Despite being in early stages of the paediatric ART scale up, children are already failing treatment and needing second-line regimens. Current United Nations estimates of paediatric second-line use in low- and middle-income countries (LMICs; outside of the Americas) are around 3% [1]. However, this is much lower than in single cohort reports in settings where ART has been available for longer periods of time. A survey of 17 centres in LMICs in Asia reported that 20% of the more than 3600 children under care were already past their first ART regimens [3]. Other single-institution cohorts have reported as much as 5.8% (South Africa [4]), 9% (Thailand [5]), and 19.4% (south India [6]) of patients switching to second-line regimens.

Evidence-based strategies for selecting second-line regimens are needed, but are also dependent on local antiretroviral (ARV) options. Children have consistently faced greater disadvantages with regards to the availability of ARV formulations that can be dosed and delivered to children, and that are safe to use during growth and development [7,8].

All recommended second-line regimens for children failing NNRTI-based first-line ART included ritonavir-boosted lopinavir. The NRTI combination varied from the WHO-recommended combination of abacavir and didanosine to substituting with another thymidine analogue (i.e., zidovudine for stavudine). A third of the sites continued lamivudine in second-line regimens. Malaysian and South African sites, representing 42% of all sites, had specific national recommendations for second-line regimens after initial PI failure that advised use of two new NRTIs and either nevirapine or efavirenz (data not shown).

There was some variability in levels of drug access between the regions (Table ​(Table2).2). IeDEA Southern Africa had better access to abacavir and ritonavir suspension; TREAT Asia sites had better access to tenofovir and paediatric, heat-stable boosted lopinavir tablets. Although all of the African sites had access to the adult version of the boosted lopinavir, 80% found it either difficult to access the liquid or paediatric formulation of the tablet, or did not use it for their patients. This was related to delays at the time of the survey in the drug's approval by the South African Medicines Control Council that have since been resolved.

A total of 1301 children in the TREAT Asia and 4561 children in the IeDEA Southern African cohorts met inclusion criteria for the cross-sectional analysis (Tables ​(Tables33 and ​and4).4). Although stavudine was infrequently used in Asia, it was part of the first-line regimen in 92% of children in southern Africa. Ten percent of Asian and 3.3% of African children were on second-line ART at the time of data transfer. Asian children were on second-line ART for longer periods and were older at the time of switch. African children on second-line ART were more frequently male (67%). Regimens varied widely, and the WHO-recommended combination at the time of the data transfer of abacavir and didanosine [10] was used in less than 5% of children in each region.

In fact, we are likely to have underestimated the use of second-line ART in the Asian cohort, since 18% of children excluded from this analysis had a previous exposure to mono- and dual-NRTI regimens. In addition, these differences may be related to regional variation in the availability of clear second-line switch criteria, and broader access to viral load testing in Asia.

However, these data reflect only those currently on second-line treatment. Estimates for how many children are ready to switch to second-line ART now and projections for the future are critically needed in order to prepare providers, governments and donors. If the need for second-line ART is based on virologic failure alone, the numbers in need would be much higher.

In Asia, 15% of children in a Cambodian study and 37% of children in a Chinese study had viral loads of more than 1000 copies/ml after 12 months of first-line ART [11,12]. An earlier Thai cohort reported that 17% of children had virologic failure after 192 weeks of ART [5]. Similarly, a study done in southern Africa using the cut-off of more than 1000 copies/ml reported a cumulative probability of failure by three years after ART initiation of 19.3% [13], and a study of children and adolescents in Uganda reported 26% with viral loads of more than 400 copies/ml after 12 months of treatment [14].

Even in settings where viral load is routinely available, paediatricians are less inclined to switch children who have persistent viremia unless adherence to a new regimen can be assured and the benefits of a new regimen outweigh the risks of running out of ART options. Furthermore, when the initial regimen includes a boosted PI, low-level viremia may not indicate resistance to the PI. Most importantly, the decision to switch ART at a young age in countries that only have two lines of national ART regimens can leave children with no suppressive regimens by adolescence. That the median age at switch in IeDEA Southern Africa was 5.5 years was especially concerning because of the lack of available third-line options that these young children now have. This may reflect the impact of NNRTI resistance after prevention of mother to child transmission interventions, which can also be a factor in ART management after first-line PI failure in those infants who are started on boosted lopinavir.

Another notable finding was that only 33% of the children on second-line treatment in the southern African cohort were female. However in an analysis using the same data of factors that predict switch to second-line in southern Africa, gender was not predictive after adjustment for age, duration on ART, disease severity at the time of failure and first-line regimen [13].

A wide range of second-line regimens was in use. Unlike the United Nations data reporting that at least 46.7% of paediatric second-line regimens in the 59 LMICs it surveyed contained abacavir [1], this ARV was infrequently used in either the TREAT Asia or the IeDEA Southern Africa cohorts. Most of the second-line regimens included recycling of a thymidine analogue (i.e., zidovudine). It was unexpected that abacavir was more difficult to access by clinical sites in Asia despite being part of the WHO-recommended second-line regimen. The relatively higher cost of abacavir compared with zidovudine may also be a deterrent to its use. Access to a broader range of paediatric ARVs is needed in order to maximize the potency of second- and third-line regimens, whenever possible.

Another outcome of this survey was to document the differences in use of stavudine between the regions. Recent WHO recommendations for adult ART have proposed setting up plans for phasing out stavudine by 2011 because of long-term toxicity with this drug [15]. Similar recommendations for children may also be justified [16]. Scaling up of paediatric treatment in many developing countries depends on simple fixed-dose combinations and child-friendly adapted formulations, such as dispersible tablets, improved palatability and heat-stable formulations (for storage in tropical climates). Examples include the need for ritonavir-boosted atazanavir and heat-stable ritonavir-boosted lopinavir in palatable paediatric formulations.

In addition, given the difficulties of accessing clean water in many resource-limited rural settings, formulations that require reconstitution should ideally be avoided. Efforts are also needed to ensure that newer drugs, such as raltegravir, darunavir and etravirine, are also developed as heat-stable formulations and tested for use in infants and young children as these represent important potential options for both, and for improving first-line regimens and as salvage therapy.

Finally, improving access to effective paediatric treatment also requires improved access to diagnostic tools, including PCR for early infant diagnosis and more widespread access to viral load technologies for early diagnosis of treatment failure. Although rarely available, the role of resistance testing in LMIC settings continues to be unclear. Further research on when and how HIV genotyping in heavily experienced children can be cost-effective is needed to identify possible strategies for its use.

Our data are limited by their cross-sectional nature and depth. The potential impact of changes in drug access and national or global paediatric treatment guidelines are difficult to assess from our surveys and the regional databases. Additional detail on the durability of first-line regimens in the children with treatment failure is available for the southern Africa cohort in a previous publication [13], but has not yet been analyzed for the Asian cohort. The survey on drug access did not separate out drugs that could not be accessed from those there were simply not used in the clinic.

V Saphonn* and S Saramony, National Centre for HIV/AIDS Dermatology and STDs, Phnom Penh, Cambodia;

U Vibol* and S Sophan, National Pediatric Hospital, Phnom Penh, Cambodia;

J Tucker, New Hope for Cambodian Children, Phnom Penh, Cambodia;

FJ Zhang and N Han, Beijing Ditan Hospital, Beijing, China;

N Kumarasamy* and S Saghayam, YR Gaitonde Centre for AIDS Research and Education, Chennai, India;

N Kurniati*‡ and D Muktiarti, Cipto Mangunkusumo General Hospital, Jakarta, Indonesia;

SM Fong* and M Thien, Hospital Likas, Kota Kinabalu, Malaysia;

NK Nik Yusoff* and LC Hai, Hospital Raja Perempuan Zainab II, Kelantan, Malaysia;

K Razali* and NF Abdul Rahman, Pediatric Institute, Hospital Kuala Lumpur, Kuala Lumpur, Malaysia;

R Nallusamy* and KC Chan, Penang Hospital, Penang, Malaysia;

V Sirisanthana*and L Aurpibul, Chiang Mai University, Chiang Mai, Thailand;

R Hansudewechakul* and A Khongponoi, Chiangrai Prachanukroh Hospital, Chiang Rai, Thailand;

P Lumbiganon* and P Kosalaraksa., Khon Kaen University, Khon Kaen, Thailand;

G Jourdain, Program for HIV Prevention and Treatment, Chiang Mai, Thailand;

J Ananworanich*† and T Suwanlerk, The Netherlands, Australia, Thailand Research Collaboration (HIV-NAT), Bangkok, Thailand;

K Chokephaibulkit* and O Wittawatmongkol, Siriraj Hospital, Mahidol University;

HK Truong* and DAN Mai, Children's Hospital 1, Ho Chi Minh City, Vietnam;

CV Do* and MT Ha, Children's Hospital 2, Ho Chi Minh City, Vietnam;

HV Bui *and VL Nguyen, National Hospital of Pediatrics, Hanoi, Vietnam;

ON Le, Worldwide Orphans Foundation, Ho Chi Minh City, Vietnam;

AH Sohn*, L Messerschmidt and J Pang, TREAT Asia, amfAR - The Foundation for AIDS Research, Bangkok, Thailand;

DA Cooper, MG Law* and A Kariminia, National Centre in HIV Epidemiology and Clinical Research, The University of New South Wales, Sydney, Australia;

*TApHOD Steering Committee member

† Current Steering Committee Chair; ‡ co-Chair

IeDEA Southern Africa Paediatric Group

Mary-Ann Davies, School of Public Health and Family Medicine, University of Cape Town, South Africa;

Brian Eley, Red Cross Children's Hospital and the School of Child and Adolescent Health, University of Cape Town, Cape Town, South Africa;

Janet Giddy, McCord Hospital, Durban, South Africa;

Harry Moultrie, Institute for Sexual Reproductive Health, HIV and Related Diseases, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa;

Margaret Pascoe, Newlands Clinic, Harare, Zimbabwe;

Helena Rabie, Tygerberg Academic Hospital and University of Stellenbosch, Cape Town, South Africa;

Karl Technau, Empilweni Service and Research Unit, Rahima Moosa Mother and Child Hospital, University of the Witwatersrand, Johannesburg, South Africa;

Gilles Van Cutsem, Khayelitsha ART Programme, Médecins Sans Frontières and School of Public Health and Family Medicine, University of Cape Town, Cape Town, South Africa;

Paula Vaz, Paediatric Day Hospital, Maputo, Mozambique;

Ralf Weigel, Lighthouse Trust, Lilongwe, Malawi;

Robin Wood, Gugulethu Community Health Centre and Desmond Tutu HIV Centre, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa

IeDEA Southern Africa Steering Group

Member sites: Anna Coutsoudis, PMTCT Plus, Durban, South Africa; Diana Dickinson, Gaborone Independent Hospital, Gaborone, Botswana; Brian Eley, Red Cross Children's Hospital, Cape Town, South Africa; Lara Fairall, Free State provincial ARV roll out, South Africa; Tendani Gaolathe, Princess Marina Hospital, Gaborone, Botswana; Janet Giddy, McCord Hospital, Durban, South Africa; Timothy Meade, CorpMed Clinic, Lusaka, Zambia; Patrick MacPhail, Themba Lethu Clinic, Helen JosephHospital, Johannesburg, South Africa; Lerato Mohapi, Perinatal HIV Research Unit, Johannesburg, South Africa; Margaret Pascoe, Newlands Clinic, Harare, Zimbabwe; Hans Prozesky, Tygerberg Academic Hospital, Stellenbosch, South Africa; Harry Moultrie, Enhancing Children's HIV Outcomes (Harriet Shezi Children's Clinic, Chris Hani Baragwanath Hospital, Soweto); Karl Technau, University of Witwatersrand Paediatric HIV Clinics (Empilweni Service and Research Unit, Rahima Moosa Mother and Child Hospital), Johannesburg, South Africa; Gilles van Cutsem, Khayelitsha ART Programme and Médecins sans Frontières, Cape Town, South Africa; Paula Vaz, Paediatric Day Hospital, Maputo, Mozambique; Ralf Weigel, Lighthouse Trust, Lilongwe, Malawi; Robin Wood, Gugulethu and Masiphumelele ART Programmes, Cape Town, South Africa.