is still in reachBut Elimination8countries struggle withcontinued outbreaksPage 6
A s fear over the Ebola out-break took hold acrossSierra Leone during 2014,doctors began to fret abouthow to deal with an unex-
pectedsideeffect.Ratherthanasurge inconsultations as the deadly feverspread,patientattendanceatclinicswasdroppingsharply.
Ebola was sparking international con-cern and ultimately levied a heavydeath toll in Sierra Leone, claimingnearly4,000lives.
However, officials soon realised Ebolawas leaving a still greater body-count inits wake from an underlying epidemicmore neglected than usual as a result ofthe panic: malaria. The disease sharessome symptoms with Ebola and some patients stayed at home rather than riskinfection or misdiagnosis with Ebola.
This meant they could not receive life-savingmalaria treatment.
In response, public health expertshatched a radical plan that drew on anapproach first deployed 80 years ago:large-scale mass drug administration(MDA) of anti-malarial medicines tolocalcommunities.
Rather than focus laboriously on try-ing to diagnose and treat those with theparasite, they distributed antimalarialdrugs to 2.7m people regardless ofwhethertheywere infected.
The result was to reduce the numberof suspected and confirmed cases ofmalaria by between two-fifths and half,and to cut the number of false alertsoverEbola infectionsby30percent.
Pedro Alonso, head of the GlobalMalaria Programme at the WorldHealth Organization, who has argued in
recent years for wider use of MDA, says:“We have tools that can significantlyreduce mortality. We should be usingthemwhererequired.”
MDA as a technique to fight malariawas first deployed as early as the 1930sin Italy and Liberia. The premise wasthat it could both reach those in need oftreatmentmoreeffectivelyandwipeoutthe parasite in others who were infectedbut had no symptoms or significant illeffects. The aim was to eliminatemalaria by breaking the cycle of trans-mission of parasites between infectedpeopleviamosquitoes.
TheuseofMDAtookoff sharply inthepostwar era, when synthetic drugs ledby chloroquine made it far easier and
cheaper to mass-produce treatments. Itwas applied from the late 1940s inAfrica, and then in Latin America,China,andcentral, southandsouth-eastAsia.
From the 1950s, in an effort to ensureit was taken up more widely, “indirect”MDA programmes were devised, mix-ing chloroquine with cooking salt forfree distribution, notably in Brazil andin south-east Asia. In 1957, at a meetingin Brazzaville, Republic of the Congo,theWorldHealthOrganizationofficiallyendorsedMDA.
Yet as signs of malaria’s resistance todrugs grew — notably in regions whereMDAhadbeenapplied—therewassoona counter-movement to halt the prac-tice. Specialists argued that it riskedtriggering the preferential selection of
Continued on page 2
Officials placerenewed hopein mass drugadministrationStrategy saves lives, but there are concerns it couldspur resistance and backfire, says Andrew Jack
Heavy toll: Ebola meant malaria sufferers did not seek treatment — AFP/Getty Images
‘We have tools that canreduce mortality. We shouldbe using them’
tougher strains of the parasite, provok-ing resistance especially when the drugwastakenin lowdoses.
Furthermore, there were few exam-ples of MDA leading to the local elimina-tionofmalaria. If justasmallproportionof people with parasites did not take themedicine, the parasite continued to betransmitted. Even when the incidenceof malaria temporarily fell during andafter MDA programmes, it typicallyrecurred. People who had lost their nat-ural immunity were then left more vul-nerable insubsequentoutbreaks.
Brian Greenwood from the LondonSchool of Hygiene and Tropical Medi-cine recalls heavy official pushbackwhen he tried to launch a clinical trial inGambia in 1985 for a novel applicationof MDA: using it to provide “intermit-tent” protection for pregnant womenduring the malaria season to reduce therisks of infection for them and theirnewborns.
“The WHO sent someone to the min-istry to tell them not to do it,” he recalls.“It didn’t seem right to me. The messagewas that we could give malaria prophy-laxis to expats but not to local children.The argument that it could encourageresistance and impair immunity wastrue, but MDA could also save a lot oflives.”
In the past few years, the mood hasstarted to swing back towards wider useof MDA in carefully controlled circum-stances. The process has been acceler-ated by the launch of MDA programmesto tackle a number of neglected tropicaldiseases inmanypartsofAfricawiththewidespread provision of a single doseeachyear.
Intermittent preventive treatmentusing antimalarials for pregnantwomen, for newborns and increasinglyfor children aged up to five in areas ofhigh risk of malaria has grown substan-
tially in the current decade, contribut-ing to a significant drop in illness anddeathfromtheparasite.
MDA is also being used duringhumanitarian crises in regions withfragile health systems, such as in SierraLeoneduring itsEbolaoutbreak.
Elsewhere, MDA against malaria wasrecently used in northern Nigeria, inareas until recently occupied by BokoHaram, the militant Islamist group,where health facilities had collapsed.Plans are currently being developed forits deployment in South Sudan, along-side feeding programmes to tackle mal-nutrition.
The most controversial application ofMDA remains around efforts to elimi-nate malaria. There have been a fewexamples such as Vanuatu, a Pacificisland where, in combination with otherapproaches, it does appear to have suc-ceeded. But most others have ended infailure, with a subsequent resurgence inthedisease.
Guidelines published by the WHO in2015 state that MDA can be used when itis accompanied by other interventionssuch as the distribution of bed nets, acampaigntoensurestrongsupport fromthe local community and close monitor-ing to track any side effects in patients,the spread of the disease and any resist-ancethatmayarise.
Many now suggest that MDA couldhave the greatest impact targeting elim-ination in regions where the burden ofmalaria has already been declining andothertools—includingthebestdiagnos-tics, drugs, bed nets and insecticidespraying — are already being used, as isthecase inZambia.
“MDA can be an accelerator to elimi-nation where you have other interven-tions in place,” says Sir Nicholas White,professor of tropical medicine at Oxforduniversity.
“It’s useful if you want to put out thefire quickly. You have to be smart aboutit, but my own view is that the risk ofresistancehasbeenoverdone.”
Continued from page 1
Officials placerenewedhope in MDAprogrammes
‘It’s useful if you want to putout the fire quickly. Youhave to be smart about it,but my own view is thatthe risk of resistance hasbeen overdone’
The battle against malaria often focuseson nets and sprays, but scientists arefinding potential in techniques that har-nessormanipulatenature itself.
Researchers at the DimopoulosGroup, part of the Johns HopkinsMalaria Research Institute (JHMRI),havediscovered, forexample, thatmod-ifying the bacteria in mosquito intes-tines can block the malaria parasite,leaving the insect unable to transmitdisease.
“We’ve found ways to make [the mos-quito’s] immune system slightlystronger, resulting in the blocking of theparasite,” explains George Dimopoulos,the Johns Hopkins professor leading theresearch, which involved geneticallymodifyingmosquitoes.
“It does enter the gut of the mosquitobut as it makes its way through the gutcells, it’s attacked by the mosquito’simmunesystem.”
Armed with the ability to under-stand and edit genes, scientistshave many new possiblelinesofattack.
Fo r ex a m p l e ,recently publishedresearch fromJHMRI shows it ispossible to useCrispr, the geneediting technology,to delete a single genefrom the mosquito.Deletingthis“host factor”makes the insect highlyresistant to the malaria parasiteand so less likely to transmit it tohumans,explainsProfDimopoulos.
Inothercases, researchersare lookingat using genetic modification to alter thenature of malaria-carrying mosquitopopulations.
“Malaria is only transmitted by thefemale mosquito, so one of the thingswe’re looking at is distorting the sexratio so that the population becomespredominantly male, which wouldreduce transmission,” says Austin Burt,professor of evolutionary genetics atImperial College London. Since females
are needed for reproduction, this couldalso reduce the absolute numbers ofmosquitoes.
Here, the research community isexercising caution and looking for theeffectsonotherspeciesofreducingmos-quitopopulations.
“That’s certainly at the top of every-body’s list,” says Zach Adelman, associ-ate professor at Texas A & M University,whose focus is mosquitoes carrying thedenguefeverandZikaviruses.
Meanwhile, some believe that under-standing the genes of the malariaparasite could open the way for newtreatments. For instance, scientists attheLondonSchoolofHygieneandTrop-ical Medicine (LSHTM) are investigat-ing the parasite’s genes to identify cer-tain proteins that the parasite makes atthe infection stage and to find out ifthosecouldbeusedtocreateavaccine.
“A lot of [the study of the] genetics ofthe parasite is trying to unravel thatmechanism,” says David Conway, anLSHTM professor who runs a researchgroup conducting population genetic,experimental and epidemiological stud-iesofmalariaparasites.
The group is also exploring what trig-gers a parasite’s decision to transmit byentering a mosquito. “It has to undergodevelopmental switches and developnew types of cells,” says Prof Conway.
Understanding this switch, heexplains, could lead to the
development of a treat-ment — whether adrug or a vaccine —that could blocktransmission.
Whilegenomics isseen as a powerfulweapon in the battle
against malaria, thenumber of different
malaria-carrying mos-quitoes, each with different
biologies, different habitats anddifferent mating behaviours, mean it isnosilverbullet.
“Malaria is very complex,” says ProfAdelman. “This technology may workagainst some of them but others mayrequiredifferent typesofcontrol.”
However, given the rise in resistanceto traditional tools, scientists are awareof theneedforalternatives.
“The idea is not to wait till the insecti-cides or bed nets fail, because then youhave a catastrophe on your hands,” saysProf Adelman. “We’re in a race againsttime.”
Gene tech offersfresh lines of attackGenomics
While scientists have foundsome powerful weapons,there is no silver bullet,writes Sarah Murray
T he extraordinary biologicalcomplexity of malaria,which features a parasitewith an elaborate life cycleinvolving two hosts — mos-
quitoes and humans — may be a scien-tific challenge but it presents medicalresearchers with many potential oppor-tunities tostopthedisease in its tracks.
Scientists are targeting the Plasmo-dium parasites at various stages ofdevelopment inside insectsandhumanswith genetic and chemical weapons, aswell as finding new ways to attack theAnopheles mosquitoes that carry thembetweenpeople.
The need for new treatments isbecoming urgent as the parasite evolvesresistance to the most effective drugsavailable: compounds based on artem-isinin, a herbal derivative originallydeveloped as an antimalarial in 1970sChina. These have largely replaced thetraditional remedy of quinine as first-linetreatment forseveremalaria.
A large-scale clinical study of fourartemisinin combination therapies(ACTs) in west Africa, published inmedical journal The Lancet last month,confirmed that all work well and safelyin children and adults. That finding“underscores the importance of pro-tecting these highly effective drugs fromresistance”, says David Reddy, chiefexecutive of Medicines for Malaria Ven-ture. MMV, a public-private partner-ship, has a portfolio of eight new drugsinclinicaldevelopment.Oneof themost
promising is KAF156, which Novartis,the Swiss company, is developing withMMV and charities including the GatesFoundation and Wellcome Trust. Fivehundred adults and children withmalaria are taking part in a two-yeartrial across Africa and Asia. They willtake KAF156 in combination with an oldantimalarialcalled lumefantrine.
Resistance to ACTs is spreading rap-idly in south-east Asia. A study led bythe Wellcome Sanger Institute, a non-profit British research body, and pub-lished in February in The Lancet Infec-tious Diseases, traces this to two geneticmutations in Plasmodium that com-bined in western Cambodia during2008. The drug-resistant parasite thenspread through the region for five years,unnoticed by health workers, until theoutbreakbecameapparent in2013.
“Malaria policymakers now face adilemma,” says Roberto Amato, firstauthor of the paper. “On one hand,malaria remains treatable and its preva-lence has been reduced to low enoughlevels to aim to eliminate the disease inCambodia and neighbouring countries.However, thesituation is fragile,andit isunclear how the parasite populationwill evolve in response to newinterventions.”
Dr Amato adds: “While it would becatastrophic if resistance developed inthe same way for the last remaininganti-malarial drugs, it is now possible toconduct genetic surveillance of malariacases, allowing researchers to respond
as soon as possible to changes in the par-asitepopulation.”
An intriguing prospect is to produce atreatment that can kill both parasitesand mosquitoes at the same time. Aclinical trial in Kenya suggests that thiscould be achieved by supplementingACTs with ivermectin, an old drug dis-covered in the 1980s that is used exten-sively to kill parasitic worms in tropicaldiseasessuchasriverblindness.
The study, published last month inThe Lancet Infectious Diseases, showsthat multiple high doses of ivermectin,paired with a standard ACT, can killmosquitoes feeding on humans for atleast a month after treatment. Model-ling suggests that the addition of iver-mectin to antimalarials could cutmalaria prevalence by half, and help toeliminatethedisease insomeregions.
“This is the first study to show thesafety and efficacy of multiple highdoses of ivermectin on mosquito mor-tality,” saysMennoSmitof theLiverpoolSchool of Tropical Medicine, who ledthe research. “Despite these encourag-
ing findings, further rigorous safety andefficacy trials in younger age groups areneeded before high-dose ivermectin canbeadministeredatscale.”
Scientistsareusingnewresearchtoolsto find other antimalarial compounds.A recent example is the discovery —made by a “robot scientist” called Eve atCambridge university — that triclosan,an anti-bacterial chemical often incor-porated in toothpaste, could be effectiveagainstdrug-resistantmalaria.
Using artificial intelligence and auto-mation for rapid testing, Eve found thattriclosan attacks Plasmodium by inhib-iting two of its vital enzymes, DHFR andENR. Results were published in thejournalScientificReports.
“The discovery by our robot colleagueEve that triclosan is effective againstmalaria targets offers hope that we maybe able to use it to develop a new drug,”says leadauthorElizabethBilsland.“Weknow it is a safe compound, and its abil-ity to target two points in the malariaparasite’s lifecycle means the parasitewill find itdifficult toevolveresistance.”
Urgencygrows in thehunt for newtreatmentsMedicines The parasite is evolving resistance to themost effective drugs, writes Clive Cookson
Infected: asection from apatient withcerebral malariashows bleedingon the brainThe Wellcome Collection
‘It would becatastrophicif resistancedevelopedin the sameway for thelastremaininganti-malarialdrugs’
ContributorsClive CooksonScience editorDarren DoddFT Health editor/writerLauren FedorEarly UK news editorZoe FloodFreelance writerAndrew JackFT Health editor
Sarah MurrayFreelance writerSarah NevilleGlobal pharmaceuticals editorDavid PillingAfrica editor
Emma BoydeCommissioning editorSteven BirdDesigner
Alan Knox/Michael CrabtreePicture editors
For advertising details, contact:Ian Edwards, +44 (0)20 7873 3272 [email protected], or your usual FTrepresentative.All editorial content in this report isproduced by the FT. Our advertisers haveno influence over or prior sight of thearticles.
Insecticide-treated nets remain themost widespread and effective inter-vention against malaria. But as resist-ance grows to existing insecticides —whether coated on nets or sprayed onwalls — the search for new products isintensifying.
“Resistance is a big worry,” says JanKolaczinski, who co-ordinates vectorcontrol for the World Health Organiza-tion’sGlobalMalariaProgramme.
The importance of effective newinsecticides cannot be overstated.According to a study published inNature in 2015, treated nets wereresponsible for 68 per cent of all malariacasesavertedsince2000.
Yet the WHO’s latest World MalariaReport shows that resistance to one ormore of the four types of insecticideused is now common. For pyrethroids —the only class used on nets — resistanceis widespread, rising from 71 per cent ofcountries inwhichmalariawasendemicin2010to81percent in2016.
Vector control specialists remainoptimistic, pointing to a string of newproducts either in development orundergoingtrials.
The funding community is keenlywatching the first mass deployment ofnets with added piperonyl butoxide(PBO) — an enzyme that hinders a mos-quito’s ability to build up resistance topyrethroids. The Against Malaria Foun-dationhasboughtalmost6mofthenets,made by Vestergaard and SumitomoChemical, forahugetrial inUgandacov-ering almost 23m people — more thanhalf the country’s population. Positive
data, reportedlastweekinmedical jour-nal The Lancet, have already promptedthe WHO to recommend their morewidespreaduse.
Mikkel Vestergaard, chief executiveand owner of Vestergaard, hopes theresults of the Uganda trial — expected in2019 — will encourage a move awayfrom the “one-size-fits-all” approach ofthe past. “This is the first time we’veseen donors being active and wanting toput real money behind the number-onereason why we’re not having gainsagainstmalariaanymore:resistance.”
BASF, the German chemicals group,meanwhile, has developed the first netcoating that is not based on pyrethroids.Its Interceptor G2 uses chlorfenapyr, aninsecticide repurposed from agriculturethat interrupts a mosquito’s energy pro-duction — unlike pyrethroids, whichinterferewith itsnervesignalling.
The much more expensive method ofindoor residual spraying has its ownbreakthrough products. This monththere will be the first mass deploymentof a new active IRS ingredient in 40years as Sumitomo Chemical’s Sum-iShield 50WG — based on a neonicoti-noid insecticide called clothianidin —starts being sprayed in Ghana after apilotcampaigninTanzania.
Nets and IRS of course only tacklethose mosquitoes that come indoors.“There’s quite a bit of transmissionwe’re just not controlling,” says Mr Kol-aczinski. In one attempt to combat this,IVCC, a UK-based product developmentpartnership, is funding trials in Malawion an “attractive toxic sugar bait” fromWestham,anIsraeli company.
New products, however, are also moreexpensive, throwing up problemsaround“effective”coverage.
Mr Kolaczinski describes the dilemmafacing providers: “Should I carry onwhat I’ve been doing, using a tool thatmightbe lessefficient,orshall I switchtosomething new — and by doing that pro-
tect some people better but not protectothersatall? It’sa toughdecision.”
Getting a WHO recommendation canbe another stumbling block. Approval isnot a legal requirement but is favouredbydonors.
Some producers are critical howeverof theWHO’s lackofconsistency.
Helen Pates Jamet, Vestergaard’shead of market access and entomology,says: “The issue of how to bring brandnew products to the market still needs alot more work and a lot more clarity.There remains some confusion and sig-nificant barriers to be able to bring anew bed net to market in a relativelyshort timeframe.”
Development costs are high in a mar-ket riddled with uncertainties andinvolving a large patchwork of organisa-tions, from big donors such as The Glo-bal Fund and the President’s MalariaInitiative to governments, NGOs, chari-tiesandimplementationspecialists.
“I don’t think there’s ever been a situ-ation where we’ve got so many reallycool and interesting tools. The challengeis getting them to market and then whopays for them.Weneedasmuchinnova-tion in how to bring and pay for theseproducts in the marketplace as we do inthe technology,” says Nick Hamon,IVCC’schiefexecutive.
Egon Weinmueller, head of businessmanagement, global public health, atBASF, thinks the growing awareness ofresistance could force the pace ofchange. “Some countries and somedonors may not want to wait any longerontheWHO,”hesays.
A s the leaders of the Com-monwealth gather thisweek for a summit in Lon-don, they face fresh pres-sure to step up their focus
on a disease that still exacts a heavy bur-den on the lives of their peoples and thedevelopmentof theireconomies.
Ninety per cent of the inhabitants ofthe Commonwealth live in areasaffected by malaria. They also representtwo-thirds of the global population atrisk from a parasite that still claimsmore than 440,000 lives each year,despite significant progress since thestartof themillennium.
Yet aside from the UK, Australia andCanada, few Commonwealth countriesare net donors in efforts to tackle whatremains one of the world’s leading infec-tious killers. This is despite the fact thattwo of the richer emerging economies inthe grouping, Nigeria and India,
accounted for 27 per cent and 6 per centrespectively of global malaria cases in2016, according the WHO’s WorldMalariaReport2017.
“The story over the past 20 years hasbeenoneofsuccessduringwhichwehavesaved 7m lives,” says Kesete Admasu,head of the Roll Back Malaria partner-ship, which brings governments togetherwith the private sector and other organi-sations tackling the disease. “But we areat a critical juncture. We have the oppor-tunity to accelerate progress but werequire significant investment. Themajority today is financed by externalresources. This is not sustainable. Coun-triesneedtostepup.”
Pedro Alonso, head of the GlobalMalaria Programme at the WorldHealth Organization, highlights therecent “golden period”, with countriesincluding China, Paraguay and Algeriamoving towards elimination andaround 20 others getting close. Yet, witha few exceptions, progress has been tooslow in countries with a higher burdenofmalaria.
“We need political commitment tobring back attention to the problemand a translation of that commitment into budget lines,” he says. “For thereto be meetings of leaders who issue a
statement is useful, but what reallychangesthings isactionandfinance.”
Investment in new tools should be apriority. Compared with many otherdiseases, malaria has relativelyeffective and cheap prevention and
treatment tools in insecticides, diagnos-ticsanddrugs.
But David Reddy, head of the Medi-cines for Malaria Venture, a non-profitpartnership between academics, thepublic sector and pharmaceutical
companies to develop new treatments,isnervous.
“I didn’t think I would be fightingresistance on three fronts,” he says.First, there are widespread signs thatmosquitoes — the so-called vector thattransmits malaria between humans —are proving resistant to insecticidessprayed or integrated into bed nets. Sec-ond, the parasites mosquitoes transmitthat cause malaria are showing growingresistance to even the best drugs. Thirdand less expected, some strains haveadapted so they can no longer be identi-fiedbydiagnostic tools.
As a result, scientists are calling forrenewed support for research anddevelopment including prototypemalaria vaccines, new generations ofinsecticides and the genetic modifica-tion of mosquitoes designed to kill themor prevent transmission. Mr Reddy isalso working on new efforts to expandthepipelineofexperimentaldrugs.
Sir Nicholas White, professor of tropi-cal medicine at Oxford university, whofocuses on south-east Asia, adds afourth type of resistance to progressagainst malaria: humans. “Therereally isn’t the political will or leader-ship,” he says. “People are happy justto carry on carrying on. We haven’t
provided suitable incentives forelimination.” He would like to seegreater transparency of data and pro-grammes,andtougheraccountability.
Dr Kesete argues for the need toinclude the private sector more exten-sively and to shift government responsi-bilities from health departments tofinance ministries and public sectoragencies responsible for agriculture,housing, transportandeducation.
Brian Greenwood from the LondonSchool of Hygiene and Tropical Medi-cine says: “There has been incredibleprogress, and the money from political
leaders has saved many lives. But weneed to keep going, get coverage higherand maintain investment to find newapproaches. We know from past experi-ence that malaria comes back as soon asyoutakeyourfootoff thepedal.”
Treatment for malaria has improvedsubstantially in recent years but onegroup continues to represent a chal-lengeforphysiciansandhealthsystems.
In parts of the world where malaria ismost prevalent there is also a far aboveaverage incidence of HIV infection, andthe coexistence of the two conditionsraises particular questions about how tomanagethediseasessimultaneously.
The World Health Organization lastyear estimated that combined malariaand HIV causes more than 2m deathseachyear.
It said that additional research wouldbe needed “to investigate the impact ofmalaria on the natural history of HIV,potential therapeutic implications,interactions at a cellular and molecularlevel and drug interactions betweenantiretroviral and antimalarial medi-cines”.
Anthony Fauci, who for more than 30years has been the director of the US-based National Institute for Allergyand Infectious Diseases, says thequestion goes well beyond asking howmedications that one might take formalaria might interact with treatmentsthathelpcounter infectionwithHIV.
“It’s really more of a rather significantpublic health issue because of the co-existence, geographically, of the highdensityofHIVinfection inregionsof theworld, particularly in sub-SaharanAfrica, that have the highest densities ofmalaria, particularly Plasmodium falci-parum”, which is the deadliest malaria-causingparasite forhumans.
It has been known for years, he says,that even though the HIV virus sup-presses the body’s immune system, thevirus also replicates much more easilywhen the immune system is fired up oractivated by, for example, anotherinfection.
One of the most significant activatorsof the immune system is a bout ofmalaria and acute parasitaemia, hesays.
“If you have someone who is beingwell-maintained on antiretroviral ther-apy and all of a sudden, they get a boutof malaria, invariably you will see a blipor a transient increase in their viralload,”headds.
Care must be taken, however, beforemaking a major change in a patient’santiretroviral therapy in those circum-stances,hewarns.
He says the ill health caused bythis interaction between the malaria-challenged immune system and the HIV
virus is more important than any possi-ble interaction between drugs thatmightbeprescribedforbothconditions.
For certain groups of people the dan-gers of co-infection are even higher thanforthegeneralpopulation.
The WHO has highlighted the partic-ular problems faced by pregnantwomen when they become dual-in-fected with malaria and HIV. Last yearthe organisation warned that HIV-in-fected pregnant women who becameinfected with malaria were “atincreased risk of all the adverse out-comes of malaria in pregnancy”. Thisco-infected group of mothers-to-be was“more likely to have symptomaticmalaria infections, anaemia, placentalmalaria infection and low birth weight”,it said.
Dr Fauci says: “We know from dec-ades of experience that malaria duringpregnancy is a very serious issue, evenintheabsenceofHIV.”
A woman who is infected withmalaria, but not HIV, “generally has areasonably good immune system,except that during pregnancy . . . theimmune system is temporarily sup-pressed so that the mother doesn’treject the baby. So, normally, pregnantwomen are physiologically immuno-suppressedanyway.”
If she is also HIV infected, however,“she has a double whammy and adouble risk there, because notonly is her immune system suppressedtemporarily because she’s pregnant,but her immune system is deficientbecause she’s HIV infected, andthat’s the reason why HIV-infectedpregnant women who also get malariahave an increased incidence of adverseevents”.
The WHO notes that, although HIV-related immuno-suppression has been shown to be associated with increasedtreatment failure rates for malaria, “atpresent there is insufficient informationtomodifythegeneralmalaria treatmentrecommendations for patients withHIV/Aids”.
In addition to these concerns, DavidMabey, professor of communicable dis-eases at the London School of Hygieneand Tropical Medicine, argues thatanother infection is now having agreater impact on treatment for malariathanHIV:salmonella.
While the condition normally causesnothing worse than a bout of diarrhoea,or even no symptoms at all, “if youhave malaria, it’s much more likely toinvade your bloodstream, and makeyouverysick”.
HIV and malariacombine to createa lethal cocktailDual infection
The coexistence of bothdiseases is responsible for2m deaths each year,writes Sarah Neville
Political clout will help fight killer disease
Prime minister Narendra Modi: malaria exacts a heavy toll in India — Getty Images
Anthony Fauci: the diseases areprevalent in the same countries
‘At present, there isinsufficient information tomodify general treatmentrecommendations forpatients with HIV/Aids’
FundingMalaria will rebound ifgovernments do notinvest in new tools,writes Andrew Jack
‘We know from pastexperience that malariacomes back as soon as youtake your foot off the pedal’
W hen Cecilia Stali’s nine-year-old son fell sickwith fever in Sikombwain early April and wasdiagnosed with malaria,
therewasaquickresponse.Rudia Mundia, a volunteer commu-
nity health worker, made her way to thedusty farming village in southern Zam-bia by bicycle and began asking the 31people who lived within a 140m radiusof Ms Stali’s hut for permission to take asample of their blood for a rapid diag-nostic test.
The technique, known as “active casedetection”, is designed to stamp out anyfurther spread of the disease by offeringrapid treatment. It highlights both thedetermination and the difficulties onthe frontline of Zambia’s ambitiousefforts not just to control but to elimi-natemalariaby2021.
Ms Mundia is one of 8,000 volunteercommunity health workers in the coun-try who receive in compensation onlyan orange T-shirt, a pen, a bicycle to getaround and modest phone credits tosendinreportsof theiractivities.
Every week, she and other volunteersin Kazungula district offer anyone withsuspected malaria a test that is ready in15 minutes and a free three-day drugtreatment programme for anyone whotestspositive.
Periodically, they also help distributeinsecticide-treated bed nets, train peo-ple how to use them and inspect theirhouses and nearby to try to preventabuse — there have been instances ofnets being used for fishing, as fencingfor hen coops and even as weddingdresses.
The volunteers’ efforts are one in aseries of innovations implemented inZambia. The country was one of the firstin southern Africa to adopt newer, moreeffective, but costlier drugs. It co-oper-
ated with foreign organisations to con-duct a first survey of malaria practicesin 2006, and has followed up every twotothreeyears.
More recently, it has set still moreambitious goals. Last year, Zambiarebranded its National Malaria ControlCentre, renaming it the NationalMalaria Elimination Centre to under-line its commitment to eradicate thedisease.
Zambia last year stepped up itsannual domestic funding of anti-ma-laria initiatives from$8mto$25m.
Chitalu Chilufya, minister of health,says: “We have an inescapable duty toeliminate malaria for a healthy Zambia.It is a huge public health challengeclaiming thousands of lives. Thenumber of hours we lose in productivityandofstudylost inschools ishuge.”
Elizabeth Chizema, head of theNational Malaria Elimination Pro-gramme, talks about the initiatives sheis overseeing including the collectionand surveillance of mosquitoes, geneticanalysis of parasites, and testing of larv-icides, repellents, insecticide-treated“sugar traps”, ceiling meshes, wall
paints and innovative bed net designs.Two years ago, Zambia began usingmass drug administration to tacklemalaria in infectionhotspots.
She says she is actively seeking toempower local government malariaofficials, and has strengthened co-oper-ation with non-governmental groupsandforeignorganisations.
Yet moving from control to elimina-tion will not prove easy. The 2021 goal is“beyond ambitious”, according to oneregional expert. The southern part ofZambiahasprogressedsignificantly,butofficials had to step up their responseafteraresurgenceofcases in2016.
Many of the more inaccessible ruralzones there and in other parts of thecountry remain hotspots. Even in low-prevalence areas such as Kazungula,staffwillneedtoremainvigilant.
Zambia’s southern neighboursNamibia and Botswana are fellow mem-bers of the regional malaria Elimination8 network of nations and have relativelylittleof thedisease.
However, Zambia also borders thehigh-burden countries of Angola,Mozambique and Democratic Republic
of Congo, which are making far lessprogress.
At the voluntary malaria diagnosticcheckpoints in Kazungula andnearby Livingstone, along theborder with Zimbabwe, there havebeen more “imported” than“exported” cases detected in the pastfewmonths.
Failure toreachZambia’sownself-im-posed target within the next three yearscould be a setback, breeding frustrationor fatalism. Yet the government is beinghelped by fresh momentum from com-munity leaders. Bishop David Njovufrom the Anglican church in Lusaka hasactively encouraged his priests topreach the importance of malaria pre-vention in sermons and is mobilisingChristian congregations to help, withsupport in turn from groups includingtheIsdell-FlowersFoundation intheUS.
Asked whether he believes the targetof 2021 is achievable, he replies: “We aremaking strides. It may not be realistic.Zambia is huge and we are surrounded.But there is a determination and I’drather have something to look forwardtoandfocuson.”
Zambia’s aim is ‘beyond ambitious’MobilisationThe country has givenitself until 2021 to getrid of the disease,despite a resurgence in2016, writes Andrew Jack
I n 2010, just over a third of sus-pected cases of malaria in the pub-lic health sector in Africa were sub-ject to diagnostic testing, accordingto the World Health Organization.
Six years later, that had risen to nearlynine in10.
The huge growth in the use of suchtests is thanks largely to developmentsin the production of rapid diagnostictests, or RDTs. These allow health work-ers and volunteers in the field to quicklyassess whether a patient has malariausing a small blood sample. Accordingto the WHO, an estimated 312m RDTswere delivered across the world in 2016—nearlyallatacostof less than$1atest.
But thedemandforRDTscontinuestooutstrip supply. Microscopy — the tradi-tional way of inspecting blood samplesfor parasites by looking at them under amicroscope — is largely seen as tooexpensiveandtime-consuming.
Unitaid, a global health non-profitbased in Geneva, has estimated thatmore than 1bn diagnostic tests areneeded to diagnose patients with feversacross theworldeachyear.
“Our main priority is to try to developor support the development of moresensitive tests,” says Gonzalo Domingo,malaria diagnostics portfolio lead at
Path, a Seattle-based global healthorganisation. He explains that individu-als can often be infected with such lowlevels of malaria-causing parasites thatwhile they can transmit it their infec-tionscannotbedetectedbymostRDTs.
Progress is being made, and DrDomingo points to a product launchedby Alere, a US medical device companythat was bought by rival Abbott lastyear. He says the product improves thedetection of the HRP2 protein that ispresent in malaria-infected blood by an“orderofmagnitude”.
The test targets malaria caused byPlasmodium falciparum, the most prev-alent and most deadly type of the dis-ease and the dominant variant in Africa.But most RDTs cannot detect malariacases caused by Plasmodium vivax, thesecond-most common type of the dis-ease that is usually found in SouthAmerica — and none can directly detectparasites that live in the liver, ratherthanthebloodstream.
“Half of the malaria cases are outsideof Africa,” said Xavier Ding, leader ofthe malaria team at Find, a global healthnon-profit based in Geneva. “If youwant to have the chance to eliminatemalaria, you need to develop specifictools for thatspecies.”
More sensitive rapid tests are alsoneeded to diagnose malaria in pregnantwomen, who are at higher risk of con-tractingthedisease.
While most researchers continue toevaluate ways of diagnosing malariathrough blood samples, Mr Ding and hiscolleagues are also exploring whetherthe disease can be detected with lessinvasivetestsonurineorsalivasamples.
“If you could use an RDT where youcan take a saliva sample, that wouldincrease the probability of testing formalaria,” said Sabine Dittrich, head ofFind’smalariaandfeverprogramme.
Meanwhile, other researchers arerevisiting microscopy and exploringDNA testing and artificial intelligencetechniques in an effort to improve theaccuracyandspeedof tests.
QuantuMDx, a biotechnology com-pany based in Newcastle in the UK, isworking on a tool to identify the malariaparasite DNA in blood samples. Thecompany is also testing a product thatwould detect malaria parasites in bloodsamplesusingelectric fields.
Global Good, a Seattle-based tie-upbetween Bill Gates and Nathan Myhr-vold, founder of Intellectual Ventures,an invention investment company, islooking at “automated microscopy”,using AI and machine learning. DavidBell, who leads the global health tech-nologies portfolio at Global Good, saysthegoal is tomaketheanalysis“assensi-tive as an expert human” and “maintainthat quality” to make microscopy moreefficientandlessexpensive.
Keeping costs down is one of the big-gest challenges facing researchers, espe-cially in a market where RDTs can besoldforas littleas30centseach.
“We have a real problem at themoment with malaria in the sense thatwe know what the problem is, we knowhow to treat it, we understand the biol-ogy but the economics don’t match upwith the technicalities that we need todo in terms of the diagnostics,” saysJonathan O’Halloran, chief scientificofficer at QuantuMDx. “We want to takethe lab to the patient, not the patient tothe lab.”
Demand forgood, rapidtests outstripssupplyDiagnostics Developersare prioritisingincreased sensitivityand low costs in thequest for new solutions,says Lauren Fedor
Vital: patients are tested for malaria in the Democratic Republic of Congo — Alamy
A vaccine against malaria could be avital new tool in the fight against thedebilitating illness.
But before the first children areimmunised in the world’s first large-scale trial of RTS,S — the candidatevaccinethat is furthestalong indevelop-ment — a broad grouping of scientists,clinicians, governments, donors andthe private sector must finish navigat-ing a complex and delicate planningprocess.
It is a process that has already faceddelays. In 2011, some hoped that RTS,Scouldbe licensedandrolledoutby2015.In April last year, it was announced thata three-country pilot, in Ghana, KenyaandMalawi,would launchin2018.
Now, cautious projections suggestthat the large-scale pilot of RTS,S — orMosquirix as it is also known — willbegin in at least one of those countriesbefore the end of the year, although it isnotclearwhichonemightbefirst.
“We may have been over-optimisticwith the timelines,” says David Schel-lenberg, scientific adviser to the WorldHealth Organization’s Global MalariaProgramme.
“We have to keep pushing — everymonth that there is a delay, that’s amonth delay in the time that kids canstartbenefiting fromthevaccine.”
The national health authorities inKenya, Malawi and Ghana will be incharge of the implementation. An esti-mated 120,000 children will be vacci-nated ineachcountryeveryyear.
The pilot countries were chosen inpart for their well-functioning immuni-sation systems. But rollout logistics aredemanding given the volumes. The pilotwill demand hundreds of thousands ofvaccination cards and a temperature-controlled supply chain to handle themulti-dosevaccine.
Monitoring and evaluation of thevaccine are essential — health workershave to be trained to identify and ana-lyseanyadversereactions.
“All the parallel streams have to beready at the same time, and that’s wherethe complexity lies,” adds Dr Schellen-berg. “You want to deploy as soon aspossible but you have to balance thatagainst therealneedtohavethesystemstomonitorandimplementthevaccine.”
Funding isalsoabalancingact.GSK, the pharmaceutical company
that did the early clinical developmentof the vaccine in the 1980s, entered intoa public-private partnership with thePath Malaria Vaccine Initiative withfunding from the Bill & Melinda GatesFoundation. The partnership is donat-ingupto10mdosesof thevaccine.
“Companies usually work on vaccinesthat are associated with high profit, sothey can recoup development costs,”explains Ashley Birkett, who heads thePathMalariaVaccineInitiative.
The Bill & Melinda Gates Foundationhas played a significant supporting role,whileotherpartners—Gavi, theVaccine
Alliance, the Global Fund to Fight Aids,Tuberculosis and Malaria, and Unitaid— are helping to cover the estimated$49.2mcostof thefirstphase.
Despite the delays, the work towardsgetting ready for the vaccine rollout isalready adding value, health executivessay. “The process is helping usstrengthen our systems,” says RebeccaKiptui, who is working on the pilot forKenya’s National Malaria Control Pro-gramme. “As the ministry of health, weare strengthening our pharmacovigi-lance [tracking reactions to treatment]for all vaccines. It’s helping Kenyanresearchers.”
“It does feel like we’re in a super-tanker trying to get it out of the har-bour,” says Dr Schellenberg. “But itreally isgatheringmomentum.”
Vaccine pilot steerspast final delaysImmunisation
Health officials in Ghana,Kenya and Malawi have toget the right systems inplace, writes Zoe Flood
Health workershave to be trained:a GSK malariaresearcher inKenya examines aa sample
‘The economics don’tmatch up with what weneed to do . . . we want totake the lab to the patient’
I n Windhoek, capital of Namibia, asmall office staffed by three peopleserves as “the Situation Room”.Onceaweek,experts fromtheeightsouthern African states involved in
a joint project participate in a telecon-ference call. They discuss trends in thedata, potential outbreaks of trouble andpossibleemergencyaction.
They work for “Elimination8”, thename given to Africa’s first regionallyco-ordinatedeffort totacklemalaria.
In 1998, the African island of Mauri-tius put an end to a disease that still killsmore than 400,000 people every yearworldwide, the vast bulk in Africa. Butin the two decades since then, no coun-try in sub-Saharan Africa has matchedthat feat. Now, there is an ambitiouseffort to make up for lost time by elimi-nating malaria in not just one country,but ineight.
Elimination — sometimes confusedwith eradication — means ending localtransmission of the disease, thougheven when that is achieved some infec-tions may still be “imported” by travel-lers or migrant workers. (Eradicationsignifies ending all cases of malariaworldwide, a milepost that would meanthe battle against the disease had beenwon.)
Under the Elimination8 plan, the ideais to end malaria by 2020 in four so-called frontline states where transmis-sionlevelsarealreadylow—below10per1,000. These are Botswana, Namibia,South Africa and Swaziland. Four high-er-transmission, “second line” countries— Angola, Mozambique, Zambia andZimbabwe,wheretransmissionratescanclimb as high as 400 per thousand —haveuntil2030toget the jobdone.
The data collection and planningthat go on in the Situation Room sound,on the face of it, pretty routine. But,says Kudzai Makomva, a member ofthe secretariat, the data-sharing isgroundbreaking in many ways. “Getting
countries to part with sensitive countrydata for wider sharing for everyone’sbenefit is politically very challenging,”she says. “It has been one of the greatestchallenges of the partnership, but alsoone of the best stories of turnaroundand success, because this is really com-ingtogethernow.”
It makes sense to try to combat thedisease on a regional basis, says KevinMarsh, professor of tropical medicine atOxford university and an expert onmalaria.
Neither mosquitoes nor potentialhuman carriers of the disease, such asmigrant workers, recognise borders.Best practice — and even diagnosticequipment — in one country can beshared with others, improving both effi-cacyandprovidingeconomiesofscale.
“Cross-border surveillance is key,”says Prof Marsh, adding that eradica-tion efforts can be set back if malariacreeps across the border from a countrythat has not been able to control the dis-easeaseffectively.
Working regionally, he says, is also agood way of galvanising political willbecause it can turn co-operation intocompetition. “Heads of state have ascorecard,” he says. Leaders hate beingoutshone by their counterparts inneighbouring countries. “It sounds triv-ialbut it is surprisinglyeffective.”
Ms Makomva says cross-border co-operation can change priorities. Shecites the example of Angola, a high-transmission country with a stretchedhealth system. Understandably,she says, Angolan health authorities
Bold target of elimination is still within sightRegional pledgeDespite outbreaks,some progress hasbeen made, writesDavid Pilling
ZAMBIA
BOTSWANA
SOUTHAFRICA
ZIMBABWE
SWAZILAND
NAMIBIA
ANGOLA
MOZ
AMBIQUE
LESOTHO
FT graphic Source: Elimination8 annual report, 2017 * The four so-called frontline states have pledged to end malaria by 2020 ** Second line countries have until 2030 to eliminate malaria
Elimination8 - southern Africa’s regional plan to tackle malaria
Frontline countries*Second line countries**
Elimination8 countries
Malaria incidence rate
Second line member states
Number of cases per 1,000 population
0
100
200
300
400
2013 16
Zambia
0
100
200
300
400
2013 16
Mozambique
0
100
200
300
400
2013 16
Angola
0
100
200
300
400
2013 16
Zimbabwe
Frontline member states
0
2
4
6
8
10
2013 16
Namibia
0
2
4
6
8
10
2013 16
Swaziland
0
2
4
6
8
10
2013 16
South Africa
0
2
4
6
8
10
2013 16
Botswana
‘The year 2017 has been awake-up call . . . theelimination goals of 2020are at great peril’
concentrate their efforts on the north ofthe country, where the incidence ofmalaria is much higher. But that leavesthe south, which borders Namibia, rela-tivelyunattended.
“We say, ‘Look Angola. We under-stand the decisions you are taking, but itwould be good if Angola could put someresources in the southern part of thecountry.’ It means focusing on areas thathave a regional impact, as opposed tojustanational impact.”
Ms Makomva says the project, whichonly properly got going with the forma-tion of the secretariat in 2015, was setback initially by a number of outbreaksin several of the countries. So instead ofmaking progress, the number of deathsandtransmissionsactuallyrose.
“The year 2017 has been a wake-upcall for the Elimination8 as the elimina-tiongoalsof2020areatgreatperil,”saysthe project’s annual report, published inMarch 2018. “With only three years togo until 2020, the collective strategy tozero local malaria transmission needs tobe revisited to accelerate makingprogress in ‘bending the curve’ and toremake the lost gains as a result of seri-ousoutbreaks.”
But a review by the Global Fund,which is providing a three-year grantworth $6.5m to the project, has foundsome promising signs. One of the signifi-cant achievements has been the estab-lishmentof46“malariaposts” inunder-served border areas between the coun-tries.
The posts, according to the project’sown assessment, have increased the“ability to identify infections andhotspots of transmission . . . minimis-ing the risk of the outbreaks witnessedin2016/17.”
One problem with elimination drives,says Prof Marsh, is that if they fail, polit-ical will can quickly evaporate. That iswhy only realistic targets should be set.On the other hand, he says, aiming foroutright elimination makes sense sinceanythingshortof thatmeans thediseasewill bounce back, requiring a freshroundof funding.
Ms Makomva says of the eliminationdrive: “It is bold and ambitious. It wouldbe the first elimination by a mainlandcountry in sub-Saharan Africa. We arestillverycommittedtothisgoal.”
