{"id":326,"date":"2008-12-27T00:45:05","date_gmt":"2008-12-26T23:45:05","guid":{"rendered":"http:\/\/localhost\/new\/htb\/?p=326"},"modified":"2013-08-23T12:49:06","modified_gmt":"2013-08-23T12:49:06","slug":"lack-of-efficacy-of-isoniazid-inh-prophylaxis-and-pk-evaluation-in-south-african-infants","status":"publish","type":"post","link":"https:\/\/i-base.info\/htb\/326","title":{"rendered":"Lack of efficacy of isoniazid (INH) prophylaxis and PK evaluation in South African infants"},"content":{"rendered":"

Polly Clayden, HIV i-Base<\/strong><\/p>\n

A South African study looked at isoniazid (INH) prophylaxis in young infants and found no increase in TB free survival.<\/strong> [1]<\/p>\n

PACTG 1041 was a phase II\/III double blind, randomised, placebo-controlled study of primary INH prophylaxis for prevention TB disease and latent infection infants with perinatal HIV-exposure.<\/p>\n

In this study, HIV-positive, BCG vaccinated infants of 3-4 months of age were randomised to daily INH (10-20mg\/kg\/day) or placebo for 96 weeks. The infants also received cotrimoxazole, and ART where indicated, in accordance with WHO guidelines.<\/p>\n

The primary objective of the study was to investigate whether INH increases TB disease-free survival in young infants.<\/p>\n

Endpoints were TB disease and mortality at 96 weeks.<\/p>\n

HIV-positive children (n=452, 226 per arm) with median age 96 days were enrolled between December 2004 and March 2008.<\/p>\n

The children’s baseline median CD4% was 27% (range: 6-58%); 91% were CDC clinical category N\/A, their median viral load was 666,500 copies\/mL and 28% were receiving ART. At time of this scheduled interim analysis 66% of children were receiving ART.<\/p>\n

The investigators found, at a median of 36 weeks follow up, 39 (17.3%) and 32 (14.2%) children in the INH and placebo groups, respectively, had TB or died, p=0.34. There were 24 (10.6%) and 22 (8.4%) (p=0.69) cases of TB and 15 (6.6%) and 10 (4.4%) non-TB related deaths in the INH and placebo groups, respectively. They reported no significant difference in rates of adverse event rates between the two groups.<\/p>\n

In this study the overall cumulative incidence of TB by 96 weeks was high (22.2%; 95%CI: 15.7, 31.0).<\/p>\n

The investigators wrote: “INH prophylaxis did not improve TB-disease free survival in HIV-positive African children with access to ART, indicating the need for alternative strategies to reduce the high public-health burden of childhood TB.”<\/p>\n

As the appropriate INH infant dose is unknown, PACTG 1041 also investigated INH PK, and determined N-acetyltransferase-2 (NAT2) genotype to evaluate if PG explains INH PK [2].<\/p>\n

The PK study target enrollment is 336 infants. Half of the infants were sampled at weeks 0 and 84 at 2 and 4 hours post dose, and the remaining children at weeks 12 and 84 at 1 and 3 hours post dose. INH was quantified in plasma (HPLC). NAT2 genotype was determined using RFLP and phenotypes assigned as slow (S), intermediate (I), and fast (F) acetylators.<\/p>\n

This study used a 1-compartment model with first-order absorption and elimination (NONMEM v.VI). Covariates, including NAT2 phenotype, age, weight, sex, and HIV status, were evaluated using stepwise forward inclusion (p=0.05) and backward elimination (p=0.01).<\/p>\n

The investigators modeled 306 INH concentrations from 131 infants. The infants had a median age of 171 days (range 91-717 days) at sampling; 53 were HIV-positive; 65 were girls; NAT2 phenotype, 32 S, 46 I, 30 F. Mean (SD) INH dose, 14 (3) mg\/kg\/d. Mean (SD) INH concentrations at 1, 2, 3, and 4 hours post dose were 12.0 (4.7), 8.3 (3.8), 6.3 (3.0), and 4.4 (3.0) mg\/L, respectively.<\/p>\n

They found the infants’ weight and NAT2 phenotype but not HIV status explained most of the interpatient variability in INH oral clearance (CL\/F). Typical CL\/F at weeks 0 and 12 for F phenotype were 3.3 and 3.9 L\/hr and were 1.4 and 1.7 L\/hr for S.<\/p>\n

They wrote: “INH PK at a dose of 10-20 mg\/kg\/d in these infants are similar to published data in older (median 3.8 years) children receiving 10 mg\/kg\/d. The comparability of PK supports continued evaluation of this dose, which is at least twice that recommended by WHO.”<\/p>\n

COMMENT<\/strong><\/p>\n

The full results of this trial are not yet out (but are unlikely to change). The investigators are studying the data to explain why no benefit was found for pre-exposure prophylaxis despite a high rate of incident TB.<\/strong><\/p>\n

References:<\/p>\n

    \n
  1. Madhi SA, Nachman S, Violari A et al. Lack of efficacy of primary isoniazid (INH) prophylaxis in increasing tuberculosis (TB) free survival in HIV-infected (HIV+) South African children. 48th ICAAC, 25-28 October 2008. Washington. Abstract G2-1346a.<\/li>\n
  2. Kiser J, Zhu R, Nachman S et al. Pharmacokinetics (PK) and Genetics (PG) of Isoniazid (INH) in South African HIV-Exposed Infants-PACTG 1041. 48th ICAAC, 25-28 October 2008. Washington. Abstract A-1826.<\/li>\n<\/ol>\n","protected":false},"excerpt":{"rendered":"

    Polly Clayden, HIV i-Base A South African study looked at isoniazid (INH) prophylaxis in young infants and found no increase in TB free survival. [1] PACTG 1041 was a phase II\/III double blind, randomised, placebo-controlled study of primary INH prophylaxis …<\/p>\n","protected":false},"author":4,"featured_media":0,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[4,32,37],"tags":[102],"class_list":["post-326","post","type-post","status-publish","format-standard","hentry","category-conference-reports","category-paediatric-care","category-tb-coinfection","tag-icaac-48th-2008"],"_links":{"self":[{"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/posts\/326","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/users\/4"}],"replies":[{"embeddable":true,"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/comments?post=326"}],"version-history":[{"count":0,"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/posts\/326\/revisions"}],"wp:attachment":[{"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/media?parent=326"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/categories?post=326"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/tags?post=326"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}