6.1. Recommendations
6.1.1. Infants
For infants not exposed to ARVs, start ART with nevirapine (NVP) + 2 nucleoside reverse transcriptase inhibitors (NRTIs).
(Strong recommendation, moderate quality of evidence)
For infants exposed to maternal or infant NVP or other NNRTIs used for maternal treatment or PMTCT, start ART with lopinavir/ritonavir (LPV/r) + 2 NRTIs.
(Strong recommendation, moderate quality of evidence)
For infants whose exposure to ARVs is unknown, start ART with NVP + 2 NRTIs.
(Conditional recommendation, low quality of evidence)
6.1.2. Children
- 4.
For children between 12 and 24 months of age exposed to maternal or infant NVP or other NNRTIs used for maternal treatment or PMTCT, start ART with lopinavir/ritonavir (LPV/r) + 2 NRTIs
(Conditional recommendation, low quality of evidence)
- 5.
For children between 12 and 24 months of age, not exposed to NNRTIs, start ART with NVP + 2 NRTIs.
(Strong recommendation, moderate quality of evidence)
- 6.
For children more than 24 months and less than 3 years of age, start ART with NVP + 2 NRTIs.
(Strong recommendation, moderate quality of evidence)
- 7.
For children 3 years of age and above, start ART with an NVP or efavirenz (EFV)-containing regimen + 2 NRTIs.
(Strong recommendation, moderate quality of evidence)
- 8.
For infants and children, the nucleoside backbone for an ART regimen should be one of the following, in preferential order:
(Conditional recommendation, low quality of evidence)
6.1.3. Infants and children with specific conditions
- 9.
For children >3 years of age with TB, the preferred regimen is EFV + 2 NRTIs.
(Conditional recommendation, very low quality of evidence)
- 10.
For infants and children less than 3 years of age with TB, the preferred regimens are NVP + 2 NRTIs or a triple nucleoside regimen.
(Conditional recommendation, very low quality of evidence)
- 11.
For a child or adolescent with severe anaemia (<7.5 g/dl) or severe neutropenia (<500 cells/mm3), the preferred regimen is NVP + 2 NRTIs (avoid AZT).
(Conditional recommendation, very low quality of evidence)
- 12.
For adolescents >12 years of age with hepatitis B, the preferred regimen is tenofovir disoproxil fumarate (TDF) + emtricitabine (FTC) or 3TC + NNRTI.
(Conditional recommendation, very low quality of evidence)
6.2. Antiretroviral treatment using a public health approach
Countries are encouraged to use a public health approach to support and facilitate wider access to ART [6]. Among the key tenets of this approach are standardization and simplification of ART regimens. Therefore, it is suggested that countries select a limited number of first-line regimens and suitable second-line regimens, recognizing that children who cannot tolerate or who fail the first-line and second-line regimens may require input from more experienced physicians. The use of three ARV medications is the current standard treatment for HIV infection, in order to achieve the best possible suppression of viral replication and to arrest the progression of HIV disease. It is important to maximize the durability and efficacy of any first-line regimen by incorporating approaches to support adherence.
Box 1Standard regimen for first-line ART
2 NRTIs + 1 NNRTI
NRTI/NNRTI-based regimens are efficacious and generally less expensive. In addition, generic formulations may be available, and a cold chain is not required.
Table 9Examples of NRTIs and NNRTIs
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| NRTIs include |
|---|
Thymidine analogue:
zidovudine (AZT)
stavudine (d4T) | Cytidine analogue:
lamivudine (3TC) | Guanosine analogue:
abacavir (ABC) |
| NNRTIs include |
|---|
| efavirenz (EFV)
nevirapine (NVP) | |
When appropriate ARV regimens are being selected for the national formulary, the following programme-level factors should be taken into consideration:
ability to treat all ages
suitability of drug formulation, particularly for dosing in infants, young children
ease of dispensing for pharmacists and caregivers
licensing approval by national drug regulatory authorities for the product and the recommended dose
toxicity profile
laboratory monitoring requirement
potential for maintenance of future treatment options
possibility of infant exposure to maternal ART or preventive ARV regimens, which could result in drug resistance
issues of adherence
prevalent coexisting conditions (e.g. coinfections, malnutrition, malaria, TB, hepatitis B and hepatitis C)
availability and cost-effectiveness
capacity of drug procurement and supply systems.
The choice of an appropriate ARV regimen may be further influenced by:
access to a limited number of ARVs in forms suitable for the treatment of infants and young children (see special considerations below);
limited health service infrastructures (including human resources);
the presence of varied HIV types (e.g. HIV-2).
6.3. Considerations for drug formulations and doses for infants and children
Quality-assuredi ARV drugs in fixed-dose combinations (FDCs)ii or blister co-packsiii were previously used for adults and older children but have recently become available for use by young children. Once-daily dosing has become available for some adult ARV combinations and further simplifies drug regimens. The advantages of FDCs and once-daily dosing include improved adherence which, in turn, limits the emergence of drug resistance. FDCs also simplify ARV storage and distribution logistics.
WHO strongly encourages the continued development of new formulations specifically for infants and children.
Syrups, solutions and sprinkles may remain necessary for treating infants and very young children who cannot swallow tablets or capsules, but they have shortcomings including limited availability, high cost, storage difficulties, reduced shelf-life, sometines high alcohol content and poor palatability. As children become older, it is preferable to give solid formulations. See the report of the WHO Paediatric Antiretroviral Working Group on ARV formulations for children at http://www.who.int/hiv/pub/paediatric/antiretroviral/en/index.html) [44]. For most ARVs, capsules and tablets are available in sufficiently low doses to enable accurate dosing for children. Some drugs, however, do not have solid formulations in doses appropriate for paediatric use. The pharmacokinetic profile of some but not all crushed tablets or sprinkled capsule contents have been evaluated.
Using tablets that must be cut can result in underdosing or overdosing, particularly if the tablets are unscored, and this may increase the risk of resistance or toxicity. Some solid formulations do not have even distribution of drug throughout the tablet. However, while suboptimal, cutting adult-dose solid formulation ARVs may be considered when no alternatives are available. When cutting un-scored tablets, the use of tablet cutters is preferred. Unscored tablets should not be cut to fractions below one half. Pharmacokinetic studies have confirmed that for younger children the use of single-drug liquid formulations is better than splitting adult FDCs [45].
Dosing in children is usually based on either weight or body surface area [46]. As these change with growth, drug doses must be adjusted in order to avoid the risk of underdosing. Standardization is important and it is recommended that health-care workers be provided with tables of simplified drug doses for administration. Such tables may vary with the local availability of ARV drugs and formulations. WHO has developed prototype weight-band based dosing tables, as well as tools to assist countries with the standardization and calculation of drug dosesiv (see
Annex E). A range of fixed-dose formulations for children are available including d4T/3TC/NVP, AZT/3TC/NVP and ABC/3TC.
6.4. Choice of a first-line regimen
Studies of many different potent ARV regimens in children have demonstrated that similar improvements to those obtained in adults are seen in morbidity, mortality and surrogate markers [38, 47-52].
6.4.1. Infants and children <24 months
The recommended first-line regimen for infants and children <24 months with no prior exposure to maternal or infant NNRTIs, or whose exposure to maternal or infant ARVs is unknown, is to start standard NVP-containing triple therapy.
Box 2Preferred regimen for NVP-naive infants or children <24 months with no known prior exposure to NVP
NVP + 3TC + AZT
Two NRTIs are combined with NVP as the NNRTI (Box 2). Reverse transcriptase inhibitor drugs prevent HIV replication by inhibition of the action of reverse transcriptase, the enzyme that HIV uses to make a DNA copy of its RNA. EFV is not currently recommended for use in children less than 3 years of age due to lack of information on appropriate dosing.
Data from a recent meta-analysis and from observational studies confirm that HIV-infected infants exposed to NNRTIs through infant prophylaxis or maternal treatment or prophylaxis have demonstrable viral resistance [53, 54]. An observational study [53] and a recent RCT [55] demonstrate that response to NVP-containing first-line treatment regimens may be compromised in infants and older children who acquire HIV despite intrapartum or peripartum exposure to NVP. Therefore, for HIV-infected infants and children under 24 months of age with a history of exposure to NVP or other NNRTIs used for maternal treatment or PMTCT, a PI-based triple ART regimen is recommended. Where PIs are not available, affordable or feasible, NVP-based therapy is recommended [56] (see ).
Box 3Preferred initial regimen for NNRTI-exposed infants or children <24 months
LPV/r + 3TC + AZT
While the guidelines panel felt the evidence and risk – benefit analysis warranted the above recommendation to be strong, they also recognized that in many resource-limited settings, LPV/r is not available, affordable or, due to cold chain requirements, not feasible for use. It is also acknowledged that the use of LPV/r in a first-line regimen may compromise the potential to construct a potent second-line regimen.
6.4.2. Children ≥24 months
The recommended first-line regimen for HIV-infected children ≥24 months of age, is two NRTIs plus one NNRTI (Box 1). There are two exceptions: the use of EFV should be avoided in adolescent girls (due to the teratogenic potential of EFV in the first trimester of pregnancy) and in children less than 3 years of age (due to lack of appropriate dosing information in this age group). (See for a summary of recommended first-line ART regimens for infants and children.)
The use of a triple NRTI regimen (i.e. [AZT or d4T] + 3TC + ABC) can be considered as an option for initial therapy in special circumstances (see Box 4). Of concern is the somewhat lower virological potency of this regimen compared with a two-class triple-drug combination in adult studies [57-60]. Currently, a triple NRTI regimen is only recommended in children less than three years of age who are receiving treatment for TB, a situation where NVP may not be an optimal choice because of drug interactions with rifampicin (see Chapter 13). This regimen could be considered for adolescents who may become pregnant, or adolescents with anticipated or documented poor adherence (see Chapter 15).
Box 4Recommended alternative ARV regimen for infants and children to simplify management of toxicity, comorbidity and drug – drug interaction
AZT or d4Ta+ 3TCb+ ABC
- a
AZT should not be given in combination with d4T.
- b
FTC can be used instead of 3TC in children more than 3 months of age.
6.5. Choice of NRTIs
NRTI drugs recommended for children are described below.
Lamivudine (3TC) is a potent NRTI with an excellent record of efficacy, safety and tolerability in HIV-infected children, and is a core component of the dual NRTI backbone of triple therapy. It is usually given twice daily in children and has been incorporated into a number of FDCs. Once-daily dosing is possible in older children.
Emtricitabine (FTC) is a newer NRTI that has recently been included in WHO's recommended first-line regimens for adults as an option and is also available for use in children; it can be given once daily. FTC is structurally related to 3TC and shares its resistance profile [61]. Where available, it can be used in children more than three months of age as an alternative to 3TC [62].
Stavudine (d4T) initially is better tolerated than AZT and does not require haemoglobin or laboratory monitoring. However, among the NRTIs, d4T has been most often associated with lipoatrophy and lactic acidosis [63]. In addition, peripheral neuropathy, elevated hepatic transaminases and pancreatitis have been observed.
Zidovudine (AZT) is generally well tolerated in children but has been associated with metabolic complications, although to a lesser extent than d4T. Initial drug-related side-effects are more frequent with AZT and the drug can cause severe anaemia and neutropenia; haematological monitoring is advised [64]. This is particularly important in areas where malaria is endemic or where malnutrition is common and anaemia is highly prevalent in young children. Large volumes of AZT liquid formulation are often poorly tolerated, and FDCs containing AZT are now available for children. In the event of intolerance, ABC or d4T can be substituted for AZT, except in cases of suspected lactic acidosis, where ABC is preferred.
Abacavir (ABC) is an alternative NRTI in first-line therapy. Data from clinical trials indicate a similar safety profile in children to that in adults, with very little haematological toxicity [65]. However, two large clinical trials found an association between ABC and myocardial infarction in adults [66, 67] but a meta-analysis from 54 clinical trials of ABC and another more recent clinical trial did not find this predisposition to cardiovascular diseases [68, 69]. Therefore, NRTI combinations containing ABC provide a good NRTI backbone for use with NNRTIs or as part of a triple nucleoside regimen. Of all the NRTI drugs, ABC has the least effect on mitochondrial DNA [70] and would be the preferred substitute for d4T or AZT in children developing lactic acidosis. However, in studies in Europe and the United States, ABC is associated with a potentially fatal hypersensitivity reaction in about 3% of children [71]. The frequency of ABC hypersensitivity in other regions is not known. In infants and children suspected of having a hypersensitivity reaction, ABC should be stopped and never restarted (see Annex F). Children starting ABC and/or their caregivers should be advised about the risk of hypersensitivity and the need to consult their care provider immediately if signs or symptoms of hypersensitivity occur.
Tenofovir (TDF) is included as an option for first-line regimens in adults. In adults, TDF is generally well tolerated [72] although there are numerous reports of renal insufficiency [73-75]. Because of limited paediatric safety data (especially the potential for effects on bone mineralization), the use of TDF in younger children is not yet recommended. A study in 16 HIV-infected children (age range 6.4 – 17.9 years) comparing TDF and d4T after 12 months of treatment reported that TDF did not impair bone mineral accrual and resulted in a good immunological response to ART [76]. However, a study using TDF as part of salvage therapy in children (age range 8.3 – 16.2 years) demonstrated a 6% decrease in bone density in 30% of children after 48 weeks of TDF [77]. Subsequent research has shown similar results [78], suggesting that TDF may be of limited use in prepubertal children. Additional clinical trials in ART-naive children as young as 2 years are ongoing.
Didanosine (ddI) is an adenosine nucleoside analogue NRTI. Its use is usually reserved for second-line regimens (see Chapter 12).
6.5.1. Choosing between NRTIs for first-line
The decision to use d4T, AZT or ABC in the first-line regimen needs to be made at the country level on the basis of local considerations, but it is recommended that at least two of these NRTIs be available to allow the substitution of one drug for the other should there be toxicity.
Fewer laboratory monitoring requirements may be a good reason to favour d4T over AZT as the chosen NRTI component, in particular, during the rapid scale-up of programmes. However, there is a long term risk of toxicity, particularly lipoatrophy in children treated with d4T-containing regimens. The use of d4T is being reduced in adults because d4T toxicity is frequently irreversible. D4T toxicity relates to the intracellular accumulation of the drug and its metabolites, and the subsequent poisoning of mitochondrial function. This explains why d4T toxicity develops gradually, over a longer time frame than toxicity to other ARVs. In children, however, d4T clearance is enhanced and intracellular levels are typically lower than in adults. Children can and do develop d4T toxicity but it is reported less often than in adults [64, 79-81].
Unlike d4T, AZT toxicity is increased in children compared with adults, with a high proportion developing anaemia over the first few months of therapy. However, in the long term, AZT is much better tolerated than d4T and is preferred over d4T despite the problem of anaemia and the relatively higher cost.
These guidelines introduce ABC as a preferred NRTI for first-line therapy. The choice of first-line NRTIs impacts second-line ART. Both AZT and d4T are thymidine analogues with very similar resistance profiles. Failure of AZT or d4T therapy results in the accumulation of thymidine analogue mutations (TAMs). The longer a child stays on a failing d4T- or AZT-based regimen, the more TAMs accumulate. Multiple TAMs reduce susceptibility to ABC, and thus may impact the success of future second-line therapy. By contrast, resistance to ABC does not result in resistance to thymidine analogues and one important advantage of ABC as a first-line drug is that both AZT and d4T will remain active in second-line.
There are limited options for paediatric treatment but all of these first-line choices are now available as generic, child-friendly FDCs. These guidelines recommend a preferential order of NRTIs to be used in first-line regimens, with AZT preferred over ABC, and ABC preferred over d4T. This recommendation seeks to balance toxicity, cost and practicality. National programmes should take into account the comparative short and long-term toxicities, as well as the relative risks and benefits to determine the optimal choice of NRTI for use in first-line therapy. Because of proven antagonism, d4T and AZT should never be used together [82, 83].
6.6. Choice of NNRTIs
NNRTI-based regimens are now the most widely prescribed combinations for initial therapy. They are potent, i.e. they rapidly reduce viral load, but are inactive with respect to HIV-2 and group O of HIV-1. In addition, a single mutation can induce cross-class resistance to the currently available NNRTIs. The NNRTIs EFV and NVP have both demonstrated clinical efficacy when administered in appropriate combination regimens in children. However, differences in toxicity profile, the potential for interaction with other treatments, a lack of dosing information for EFV in young children and cost are factors that need to be taken into consideration when choosing an NNRTI [84-91].
Efavirenz (EFV) is not currently recommended for use in children less than three years of age because there is no established dosing. EFV is primarily associated with toxicities related to the central nervous system (CNS), teratogenicity and rash. Rash is more frequent in children than in adults, is generally mild, and usually does not require discontinuation of therapy. The CNS symptoms typically abate after 10 – 14 days in the majority of patients; observational studies have revealed transient CNS disturbance in 26 – 36% of children receiving EFV [52, 91]. EFV should be avoided in children with a history of severe psychiatric illness, where there is a potential for pregnancy (unless effective contraception can be assured) and during the first trimester of pregnancy. In these situations, NVP may be the better choice (see below). EFV is preferred as the NNRTI of choice in children more than three years of age with TB/HIV coinfection [92] (see Chapter 13).
Nevirapine (NVP) should be given only in combination with other ARVs, except when used for prophylaxis to reduce the risk of perinatal HIV transmission. NVP has a higher incidence of rash than other ARVs. NVP-related rash may be severe and life-threatening, including Stevens – Johnson syndrome and, as noted below, NVP is associated with a rare but potentially life-threatening risk of hepatotoxicity. In these situations, NVP should be permanently discontinued and not restarted (see Chapter 9 and Annex F). This makes the drug less suitable for treating children who are on other hepatotoxic medications, or drugs that can cause rash. There are limited data on the use of NVP in children coinfected with HIV and hepatitis B. NVP is currently the only NNRTI that can be used in infants. In addition, NVP is a component of all the three-drug FDCs currently available.
NVP may be the preferred choice in adolescent girls when there is potential for pregnancy or during the first trimester of pregnancy when EFV should be avoided because of its potential teratogenic effect. While there have been reports of possible NVP-associated hepatotoxicity or serious rash, a review of NVP safety in pregnant women with CD4 between 250-350 cells/mm3 has not confirmed an increased risk of any serious adverse events, leading to the conclusion that the benefits of using NVP in pregnancy outweigh the risks [21]. Careful monitoring is none-the-less warranted for initiation of ART in adolescent, HIV-infected pregnant girls.
Limited data indicate that both EFV and NVP may interact with estrogen-based contraceptive pills. Because exposure to EFV should be avoided in the first trimester of pregnancy, it is recommended that sexually active adolescent girls receiving EFV consistently use barrier methods to prevent pregnancy in addition to or instead of oral contraceptives. Studies are in progress to evaluate interactions between injectable depot medroxyprogesterone acetate (DMPA) and selected PIs and NNRTIs. Despite initial pharmacokinetic studies suggesting some compromise of contraceptive efficacy, a large clinical study evaluated potential interactions between DMPA and selected PI and NNRTI drugs, and did not find significant clinical interactions [93-96].
Etravirine (ETV) is a new NNRTI that maintains activity against HIV with some NNRTI resistance mutations It is well tolerated in adults. A paediatric 25 mg tablet is in clinical trials.
Annex E provides more detailed information on dosing, preparations, storage and special instructions on the administration of the above-listed drugs.
6.7. Use of PIs in initial therapy
The efficacy of PIs in ARV-naïve children has been demonstrated, but in order to preserve a potent new class for second-line regimens, PIs usually are not used in first-line therapy. However, for infants and children <24 months who have been exposed to NVP or other NNRTIs, either directly or via maternal treatment before labour, during delivery or when breastfeeding, the PI LPV/r is now recommended as part of a first-line regimen.
PIs prevent viral replication by inhibiting the activity of an enzyme called protease that is used by HIV to cleave proteins required in the assembly of new virus particles. The PIs in use for children include LPV, RTV, nelfinavir (NFV), atazanavir (ATV), fos-amprenavir (FPV), darunavir (DRV) [97] and additional new PIs that are currently available to treat adults. RTV is exceptional as it inhibits the liver enzyme that normally metabolizes PIs. It is not used for its own antiviral activity but remains widely used in low doses to boost the effects of other PIs. LPV/r is the only PI available to date in a co-formulation and has been used extensively in children.
Further more detailed information on currently available PIs is available in in Chapter 12.
6.8. Summary of Chapter 6 – First Line ARV Regimens
Table 10Summary of preferred first-line ARV regimens for infants and children
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| Patient group | Standard first-line regimen |
|---|
| INFANTS |
|---|
| Infant or child <24 months not exposed to ARVs | NVP + 2 NRTI |
| Infant or child <24 months exposed to NNRTI | LPV/r + 2 NRTI |
| Infant or child <24 months with unknown ARV exposure | NVP + 2 NRTI |
| CHILDREN |
|---|
| Children 24 months to 3 years | NVP + 2 NRTI |
| Children >3 years | NVP or EFV + 2 NRTI |
Box 5Nevirapine-based regimens
Nevirapine + AZT/3TC (preferred)
OR
Nevirapine + ABC/3TC
OR
Nevirapine + d4T/3TC
Box 6Efavirenz-based regimens
Efavirenz + AZT/3TC (preferred)
OR
Efavirenz + ABC/3TC
OR
Efavirenz + d4T/3TC
Box 7Protease inhibitor-based regimens
Lopinavir/ritonavir + AZT/3TC (preferred)
OR
Lopinavir/ritonavir + ABC/3TC
OR
ORLopinavir/ritonavir + d4T/3TC
Table 11Preferred first-line regimens for specific situations
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| Situation | Preferred first-line regimen |
|---|
| CONCOMITANT CONDITIONS | |
| Child or adolescent with severe anaemia | NVP + 2 NRTIs (avoid AZT) |
| Child <3 years with TB treatment | NVP + 2 NRTIs
OR
3 NRTIs:
AZT or d4T + (3TC + ABC) |
| Child >3 years or adolescent with TB treatment | EFV + 2 NRTIs
OR
3 NRTIs:
AZT or d4T + (3TC + ABC) |
| Adolescent with hepatitis B | TDF + FTC or 3TC + NNRTI* |
- *
EFV should not be initiated in the first trimester of pregnancy or prescribed to women with the potential to become pregnant, unless effective contraceptive use is assured.
- i
In the context of this document, quality-assured medicines assembled in FDCs include individual products deemed to meet international standards of quality, safety and efficacy. For WHO's work on the prequalification of ARVs, see http://www.who.int/hiv/amds/en/
- ii
FDCs include two or more active pharmacological products in the same pill, capsule, granules, tablet or oral liquid.
- iii
A blister co-pack is a plastic or aluminium blister containing two or more pills, capsules or tablets.
- iv
