HIV – a new hori­zon

HIV mu­tates 4 000 times faster than most viruses, evolv­ing and re­pro­duc­ing it­self at a re­lent­less pace. As a re­sult, treat­ments that may have been ef­fec­tive against the orig­i­nal virus be­come in­ef­fec­tive, cre­at­ing drug resistance. RISKSA looks at a ground-

RISKSA Magazine - - CONTENTS - Sarah Bas­sett

Ac­cord­ing to the World Health Or­gan­i­sa­tion ( WHO), nearly one in ev­ery 20 adults in sub- Sa­ha­ran Africa lives with HIV. There are be­tween five and six mil­lion HIV- pos­i­tive in­di­vid­u­als in South Africa alone. Cur­rently, pa­tients are given a first line of ARV treat­ment. If this fails, the pa­tient is moved on to sec­ond­line treat­ment. If this treat­ment fails, there are cer­tain third line treat­ments pos­si­ble, but this is where govern­ment fund­ing and a lot of med­i­cal aid fund­ing will stop. WHO pro­to­col re­quires that ev­ery per­son re­ceiv­ing an­tiretro­vi­ral treat­ment should be tested for drug resistance. How­ever, in the ma­jor­ity of de­vel­op­ing, re­source- limited coun­tries, in­clud­ing South Africa, this is not the case. Such testing is ex­pen­sive and lo­gis­ti­cally in­ten­sive. Re­searchers from the Univer­sity of the Western Cape’s ( UWC) South African Bioin­for­mat­ics In­sti­tute ( SANBI) have spent two and a half years de­vel­op­ing a soft­ware tool to dra­mat­i­cally speed this process, re­duce costs and sim­plify the lo­gis­tics re­quired.

The drug resistance prob­lem

“There are mul­ti­ple ge­netic vari­ants of HIV. Each one can be re­sis­tant to dif­fer­ent drugs and each one re­sponds bet­ter or worse to dif­fer­ent treat­ments,” ex­plains Imo­gen Wright, PhD can­di­date and re­searcher on the project. For this rea­son, over the course of a hu­man life, al­most ev­ery pa­tient re­ceiv­ing ARV treat­ment will de­velop some form of resistance, but the amount of time taken to build up resistance varies be­tween pa­tients. Once resistance de­vel­ops, pa­tients progress from HIV pos­i­tive to full- blown Aids cases. “For some, the strain they are ini­tially infected with, is al­ready re­sis­tant and their treat­ment will im­me­di­ately fail as a re­sult.” Wright’s back­ground is com­puter science and physics, but the in­ter­dis­ci­pli­nary field of bioin­for­mat­ics, which uses a com­bi­na­tion of com­puter science, math­e­mat­ics and en­gi­neer­ing to gen­er­ate use­ful in­for­ma­tion from bi­o­log­i­cal data, has al­lowed a fresh ap­pli­ca­tion of her skills. “If you give some­one a drug and they are re­sis­tant to that drug, re­search has shown that the re­sis­tant vari­ant will ex­plode in their body and be­come dom­i­nant. If they in­fect some­one else, this will be the vari­ant passed on. So, you are ac­tu­ally prop­a­gat­ing drug resistance when you give some­one a drug and they are re­sis­tant to it,” she ex­plains. Ac­cord­ing to the WHO's global strategy for preven­tion and assess­ment of HIV drug resistance, the con­se­quences of drug resistance in­clude treat­ment fail­ure, in­creased di­rect and in­di­rect health costs as­so­ci­ated with the need

to start more costly se­cond- line treat­ment for pa­tients, the spread of re­sis­tant strains of HIV and the need to de­velop new HIV drugs. Since the roll­out of an­tiretro­vi­ral treat­ment in South Africa be­gan in 2004, HIV mor­tal­ity rates have de­creased sub­stan­tially. Once seen as an im­me­di­ate death sen­tence, the dis­course around HIV in the in­sur­ance and med­i­cal man­age­ment con­text is that, if man­aged prop­erly, it is no more high- risk than di­a­betes or any other chronic con­di­tion. Stud­ies in­di­cate that by not con­trol­ling the resistance as­pect, South Africa is po­ten­tially cre­at­ing a sit­u­a­tion that we will not be able to con­trol in the fu­ture.


HIV drug resistance can be tested us­ing two dif­fer­ent method­olo­gies; phe­no­typic testing, a highly ac­cu­rate but ex­pen­sive cul­ture test; or geno­typic testing, which se­quences strands of RNA from the virus to de­ter­mine resistance. For geno­typic testing, se­quenc­ing can be achieved in two ways. Tra­di­tional Sanger se­quenc­ing re­quires the man­u­ally guided se­quenc­ing of in­di­vid­ual strands of RNA. Again, while highly ac­cu­rate, this is ex­tremely ex­pen­sive and not prac­ti­cal for large- scale roll out. The se­cond ap­proach to geno­typic testing is called next- gen­er­a­tion se­quenc­ing. By us­ing com­puter tech­nol­ogy to se­quence many strands of RNA, po­ten­tially from mul­ti­ple pa­tients, at high speed, the cost of the process is re­duced sub­stan­tially. For this rea­son, there is a strong drive to use this method for wide- scale drug resistance testing. The lim­i­ta­tion with next gen­er­a­tion se­quenc­ing is that se­quenc­ing ma­chines, while fast, are er­ror prone and fre­quently se­quence with in­ac­cu­ra­cies, mak­ing re­li­able re­sults dif­fi­cult. To counter this, it is nec­es­sary to se­quence the same RNA strand thou­sands of times. It is then nec­es­sary to cross ref­er­ence the re­peated se­quenc­ing to elim­i­nate in­con­sis­ten­cies, iden­tify the cor­rect se­quence and ob­tain the ac­cu­rate re­sult. Wright and her team have built a tool to tackle this as­pect of the process. Cur­rently, the cross ref­er­enc­ing process takes days and adds con­sid­er­ably to the cost of the test. By cre­at­ing a means for the rapid cross ref­er­enc­ing through rapid math­e­mat­i­cal prob­a­bil­ity mod­el­ling, soft­ware en­ables con­sis­tent ac­cu­racy and can draw a re­sult from thou­sands of dif­fer­ent read­ings of the same se­quence in sec­onds. The tool is now ca­pa­ble of com­plet­ing this process for 48 pa­tients in less than 15 min­utes. The re­sults are re­turned in a re­port de­tail­ing if a per­son is drug re­sis­tant or not and what course of treat­ment should be im­ple­mented.

A rea­son that HIV is less of a prob­lem in First World coun­tries is that any per­son with HIV is tested for resistance.

Pre­vi­ously, each in­di­vid­ual se­quence read was sent to the HIV Drug Resistance Data­base at Stan­ford Univer­sity, where the al­go­rithm used to de­ter­mine drug resistance was first de­vel­oped, for anal­y­sis. As there are thou­sands of se­quence reads re­quired for one pa­tient, this rep­re­sented a sig­nif­i­cant bot­tle­neck in the process.

How it will op­er­ate

The tool will run as a web ser­vice, ac­ces­si­ble from any­where in the coun­try via a log- in. “The ul­ti­mate pipe- dream is to have a se­quenc­ing ma­chine avail­able to ev­ery doc­tor any­where in the coun­try. Right now ac­cess to a well- equipped lab is nec­es­sary, but re­searchers at Ox­ford Nanopore have cre­ated an ex­per­i­men­tal se­quenc­ing ma­chine on a USB flash drive, so we hope to see im­prove­ment in ac­cess soon." " The data file would then be com­pressed so that it can be sent from a low band­width con­nec­tion and up­loaded to the web ser­vice at UWC. A re­port is then gen­er­ated at UWC and re­turned with rec­om­men­da­tions for each pa­tient’s treat­ment pro­gramme,” Wright ex­plains.

The cur­rent phase

Funded by the Bill and Melinda Gates Foun­da­tion, the Depart­ment of Science and Tech­nol­ogy, the At­lantic Phi­lan­thropies and the Ger­man Aca­demic Ex­change Pro­gramme, the pipe­line, soft­ware and front- end de­vel­op­ment for the tool is com­plete. The project will now move into a wide- scale re­search and testing phase, to be im­ple­mented by hos­pi­tals and re­search teams across the coun­try, be­fore it can be used to de­ter­mine pa­tient treat­ment. Data from across the con­ti­nent will be used for the study. “We’re hop­ing to even­tu­ally black box the tech­nol­ogy and ship it out to ev­ery lab in the coun­try and let them all run it. Right now it runs on my lap­top just fine. Hope­fully that means that it can be run on a lap­top in ru­ral Malawi,” says Wright.

The im­pact

When a per­son is on the right ARV treat­ment, their viral load is fully sup­pressed and when they have no viral load, they are not con­ta­gious. “A rea­son that HIV is less of a prob­lem in First World coun­tries is that any per­son with HIV is tested for resistance and then put on, and ad­here to, the cor­rect course of treat­ment for the HIV vari­ants in their body, keep­ing their

viral load sup­pressed and thus con­tain­ing the spread of in­fec­tion,” says Wright. Be­cause there is no testing, there is lit­tle data to de­ter­mine the resistance rates in de­vel­op­ing coun­tries. Wright es­ti­mates that two to three per cent are infected with a re­sis­tant strain and that within five years of the in­cep­tion of treat­ment, 20 to 30 per cent of infected pa­tients de­velop resistance. “Ul­ti­mately, resistance will de­velop in ev­ery case. It is only a mat­ter of how long it takes,” she adds. Ac­cord­ing to the WHO, the ex­tent of HIV drug resistance re­sult­ing from re­cent ART scale- up in re­source- limited coun­tries has not sys­tem­at­i­cally been quan­ti­fied due to the lack of re­li­able data and in­for­ma­tion. “Ide­ally, this se­quenc­ing is not some­thing that would hap­pen once, it would hap­pen once ev­ery one to two years and ide­ally as soon as a pa­tient ex­pe­ri­ences a prob­lem such as a per­sis­tent ill­ness or in­fec­tion.” Given the dramatic di­rect and in­di­rect costs to the econ­omy and the im­pact on the labour force and pro­duc­tiv­ity, the po­ten­tial ben­e­fits for South Africa and the con­ti­nent as a whole are sig­nif­i­cant. For the fi­nan­cial in­dus­try, the prin­ci­pal ad­van­tages will be in cost re­duc­tions for the testing it­self, dis­abil­ity claims as­so­ci­ated with sec­ondary in­fec­tions and as­so­ci­ated with se­cond- line treat­ments and even third- line treat­ments where this is cov­ered by med­i­cal aid schemes. The cost ben­e­fits will also be felt by HIV­pos­i­tive con­sumers, notes Dr Pi­eter Coet­zer, chief med­i­cal ad­viser at San­lam Life. “It will be ben­e­fi­cial to peo­ple liv­ing with HIV to have ac­cess to reg­u­lar and af­ford­able resistance testing. It should re­duce trans­mis­sion rates of the dis­ease and in­crease the life ex­pectancy of the client. This should ul­ti­mately trans­late into cheaper pre­mi­ums for life in­sur­ance.”

Ul­ti­mately, resistance will de­velop in ev­ery case, it is only a mat­ter of how long it takes.

A home- grown so­lu­tion

Given the road South Africa has trav­elled in treat­ing and man­ag­ing HIV and Aids, it seems re­mark­able that a South African in­no­va­tion has the po­ten­tial to en­able a trans­formed ap­proach to ART pro­to­col across the de­vel­op­ing world. It is a stark and wel­come con­trast with the de­nial­ism, mis­in­for­ma­tion and in­ac­tion of the past. “I think that hope­fully the up­shot of owning the so­lu­tion is that the so­lu­tion will be free for­ever for peo­ple in this coun­try. We will never charge a govern­ment lab to use this tech­nol­ogy. It is also sig­nif­i­cant that we are the na­tion with the prob­lem." " We’re in a po­si­tion where our econ­omy is suf­fer­ing so we need to make this an eco­nomic pri­or­ity and put in the fund­ing to de­velop the pro­to­col. In the West it’s hard to make the ar­gu­ment for fund­ing be­cause the prob­lem is so much smaller and more con­tained,” Wright con­cludes.

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