Paediatric care in lower income settings
Polly Clayden, HIV i-Base
Resistance in infected infants exposed to maternal or infant MTCT strategies
Two studies looked at resistance in infected infants exposed to maternal or infant MTCT strategies.
Marina Giuliano presented data from an analysis of samples from infected infants and transmitting mothers in the SIMBA study.
In SIMBA, 404 infants of HIV infected women (in Uganda and Rwanda), who had received AZT and ddI from 36 weeks gestation until 1 week post-partum, were randomised to receive daily prophylaxis of 3TC or nevirapine for the duration of breastfeeding (as long as 6 months) or until HIV infection was confirmed. The study achieved a very low breastfeeding transmission rate among the infants (1% in the first six months of life).
Thirty children were HIV infected, 7% in week 0-4 and 1% between 4 weeks and 6 months.
Of the 26 children for which data were available, 13 had received prophylaxis with nevirapine and 13 with 3TC. 20 were diagnosed with HIV infection at birth; 3 by week 3; and 1 at week 6.
12/13 (92%) of samples from the infants who had received nevirapine prophylaxis, had detectable nevirapine associated mutations (9 – Y181C, 3 – G190A, 2 – K103N, 1 – Y188H, 1 – V106A); 3 infants had multiple mutations.
These were compared to the maternal samples and none of these mutations were present in the maternal virus. At 6 to 9 months follow up, in the 9 available infant samples; the nevirapine-associated mutations were still present.
The M184V mutation was detected in 9/13 (69%) samples from infants who had received 3TC prophylaxis. The mutation was no longer detectable -“faded” – at 3 to 6 months in the majority of infants (it only remained detectable in 2).
The presentation provoked discussion about using both nevirapine and 3TC as prophylaxis in this way due to the low genetic barrier of both drugs. Dr Giuliano explained that both drugs were available as syrups.
The authors concluded: “Post-partum prophylaxis with nevirapine or lamivudine leads almost invariably to the selection of resistance mutations in the children who are diagnosed with the infection while receiving these drugs; this should be considered when choosing the antiretroviral regimen for these children. The presence of resistance-associated mutations in untreated women in Africa needs to be evaluated in a larger sample.”
Note: All 15 children who were HIV-positive and alive in June 2003 from the SIMBA study started a combination of antiretroviral therapy with either AZT/3TC/Kaletra or AZT/NVP/Kaletra within SIMBA Plus .
Infant nevirapine resistance at 6 weeks
A poster from Nicole Ngo-Giang-Huong and colleagues showed an analysis of nevirapine resistance patterns exposed to maternal or infant dose of nevirapine and maternal or infant AZT.
Two groups of infants were evaluated. The first included 33 infants born to mothers enrolled in PHPT-2 trial, in which mothers received AZT from 28 weeks gestation and single dose nevirapine and infants were randomised to receive nevirapine or placebo. Of this group, 30 infants received 7 days of AZT and 3 infants received 6 weeks of AZT post partum.
The second group included 20 children born to mothers who received AZT for < 2 weeks and single dose nevirapine. All children received a single dose nevirapine and AZT for 6 weeks.
Standard genotype was performed at 6 weeks in infant samples. The prevalence of nevirapine-associated mutations was analysed according to the duration of infant and maternal AZT prophylaxis. Results were available for 50/53 (94%) of infant samples. The authors reported that all viruses were the circulating recombinant form CRF01_AE.
Nevirapine associated mutations were detectable in 4/50 (8%) of available samples. The mutations detected were: K103N alone or associated with the G190A in 3 children and Y181C in 1 child. Of the 4 nevirapine mutations detected, 3/29 occurred in infants who received 7 days of AZT, and 1/21 occurred in an infant who received 6 weeks of AZT prophylaxis.
The authors concluded: “The incidence of NVP-resistance mutations in perinatally HIV-infected children exposed to perinatal NVP plus ZDV is lower than what has been described in others studies after exposure to NVP only.” They add: “Our data do not show a difference in the prevalence of NVP-resistance mutations according to the duration of infant or maternal ZDV prophylaxis. The pattern of NVP mutations observed could be associated with the CRF01_AE subtype as well as ZDV prophylaxis.”
Successful Thai paediatric HAART programme
In an oral presentation Thanayawee Puthanakit presented 72 week data from a paediatric study – part of the national treatment programme – to assess the effectiveness of NNRTI containing regimens in children, conducted at four government hospitals in Thailand.
From August 2002 to July 2003, 107 treatment naïve children between 2 and 15 years with advanced HIV: CD4 <15% (median 3%), were enrolled. Non-paediatric fixed dose combination of nevirapine, 3TC and d4T (GPOvir) or efavirenz plus 3TC and d4T were used, manufactured by the Thai generic company GPO. Dosages were calculated based upon the children’s body weight. Pills were divided into quarters or halves if necessary.
The primary endpoint of the study was the percentage of children with HIV RNA < 50 copies/ml at 72 weeks. Secondary endpoints were the change in percentage of CD4 and the incidence of resistance mutation virus.
The authors reported a high adherence rate, >95% of prescribed dose at every visit in 86% of children; 64% of the nevirapine group and 91% of the efavirenz group achieved HIV RNA < 50 copies/ml and a CD4 increase to a median 21% at 72 weeks.
The most common resistance mutation pattern was that which conferred resistance to both 3TC and NNRTI.
The authors concluded: “The use of generic fixed-dose formulations and non-paediatric formulations are feasible and effective in resource-limited settings.”
Dr Puthanakit also noted that one bottle of 60 tablets of adult GPOvir contains the equivalent doses of 41 bottles of paediatric formulations.
Stability of paediatric formulations at varying temperatures
Choices of antiretrovirals for paediatric use are particularly scant. Kaletra capsules and ddI and d4T oral solutions are sometimes recommended and prescribed in lower income settings.
Refrigerated storage is recommended for these formulations (2-8 degrees C or up to 25 degrees C for Kaletra) but many countries lack refrigeration and have climates where temperatures reach more than 40 degrees C. Data are lacking on the stability of these formulations at higher temperatures.
A poster from Shahin Lockman evaluated the stability of these antiretroviral formulations after storage under experimental conditions for as long as 11 weeks at temperatures up to 55 degrees C.
Stability was assayed with reversed phase high performance liquid chromatography (HPLC) with UV detection.
The investigators found paediatric oral solutions of ddI were stable at temperatures as high as 35°C for 8 weeks; d4T oral solutions, however, showed significant loss of stability after 4 weeks at 25 degrees C, and the majority of drug was lost after even after one week at 35 degrees C. The lopinavir component of Kaletra is stable at temperatures as high as 45 degrees C for 11 weeks, and the ritonavir component is stable at temperatures as high as 35 degrees C for 11 weeks.
Of the WHO 2004 estimated 4.9 million people currently living with HIV, 700,000 are estimated to be children. The 3×5 target for people on antiretrovirals includes 10-15% children, although there is not much data it is estimated that 10,000 to 14,000 children are currently receiving treatment.
Treating children with HIV can be complicated and treating children with HIV in lower income settings can be more complicated still, as Di Gibb reminded us in an excellent overview at this CROI entitled “Antiviral therapy for children: challenges and triumphs”, and these studies also illustrate some of the hurdles (and successes).
Dr Gibb asked: “What are the implications for first line strategies for children exposed to antiretrovirals through maternal or infant MTCT prophylaxis? A mother may not even know she’s received nevirapine. What should children receive? There has been lots of talk at this conference and it is clearly of concern. South Africa is so concerned that their paediatric guidelines recommend starting with LPV/r in children under 3 years”. She explained that the PACTG 1060 trial will look at d4T/3TC/NVP vs d4T/3TC/LPV/r in infants with prior exposure to nevirapine with CD<20%. These data are urgently needed.
In terms of the infant resistance data from Thailand, it is unclear if this is low because of the AZT or if it is low because this is a subtype E virus (or recombinant E), which have much lower rates of resistance than do C or D (C highest, D next, A next, E/B may be lower than A or similar). So we cannot directly compare these rates to those reported from Africa, where different subtypes predominate. But they do seem lower than most reports.
The results from the Thai paediatric treatment programme are impressive and raise issues around dosing, formulations and PK. As in this study, cut up adult fixed dose combination tablets are being used in for treating children by some groups. As Dr Gibb noted, liquid formulations present major problems in terms of volume, storage and transport. And as Dr Puthanakit also pointed out, they are 3 to 10 times more expensive than equal adult dose. Additionally as the stability study shows there are problems with d4T at higher temperatures.
Urgently needed are PK data for cut up tablets for children across different age bands and nutritional status.
Dr Gibb emphasised that the “way forward” is FDCs specifically for children and showed the CIPLA “Pedimune” currently in development. These FDCs will be in more than one size: “Junior” – d4T 12mg/ 3TC 60mg/ nevirapine 100mg and “Baby” – d4T 6mg/3TC 30mg/NVP 50mg, giving infants an accurate dose of nevirapine (they are underdosed with cut up adult tablets). The tablets will also be scored for more accurate cutting and doses will be calculated in 5 kilo bands.
Additionally, GPO is working on a paediatric formulation of GPOvir, interestingly with slightly less d4T and slightly more 3TC as are other Indian generic manufacturers.
She also included a wish list of other co-formulated scored pills for children.
Finally she emphasised that despite the sobering comments in the recent WHO report, “…children have been tragically neglected in efforts to accelerate access to ARVs…despite proof to the contrary, policy-makers and caregivers are often unconvinced that ARV therapy works for children…” ARV treatment works in children.
- Marina Giuliano, C Galluzzo, E Germinario et al. Selection of resistance mutations in children receiving prophylaxis with lamivudine or nevirapine for the prevention of postnatal transmission of HIV. 12th CROI, Boston, 2005.
- SIMBA and SIMBA Plus and
- Ngo-Giang-Huong N, Jourdain G, Tungyai P et al. Infant zidovudine prophylaxis and emergence of nevirapine resistance at 6 weeks in perinatally HIV-infected infants exposed to intra-partum or newborn nevirapine. 12th CROI, Boston, 2005.
- Puthanakit T, Oberdorfer A, Akarathum N et al. Effectiveness of NNRTI-based HAART in ART-naive HIV-infected children participating in Thailand’s National Access Programme: 72-week Result. 12th CROI, Boston, 2005.
- Lockman S, Ndase P, Holland D et al. Stability of didanosine and stavudine paediatric oral solutions and Kaletra capsules at temperatures from 4°C to 55°C. 12th CROI, Boston, 2005.