Sickle-cell dis­ease treat­ment proves ef­fec­tive in Africa

Hy­drox­yurea — a cheap, e≠ec­tive and easyto-take pill — can safely be given to chil­dren

The East African - - OUTLOOK - By DON­ALD G. MCNEIL JR

Adrug that pro­tects chil­dren in wealthy coun­tries against painful and some­times lethal bouts of sickle-cell dis­ease has been proven safe for use in Africa, where the con­di­tion is far more com­mon, sci­en­tists re­ported Satur­day.

More re­search re­mains to be done, ex­perts said, but know­ing that hy­drox­yurea — a cheap, ef­fec­tive and easy-to-take pill — can safely be given to African chil­dren may save mil­lions of young­sters from ag­o­nis­ing pain and early deaths.

“I think this is go­ing to be amaz­ing,” said Dr Ifey­inwa Osunkwo, who di­rects a sickle-cell dis­ease pro­gramme in Char­lotte, North Carolina, but was not in­volved in the new study.

“There is cur­rently no treat­ment in Africa, and a lot of chil­dren die be­fore the age of five,” said Dr Osunkwo, who has treated chil­dren in the US and Nige­ria. “We’re go­ing from noth­ing to gang­busters.”

The dis­ease, in which blood cells twist them­selves into stiff semi­cir­cu­lar shapes, is caused by a ge­netic mu­ta­tion thought to have arisen in Africa about 7,000 years ago.

About 300,000 ba­bies are born with the dis­ease each year; about 75 per cent of them are in Africa, and about 1 per cent in the United States.

The con­di­tion is found through­out the Amer­i­cas and the Caribbean among descen­dants of Africans brought to the hemi­sphere by the slave trade. Sickle-cell dis­ease also is found, though less fre­quently in south­ern Europe, the Mid­dle East and In­dia.

These are also places where malaria is still en­demic or was un­til a few decades ago. Peo­ple who in­her- it one copy of the sickle-cell gene are par­tially pro­tected against malaria, which is pre­sum­ably why the mu­ta­tion has per­sisted in Africa.

But chil­dren who in­herit the gene from both par­ents are of­ten left breath­lessly weak from anaemia, prone to in­fec­tions and li­able to have crises in which their blood cells clump and jam cap­il­lar­ies in the brain, lungs and other or­gans.

The pain is of­ten so ex­cru­ci­at­ing that only opi­oids can help. Treat­ment may re­quire blood trans­fu­sions or, in wealthy coun­tries, bone mar­row trans­plants, which them­selves carry a risk of death.

With­out treat­ment, many chil­dren die from strokes or or­gan da­m­age.

Hy­drox­yurea has been used for decades in the US and Europe. But some early an­i­mal stud­ies led re­searchers to fear it would make African chil­dren more sus­cep­ti­ble to lo­cal in­fec­tions, par­tic­u­larly malaria.

The new study fol­lowed 600 chil­dren in An­gola, Uganda, Kenya and the Demo­cratic Repub­lic of Congo who were given the drug for more than two years.

As with chil­dren in wealthy coun­tries, tak­ing the drug daily also made it far less likely they would die or need a blood trans­fu­sion be­cause of their sickle-cell dis­ease. They were about half as likely to suf­fer bouts of se­vere pain, and some­what less likely to get other in­fec­tions. In an un­ex­pected twist, in­ves­ti­ga­tors dis­cov­ered that the chil­dren were about half as likely to get malaria while us­ing hy­drox­yurea as they had been be­fore the trial started. The rea­sons are not known.

“With all the malaria, mal­nour­ish­ment and vi­ta­min de­fi­ciency in Africa, we couldn’t as­sume it would work as well as it did,” said Dr. Rus­sell E. Ware, di­rec­tor of haema­tol­ogy at the Cincin­nati Chil­dren’s Hos­pi­tal and a co-au­thor of the study, which was pre­sented at a meet­ing of the Amer­i­can So­ci­ety for He­ma­tol­ogy and si­mul­ta­ne­ously pub­lished in the New Eng­land Jour­nal of Medicine. Even though the study was fairly large, it had some lim­i­ta­tions.

It was in­tended to prove only that the drug was safe for chil­dren aged one to 10. It was not de­signed to test var­i­ous dosages to find the ideal one, nor to de­ter­mine how many lab tests are needed to mon­i­tor chil­dren tak­ing the drug, nor to de­ter­mine the long-term ef­fects. So fur­ther work will be needed, re­searchers said.

Also, the re­search was done with­out a placebo con­trol — a group of sim­i­lar chil­dren not get­ting the drug. Over­sight boards in the four test coun­tries felt it would be un­eth­i­cal to deny the drug to any child, since it was known to work else­where, said Dr Leon Tshilolo, a pae­di­atric haema­tol­o­gist at the Monkole Hos­pi­tal Cen­tre in Kin­shasa, DR Congo, and the study’s lead au­thor.

To com­pen­sate for the lack of a placebo group, the re­searchers watched chil­dren for two months be­fore start­ing them on hy­drox­yurea. That es­tab­lished the base­line rates at which the chil­dren nor­mally suf­fered pain crises, needed blood trans­fu­sions and got malaria or other in­fec­tions.

The re­sults “mean sur­vival will be bet­ter even in very low-re­source set­tings,” Dr Tshilolo said.

In 1998, the US Food and Drug Ad­min­is­tra­tion ap­proved the drug for Amer­i­can adults with sickle-cell dis­ease; pae­di­a­tri­cians soon be­gan giv­ing it off-la­bel to chil­dren, Ware said.

Tri­als prov­ing it was safe in Amer­i­can chil­dren were not fin­ished un­til 2016, and the FDA ap­proved pae­di­atric use last year, open­ing the way for a trial in chil­dren in Africa.

For years, many black Amer­i­cans with sickle-cell dis­ease were re­luc­tant to en­rol them­selves or their chil­dren in drug tri­als, Dr Osunkwo said, be­cause of the United States’ sor­did his­tory of med­i­cal ex­per­i­men­ta­tion on black pa­tients — in­clud­ing the in­fa­mous Tuskegee Study, in which black men with syphilis were left un­treated even af­ter the in­ven­tion of peni­cillin.

Also, she said, the drug is known to lower men’s sperm counts, break off women’s hair and turn fin­ger­nails dark gray. For safety rea­sons, it is not nor­mally given to preg­nant women even though they may suf­fer se­vere sickle-cell crises.

Dr Osunkwo said she slowly over­came pa­tients’ re­luc­tance by let­ting them help de­sign the tri­als.

“And,” she added, “I would say, ‘Be­ing dead is worse than hav­ing dark nails.’”

There is cur­rently no treat­ment in Africa, and many chil­dren die be­fore age five.” Dr Ifey­inwa Osunkwo, di­rects a sick­le­cell dis­ease pro­gramme in Char­lotte, North Carolina

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