Our study provides information on outcomes of second-line ART in NNRTI-failing children as part of a large multicenter observational study in a RLS. This study showed good virologic efficacy of second-line boosted PI regimens with 81% achieving HIV RNA
400 copies/ml at 48
weeks of treatment. Children with more advanced HIV disease were preferentially treated with double-boosted PI versus single-boosted PI regimens. Both regimen types performed equally well in suppressing HIV below 400 copies/ml but further suppression to less than 50 copies/ml was significantly less with double-boosted PI.
This study supports recycling of 2NRTIs in combination with a potent boosted PI as second-line therapy in children. The 2010 WHO guideline recommend replacing AZT/3TC or d4T/3TC in the first line regimen with abacavir (ABC)/3TC or ABC/ddI [17
]; however, that practice is rare in Thailand due to the high cost of ABC rendering it unavailable in the Thai national ARV program. Therefore, recycling of inactive or partially active 2NRTIs such as AZT/3TC, AZT/ddI or ddI/3TC was common in this study. At the time of the study, tenofovir (TDF) was not yet approved for adolescents nor was it available in Thailand. Similarly, LPV/r is the PI of choice in the WHO guideline but it was in limited supply in Thailand before 2005, resulting in the use of a more toxic drug, IDV, in half of our children.
The virologic response to second-line single boosted PI regimen in our study compares favorably to reports from other countries [15
]. In a French cohort, 92% on LPV/r second line regimens had HIV RNA
400 copies/ml despite having lower CD4 (14.8%) and higher HIV RNA (4.8 log10
copies/ml) than our children. The Spanish multicenter retrospective observational study showed 71.5% of PI-experienced children on LPV/r-based having HIV RNA
400 copies/ml [10
]. A long term cohort of children treated with LPV/r-based regimen showed that 81% remained on therapy after more than 4
years; 75% of those children had HIV RNA
400 copies/ml at their last visit. [18
] In another pediatric study, patients tended to have better virologic outcome if they were on LPV/r as supposed to unboosted PI, nelfinavir [19
]. We also saw a trend towards better virologic outcome among children who received LPV/r, but this did not reach statistical significance. In Malawi, 10% of adults died after initiating second-line regimen and 85% of the survivors had viral suppression at 12
Double-boosted PI is an acceptable alternative second-line therapy option in Thailand for children with late treatment failure who have few or no fully active drugs aside from PIs [15
]. The pediatric HIV-NAT 017 study which treated children with second-line SQV and LPV/r reported a viral suppression rate similar to that observed in our study with 64% having HIV RNA
50 copies/ml at week 48 [21
]. A non-randomized study in Thai adults showed that the double-boosted PI regimen was not as potent in suppressing HIV RNA to below 50 copies/ml when compared to the single-boosted PI regimen among patients with low grade multi- NRTI resistance mutations [22
]. Of note is the inability of that study to compare the two regimen types among patients with high grade multi-NRTI resistance mutations. Our study showed that double-boosted PI had a higher rate of low level viremia, HIV RNA between 50 and 400 copies/ml, compared to single-boosted PI. This could possibly be confounded by indication that children with more advanced disease received double-boosted PI regimen or due to inferior potency of a PI mono-class regimen. A recent randomized study of second-line PIs in Thai adults showed mono LPV/r treatment to result in significantly more low level viremia than a 3-drug regimen with TDF, 3TC and LPV/r [23
]. Another second-line study in Thai adults who received a single active drug, LPV/r, together with 3TC to reduce viral fitness also showed that only 67% achieved HIV RNA <50 copies/ml with 16% having low viremia between 50–400 copies/ml [24
]. The recent review literature [25
] and meta-analysis [26
]on protease inhibitor monotherapy also showed a slightly inferior virological efficacy of protease inhibitor monotherapy than that of protease inhibitor plus nucleosides. However, failure of protease inhibitor monotherapy does not imply losing therapeutic options, usually reintroduction of nucleosides can lead to virologic suppression. [25
] The higher rates of dyslipidemia with double-boosted PI and the higher pill burden further limits its use particularly if newer and more potent ARVs with favorable lipid profile e.g. atazanavir, darunavir, and raltegravir becomes available to children in RLS.
There is a lack of evidence to inform the optimum time to switch to second line regimens in RLS. The WHO guideline, relying heavily on a public health approach to care, recommends switching to second-line regimen when CD4 is
or HIV RNA is
5,000 copies/ml [27
]. We demonstrated a trend towards better virologic suppression following second-line therapy in children who switched when their CD4 was
or HIV RNA was
10,000 copies/ml. Delayed in switching to second-line therapy may lead to resistance mutations accumulation which would be problematic in RLS where ARV options are limited. The PENPACT-1 study showed that children failing first-line NNRTI who were randomized to a delayed switch at HIV RNA
30,000 copies/ml had more TAMs compared to those who switched at HIV RNA
1,000 copies/ml [28
] This however did not affect the overall virologic outcome after second-line therapy in that study likely due to several reasons: children who failed had low rates of NRTI resistance of 1-5%, they had no CD4 failure, and they had access to routine HIV RNA monitoring, genotyping and good ARV options. The situation in RLS may be quite different as switching occurs later with immunologic or clinical failure coupled with the lack of HIV RNA and genotyping monitoring, and limited ARV options.
This study has several limitations. First is incomplete data, which is an inherent limitation of a retrospective study design. The information of adherence to treatment is not captured. Second, the lack of randomization of single- versus double-boosted PI regimens hinders the ability to directly compare the outcome between these two regimens. Third, the duration of NNRTI-based first line regimen in our study was relatively short, around 2
years. Furthermore, we have access to laboratory monitoring including CD4, plasma HIV RNA and genotypic resistance testing to guide the design of the new regimens which may limit the applicability of our results to other resource-limtted settings where treatment failure is detected later and genotyping is unavailable. However, the constraint in available ARV choices in our population prohibited us to fully utilize genotyping information. Therefore, we believe that our data represent typical clinical care settings in most resource-limited countries.
In conclusion, this study provides security to clinicians in RLS to give children second-line treatment despite drug choice and laboratory monitoring constraints. Although we saw a good success rate in our study, one-fifth did not achieve viral suppression. Such children in RLS currently have no treatment option beyond second-line regimens. This emphasizes the urgent need to derive strategies to study, plan and procure new drugs and drug classes for children with treatment failure worldwide.
The HIV-NAT 086 study team
The HIV Netherlands Australia Thailand Research Collaboration (HIV-NAT), The Thai Red Cross AIDS Research Centre, Bangkok: T. Bunupuradah, C. Phasomsap, P. Kaew-on.
Institut de Recherche pour le Développement (IRD), UMI 174, Program for HIV Prevention and Treatment, Department of Medical Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand, The Global Fund to Fight AIDS, Malaria and Tuberculosis supported drug and laboratory monitoring for some children: S Kanjanavanit, Nakornping Hospital, Somdej Pranangchao Sirikit Hospital, Chonburi, Somdej Pranangchao Sirikit Hospital, Chonburi: T Hinjiranandana, Bhumibol Adulyadej Hospital, Bangkok: P Layangool, Somdej Prapinklao Hospital, Bangkok: N Kamonpakorn, Mae Chan Hospital, Chiang Rai: S Buranabanjasatean, Prapokklao Provincial Hospital, Chantaburi: C Ngampiyaskul.
Queen Sirikit National Institute of Child Health, Bangkok: T. Chotpitayasunondh, S. Chanpradub, P. Leawsrisuk. Department of Pediatrics, Faculty of Medicine, Siriraj Hospital, Mahidol University: S. Chearskul, N. Vanprapar, W. Phongsamart, K. Lapphra, P. Chearskul, O. Wittawatmongkol, W. Prasitsuebsai, K. Intalapaporn, N. Kongstan, N. Pannin, A. Maleesatharn, B. Khumcha.
Research Institute for Health Sciences (RIHES), Chiang Mai University, Chiang Mai: L. Aurpibul, N. Wongnum, R. Nadsasarn.
Department of Pediatrics, Faculty of Medicine, Khon Kaen University: P. Lumbiganon, P. Tharnprisan, T. Udompanich. Petchburi Hospital, Petchburi: M. Yentang.
Chiang Rai Regional Hospital, Chiang Rai: A. Khonponoi, N. Maneerat, S. Denjunta, S. Watanaporn, C. Yodsuwan, W. Srisuk, S. Somsri, K. Surapanichadul