Commentary: When to Start and What to Use in Children – Recommendations and Rationale

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Commentary: When to start and what to use in children – recommendations and rationale

George Siberrya and Denis Tindyebwab

AIDS 2014, 28 (Suppl 2):S133–S135

The 2013 WHO consolidated guidelines recommend reverse transcriptase inhibitor (NRTI) backbone in first- treating all HIV-infected children under the age of 5 years line ART for children under age 3 years is abacavir or regardless of CD4þ T-cell count or WHO clinical stage, zidovudine in combination with lamivudine; tenofovir and treating children aged 5 years and older according to disoproxil fumarate is a recommended NRTI option for the same criteria as for adults: WHO clinical stage 3 or 4 children age 3 to less than 10 years and is the preferred or CD4þ T-cell count of 500 cells/ml or less [1]. NRTI for adolescents (ages 10–19 years). When second- Guideline recommendations for what drugs to use for line therapy is required because of first-line treatment initial antiretroviral therapy (ART) vary by age group: less failure, children who were receiving an NNRTI-based than 3 years, 3–10 years and above 10 years. initial ART regimen should switch nevirapine to lopinavir/r, continue lamivudine and switch their other Table 1 summarizes the criteria for when to start ART in NRTI (abacavir or tenofovir disoproxil fumarate to HIV-infected children; a review of supporting evidence zidovudine, zidovudine to abacavir, or, if 2 years old, for these recommendations has been published [2]. The zidovudine to tenofovir disoproxil fumarate). Children at CHER study [3] provides evidence for treating all least 3 years old who are failing a lopinavir/r-based initial children less than 12 months of age (infants), and ART regimen should receive efavirenz in place of therefore for this age group, the recommendation was lopinavir/r, continue lamivudine and switch their other categorized as strong with moderate quality of evidence. NRTI (abacavir or tenofovir disoproxil fumarate to But for children aged 1 to less than 5 years, evidence to zidovudine, zidovudine to tenofovir disoproxil fumarate support this recommendation is lacking. The recom- or abacavir). For children less than 3 years old failing a mendation to treat all children less than 5 years of age lopinavir/r-based initial ART regimen, no change in regardless of WHO clinical stage or CD4þ T-cell count regimen is recommended unless there is advanced clinical was largely driven by programmatic reasons: to scale up disease progression or lack of adherence specifically paediatric ART in light of low coverage compared with because of poor palatability of lopinavir/r; in such cases, adult ART, to simplify treatment especially with limited an nevirapine-based ARTregimen should be considered. access to CD4þ T-cell count tests and to improve retention, as many programmes were reporting poor The WHO recommendations emphasize the choice of follow up of children on pre-ART care. It remains to be lopinavir/r over nevirapine in first-line therapy for seen whether indeed this recommendation will indeed children less than 3 years old, based on randomized increase paediatric ART uptake and retention. clinical trials that demonstrated superior efficacy of lopinavir/r, both for infants with and without prior The evidence informing the choice of initial ART nevirapine exposure through regimens used for preven- regimens for children under age 3 years and children at tion of mother-to-child transmission (PMTCT) [6,7]. least age 3 years (including adolescents) has been The preference for protease inhibitor based initial ART in summarized in systematic reviews [4,5]. The WHO this age group is unique, as NNRTI-based therapy is recommendations for first-line ART in children and recommended by WHO as first-line for all other adolescents are summarized in Table 2. populations, including older children (3 years old). However, liquid lopinavir/r presents major logistic In general, WHO recommends that all children under age barriers to widespread use, including high cost, cold- 3 years receive a lopinavir/r-based ART regimen; chain requirement and poor palatability. As a result, the nevirapine-based ART is recommended only if use of WHO recommendations advise initiation of a nevira- lopinavir/r is not feasible. The preferred dual nucleoside pine-based ARTregimen for this age group if lopinavir/r

aMaternal and Pediatric Infectious Disease (MPID) Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA, and bANECCA, Kampala, Uganda. Correspondence to George K Siberry, MD, MPH Maternal and Pediatric Infectious Disease (MPID) Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health 6100 Executive Boulevard, Room 4B11H Bethesda, MD 20892-7510, USA. Tel: +301 496 7350; fax: +301 496 8678; e-mail: [email protected]

DOI:10.1097/QAD.0000000000000241

ISSN 0269-9370 Q 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins S133 Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. S134 AIDS 2014, Vol 28 (Suppl 2)

Table 1. Summary of recommendations on when to start antiretroviral therapy in children in the 2013 WHO consolidated guidelines [1].

Age group Recommendation Strength of recommendation and quality of evidence

All ages WHO Stage 3 or 4 regardless of CD4þ T-cell count Strong recommendation, moderate quality of evidence Initiate ART in a child younger than 18 months with Strong recommendation, low quality of evidence presumptive clinical diagnosis of HIV infection

<5 years Initiate ART in all regardless of WHO clinical stage Infants in ﬁrst year of life – strong recommendation, or CD4þ T-cell count moderate quality of evidence 1to<5 years – conditional recommendation, very low quality of evidence

5 years and older Initiate ART in all with CD4þ T-cell count CD4þ T-cell count 350 cells/ml–strong recommendation, 500 cells/ml moderate quality of evidence CD4þ T-cell count between 350 and 500 cells/ml–conditional recommendation, very low quality of evidence

is not available or feasible, as deferring ART completely provide an option for substituting an NNRTI for would be expected to carry a higher risk of morbidity and lopinavir/r in those infants and young children who have mortality in this age group than initiating therapy with a achieved sustained virologic suppression (plasma viral load regimen that has a somewhat higher risk of virologic <400 copies/ml). This strategy may also preserve protease failure. As these guidelines were being finalized, efavirenz inhibitor activity for patients who develop treatment was licensed for infants and young children (3 months failure and NNRTI drug resistance later. This approach old), but further evaluation will be required in order to depends upon the availability of virologic monitoring, determine whether this drug will assume a role in initial which may limit the extent of its use. therapy of children less than 3 years old in the future, as there remain concerns regarding the pharmacokinetics Tuberculosis remains a major problem for children and appropriate dosing of efavirenz in young children [8]. with HIV infection, and interactions between antitu- Studies underway to evaluate raltegravir and other drugs berculosis and antiretroviral drugs are an even greater in infants and young children offer hope for new and problem for young children who cannot use efavirenz. improved options for initial therapy in the future. On the basis of results of the ARROW trial that demonstrated high efficacy of triple NRTI therapy The WHO recommendations include another strategy (zidovudine þ abacavir þ lamivudine) in maintaining vir- to address the difficulties of continued use of lopinavir/ ologic suppression in children who achieved virologic r-based ART in young children. On the basis of the results suppression on a full NNRTI-based ART regimen [10], of the NEVEREST study [9], the WHO guidelines there is a new recommendation to use this triple NRTI

Table 2. Summary of recommended ART regimens in the 2013 WHO guidelines [1].

Recommendation Strength of recommendation/quality of evidence

A lopinavir/ritonavir (lopinavir/r)-based regimen should be used as ﬁrst-line ART Strong recommendation, moderate-quality evidence for all HIV-infected children younger than 3 years (36 months) of age, regardless of NNRTI exposure. If lopinavir/r is not feasible, treatment should be initiated with an nevirapine-based regimen

Where viral load monitoring is available, consideration can be given to substituting Conditional recommendation, low-quality evidence lopinavir/r with an NNRTI after virological suppression is sustained

In HIV-infected infants and children younger than 3 years of age, abacavir þ Strong recommendation, moderate-quality evidence lamivudine þ zidovudine is recommended as an option for children who develop tuberculosis while on an ART regimen containing nevirapine or lopinavir/r. Once tuberculosis therapy has been completed, this regimen should be stopped and the original regimen should be restarted

For HIV-infected infants and children younger than 3 years of age, the NRTI Strong recommendation, low-quality evidence backbone for an ART regimen should be abacavir or zidovudine þ lamivudine

For HIV-infected infants and children 3 years and older (including adolescents), Strong recommendation, low-quality evidence efavirenz is the preferred NNRTI for ﬁrst-line treatment and nevirapine is the alternative

For adolescents infected with HIV (10 to 19 years old) weighing 35 kg or more, Strong recommendation, low-quality evidence the NRTI backbone for an ART regimen should align with that of adults and be one of the following, in preferential order: tenofovir disoproxil fumarate þ lamivudine (or emtricitabine); zidovudine þ lamivudine; abacavir þ lamivudine

strategy temporarily for the duration of tuberculosis r-based ART, however, the WHO no longer recom- therapy and then resume the original, standard ART mends a change in therapy, because protease inhibitor regimen once tuberculosis therapy has been completed. resistance takes much longer to accumulate, nevirapine Other options include optimizing the nevirapine dose, has relatively poor performance in this age group and no substituting nevirapine for lopinavir/r or super-boosting other options currently exist. lopinavir/r with additional ritonavir. All of these approaches have drawbacks, however, and evaluation of The 2013 WHO guidelines afﬁrm that ART inter- efavirenz and other drug options (e.g. raltegravir) in ruption is not recommended for children in this age children less than 3 years old who are receiving group. The guidelines also include a new section tuberculosis therapy are warranted. For children more outlining considerations for simplifying and harmoniz- than 3 years old who develop tuberculosis while on an ing ART regimens in children who have no prior ART regimen, no change is required for those already history or current evidence of treatment failure. A receiving efavirenz-based regimens and changing transition to simpler and better tolerated regimens as nevirapine or lopinavir/r to efavirenz is a recommended children grow older and new drug options become option, provided there is no history of NNRTI treatment available will be increasingly commonplace in many failure. programmes.

The choice of preferred NRTI backbone for children is limited by those drugs that are available in appropriate formulations and that have data available for at least safety Acknowledgements and pharmacokinetics to allow appropriate dosing, and ideally for efficacy as well. Although there is a stated Conflicts of interest preference for abacavir over zidovudine based on the There are no conflicts of interest. general principle of using nonthymidine analogues (such as abacavir) in first-line regimens and thymidine analogues (such as zidovudine) in second-line regimens, both of these drugs, together with lamivudine, are first- References line recommended NRTI backbones for children under age 3 years. Tenofovir disoproxil fumarate is part of 1. World Health Organization. Consolidated guidelines on the use of WHO-recommended first-line regimens for adolescents, antiretroviral drugs for treating and preventing HIV infection: recommendations for a public health approach. Geneva: World pregnant women and nonpregnant adults and is included Health Organization; 2013, http://whqlibdoc.who.int/publica in NRTI options for first-line ART regimens in children tions/2010/9789241599764_eng.pdf. [Accessed 26 January 2014] ages 3 to more than 10 years, but there are no safety or 2. Siegfried N, Davies MA, Penazzato M, Muhe LM, Egger M. pharmacokinetic data for use of tenofovir disoproxil Optimal time for initiating antiretroviral therapy (ART) in HIV- fumarate in children under age 2 years and very limited infected, treatment-naive children aged 2 to 5 years old. Cochrane Database Syst Rev 2013; 10:CD010309. information about its use in children 2–3 years old, 3. Violari A, Cotton MF, Gibb DM, Babiker AG, Steyn J, Madhi SA, though it is licensed for children at least 2 years old. A dual et al. Early antiretroviral therapy and mortality among HIV- NRTI backbone of tenofovir disoproxil fumarate in infected infants. N Engl J Med 2008; 359:2233–2244. 4. World Health Organization. What ARV regimen to start with in combination with lamivudine (or emtricitabine) is children older than or equal to three years of age? Geneva: generally recommended for people with hepatitis B World Health Organization; 2013, http://apps.who.int/iris/bit (HBV)-HIV coinfection, but for young children with stream/10665/90744/1/WHO_HIV_2013.27_eng.pdf. [Acces- sed 26 January 2014] HBV coinfection, the optimal ART regimen is not 5. Penazzato M, Prendergast AJ, Muhe LM, Tindyebwa D, Abrams known. Although d4T has been strongly discouraged for EJ. Optimization of antiretroviral therapy in HIV-infected first-line regimen options for adolescents and adults based children under 3 years of age: a systematic review. AIDS 2014; 28 (Supp 2):S137–S146. on toxicity concerns, it remains an option in first-line 6. Palumbo P, Lindsey JC, Hughes MD, Cotton MF, Bobat R, Meyers ART for children less than 3 years old in special T, et al. Antiretroviral treatment for children with peripartum circumstances. The currently limited availability of nevirapine exposure. N Engl J Med 2010; 363:1510–1520. 7. Violari A, Lindsey JC, Hughes MD, Mujuru HA, Barlow-Mosha abacavir, inability to use zidovudine in children with L, Kamthunzi P, et al. Nevirapine versus ritonavir-boosted severe anaemia and lack of other NRTI options mean that lopinavir for HIV-infected children. N Engl J Med 2012; 366:2380–2389. these special circumstances are relatively common. 8. Bristol-Myers Squibb Company. Sustiva [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; May 2013. Recommended second-line ART regimens are also 9. Coovadia A, Abrams EJ, Stehlau R, Meyers T, Martens L, Sherman G, et al. Reuse of nevirapine in exposed HIV-infected constrained by limited drug options available for children children after protease inhibitor-based viral suppression: a under age 3 years. Because resistance is almost uniform randomized controlled trial. JAMA 2010; 304:1082–1090. when NNRTI-based regimens fail, lopinavir/r replaces 10. ARROW trial team. Routine versus clinically driven laboratory monitoring and first-line antiretroviral therapy strategies in nevirapine or efavirenz in cases of ART failure. For most African children with HIV (ARROW): a 5-year open-label children less than 3 years old who fail first-line lopinavir/ randomised factorial trial. Lancet 2013; 381:1391–1403.