{"id":15531,"date":"2011-08-01T11:09:46","date_gmt":"2011-08-01T11:09:46","guid":{"rendered":"http:\/\/i-base.info\/htb\/?p=15531"},"modified":"2011-08-01T11:09:46","modified_gmt":"2011-08-01T11:09:46","slug":"treating-children-previously-exposed-to-single-dose-nevirapine-update-on-impaact-p1060-and-neverest","status":"publish","type":"post","link":"https:\/\/i-base.info\/htb\/15531","title":{"rendered":"Treating children previously exposed to single dose nevirapine: update on IMPAACT P1060 and NEVEREST"},"content":{"rendered":"

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

Two oral presentations at CROI 2011 showed further findings from studies looking at treatment in children previously exposed or unexposed to maternal\/infant single dose nevirapine (NVP) in prevention of mother to child transmission (PMTCT) programmes.<\/p>\n

IMPAACT 1060<\/strong><\/h2>\n

IMPAACT P1060 was a randomised trial to determine whether NVP- or lopinavir\/ritonavir (LPV\/r)-based treatment performed better in young children exposed and unexposed to single dose NVP. All children received AZT plus 3TC. The trial comprised of Cohort 1 (exposed children) and Cohort 2 (unexposed children). Data from Cohort 1 have previously been reported and this part of the study was stopped early after a scheduled Data Safety Monitoring Board (DSMB) review, as there was an unsurprising trend towards more failure in the children receiving NVP- compared to LPV\/r-based treatment.<\/p>\n

Peter Palumbo presented results from Cohort 2. This cohort enrolled <\/strong>children aged 2 to 36 months, who met WHO criteria for treatment and were unexposed to single dose NVP. Children were stratified by age < or = 12 months. Children with TB were excluded from the trial.<\/p>\n

The study had a composite primary endpoint of treatment failure, which comprised viral failure (<1 log10 decline from baseline to after 12 to 24 weeks or >400 copies\/mL at week 24), or permanent discontinuation of NVP or LPV\/r, including death by 24 weeks. Rates were calculated from Kaplan-Meier curves for each treatment group and age group.<\/p>\n

Secondary endpoints included time to virological failure by 24 weeks, time to treatment failure throughout follow up and time to virological failure or death throughout follow up.<\/p>\n

P1060 Cohort 2 was fully enrolled with 288 children by March 2010 and had 48-week planned follow-up to March 2011.\u00a0 In October 2010, the DSMB recommended that the study was unblinded. All children had completed 24 weeks of follow up.<\/p>\n

Dr Palumbo reported that the children\u0092s median age at enrollment was 1.7 years (73% >12 months) and their median baseline viral load and CD4 percentage were 535,632 copies\/mL and 15% respectively. The majority (79%) of children were subtype C.\u00a0 The median follow-up was 72 weeks.<\/p>\n

At week 24, 87 children had reached an endpoint; 60 in the NVP and 27 in the LPV\/r arms. The overall difference in failure rate was 21.5% (95% CI, 11.2-31.8) in favour of LPV\/r, p<0.001. This was similar in both age groups: 22.0% (<12 months) and 21.3% (>12 months).<\/p>\n

There was also a significant difference in time to off study drug, over the full length of the trial, p<0.001. There were 10 vs 3 deaths in the NVP vs LPV\/r arms during the entire follow-up<\/p>\n

period (none judged related to study drugs), but this did not reach statistical significance, p=0.63.<\/p>\n

There was a notable amendment during the course of the trial. In 2007 the recommended NVP dose in WHO guidelines increased from the FDA recommended dose of 7mg\/kg to 160-200mg\/m2 (max 200mg). Only 32 children were enrolled under the lower dose compared to 115 at the higher one but the investigators saw no effect associated with this change.<\/p>\n

Dr Palumbo noted that the main reasons for off study were more virological failure, toxicity and death in the NVP arm.<\/p>\n

As both the NEVEREST and P1060 Cohort 1 data had suggested poorer weight and CD4 improvement in children receiving LPV\/r compared to NVP, the investigators also looked at this in Cohort 2. They did not find a statistically significant difference in CD4 improvement between the two arms but there was a difference in weight z-score favouring NVP at 24 and 48 weeks, respectively p=0.007 and p=0.009.<\/p>\n

When the investigators looked at NVP resistance in samples from subsets of children at baseline and time of virological failure, they found 2.4% (5\/206) with resistance at baseline compared to 56% (10\/18) at time of virological failure.<\/p>\n

These results were different to those in the sister study, OCTANE P1060, in which maternal data demonstrated non-inferiority of NVP- to LPV\/r-based treatment, by the study definition, for NVP- unexposed women.<\/p>\n

This highlighted the \u0093unique and challenging situation of early paediatric HIV infection\u0094, Dr Palumbo said, including very high baseline viral load and the unforgiving nature of NVP resistance. LPV\/r is already recommended for NVP-exposed children and discussions are ongoing as to whether this recommendation should expand to all young children, possibly up to three years of age.<\/p>\n

These data once again point to the importance of developing new first and second line options for use in this age group.<\/p>\n

NEVEREST<\/strong><\/h2>\n

Louise Kuhn presented data from NEVEREST, a study designed to evaluate a treatment switch strategy from LPV\/r to NVP in NVP-exposed children.<\/p>\n

In this study, 323 children aged 6 weeks to 2 years and eligible for treatment were initiated on LPV\/r plus 3TC plus d4T. After achieving a viral load <400 copies\/mL and maintaining it for > 3 months, children were randomised (n=195) to either remain on LPV\/r (n=99) or switch to NVP (n=96). Time to any viral load >50 copies\/mL or confirmed >1000 copies\/mL was compared using Kaplan-Meier methods and log-rank tests.<\/p>\n

Fifty-two week data post switch from this study has been reported previously. These data revealed a higher proportion of children suppressed to <50 copies\/mL (the primary endpoint) in the NVP arm but also a higher proportion in that group with confirmed >1000 copies\/mL.<\/p>\n

Dr Kuhn showed longer term results from this study with follow up of 18-53 months.<\/p>\n

There were three deaths in each group. At 36 months post randomisation, as with the earlier analysis, more children in the NVP group (40.5%) maintained viral load <50 copies\/mL than those in the LPV\/r group, p=0.01. Again, more in the NVP (23.9%) than in the LPV\/r (11.1%) had confirmed >1000 copies\/mL, p=0.01.<\/p>\n

This difference persisted at 48 months, for <50 copies\/mL and >1000 copies\/mL, respectively p=0.02 and p=0.08.<\/p>\n

At 6 months 59.1% of the failures in the NVP group had occurred vs 10% in the LPV\/r group. By 12 months these proportions were 100% in the NVP group and 50% in the LPV\/r group. Dr Kuhn noted that among children in the LPV\/r group, 6% of failures occurred between 12 and 48 months.<\/p>\n

Treatment failure >1000 copies\/mL was associated with the presence of pre-treatment NVP mutations, p=0.02. There was no difference in response between children in the NVP and LPV\/r groups in children who had no pre-treatment NVP resistance. Half the children with detectable NVP mutations failed when re-challenged with NVP.<\/p>\n

Dr Kuhn concluded that viral load testing can identify all switch failures and that switching can be accomplished safely if viral load testing is available. Also that pre-treatment screening for resistance can be used to identify the children who could benefit from this strategy.<\/p>\n

References<\/p>\n

    \n
  1. Palumbo P et al. NVP- vs LPV\/r-based ART among HIV+<\/sup> infants in resource-limited settings: the IMPAACT P1060 Trial. 18th CROI, 27 February\u00962 March 2011, Boston. Oral abstract 129LB<\/a>.<\/li>\n
  2. Kuhn L et al. Long-term outcomes of switching children to NVP-based therapy after initial suppression with a PI based regimen. 18th CROI, 27 February\u00962 March 2011, Boston. Oral abstract 128<\/a>.<\/li>\n<\/ol>\n","protected":false},"excerpt":{"rendered":"

    Polly Clayden, HIV i-Base Two oral presentations at CROI 2011 showed further findings from studies looking at treatment in children previously exposed or unexposed to maternal\/infant single dose nevirapine (NVP) in prevention of mother to child transmission (PMTCT) programmes. IMPAACT …<\/p>\n","protected":false},"author":2,"featured_media":0,"comment_status":"open","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[4,35,32],"tags":[65],"class_list":["post-15531","post","type-post","status-publish","format-standard","hentry","category-conference-reports","category-pmtct-and-maternal-health","category-paediatric-care","tag-croi-2011"],"_links":{"self":[{"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/posts\/15531","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\/2"}],"replies":[{"embeddable":true,"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/comments?post=15531"}],"version-history":[{"count":0,"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/posts\/15531\/revisions"}],"wp:attachment":[{"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/media?parent=15531"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/categories?post=15531"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/tags?post=15531"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}