Treating children previously exposed to single dose nevirapine

23 August 2009. Related: Conference reports, Paediatric care, IAS 5th Cape Town 2009.

Polly Clayden, HIV i-Base

Two studies presented at the 1st International Workshop on HIV Pediatrics, 17-18 July 2009, Cape Town, South Africa and 5th IAS Conference on HIV Pathogenesis Treatment and prevention 19-22 July 2009 looked at strategies for treatment of HIV-infected children with prior exposure to nevirapine (NVP) to prevent mother to child transmission.

IMPAACT  P1060

In an oral presentation at the paediatric workshop, Avy Violari from the University of Witwatersrand, Johannesburg, South Africa, presented preliminary findings from the IMPAACT P1060 trial. [1] These data were also shown at the 5th IAS Conference as a late breaker poster. [2]

IMPAACT 1060 was a randomised trial conducted at 10 sites in 7 African countries. In this trial, two groups of HIV-infected children age 6 months to 3 years and eligible for treatment according to WHO criteria: Cohort 1, exposed (n=288) and Cohort 2, unexposed (n=288) to single dose NVP, were randomised to receive either lopinavir/r or NVP plus zidovudine (AZT) and lamivudine (3TC), with 144 children in each treatment group.

Children were stratified by age <12months vs. >=12 months with equal number to be enrolled in each age group.

The primary endpoint was virologic failure (defined as <1 log decrease in viral load between weeks 12 -24 or >400 copies/mL at week 24), treatment discontinuation or death by week 24.

The investigators used Kaplan-Meier curves to estimate failure rates at week 24. Differences between treatment arms were weighted by the inverse of the variance in each age group.

A similar study of mothers exposed and unexposed to single dose NVP had also been conducted (A5208). In this trial – which we reported in previous issues of HTB – the arm in which exposed mothers received NVP-containing HAART was stopped early by the Data Safety Monitoring Board (DSMB) due to superior performance of the LPV/r- containing HAART arm. [3, 4]

Dr Violari reported that following a scheduled DSMB review of IMPAACT 1060 on 20 April 2009, enrolment to Cohort 1 had also closed prematurely due to a trend towards consistency with the A5208 results. Children in Cohort 1 were evaluated and discussions with their parents or guardians were held to decide whether to switch children receiving NVP to LPV/r. Cohort 2 is to continue enrolment and study as planned.

At the time of the DSMB review, Cohort I had enrolled 153/288 children with a median follow up of 48 weeks. The median baseline age of the children was 0.7 years (75% <12 months), median CD4 percentage 19%, and median viral load >750,000 copies/mL. Results at week 24 by primary endpoints are detailed in Table 1.

Table 1: Cohort 1, week 24 primary endpoints (from Kaplan- Meier curve)

Difference in week 24 failure rate (NVP-LPV/r): all 18% (95% CI 2%-33%), p=0.015.

Of 115 children tested, 16 (14%) had baseline NVP resistance, mostly Y181C (n=14). The investigators found the difference in viral failure between arms was greater among the 16 children with baseline resistance (57%) compared to the 99 without resistance (17%).

The investigators suggested these data emphasise the need for better prevention of mother to child transmission strategies including post partum “tail” coverage and maternal HAART. And that prioritisation of resources for mother-infant pairs should be encouraged.

NEVEREST

Several guidelines already recommend using LPV/r-based treatment for single dose NVP-exposed infants.

Louise Kuhn from Colombia University, New York, USA and Ashraf Coovadia from the University of the Witswatersrand, Johannesburg, South Africa, presented findings from the NEVEREST study. NEVEREST is an investigation to see if NVP-exposed children, initially suppressed on LPV/r-based HAART can safely switch to a NVP based regimen.

In this study children 6 weeks to 2 years of age and eligible for treatment (n=323), were initiated on LPV/r plus 3TC and d4T. After achieving a viral load <400 copies/mL and maintaining it for >= 3months, children were randomised (n=195) to either remain on LPV/r (control, n=99) or switch to NVP (switch, n=96), and then followed to 52 weeks post randomisation.

Baseline (pre-treatment) characteristics of the randomised children were mostly similar: median age, 11 months vs. 9 months; median CD4 percentage 19.0% vs. 18.4%; and 57% vs. 54% had a viral load >750,000 copies/mL in the control and switch groups respectively. There was a larger group of younger children age 1-12 months in the switch group, 57.6% vs. 68.8%, but this difference was not significant.

At randomisation the median age of the children were 20 months vs. 19 months; median CD4 percentage 28.9% vs. 28.5% and 61% vs. 66% had a viral load <50 copies/mL in the control and switch groups respectively. The median time on LPV/r based therapy was 9 months in both groups.

Two children in each group died; 3 children in the control and 5 in the switch group were lost to follow up and 3 children in the control and 5 in the switch group started TB treatment.

The investigators reported 80% vs. 86% of children were adherent to the study medication at 36 weeks post randomisation in the control and switch groups respectively.

When the investigators looked at viral load <50 copies/mL to 52 weeks they found 42.4% children in the control group and 56.2% in the switch group sustained viral suppression, p=0.01. But allowing for one elevated result (blip) the two groups were similar, 72.8% vs. 73.4% in the control and switch groups respectively.

They suggested that poorer adherence in the control group, due to the unpleasantness in taste of LPV/r syrup, may have led to more blipping and, in turn, unsustained viral suppression to 50 copies/mL during follow up. In contrast, when they looked at sustained suppression to <1000 copies/mL, 98% vs. 80% of children in the control and switch groups achieved this, p=0.001.

An analysis of patterns of viral suppression after the children were randomised revealed that of the children >50 copies/mL, 56% in the control group had viral load between 50-1000 copies/mL and the remaining 2% more than 1000 copies/mL. In the switch group more children had viral load more than 1000 copies/mL 20%; but fewer, 24%, were between 50-1000 copies/mL.

In the switch group, viral suppression <50 copies/mL at randomisation was predictive of sustained viral suppression <1000 copies/mL through 52 weeks: 86.1% of children with viral load <50 copies/mL at randomisation sustained viral suppression <1000 copies/mL through 52 weeks vs. 63.5% with viral load 50-400 copies/mL at randomisation, p<0.001. Likewise, the presence of NNRTI mutations prior to treatment predicted sustained viral suppression after switch: 88% children with no mutations sustained viral load <1000 copies/mL through 52 weeks vs. 55.3% with mutations, p=0.007.

The median CD4 percentage at 24 weeks in the control group was 30.0% vs. 33.2% in the switch group, p<0.0001. In the control group 16.3% of children had a CD4 percentage decline of 10% vs. 3.2% in the switch group, p=0.004. Weight for age declined >1 z-score in 13.1% of children in the control group vs. 4.2% in the switch group, p=0.03.

The investigators wrote that this study provides proof of concept that re-use of NVP is possible under some circumstances for HIV-infected children exposed to NVP prophylaxis and should be further investigated. They note that the clinical significance of low-level viraemia in the control group needs further study. Switching may provide a promising option for children originally initiated on PI-based HAART to preserve second-line options. At this stage, switching requires close virological monitoring after the switch in order to be done safely.

COMMENT

The 1060 results are unsurprising and entirely consistent with the earlier maternal data. Baseline nevirapine resistance and younger age appear to be associated with the performance of the nevirapine arm.

NEVEREST was interesting and this strategy deserves further investigation. Another NEVEREST trial of efavirenz vs. lopinavir/r is planned in nevirapine-exposed children >3 years old.

Both studies underscore the limited treatment options that are available for children, particularly in resource limited settings.

References:

1. Violari A et al. Nevirapine vs. lopinavir-ritonavir- based antiretroviral therapy (ART) in single dose nevirapine (sdNVP)-exposed HIV infected infants: preliminary results from the IMPAACT P1060 trial. HIV Pediatrics, 17-18 July 2009, Cape Town. Abstract O_08.
2. Palumbo et al. Nevirapine (NVP) vs. lopinavir-ritonavir (LPV/r)- based antiretroviral therapy (ART) in single dose nevirapine (sdNVP)-exposed HIV-infected infants: preliminary results from the IMPAACT P1060 trial. 5th IAS Conference on HIV Pathogenesis Treatment and prevention 19-22 July 2009, Cape Town. Abstract LBPEB12.
3. https://i-base.info/htb/261
4. https://i-base.info/htb/1449
5. 5. Coovadia A et al. Randomized clinical trial of switching to NVP-based therapy for infected children exposed to nevirapine prophylaxis. HIV Pediatrics, 17-18 July 2009, Cape Town. Abstract O_09.
6. 6. Coovadia A et al. Randomized clinical trial of switching to nevirapine-based therapy for infected children exposed to nevirapine prophylaxis. 5th IAS Conference on HIV Pathogenesis Treatment and prevention 19-22 July 2009, Cape Town. Abstract MOAB103.