Pos­i­tive think­ing win­ning HIV bat­tle

Treat­ment for peo­ple with the AIDS virus is about to make its big­gest leap in at least a decade. Science writer Leigh Day­ton re­ports

The Weekend Australian - Travel - - Health -

HIV with the heal­ing power of blood stem cells.

So far, the method in­volves re­mov­ing HIV-in­fected stem cells from a pa­tient’s bone mar­row, grow­ing new ver­sions tweaked to fight HIV, and then re­turn­ing the re­jigged cells to the pa­tient. ‘‘ As long as th­ese cells per­sist in the pa­tient we will have re­sis­tance to HIV in­fec­tion, with the goal that there would be re­duced vi­ral load,’’ said Rossi, who be­lieves the treat­ment could even­tu­ally be given as a shot or pill and com­bined with con­ven­tional treat­ment.Mean­while, sci­en­tists such as Perth-based Si­mon Mal­lal are giv­ing older drugs a new lease on life. On Wed­nes­day he an­nounced that by us­ing high-tech DNA screen­ing tech­niques, he and his col­leagues at the new $20 mil­lion In­sti­tute for Im­munol­ogy and In­fec­tious Dis­eases, to be built at Mur­doch Univer­sity, have de­vel­oped and tri­alled a test to de­ter­mine if a pa­tient will de­velop lifethreat­en­ing re­ac­tions to aba­cavir, a drug sold un­der the brand name Zi­a­gen, and as com­bi­na­tion pills that com­bine it with AZT or other drugs (one such com­bi­na­tion pill be­ing Trizivir).

‘‘ We’ve en­tered the era of per­son­alised medicine,’’ says Mal­lal.

As Fauci’s long-lived pa­tients at­test, all th­ese ad­vances in HIV re­search are work­ing. In fact, treat­ment is so suc­cess­ful that at the con­fer­ence Bri­tish ex­pert Brian Gaz­zard raised a new co­nun­drum fac­ing HIV clin­i­cians: geri­atric AIDS.

Ac­cord­ing to Gaz­zard, chair­man of the Bri­tish HIV As­so­ci­a­tion, it’s be­com­ing clear that HIV in­fec­tion in­creases the risk of suf­fer­ing any of the geri­atric gi­ants’’: heart dis­ease, de­men­tia and can­cers. What’s more, in­creas­ing num­bers of peo­ple are be­com­ing in­fected with HIV later in life.

Re­search has also re­vealed that HIV in­fec­tion is the cause of se­ri­ous or­gan dam­age that, un­til now, was blamed on the toxic ef­fect of anti-retro­vi­ral cock­tails. The find­ing has trig­gered a sci­en­tific re­think of when HIV peo­ple should be­gin drug ther­apy.

Usu­ally, pa­tients don’t start ther­apy un­til the level in their blood of a type of im­mune cell called CD4 cells drops be­low a cer­tain point. Fauci says ex­perts now want to con­duct tri­als to test the emerg­ing no­tion that ear­lier treat­ment is bet­ter.

He also wants more data on an­other treat­ment ques­tion: to treat or not to treat.

I’ve been con­vinced as the years go by that you many not nec­es­sar­ily treat some­one who has a triv­ial level of virus and whose CD4 count is re­ally very good,’’ he ob­serves.

Af­ter all, a triv­ial’’ level of HIV is the goal of re­searchers strug­gling to de­sign a vac­cine against HIV. A vac­cine, says John Kal­dor, is the holy grail of HIV pre­ven­tion.

From the very early days of HIV we’ve been hunt­ing for a vac­cine,’’ he says. But a vac­cine is con­sid­ered a huge (sci­en­tific) prob­lem and will be one for a long time.’’

HIV lab­o­ra­to­ries around the world are hum­ming. New dis­cov­er­ies and treat­ments are tum­bling out of the re­search pipe­line at a re­mark­able pace, one that prom­ises HIV pa­tients a longer, health­ier life. This, for a dis­ease that was a death sen­tence when it was first iden­ti­fied 26 years ago.

Lit­tle won­der that when nearly 6000 ex­perts on HIV and AIDS from 133 na­tions gath­ered in Syd­ney this week for the fourth In­ter­na­tional AIDS So­ci­ety Con­fer­ence on HIV Patho­gen­e­sis, Treat­ment and Pre­ven­tion, they buzzed.

‘‘ This is an enor­mously ex­cit­ing time,’’ says John Kal­dor, deputy di­rec­tor of the Na­tional Cen­tre in HIV Epi­demi­ol­ogy and Clin­i­cal Re­search at the Univer­sity of NSW.

‘‘ Over the past two years peo­ple have made strik­ing im­prove­ments in ther­apy, es­pe­cially for peo­ple in whom sev­eral reg­i­mens have al­ready failed. Peo­ple have also made sig­nif­i­cant de­vel­op­ments in what are con­sid­ered bio­med­i­cal tools — like mi­cro­bi­cides — to help break the cy­cle of trans­mis­sion.’’

Much, too, has been learned about how the in­sid­i­ous hu­man im­mun­od­e­fi­ciency virus in­fects its vic­tims, wreaks such dam­age and is so hard to beat. Ac­cord­ing to long-time HIVAIDS re­searcher An­thony Fauci, di­rec­tor of the US Na­tional In­sti­tute of Al­lergy and In­fec­tious Dis­eases in Bethesda, Mary­land, new in­sights into the mech­a­nisms by which HIV harms hu­mans have un­der­pinned de­vel­op­ment of over 25 anti-HIV drugs.

‘‘ Th­ese med­i­ca­tions have had an enor­mous im­pact in re­duc­ing mor­tal­ity wher­ever they have been used,’’ says Fauci who, as a clin­i­cally and sci­en­tif­i­cally trained in­fec­tious dis­eases and im­munol­ogy spe­cial­ist, was one of the first ex­perts in the world to see, treat and at­tempt to un­ravel HIV in­fec­tion.

‘‘ Pa­tients I fol­lowed 25 years ago would die within months of get­ting se­ri­ously ill. Now I’m fol­low­ing pa­tients for 10, 15 years. They’re do­ing just fine. The tri­umph has been great.’’

En­tire new classes of drugs prom­ise to keep the tri­umphs com­ing, par­tic­u­larly for pa­tients who are de­vel­op­ing re­sis­tance to the var­i­ous com­bi­na­tions of ex­ist­ing drugs. To the out­sider they sound baf­fling, but th­ese classes — in­te­grase in­hibitors, fu­sion in­hibitors, CCR5 an­tag­o­nists and mat­u­ra­tion in­hibitors — prom­ise to bring the big­gest im­prove­ment in HIV treat­ment since the dis­cov­ery in the mid-1990s that com­bined drug treat­ment, called Highly Ac­tive Anti-Retro­vi­ral Ther­apy (HAART), greatly im­proved vi­ral sup­pres­sion.

To get a feel for what such drugs are and do, it’s nec­es­sary to un­der­stand why HIV is such a knotty sci­en­tific prob­lem. Firstly, as Fauci ex­plains, it at­tacks the im­mune sys­tem: ‘‘ Vir­tu­ally all of the viruses that have been scourges of mankind — or even viruses that have been triv­ial — are viruses that come in and af­fect the lung, or the skin, or the brain, or the gas­troin­testi­nal tract and the im­mune sys­tem is in­tact and is able to fight the par­tic­u­lar virus,’’ he says.

Not so HIV. It tar­gets the im­mune sys­tem it­self, per­versely de­stroy­ing the very mech­a­nism the body en­trusts with its own defence. More­over, it’s a retro­virus, a virus that has the abil­ity to in­sert it­self di­rectly into its vic­tim’s ge­netic ma­te­rial. It can hide out there. HIV also repli­cates quickly. That quick turnover en­ables the virus to mu­tate, to change its ap­pear­ance so fast that even when it does stick its vi­ral head over the para­pet, the im­mune sys­tem can­not ef­fec­tively re­spond.

It’s a triple whammy. HIV in­fects the im­mune sys­tem. It’s a retro­virus. It mu­tates rapidly. ‘‘ You put those three things to­gether and you have a real prob­lem,’’ Fauci con­cludes.

Still, re­searchers did tar­get the cul­prit and have built weapons to fight it. The first an­tiHIV drug, AZT, was li­censed in 1987, and works by in­hibit­ing the HIV en­zyme re­verse tran­scrip­tase which the virus uses to con­vert its sin­gle strand of RNA into dou­ble-stranded DNA, a nec­es­sary first step prior to splic­ing it­self into the host cell’s genome.

AZT was hailed as a won­der drug, but the eu­pho­ria soon faded when it be­came ap­par­ent that HIV’s high rate of mu­ta­tion quickly al­lowed re­sis­tance to the drug to de­velop.

Later, other ‘‘ anti-retro­vi­ral’’ drugs were de­vel­oped, and th­ese are gen­er­ally now com­bined into triple or even quadru­ple drug cock­tails to pre­vent drug re­sis­tance de­vel­op­ing. Among the most suc­cess­ful an­tiretro­vi­rals now are Lamivu­dine, Viread and Zi­a­gen.

US in­fec­tious dis­eases spe­cial­ist Joseph Eron says the most ex­cit­ing prospects among the new drugs about to be­come avail­able are in­te­grase in­hibitors. Th­ese work by block­ing an­other en­zyme, in­te­grase, which HIV uses to in­sert its ge­netic ma­te­rial into the host cell’s DNA. Two such drugs are in de­vel­op­ment and one, ral­te­gravir, is al­ready avail­able on a trial ba­sis in Aus­tralia.

More are on the way. Last week sev­eral biotech com­pa­nies re­ported on lab­o­ra­tory, or early tri­als of even newer drugs. ‘‘ There is now an op­por­tu­nity for even our most treat­ment-ex­pe­ri­enced (re­sis­tant) pa­tients to get their vi­ral load (down) to un­de­tectable lev­els,’’ claims Eron, from the Univer­sity of North Carolina. He pre­dicts some of th­ese drugs will be op­tions for first-line ther­apy.

South­ern Cal­i­for­nia-based molec­u­lar bi­ol­o­gist John Rossi goes fur­ther. Last week his group at the City of Hope Beck­man Re­search In­sti­tute be­gan the first of two tri­als of a treat­ment com­bin­ing ge­net­i­cally en­gi­neered

Pic­ture: Alan Pryke

Ex­cit­ing times: John Kal­dor says amaz­ing leaps in treat­ments have come over the last two years

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