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Current Opinion in HIV & AIDS:
doi: 10.1097/COH.0b013e328354da1d
PHARMACOVIGILANCE OF ANTI-HIV DRUGS: Edited by Ian Weller

Recent advances in pharmacovigilance of antiretroviral therapy in HIV-infected and exposed children

Kenny, Juliaa,b; Musiime, Victorc; Judd, Alia; Gibb, Dianaa

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Author Information

aMedical Research Council, Clinical Trials Unit, London, UK

bInstitute of Child Health, University College London, UK

cJoint Clinical Research Centre, Kampala, Uganda

Correspondence to Dr Julia Kenny, MRC Clinical Trials Unit, 125 Kingsway, London, WC2B 6NH, UK. Tel: +44 20 7670 4716; fax: +44 20 7670 4685; e-mail: jmk@ctu.mrc.ac.uk

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Abstract

Purpose of review: Antiretroviral therapy (ART) has greatly improved the survival of HIV-infected children. However, ART is associated with immediate and long-term adverse events. Pharmacovigilance systems, although imperfect, have been developed in many high-income countries (HICs), but coverage in low- and middle-income countries (LMICs) is poor and uneven. This review covers the recent advances in the understanding of adverse events following perinatal ART exposure, including surveillance from birth cohorts; we also describe the adverse events of antiretroviral drugs among HIV-infected children, focussing particularly on those relevant to LMICs, where more than 90% of HIV-infected children live.

Recent findings: ART is largely safe in both HIV-infected and HIV-exposed uninfected children, in whom no significant increase in birth defects has been noted. Among HIV-infected children, toxicity to some drugs may be less frequent than in adults, possibly related to immature immune systems in younger children. As per WHO guidelines, many countries are moving from stavudine-based to zidovudine-based or abacavir-based fixed-dose combination (with nevirapine/lamivudine) paediatric mini-pills. However, reassuring data are emerging about short-term stavudine use in LMICs, as this remains an important first-line regimen for young children, as well as an alternative to zidovudine for anaemic children. Zidovudine appears to be well tolerated in young children living in nonmalarious areas, and, among African children, concerns about abacavir hypersensitivity have not been substantiated.

Summary: Optimization of first-line ART regimens needs to take account of the toxicities in HIV-infected children, in particular as they will take ART much longer than adults and during the period of growth and development. The benefits of ART in pregnancy are clear, but long-term follow-up of ART-exposed infants in LMICs through integrated surveillance systems would be invaluable.

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INTRODUCTION

Antiretroviral therapy (ART) has greatly improved the survival of HIV-infected children in both high-income countries (HICs) and low- and middle-income countries (LMICs), making HIV a chronic rather than life-limiting disease [1]. Worldwide, approximately 2.5 million children live with HIV, of whom approximately 90% live in sub-Saharan Africa; although ART provision has increased, in 2010 only approximately 23% children in need of ART worldwide were receiving treatment [2]. The population of HIV-exposed but uninfected (HEU) children who have been exposed to ART through prevention of mother-to-child transmission (PMTCT) interventions is increasing, and with this, the concern about potential effects of perinatal ART on subsequent child development.

Increasingly, HIV-infected children will face life-long ART exposure. Recent guidelines advocate early ART initiation in all HIV-infected children less than 2 years because of very high early mortality [3]; for older children (as adults), the threshold CD4 for starting ART has reduced over the last decade. Individuals are expected to continue ART indefinitely; results from the treatment interruption trials were disappointing in adults [4], and although promising in paediatrics, need further validation [5,6▪] and even then may only be possible when ART is started with good CD4 parameters and at young age [6▪,7]. Immediate and long-term ART-related adverse events have been well documented in adults [8,9]. Less data exist in paediatrics, particularly in LMICs where symptoms could be related to other common conditions.

In HICs, well established regulatory authorities influence the extent of pharmacovigilance [e.g. European Medicines Agency (EMA) and US Food and Drug Administration (FDA)] [10]. Most short-term safety data originate from trials; the quality of long-term safety data from other sources is generally lower [11]. Postmarketing surveillance was historically often limited to voluntary reporting of specific conditions and/or frequently financially supported by the pharmaceutical industry. The situation is difficult in LMICs where ART roll-out programmes generally use cheaper generic rather than innovator drugs, in environments lacking well established local and regional regulatory authorities. New initiatives to improve pharmacovigilance activities in LMICs include guidance from WHO and the Global Fund on establishment of pharmacovigilance systems [12] and continued development of the Uppsala Monitoring Centre's role in managing the WHO Programme for International Drug Monitoring [13–17].

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In this review, we first review the role of birth registries and other studies in informing evidence on pharmacovigilance of ART in HEU and HIV-infected children and secondly describe the recent advances in knowledge about adverse effects of ART in children, focussing on drugs used in LMICs.

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INFORMING THE PHARMACOVIGILANCE EVIDENCE BASE: THE ROLE OF BIRTH REGISTRIES AND PREVALENCE COHORTS OF HIV-INFECTED CHILDREN

HIV birth registries are confidential, active reporting systems in which pregnancies among HIV-infected women and the HIV infection status of their offspring are reported. Several registries also include HIV-infected children diagnosed later in life, whose mothers may not have known their HIV status in pregnancy, including children migrating into the country. Birth cohorts usually capture ART exposure occurring antenatally (in utero) or neonatally (prophylaxis or breastfeeding) in both HIV-infected and HEU children and have the potential to detect possible short-term and long-term ART-related adverse events. For example, the National Study of HIV in Pregnancy and Childhood in the UK and Ireland [18] follows infants born to known HIV-infected women until their HIV-status is definitively ascertained, and all reported HIV-infected children are subsequently followed through the Collaborative HIV Paediatric Study (CHIPS) [19]. However birth registries typically do not have complete case ascertainment and they also often have only limited follow-up of HEU children (typically to only 2 years of age). Examples of birth registries (often single centre) are reported from LMICs [20], but data are often limited by high rates of loss to follow-up [21,22].

The low prevalence of HIV among pregnant women in most HICs, coupled with the rarity of most adverse events among HEU and incomplete coverage by birth registries, has resulted in cohort collaborations being established, which pool individual-patient registry data with clinic case reports. The largest and most established of these is the Antiretroviral Pregnancy Registry (APR) (www apregistry.com), which is sponsored by the pharmaceutical industry. This American-based but multinational, voluntary collaborative register monitors antenatal ART exposure and associated birth defects through retrospective passive reporting (pregnancies have known outcome at time of reporting), clinical studies, reports from published literature and prospective reporting (pregnancies reported and follow for outcome) [23].

In Europe, the EMA now requires pharmaceutical companies to submit a paediatric investigation plan (PIP) for drugs, including measures to address long-term follow-up of potential paediatric safety issues [24]. To help with this, a pharmacovigilance programme has been developed within the European Pregnancy and Paediatric HIV Cohort Collaboration (EPPICC), a collaboration including 13 pregnancy and paediatric HIV cohorts from 15 European countries, of which some are birth registries following children from birth and others also include follow-up of HIV-infected children presenting later in childhood. EPPICC primarily conducts epidemiological research on the prognosis and outcome of HIV-infected women and children and HEU children, but is also an invaluable and cost-effective source of pharmacovigilance data for regulatory authorities. Pharmacovigilance activities to date have focussed on the data from 5000 HIV-infected children ever in follow-up and 2500 in current follow-up from eight paediatric cohorts. Data items routinely collected by most cohorts include demographics, ART history, CD4 and viral load measurements, other laboratory data and adverse and serious adverse events along with the reasons for change of ART regimen. Data are merged annually using a standardized data exchange protocol (http://www.hicdep.org/), and adverse outcomes categorized according to Division of AIDS grading tables [25]. Drug-specific reports authored independently from the pharmaceutical industry are submitted to the EMA. Findings to date suggest that there are no major safety concerns regarding currently licensed drugs and doses. However, there are issues around data completeness, and single-centre rather than multicentre cohorts are more likely to have complete reporting of adverse events. Identifying appropriate comparative populations is difficult, as rates of adverse events associated with a particular drug in isolation are hard to interpret without data for other drugs in a similar population.

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ADVERSE EFFECTS OF ANTIRETROVIRAL THERAPY IN HIV-EXPOSED UNINFECTED CHILDREN

(Table 1) [26,27,28▪,29▪,30▪▪,31,32▪▪,33,34,35▪,36,37,38▪,39] Worldwide, millions of women have taken ART for PMTCT, thereby preventing thousands of infants becoming HIV infected. Growing evidence suggests that ART is generally safe for both mother and baby [40▪]. Known side-effects are outweighed by the benefits of preventing HIV transmission, but include increased preterm delivery [41] especially with protease inhibitor use [32▪▪,33], advanced maternal immunosuppression [42▪] and mitochondrial toxicity. The latter was first described in babies exposed to perinatal zidovudine (ZDV) [43–46], but has not been confirmed in several large United States and European studies [47–49], suggesting the risk of severe mitochondrial disease is low [10]. However, diagnosis of mild disease is complex as there are no good diagnostic markers and symptoms can mimic other diseases (e.g. sepsis, which is especially prevalent in LMICs).

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Table 1 lists the short-term adverse events in HEU infants associated with ART used for PMTCT. No specific short-term toxicities have been reported with maternal use of lamivudine (3TC), stavudine (d4T), abacavir (ABC), tenofovir (TDF), nevirapine (NVP) and lopinavir (LPV/r). Maternal and neonatal ZDV has been associated with neonatal anaemia [35▪,36], and regular monitoring of neonatal bilirubin is advised with maternal atazanavir (ATV) [34]. Early concerns, based on animal data, of an association between maternal efavirenz (EFV) and neural tube defects have not been substantiated in analyses of human cohorts and meta-analysis [30▪▪]. In neonates, short-term nevirapine has a low risk of adverse events [37], while lopinavir use is not advised in premature infants because of toxicity and adrenal dysfunction (see below) [39,50,51▪].

To date, no longer term toxicities have been reported. However, nucleoside reverse transcriptase inhibitors (NRTIs) are potentially genotoxic, and long-term studies are evaluating the cancer incidence in HEU children; 5-year follow-up in the French perinatal cohort showed no increase in the overall cancer incidence compared with the general population, although unexpectedly more CNS tumours were found among children whose mothers took didanosine–lamivudine in combination, for unknown reasons, although numbers were small and this could have been a chance finding [52]. In the UK, linkage between the National Study of HIV in Pregnancy and Childhood (NSHPC) and national cancer register, known as ‘flagging’, is on-going (to the end of 2011, >8000 English-born HIV-exposed infants have been flagged) [53].

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ADVERSE EFFECTS OF ANTIRETROVIRAL THERAPY IN HIV-INFECTED CHILDREN

The aims of ART are to maximize health, growth and development for HIV-infected children, whilst minimizing the risks of short-term and long-term adverse reactions. Here, we discuss the methods used to assess toxicity and examine the data focussing on ART drugs used in LMICs; Table 2[54,55▪,56–65] lists the key toxicities in children.

Table 2-a Key short-...
Table 2-a Key short-...
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RECORDING TOXICITIES

Table 2-b Key short-...
Table 2-b Key short-...
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Assessing and attributing adverse reactions is difficult even within clinical trials. In HIV, this situation is further complicated because patients take three drugs together, and assigning causality to a single drug relies on knowledge about individual drug toxicities. Thus, the most reliable surveillance data on toxicities are generally limited to instances of toxicity resulting in stopping a particular ART drug. Postlicensing surveillance can occur through strategy trials, cohort studies and surveillance (e.g. the ‘yellow card’ passive national surveillance coordinated by the MHRA in UK – http://yellowcard.mhra.gov.uk/), although under reporting and ascertainment bias are issues for any passive reporting system. Utilizing national databases for pharmacovigilance activities is possible, an example of this is the nested case–control study used to assess tenofovir (TDF) renal toxicities that analysed longitudinal biochemistry results of HIV-infected paediatric patients in the CHIPS cohort taking and not taking tenofovir [66]; this is an example of one of the few studies in which patients taking tenofovir were compared with those who were not. Prospective cohort studies allow systematic data collection but are frequently costly. Loss to follow-up is an important problem in many cohorts, but has been helped in the UK by the fact that the CHIPS cohort is national and so patients can be tracked following transfer to another clinic (http://www.chipscohort.ac.uk).

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THE NUCLEOSIDE/NUCLEOTIDE REVERSE TRANSCRIPTASE INHIBITOR DRUGS

Development of fixed-dose combination (FDC), dispersible, scored solid formulations, with appropriate drug ratios for children, dosed according to WHO weight-band tables (see Table 3[67–70])–rather than calculations (mg/kg or mg/surface area)], has been important for simplifying paediatric ART provision by non doctor health-providers in LMICs. Few trials have compared NRTIs in children and currently ZDV, d4T and ABC are all the first-line options in 2010 WHO guidelines [67]. Stavudine is rarely used in HICs (although remaining on the EMA paediatric drug list) and is being increasingly replaced by ZDV or ABC in LMICs. TDF was recently licensed for children greater than >2 years and paediatric FDCs will follow, bringing the possibility of increased harmonization with adult formulations and thereby aiding drug distribution. The CHAPAS 3 trial (ISRCTN69078957) is a randomized open three-arm 480 children trial evaluating 96-week toxicity of ZDV vs. d4T vs. ABC in FDCs with 3TC and nevirapine in Uganda/Zambia; results will be available in 2013.

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Each NRTI has different toxicities, the importance of which varies according to setting and ethnicity. Thus, ABC hypersensitivity reaction is well described and in HIC screening for HLAB*5701 is undertaken prior to starting ABC in order to avoid the drug reaction [71]. However, this polymorphism is very rare in Africans [72], as evidenced in children from the ARROW trial (ISCRTN 24791884) in Uganda and Zimbabwe where there were only four possible cases among >1200 children [55▪]. ZDV may not be ideal in young children in areas highly endemic with malaria where anaemia is already common, but there are few data on the frequency of ZDV-related anaemia from Africa. The ARROW trial (results late 2012) will provide the first randomized comparison of ZDV vs. no ZDV short-term toxicity data (www.arrowtrial.org). In nonmalarious areas, data from the South African CHER trial suggested anaemia was uncommon in young asymptomatic babies receiving ZDV plus 3TC plus Kaletra [3].

d4T has been extensively used worldwide; for adults and children, d4T-containing FDCs have been critical to early ART roll-out and remain cheaper than alternatives. In 2009, WHO estimated that 59.7% of adults and 55.5% of children were receiving d4T as part of initial regimen [73]. Short-term toxicity is rare, but with 40 mg for adults and adolescents, long-term lipodystrophy is relatively common. Using the 1 mg/kg dose of individual drug in children, lipodystrophy has also been reported, although most studies are cross-sectional and standard definitions in growing children are problematic [74▪,75–77]. Recent reports from South Africa describe lipodystrophy using individual d4T where 1 mg/kg doses tend to round up (i.e. equivalent to at least 40 mg/kg (Steve Innes, personal communication) [77]. WHO 2007 guidelines recommended lowering the stavudine dose to 30 mg for adults and adolescents, and even lower doses are still being discussed for inclusion in trials [78▪▪]. For children, the recommended WHO ‘baby pill’ (suitable up to <10 kg) FDCs have drug ratios for NVP : 3TC : d4T of 50 : 30 : 6 (with ‘junior pills’ having double dose making them suitable for 10–30 kg children), resulting in the required higher doses of NVP, but less than the 1 mg/kg stavudine dose. Anecdotally, lipodystrophy appears uncommon in young children; however, many countries are substituting stavudine-containing FDCs for ZDV or ABC where available (or with individual components if FDCs not available) which will take time, given the large number of children on this FDC. The reversibility of subclinical stavudine-related changes (e.g. low skinfold values) may occur more readily in young children [79,80,81▪▪]; results from CHAPAS 3 will clarify whether this occurs and therefore whether starting d4T and substituting later could be a useful strategy. Of note, although the association of lipodystrophy with d4T is well documented, other reported risk factors include white ethnicity, increasing BMI, advanced disease and LPV/r and EFV use [74▪].

ABC is an alternative highly effective first-line NRTI with better efficacy than ZDV as shown in the PENTA 5 trial [82]. In adults, an increase in cardiovascular disease was reported in cohort studies whilst on ABC [4,83], although this has not been replicated in other studies [84–87]. Prescription bias, whereby adults with renal risk factors were preferentially prescribed ABC instead of tenofovir could be an explanation [88]. Alternative mechanisms include platelet hyper-reactivity [89–91], endothelial dysfunction [92] and increased inflammation, triggered by ABC [93]. Cardiovascular toxicity in children is being studied in the CHAPAS 3 trial.

Tenofovir was licensed by the FDA but not EMA for children aged 2–12 years in January 2012. Renal toxicity, hypophosphataemia and osteopenia is of concern, although even using adult formulations, the safety profile in paediatric and adolescent cohorts has been reasonable [66,94,95] and in the large 6-year African DART trial, toxicity was no more frequent in the clinically monitored compared with the clinically and laboratory monitored group [96]. None-the-less, ongoing surveillance of long-term tenofovir toxicity will be an important task among children in both HICs and LMICs, and once the drug is licensed in Europe, postlicensing cohort data would be important to collect.

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PROTEASE INHIBITORS

Ritonavir-boosted lopinavir (LPV/r) is the most widely used protease inhibitor in paediatrics, in part because it is a FDC not requiring separate ritonavir syrup (very poor palatability) or tablets (large 100 mg tablets which cannot be split). Available as Kaletra oral solution, LPV/r is approved for infants greater than 14 days by FDA but by EMA only for children greater than 2 years. Following African data suggesting superiority over NVP among babies exposed to sdNVP [97▪] (although this was a short-term trial and not replicated in other studies [98▪,99▪]), its use is likely to increase, especially if a generic sprinkle formulation shows favourable PK and acceptability [ongoing CHAPAS 2 trial (ISRCTN01946535)] Of concern, cases of toxicity in neonates (predominantly premature infants (gestation age 28–35 weeks), including cardiac toxicity, acute renal failure, electrolyte abnormalities and neurological manifestations have been reported; two overdoses have resulted in one death [50]. In addition, transient adrenal dysfunction and cardiac events (twins, one with complete heart block and dilated cardiomyopathy and the other with mild bradycardia) have been described with LPV/r in premature infants [39,51▪], and attributed to high concentrations of ethanol and propylene glycol in the oral solution which are poorly metabolized at this age. Additionally of concern is the dyslipidaemia which appears to be especially prevalent with LPV/r, the effects of this on cardiovascular risk in later life need to be considered [100].

In ART-naïve adults, once daily LPV/r dosing resulted in better adherence and similar virological response [101], although higher levels of diarrhoea were reported in adults randomized to once daily dosing [102]. The KONCERT trial (www.pentatrials.org) will provide data on safety, tolerability, PK and virological efficacy of daily LPV/r tablets in ART-experienced children weighing over 15 kg. Through the EPPICC cohorts, fosamprenavir, darunavir and atazanavir are being studied in European paediatric cohorts, as part of the post licensing requirement by EMA [103]; to date, no safety concerns regarding the current licensed doses have been found.

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NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS

Both first-generation nonnucleoside reverse transcriptase inhibitors (NNRTIs), EFV and NVP, have established efficacy, safety and tolerability profiles, and are affordable in LMICs. NVP can be used from the neonatal period onwards and is well tolerated. NVP-associated skin rashes have been reported to be less common in children than in adults [57,104,105]. However, in the CHAPAS 1 randomized trial, skin rash (all grade 2 or below) was more frequently observed with immediate full-dose NVP than using a dose-escalation approach to NVP initiation [57].

EFV can only be used in children greater than 3 years (dose not optimized in younger children <10  kg) and is once daily; however, FDCs with three drugs used in adults have not been co-formulated for children. Gynaecomastia has been described in adults and is likely underreported in children and adolescents [106]. Up to 50% adults report CNS symptoms or neuropsychiatric adverse events on EFV [107]; similar findings have been reported in children, but appear less common in younger children, although are important during adolescence. Genetic polymorphisms resulting in slow metabolism predispose some African children to very high EFV plasma levels, increasing the risk of toxicity [108]. Related pharmacokinetics to adverse events is being studied in CHAPAS 3 trial. EFV dosing, using the WHO 2006 weight bands, attempts to provide optimal dosing for virological suppression whilst minimizing the risk of toxicity and the need for multiple strengths of tablets [109].

Unfortunately, high-level resistance to EFV and NVP can develop rapidly in the presence of high viral load levels. Alternative second-generation NNRTIs including etravirine and rilpivirine (TMC278) are being evaluated in children and may be particularly useful following single-dose perinatal NVP exposure. Limited data on etravirine in children greater than 6 years suggest a good safety profile and its use in adolescents with multiresistance virus showed favourable results [110].

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CONCLUSION

As ART roll-out accelerates, consideration of short-term and long-term drug toxicity remains an important consideration for paediatric ART in addition to paediatric formulations, cost and the need to harmonize ART with adults to simplify procurement and reduce costs. Overridingly, ART saves lives and has had an enormous impact on life expectancy among HIV-infected children. Optimizing paediatric pharmacovigilance activities is not straightforward and requires international cooperation between licensing authorities, pharmaceutical companies, academics and clinicians, using complimentary and innovative approaches; existing national systems should be utilized and reporting should be as straightforward as possible to reduce additional workload for healthcare workers in already overstretched healthcare systems. Capturing adverse events in LMICs, where the majority of HIV-infected children live, is important so that safety and confidence in ART is maintained and adherence is maximized, particularly in pMTCT programmes working towards the goal of elimination in children. Birth registries have provided reassurance that antiretroviral drugs are not causing major congenital abnormalities, but reporting to the international pregnancy register must continue as the number of drugs continues to expand. Further we need long-term follow-up of both HIV-infected and HEU children into adulthood for continued pharmacovigilance of intrauterine and early childhood as well as long-term exposure to antiretroviral drugs.

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Acknowledgements

The authors acknowledge Pat Tookey and Claire Thorne for their extremely helpful comments and additions to the manuscript.

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Conflicts of interest

Julia Kenny is a Wellcome Trust clinical research fellow.

Di Gibb: Generic and nongeneric drugs are provided by companies for several trials coordinated by Medical Research Council Clinical Trials Unit. No personal payments are received from any company.

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REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

▪ of special interest

▪▪ of outstanding interest

Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 377–378).

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Follow-up of long-term outcomes of infants born to HIV-infected African women taking antiretroviral therapy (ART) in pregnancy. A total of 382 pregnancies were reported in 302 of 1867(16%) women enrolled in the DART trial. Of the 226 live-births, there were 7(3%) congenital abnormalities, with no effect of in-utero tenofovir exposure. Of 219 surviving infants, 182 (83%) were followed up to a median age of 25 months. Overall 1-year infant mortality was similar to postneonatal mortality in this region. No increase in congenital, renal or growth abnormalities was observed with in-utero tenofovir exposure.

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An updated and expanded meta-analysis offering reassurance that no increase in overall birth defects is seen amongst women receiving first-trimester efavirenz compared with women on nonefavirenz-based ART and the general population. The incidence of neural tube defects remains low at 0.07%; however, the authors note that there remains a lack of systematic recording of birth outcomes and prospective surveillance systems, particularly in developing countries, which are needed to improve data reporting and inform the assessment of risk of rare defects.

31. Ekouevi DK, Coffie PA, Ouattara E, et al. Pregnancy outcomes in women exposed to efavirenz and nevirapine: an appraisal of the IeDEA West Africa and ANRS databases, Abidjan, Cote d’Ivoire. J Acquir Immune Defic Syndr 2011; 56:183–187.

32▪▪. Powis KM, Kitch D, Ogwu A, et al. Increased risk of preterm delivery among HIV-infected women randomized to protease versus nucleoside reverse transcriptase inhibitor-based HAART during pregnancy. J Infect Dis 2011; 204:506–514.

An American RCT of 530 HIV-infected ART naive pregnant women with CD4 greater than 200 cells/mm3 who were randomized between 26 and 34 weeks to either ZDV/3TC/LPV/r (protease inhibitor group) or ABC/ZDV/3TC (NRTI group) that demonstrated that preterm delivery rates were higher in the protease inhibitor group (21.4 vs. 11.8%, P = 0.003). Protease inhibitors-based ART was the most significant risk factor for preterm delivery. No difference in infant hospitalizations or mortality was seen between groups.

33. Beckerman K, Albano J, Cohan D, et al. Exposure to combination antiretroviral regimens containing protease inhibitors during pregnancy and prevalence of low birth weight/preterm delivery among women with low preexisting risk: a stratified analysis of 10 082 prospective live births, The Antiretroviral Pregnancy Registry, 1989–2010. 6th International AIDS Society (IAS), Rome; 2011.

34. Mandelbrot L, Mazy F, Floch-Tudal C, et al. Atazanavir in pregnancy: impact on neonatal hyperbilirubinemia. Eur J Obstet Gynecol Reprod Biol 2011; 157:18–21.

35▪. Dryden-Peterson S, Shapiro RL, Hughes MD, et al. Increased risk of severe infant anemia after exposure to maternal HAART, Botswana. J Acquir Immune Defic Syndr 2011; 56:428–436.

The incidence of severe anaemia in HIV-uninfected infants in the Mashi and Mma Bana mother-to-child HIV transmission prevention trials in Botswana was compared between three groups with differing in-utero and postnatal ARV regimens. Severe anaemia was detected in 118 infants (7.4%), with infants who had been exposed to in-utero triple ART and postnatal ZDV at greatest risk. Although most anaemia was asymptomatic and improved with iron and multivitamin supplementation and cessation of ZDV exposure, 11 infants required transfusion for symptomatic anaemia. Confirmation of this finding is required and strategies to minimize neonatal anaemia considered.

36. Lahoz R, Noguera A, Rovira N, et al. Antiretroviral-related hematologic short-term toxicity in healthy infants: implications of the new neonatal 4-week zidovudine regimen. Pediatr Infect Dis J 2010; 29:376–379.

37. McKoy JM, Bennett CL, Scheetz MH, et al. Hepatotoxicity associated with long-versus short-course HIV-prophylactic nevirapine use: a systematic review and meta-analysis from the Research on Adverse Drug events And Reports (RADAR) project. Drug Saf 2009; 32:147–158.

38▪. Coovadia HM, Brown ER, Fowler MG, et al. Efficacy and safety of an extended nevirapine regimen in infant children of breastfeeding mothers with HIV-1 infection for prevention of postnatal HIV-1 transmission (HPTN 046): a randomised, double-blind, placebo-controlled trial. Lancet 2012; 379:221–228.

A trial of 1527 HIV-exposed but uninfected infants conducted in four African countries that looked at the safety and reduction in HIV transmission when NVP was given to breastfed infants (n = 762) compared with placebo (n = 765) for 28 weeks. In the extended NVP group, a 54% reduction in HIV-transmission (from 2.4 to 1.1% transmission) was noted with no effect on morbidity, mortality or rate of adverse events between the NVP and placebo group.

39. McArthur MA, Kalu SU, Foulks AR, et al. Twin preterm neonates with cardiac toxicity related to lopinavir/ritonavir therapy. Pediatr Infect Dis J 2009; 28:1127–1129.

40▪. Watts DH, Huang S, Culnane M, et al. Birth defects among a cohort of infants born to HIV-infected women on antiretroviral medication. J Perinat Med 2011; 39:163–170.

This a review of 1414 live births to mothers in the Paediatric AIDS Clinical Trials Group 316 trial that studied addition of peripartum nevirapine to established ARV regimen for prevention of mother-to-child transmission. Birth defects were detected in 60 of 1414 (4.2%; 95% CI 3.3–5.4%) infants, adding further evidence that ARV use in early pregnancy is not associated with an increased risk of birth defects overall. Of slight concern (and not seen in other studies) was an association of ARV exposure with heart defects. A heterogeneous mix of defects were described (cono-truncal, right-sided obstructive, left-sided obstructive, septal defects, cardiomyopathy) in patients with a variety of ART exposure. This confirms the need for ongoing detailed surveillance of HEU infants.

41. Broom J, Sowden D. Premature labour precipitated by highly active antiretroviral therapy: an adverse reaction in a newly diagnosed HIV-positive patient. Sex Health 2011; 8:436–438.

42▪. Van der Merwe K, Hoffman R, Black V, et al. Birth outcomes in South African women receiving highly active antiretroviral therapy: a retrospective observational study. J Int AIDS Soc 2011; 14:42.

A retrospective observational review of birth outcomes in a South African cohort with advanced maternal immunosuppression (CD4 <250 cells/mm3). In-utero HAART exposure was not associated with low birth weight; however, an association between NNRTI-based ART and preterm birth was detected. More advanced immunosuppression was a risk factor for low birth weight and preterm birth, adding further evidence that infected women need ART early in pregnancy to optimize maternal health and improve infant outcomes.

43. Blanche S, Tardieu M, Rustin P, et al. Persistent mitochondrial dysfunction and perinatal exposure to antiretroviral nucleoside analogues. Lancet 1999; 354:1084–1089.

44. Landreau-Mascaro A, Barret B, Mayaux MJ, et al. Risk of early febrile seizure with perinatal exposure to nucleoside analogues. Lancet 2002; 359:583–584.

45. Noguera A, Fortuny C, Munoz-Almagro C, et al. Hyperlactatemia in human immunodeficiency virus uninfected infants who are exposed to antiretrovirals. Pediatrics 2004; 114:e598–e603.

46. Tovo PA, Chiapello N, Gabiano C, et al. Case report Zidovudine administration during pregnancy and mitochondrial disease in the offspring. Antivir Ther 2005; 10:697–699.

47. European Collaborative Study Group. Exposure to antiretroviral therapy in utero or early life: the health of uninfected children born to HIV infected women. J Acquired Immune Deficiency Syndr 2003; 32:380–387.

48. Lindegren ML, Rhodes P, Gordon L, Fleming P. Drug safety during pregnancy and in infants: lack of mortality related to mitochondrial dysfunction among perinatally HIV-1 exposed children in pediatric HIV surveillance. Ann N Y Acad Sci 2000; 918:222–235.

49. Mofenson LM, Munderi P. Safety of antiretroviral prophylaxis of perinatal transmission for HIV-infected pregnant women and their infants. J Acquir Immune Defic Syndr 2002; 30:200–215.

50. Boxwell D, Cao K, Lewis L, et al. Neonatal toxicity of Kaletra oral solution-LPV, ethanol, or propylene glycol? 18th Conference on Retroviruses and Opportunistic Infections, Boston; 2011.

51▪. Simon A, Warszawski J, Kariyawasam D, et al. Association of prenatal and postnatal exposure to lopinavir–ritonavir and adrenal dysfunction among uninfected infants of HIV-infected mothers. JAMA 2011; 306:70–78.

A French study of 50 neonates who received LPV/r compared with neonates receiving ZDV-based treatment. Raised levels of 17OHP and DHEA-S (suggestive of adrenal dysfunction) were seen in the LPV/r-treated group compared with the ZDV group. All term LPV/r-treated neonates were asymptomatic; however, three premature neonates (one 30 week and 34 week twins) experienced life-threatening symptoms compatible with adrenal insufficiency, including hyponatremia and hyperkalemia with, in one case, cardiogenic shock. All symptoms resolved following completion of the LPV/r treatment. This study suggests the LPV/r should be avoided in premature neonates and used with extreme caution in term neonates.

52. Benhammou V, Warszawski J, Bellec S, et al. Incidence of cancer in children perinatally exposed to nucleoside reverse transcriptase inhibitors. AIDS 2008; 22:2165–2177.

53. Hankin C, Lyall H, Peckham C, Tookey P. Monitoring death and cancer in children born to HIV-infected women in England and Wales: use of HIV surveillance and national routine data. AIDS 2007; 21:867–869.

54. Fielder J, Rambiki K. Occurrence of stavudine-induced lactic acidosis in 3 members of an African family. J Int Assoc Physicians AIDS Care 2010; 9:236–239.

55▪. Nahirya-Ntege P, Musiime V, Naidoo B, et al. Low incidence of abacavir hypersensitivity reaction among African children initiating antiretroviral therapy. Pediatr Infect Dis J 2011; 30:535–537.

Extremely reassuring data from Zimbabwe and Uganda showing a very low incidence (0.3%) of suspected ABC hypersensitivity reactions in children commenced on ABC. With careful education of clinical staff, children and caregivers, ABC can be safely used in this context without the need to test for HLA-B5701.

56. Bouazza N, Urien S, Hirt D, et al. Population pharmacokinetics of tenofovir in HIV-1 infected pediatric patients. J Acquir Immune Defic Syndr 2011; 58:283–288.

57. Mulenga V, Cook A, Walker AS, et al. Strategies for nevirapine initiation in HIV-infected children taking pediatric fixed-dose combination baby pills in Zambia: a randomized controlled trial. Clin Infect Dis 2010; 51:1081–1089.

58. Strehlau R, Martens L, Coovadia A, et al. Absence seizures associated with efavirenz initiation. Pediatr Infect Dis J 2011; 30:1001–1003.

59. Tudor-Williams G, Cahn P, Chokephaibulkit K, et al. Safety and efficacy of etravirine in HIV-1-infected, treatment-experienced children and adolescents (6 to <18 years): week 24 primary analysis of the phase II PIANO study [abstract TULBPE027], 6th IAS Conference on HIV pathogenesis, treatment and prevention, Rome. 2011; pp, 17–20.

60. Nso AP, Larru B, Bellon JM, et al. HIV-infected adolescents: relationship between atazanavir plasma levels and bilirubin concentrations. J Adolesc Health 2011; 48:100–102.

61. Thuret I, Chaix ML, Tamalet C, et al. Raltegravir, etravirine and r-darunavir combination in adolescents with multidrug-resistant virus. AIDS 2009; 23:2364–2366.

62. Briz V, León-Leal JA, Palladino C, et al. Potent and sustained antiviral response of raltegravir-based highly active antiretroviral therapy in HIV type 1-infected children and adolescents. Pediatr Infect Dis J 2012; 31:273–277.

63. Wiznia A, Samson P, Acosta E. Safety and efficacy of raltegravir (RAL) in pediatric HIV infection. Preliminary analysis from IMPAACT P1066. 2009.

64. Lee JSF, Calmy A, Andrieux-Meyer I, Ford N. Review of the safety, efficacy, and pharmacokinetics of elvitegravir with an emphasis on resource-limited settings. HIV/AIDS (Auckland, NZ) 2012; 4:5–15.

65. Patel P, Song I, Borland J, et al. Pharmacokinetics of a dolutegravir pediatric granule formulation in healthy adult subjects. 19th Conference on Retroviruses and Opportunistic Infections; 2012.

66. Judd A, Boyd KL, Stohr W, et al. Effect of tenofovir disoproxil fumarate on risk of renal abnormality in HIV-1-infected children on antiretroviral therapy: a nested case-control study. AIDS 2010; 24:525–534.

67. WHO. Antiretroviral Therapy for HIV infection in infants and children: towards universal access. Recommendations for a public health approach 2010 revision. http://http://www.who.int/hiv/pub/paediatric/infants2010/en/index.html. [Accessed 27 April 2012]

68. Welch S, Sharland M, Lyall EG, et al. PENTA 2009 guidelines for the use of antiretroviral therapy in paediatric HIV-1 infection. HIV Med 2009; 10:591–613.

69. Bergshoeff A, Burger D, Verweij C, et al. Plasma pharmacokinetics of once-versus twice-daily lamivudine and abacavir: simplification of combination treatment in HIV-1-infected children (PENTA-13). Antivir Ther 2005; 10:239–246.

70. Valerius NH. Pharmacokinetic study of once-daily versus twice-daily abacavir and lamivudine in HIV type-1-infected children aged 3–<36 months. Antivir Ther 2010; 15:297–305.

71. Hughes CA, Foisy MM, Dewhurst N, et al. Abacavir hypersensitivity reaction: an update. Ann Pharmacother 2008; 42:387–396.

72. Orkin C, Wang J, Bergin C, et al. An epidemiologic study to determine the prevalence of the HLA-B* 5701 allele among HIV-positive patients in Europe. Pharmacogenet Genomics 2010; 20:307–314.

73. WHO. Towards universal access: scaling up priority HIV/AIDS interventions in the health sector. 2009. WHO, UNAIDS, UNICEF. Ref Type: Online Source.

74▪. Alam N, Cortina-Borja M, Goetghebuer T, et al. Body fat abnormality in HIV-infected children and adolescents living in Europe: prevalence and risk factors Fat abnormality in children. Journal of Acquired Immune Deficiency Syndromes 2012; 59:314–324.

Almost half of the 426 HIV-infected patients living in Europe had evidence of lipodystrophy or lipoatrophy. Risk of fat abnormality was associated with specific drugs, including stavudine and ritonavir. Ongoing surveillance is required along with the standardization of definitions of lipodystrophy and lipoatrophy.

75. Shiau S, Arpadi S, Strehlau R, et al. Lipodystrophy syndrome in young HIV-infected children in South Africa who initiate antiretroviral treatment before 2 years of age. In: Proceedings of the 19th Conference on Retroviruses and Opportunistic Infections; Seattle; 2012.

76. Were TP. Prevalence and factors associated with lipodystrophy among children on HAART at the paediatric infectious diseases clinic, Mulago Hospital. 2009.

77. Innes S, Cotton M, Haubrich R, et al. High prevalence of objectively verified clinical lipoatrophy in prepubertal children is associated with stavudine—the clock Is ticking: sub-Saharan Africa. 19th Conference on Retroviruses and Opportunistic Infections; Seattle; 2012.

78▪▪. Venter WD, Innes S, Cotton M. Low-dose stavudine trials: a public health priority for developing countries. South Afr J HIV Med 2012; 13:20–21.

A powerful debate summarizing many of the reasons to show it may be premature to move away completely from d4T. The benefits of d4T and the disadvantages of alternatives are discussed, a strong argument is made for the development of low-dose d4T trials.

79. Beregszaszi M, Dollfus C, Levine M, et al. Longitudinal evaluation and risk factors of lipodystrophy and associated metabolic changes in HIV-infected children. J Acquir Immune Defic Syndr 2005; 40:161–168.

80. Dzwonek AB, Lawson MS, Cole TJ, Novelli V. Body fat changes and lipodystrophy in HIV-infected children: impact of highly active antiretroviral therapy. J Acquir Immune Defic Syndr 2006; 43:121–123.

81▪▪. Aurpibul L, Puthanakit T, Taejaroenkul S, et al. Recovery from lipodystrophy in human immunodeficiency virus-infected children after substitution of stavudine with zidovudine in a nonnucleoside reverse transcriptase inhibitor-based antiretroviral therapy. The Pediatric infectious disease Journal 2012; 31:384–388.

An insightful and reassuring study about lipodystrophy developed in children while on stavudine, which demonstrated resolution of features of lipohypertrophy and lipoatrophy among Thai children. Forty-five lipodystrophic children with thirty-six episodes of lipohypertrophy and 22 episodes of lipoatrophy were enrolled in the study. By weeks 48 and 96 after substitution, 40 and 47% of lipohypertrophy resolved, whereas 59 and 73% of lipoatrophy resolved, respectively.

82. Green H, Gibb DM, Walker AS, et al. Lamivudine/abacavir maintains virological superiority over zidovudine/lamivudine and zidovudine/abacavir beyond 5 years in children. AIDS 2007; 21:947–955.

83. Friis-Moller N, Sabin CA, Weber R, et al. Combination antiretroviral therapy and the risk of myocardial infarction. N Engl J Med 2003; 349:1993–2003.

84. Choi AI, Vittinghoff E, Deeks SG, et al. Cardiovascular risks associated with abacavir and tenofovir exposure in HIV-infected persons. AIDS 2011; 25:1289–1298.

85. Obel N, Farkas DK, Kronborg G, et al. Abacavir and risk of myocardial infarction in HIV infected patients on highly active antiretroviral therapy: a population based nationwide cohort study. HIV Med 2010; 11:130–136.

86. Bedimo RJ, Westfall AO, Drechsler H, et al. Abacavir use and risk of acute myocardial infarction and cerebrovascular events in the highly active antiretroviral therapy era. Clin Infect Dis 2011; 53:84–91.

87. Brothers CH, Hernandez JE, Cutrell AG, et al. Risk of myocardial infarction and abacavir therapy: no increased risk across 52 GlaxoSmithKline-sponsored clinical trials in adult subjects. J Acquir Immune Defic Syndr 2009; 51:20–28.

88. Horberg M, Tang B, Towner W, et al. Impact of tenofovir on renal function in HIV-infected, antiretroviral-naive patients. J Acquir Immune Defic Syndr 2010; 53:62–69.

89. Satchell CS, Cotter AG, O’Connor EF, et al. Platelet function and HIV: a case-control study. AIDS 2010; 24:649–657.

90. De Pablo C, Orden S, Apostolova N, et al. Abacavir and didanosine induce the interaction between human leukocytes and endothelial cells through Mac-1 upregulation. AIDS 2010; 24:1259–1266.

91. Baum PD, Kosikova G, Galkina S, et al. Abacavir, a competitive inhibitor of soluble guanylyl cyclase, increases platelet reactivity. 17th Conference on Retroviruses and Opportunistic Infections, San Francisco; 2010.

92. Hsue PY, Hunt PW, Wu Y, et al. Association of abacavir and impaired endothelial function in treated and suppressed HIV-infected patients. AIDS 2009; 23:2021–2027.

93. The SMART/INSIGHT and the D:A:D Study Groups. Use of nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIV-infected patients. AIDS 2008; 22:F17–F24.

94. Riordan A, Judd A, Boyd K, et al. Tenofovir use in human immunodeficiency virus-1-infected children in the United Kingdom and Ireland. Pediatr Infect Dis J 2009; 28:204–209.

95. Vigano A, Bedogni G, Manfredini V, et al. Long-term renal safety of tenofovir disoproxil fumarate in vertically HIV-infected children, adolescents and young adults: a 60-month follow-up study. Clin Drug Invest 2011; 31:407–415.

96. Reid A, Stöhr W, Walker AS, et al. Severe renal dysfunction and risk factors associated with renal impairment in HIV-infected adults in Africa initiating antiretroviral therapy. Clin Infect Dis 2008; 46:1271–1281.

97▪. Palumbo P, Violari A, Lindsey J, et al. NVP- vs LPV/r-based ART among HIV+ infants in resource-limited settings: the IMPAACT P1060 Trial. 18th Conference on Retroviruses and Opportunistic Infections; Boston; 2011.

The results of the P1060 cohort 2 that enrolled HIV-infected infants (aged 2–36 months) from sites in Africa and India who were eligible to start treatment and were unexposed to maternal or infant NVP. Infants received a backbone of ZDV plus 3TC with either NVP or LPV/r. A total of 288 infants were enrolled before the DSMB recommended unblinding the results as the LPV/r arm demonstrated superior performance over NVP regarding viral failure and drug discontinuation at 24 weeks and beyond. This requires further investigation.

98▪. The PENPACT-1 (PENTA 9/PACTG 390) Study Team. First-line antiretroviral therapy initiation with a protease inhibitor versus nonnucleoside reverse transcriptase inhibitor combination and switch at higher versus low viral load in HIV-infected children: an open randomised controlled phase 2/3 trial. Lancet Infectious Diseases 2011; 11:273–283.

A European, North and South American study of 266 HIV-infected children recruited over 3 years and followed for 4 years that demonstrated good long-term outcomes with both protease inhibitor-based and NNRTI-based first-line ART. NNRTI resistance mutations were selected early and it was proposed that delayed switching of protease-inhibitor-based ART might be reasonable where future drug options are limited, as the risk of selecting for NRTI and protease-inhibitor resistance is low.

99▪. The European Pregnancy and Paediatric HIV Cohort Collaboration (EPPICC) study group in EuroCoord. Early antiretroviral therapy in HIV-1 infected infants in Europe, 1996–2008: treatment response and duration of first line regimens. AIDS 2011; 25:2279–2287.

Data on infants commencing ART under 1 year of age was collected from 9 cohorts in 13 European countries providing data on 437 infants followed for median 5.9) years after starting ART Superiority as measured by virological and immunological outcomes were seen with a four-drug, NNRTI regimen compared with a three-drug NNRTI or protease inhibitor-based regimen. Fewer infants on a four-drug regimen or a protease inhibitor regimen switched to ART because of failure (similar to the findings in the CHER follow up study which had very few infants on a protease inhibitor having to switch from the first-line therapy).

100. Rhoads MP, Lanigan J, Smith CJ, Lyall EG. Effect of specific ART drugs on lipid changes and the need for lipid management in children with HIV. J Acquir Immune Defic Syndr 2011; 57:404–412.

101. Foissac F, Urien S, Hirt D, et al. Pharmacokinetics and virological efficacy after switch to once-daily lopinavir–ritonavir in treatment-experienced HIV-1-infected children. Antimicrob Agents Chemother 2011; 55:4320–4325.

102. Molina JM, Podsadecki TJ, Johnson MA, et al. A lopinavir/ritonavir-based once-daily regimen results in better compliance and is noninferior to a twice-daily regimen through 96 weeks. AIDS Res Hum Retroviruses 2007; 23:1505–1514.

103. Judd A, Ene L, Goetghebuer T, et al. Use and safety of fosamprenavir in HIV-infected children in the European Union: an ongoing postmarketing surveillance study. International AIDS Society Conference Rome 2011.

104. Luzuriaga K, Bryson Y, McSherry G, et al. Pharmacokinetics, safety, and activity of nevirapine in human immunodeficiency virus type 1-infected children. J Infect Dis 1996; 174:721.

105. Montaner JSG, Reiss P, Cooper D, et al. A randomized, double-blind trial comparing combinations of nevirapine, didanosine, and zidovudine for HIV-infected patients. JAMA 1998; 279:930–937.

106. Dzwonek A, Clapson M, Withey S, et al. Severe gynecomastia in an African boy with perinatally acquired human immunodeficiency virus infection receiving highly active antiretroviral therapy. Pediatr Infect Dis J 2006; 25:183–184.

107. Munoz-Moreno JA, Fumaz CR, Ferrer MJ, et al. Neuropsychiatric symptoms associated with efavirenz: prevalence, correlates, and management. A neurobehavioral review. AIDS Rev 2009; 11:103–109.

108. Rotger M, Colombo S, Furrer H, et al. Influence of CYP2B6 polymorphism on plasma and intracellular concentrations and toxicity of efavirenz and nevirapine in HIV-infected patients. Pharmacogenet Genomics 2005; 15:1–5.

109. Fillekes Q, Natukunda E, Balungi J, et al. Pediatric underdosing of efavirenz: a pharmacokinetic study in Uganda. J Acquir Immune Defic Syndr 2011; 58:392–398.

110. Briz V, Palladino C, Navarro ML, et al. Etravirine based highly active antiretroviral therapy in HIV 1 infected paediatric patients. HIV Med 2011; 12:442–446.

Keywords:

adverse drug reactions; birth registries; neonates; paediatrics HIV; pharmacovigilance; toxicity

© 2012 Lippincott Williams & Wilkins, Inc.

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