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Expert Opinion on Pharmacotherapy
ISSN: 1465-6566 (Print) 1744-7666 (Online) Journal homepage: http://www.tandfonline.com/loi/ieop20
Developments in early diagnosis and therapy ofHIV infection in newborns
Francisco Canals, Mar Masiá & Félix Gutiérrez
To cite this article: Francisco Canals, Mar Masiá & Félix Gutiérrez (2017): Developments in earlydiagnosis and therapy of HIV infection in newborns, Expert Opinion on Pharmacotherapy, DOI:10.1080/14656566.2017.1363180
To link to this article: http://dx.doi.org/10.1080/14656566.2017.1363180
Accepted author version posted online: 02Aug 2017.Published online: 11 Aug 2017.
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REVIEW
Developments in early diagnosis and therapy of HIV infection in newbornsFrancisco Canalsa,b, Mar Masiá a and Félix Gutiérreza
aDepartment of Infectious Diseases, Hospital General de Elche, Universidad Miguel Hernández, Alicante, Spain; bDepartment of Pediatrics, HospitalGeneral de Elche, Alicante, Spain
ABSTRACTIntroduction: Infants who acquire HIV have an exceptionally high risk of morbidity and mortality if theydo not receive antiretroviral therapy (ART).Areas covered: This review aims to summarize the currently available evidence on ART in HIV-infectedneonates. Data were obtained from literature searches from PubMed, abstracts from InternationalConferences (2000–2017), and authors’ files.Expert opinion: Current evidence favors early diagnosis and prompt ART of HIV infection in newborns.The precise timing of initiation of ART remains undetermined. Very early (close to birth) ART appears tolimit the size of the viral reservoir and may restrict replication-competent virus, but the clinical benefitremains unproven. Among the current options for initial therapy, in full term neonates from 2 weeks oflife onwards, a lopinavir/ritonavir-based three-drug regimen is preferred. In term infants, younger than 2weeks a nevirapine-based regimen is recommended, although there are no clinical trial data supportingthat initiating treatment before 2 weeks improves outcome compared to starting afterwards. Existingsafety information is insufficient to recommend ART in preterm infants, with pharmacokinetic dataavailable for zidovudine only. If ART is considered in this setting, an individual case assessment of therisk/benefit ratio of treatment should be made.
ARTICLE HISTORYReceived 13 April 2017Accepted 31 July 2017
KEYWORDSHIV; AIDS; antiretroviraltherapy; mother to childtransmission; newborns;children; infants
1. Introduction
The use of antiretroviral drugs as prophylaxis in HIV-infectedpregnant women has resulted in a dramatic decrease inthe rate of HIV transmission to infants in high-income coun-tries [1-3].
The identification of perinatal HIV exposure prior topregnancy or as early in pregnancy as possible providesthe best opportunity to prevent infant infection. However,despite the effectiveness of antiretroviral drugs in preg-nancy, the global coverage of services to prevent mother-to-child HIV transmission (PMTCT) remains below 80% [2]and the number of children newly infected with HIVreached 150,000 (110,000–190,000) in 2015 [4]. Evenwhen services to PMTCT exist, residual infant HIV infectionsmay occur among women with poor drug adherence, or inthose who were HIV-uninfected at first antenatal visit andwho subsequently acquired the infection during pregnancyor postpartum. Congenital and perinatal hematogenoustransmission from mother to child may occur during preg-nancy or during labor, or by breastmilk during breastfeed-ing. In most cases, transmission is thought to occur near orduring delivery [2]. Perinatal transmission is a multifactorialprocess in which maternal viral load seems to be thestrongest predictor of HIV transmission [5,6]. Therefore,achieving and maintaining virological suppression duringpregnancy and at the time of delivery is paramount toPMTCT. Although most perinatal transmission events in
pregnant women without antiretroviral therapy (ART)occur late in pregnancy or during delivery, it should benoted that mother-to-child transmission of HIV can occurduring pregnancy (in utero), and early control of viral repli-cation may be important in preventing transmission. Arecent report from the French Perinatal Cohort foundthat, in addition to maternal viral load at delivery, timingof ART initiation was independently associated with therisk of perinatal transmission [7]. The perinatal transmissionrates were 0.2%, 0.4%, 0.9%, and 2.2%, for women startingART before conception, in the first, second, or third trime-sters, respectively. No cases of perinatal transmission weredocumented in infants born to women who started ARTbefore conception and maintained viral suppressionthroughout pregnancy and at the time of delivery [7]. Intreatment-naive pregnant women, ART should thus beinitiated as soon as possible, with the goal of suppressingplasma viremia throughout pregnancy. Ensuring thatwomen who started ART prior to pregnancy are virologi-cally suppressed throughout pregnancy may be an impor-tant component to PMTCT often neglected due to issuesaround viral load testing, particularly in low-resourcesetting.
Combined ART has dramatically reduced morbidity andmortality in HIV-infected people, including HIV-infectedchildren [8,9]. Since 2000, AIDS-related mortality amongchildren under the age of five has fallen by approximately60% globally [2]. In high-income countries, mortality in
CONTACT Félix Gutiérrez [email protected] Medicine, Infectious Diseases Unit, Hospital General Universitario de Elche, University Miguel Hernández,Alicante, Spain
EXPERT OPINION ON PHARMACOTHERAPY, 2017https://doi.org/10.1080/14656566.2017.1363180
© 2017 Informa UK Limited, trading as Taylor & Francis Group
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children with perinatal HIV infection has decreased bymore than 80–90% [8–10].
At the present time, prompt initiation of ART is recom-mended for all HIV-infected adults and adolescents, regardlessof CD4 cell count, to reduce the morbidity and mortalityassociated with HIV infection, and to prevent HIV transmission[11]. Although available data on the risks and benefits ofimmediate therapy in asymptomatic HIV-infected childrenare weaker than in adults, ART is also recommended for allHIV-infected children [12,13]. Infants and young children whoacquire HIV have an exceptionally high risk of morbidity andmortality and half will die before their second birthday if theydo not receive treatment [14]. A systematic review of rando-mized controlled trials that evaluated treatment strategies inperinatally HIV-infected infants and young children (aged < 3years) concluded that ART initiation reduces morbidity andmortality [15]. However, prompt initiation of ART remainsuncommon in infants, particularly in neonates [16–18].Obstacles to use ART in neonates include the need for virolo-gic testing for early diagnosis of HIV infection, and safetyconcerns by pediatricians arising from limited knowledgeand experience regarding the use of antiretroviral drugs inthis setting.
Over the last few years, there have been significantadvances in HIV virologic testing that have improved accu-racy and reduced performance time of laboratory-basedassays for early diagnosis of HIV infection in neonates. Inaddition, the report of a prolonged remission in an HIV-infected child treated with combined ART at approximately30 h of age [19] has generated discussion and enthusiasmabout very early initiation of therapy in HIV-infectedinfants.
This article aims to review recent developments in earlydiagnosis and therapy of HIV infection in neonates and pro-pose recommendations for managing HIV-infected infants.Data were obtained from literature searches from PubMed,abstracts from International AIDS Conferences, and authors’files, based on the pertinent key terms that identified thearticles about diagnosis and therapy of HIV infection innewborns.
2. Identifying perinatal HIV-exposed infants to stoptransmission
As stated earlier, identification of perinatal HIV exposureprovides the best chance to prevent neonatal infection, byusing antiretroviral drugs as prophylaxis in pregnant women,and to early detect neonates who become infected, allowingprompt initiation of ART. Health systems gaps in HIV diag-nosis in pregnant women or late diagnosis testing in exposedinfants will likely worsen the prognosis of HIV-infectedinfants [20].
Universal voluntary HIV testing early in pregnant is nowthe standard of care in high-income and in many low- andmiddle-income countries. Pregnant women not tested forwhatever reason earlier in pregnancy should be offered test-ing during the third trimester. Maternal HIV acquisition fol-lowing initial negative test has been reported to occur in upto 46% of the newly infected infants [20]. Thus, a second HIVtest during the third trimester should also be considered forall HIV-seronegative pregnant women, particularly for thoseknown to be at high risk of acquiring HIV or reporting symp-toms consistent with acute HIV infection [21]. In those cases,a fourth-generation combination immunoassay should beused, as these combined antigen/antibody tests show ahigher sensitivity for the detection of primary HIV infectionthan conventional tests [22]. Rapid HIV testing in labor ordelivery should be performed in all women with undocumen-ted HIV status. When HIV testing is positive, intrapartum andinfant postnatal antiretroviral drug prophylaxis should beinitiated, and additional virologic test be performed in thenewborn.
Postnatal antiretroviral drug prophylaxis should be startedin all HIV-exposed infants as soon as possible, preferablywithin 6–12 h of delivery [12]. According to the risk of peri-natal transmission, infants exposed to HIV are considered atlow risk of HIV acquisition when they are born to motherswho received ART during pregnancy with sustained viralsuppression and no concerns related to maternal adherence.Infants considered at high risk of HIV acquisition are thoseborn to HIV-infected women who have not received ante-partum or intrapartum prophylaxis with antiretroviral drugs,received intrapartum antiretroviral drugs only, were diag-nosed with acute HIV infection during pregnancy, havereceived prophylaxis but had detectable HIV viral loads neardelivery, or did not have sustained viral suppression. A drugcombination regimen during 6 weeks is recommended ininfants at higher risk of HIV acquisition [12]. There is noclear consensus on the specific regimen to use in theseinfants. In the HPTN 040/PACTG 1043 study, a large clinicaltrial enrolling 1684 formula-fed neonates whose mothers didnot receive ART during pregnancy, prophylaxis with two-drug ART regimen (zidovudine for 6 weeks plus three dosesof nevirapine during the first 8 days of life), or three-drug ARTregimen (zidovudine for 6 weeks plus nelfinavir and lamivu-dine for 2 weeks) was not superior to zidovudine alone for 6weeks for the prevention of in utero HIV transmission, butintrapartum transmissions were reduced by half in the drugcombination groups, as compared with the zidovudine-alonegroup; the two-drug regimen had less toxicity than the three-
Article Highlights
● Infants and young children who acquire HIV have an exceptionallyhigh risk of morbidity and mortality if they do not receive antiretro-viral therapy.
● Identification of perinatal HIV exposure provides the best chance toprevent neonatal infection by using antiretroviral drugs as prophy-laxis in pregnant women, and to early detect neonates who becomeinfected.
● Accurate early infant diagnosis by nucleic acid amplification tests iscrucial: virologic testing should ideally be performed as soon aspossible, particularly in HIV-exposed infants at high risk of perinataltransmission.
● Prompt initiation of antiretroviral therapy in every child infected withHIV is now considered the standard of care.
● The potential benefits of very early treatment –close to birth- includ-ing the possibility of prolonged remission in infected neonates,require further investigation.
This box summarizes key points contained in the article.
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drug regimen [6]. Although the ease of use, reduced toxicity,availability, and low cost make zidovudine plus nevirapine anattractive option, following the prolonged remission of HIV inan infant reported in 2013 [19], many clinicians prefer athree-drug regimen for prophylaxis in infants at high riskfor perinatal infection [12]. A three-drug regimen may beparticularly indicated in infants who could be at the highestrisk of HIV acquisition, such as those born to mothers diag-nosed with acute HIV infection during pregnancy or who hadvery high HIV viral loads near delivery. An ongoing clinicaltrial is investigating a three-drug prophylaxis regimen con-taining zidovudine, lamivudine, and nevirapine shortly afterbirth in infants at high risk of HIV infection (IMPAACT P1115,ClinicalTrials.gov identifier NCT02140255). Safety and phar-macokinetic (PK) data from this study will guide futurerecommendations. It is worth noting that the benefits ofpostnatal enhanced prophylaxis have only been formallyproven in untreated mothers during pregnancy. For full-term infants with low risk of perinatal transmission, a 4-week zidovudine regimen is recommended [23,24]. For theprevention of in utero HIV transmission, nevirapine is analternative to zidovudine monotherapy with potent antire-troviral effect but low barrier to resistance.
The World Health Organization (WHO) recommends thatbreastfeeding women with HIV receive ART throughoutbreastfeeding or lifelong [13]. Maternal ART dramaticallyreduces but does not eliminate breast milk transmission.Some studies of infants breastfed by women with chronicHIV infection have shown that extending postnatal antiretro-viral prophylaxis can reduce the risk of infection [25–27]
3. Virologic testing in the management of perinatalHIV exposure
In order for HIV-infected neonates to receive ART as soon aspossible, accurate early infant diagnosis of HIV is crucial.Antibody testing does not allow the diagnosis of HIV infectionin infants and children younger than 18 months with perinatalHIV exposure due to transplacental transfer of maternal anti-bodies; therefore, a virologic assay that directly detects HIVshould be performed [22] and it is strongly recommended bythe WHO [28].
The preferred assays to detect HIV-1 directly are the nucleicacid amplification tests. These tests include RNA- and DNA-based polymerase chain reaction (PCR) assays and related RNAquantitative assays. RNA-based PCR assays detect extracellularHIV-1 RNA in plasma whereas DNA-based assays detect spe-cific HIV-1 DNA in peripheral blood mononuclear cells.Although both techniques are considered to be highly speci-fic, HIV-1 RNA levels <5000 copies/mL may not be reproduci-ble and should be repeated before they are interpreted asdocumenting HIV infection in an infant [29–32]. The specificityof both HIV RNA-based (for results ≥5000 copies/mL) andDNA-based PCR assays has been shown to be 100% at birthand at 1, 3, and 6 months of age [29–32]. The effect ofmaternal or infant exposure to combination ART on the sensi-tivity of infant virologic diagnostic testing – particularly using
HIV RNA assays – remains largely unknown. Some expertsprefer to use HIV DNA PCR assays in this setting.
The main caveat of both HIV RNA and DNA assays is thattesting at birth will detect infants who were infected in uterobut not those who become infected from exposure during orimmediately prior to delivery (i.e. in the intrapartum period)[30–33]. In a substudy of the French multicenter prospectivecohort of neonates born to HIV-infected mothers, 1567 infantswere tested simultaneously with HIV RNA and DNA assays. Atbirth, sensitivity was 58% for the RNA- and 55% for the DNA-based assays; and it was 89% at 1 month and 100% at 3months for both assays. A high degree of concordance wasfound between HIV RNA and DNA assays [31]. Another studyinforming on accuracy of nucleic acid amplification tests forearly diagnosis of HIV-infected infants at different time pointswas the NICHD HPTN 040/PACTG 1043 trial. In that trial eval-uating different regimens of postpartum prophylaxis in neo-nates whose mothers did not receive ART during pregnancy,infant virologic testing was performed by HIV DNA PCR atbirth, 10-14 days, 4-6 weeks, and 3 and 6 months [6]. Theoverall transmission rate in the trial was 8.5% (140 infants). Ofthe 140 infected infants, 93 (66.4%) were identified at birth. Ofthe 47 infected infants who had negative virologic testing atbirth, 68% were identified at 4 to 6 weeks, and 100% by 3months [6].
WHO recommends that infants exposed to HIV be testedwith a nucleic acid amplification tests at the first postnatal visitor at the earliest opportunity, and that those who are infectedstart treatment immediately [13]. Virologic testing should ide-ally be performed at 14-21 days of life and at ages 1-2 monthsand 4-6 months. For settings where it is available, virologictesting at birth should be considered for HIV-exposed infantsat high risk of perinatal transmission, especially in women whohave not received antepartum or intrapartum prophylaxis,have not had good virologic control during pregnancy, or ifadequate follow-up of the infant cannot be assured. A positiveHIV virologic test should be confirmed as soon as possiblewith a second HIV virologic test on a different specimen.Although perinatal transmission of resistant virus appears tobe unusual, if feasible, any newly diagnosed infant shouldundergo HIV drug-resistance testing.
WHO and its partners have also been examining thefeasibility of testing at birth in low-resource settings,which may provide an adjunct to the earlier detection andtreatment of infected infants worldwide [2,34]. According tothe Joint United Nations Programme on HIV/AcquiredImmune Deficiency Syndrome, of an estimated 1.2 million(1.1–1.3 million) HIV-exposed infants among the 21 prioritycountries in sub-Saharan Africa participating in the GlobalPlan toward the elimination of new HIV infections amongchildren [35], only 49% received a virologic test to deter-mine their HIV status within the first two months of life(compared to 40% in 2013) [2]. In many settings, access tovirologic testing remains poor, leading to delayed infantdiagnosis of HIV and high rates of children’s lost-to-follow-up, demonstrating the importance of improving availabilityand affordability of these tests if infants are to benefit fromearly ART [2].
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Early infant diagnosis is particularly challenging in resource-limited settings and remote areas. Efforts to place infant test-ing capabilities in small health facilities and innovative point-of-care virologic tests are needed to allow for instituting earlytherapy in those settings.
4. Treating HIV infection in neonates
As stated earlier, prompt initiation of ART in every childinfected with HIV should now be considered the standard ofcare [12,13]. The recommendation for early onset of treatmentin HIV-infected children is justified by the rapid progression ofHIV disease reported in younger children [14] and supportedby data from cohort studies and clinical trials suggesting thatearlier initiation of ART may reduce the risk of mortality andprogression to AIDS [15,36–39] and improve neurodevelop-ment and motor development compared to late treat-ment [40].
4.1. Potential benefits of early ART in neonates
The benefit of immediate ART in children under 1 year of agewas clearly demonstrated in the Children with HIV EarlyAntiretroviral Therapy (CHER) trial [41]. In this trial, HIV-infected infants 6–12 (median 7.4) weeks of age with a CD4lymphocyte percentage of 25% or more were randomlyassigned to receive ART (lopinavir-ritonavir, zidovudine, andlamivudine) when the CD4 percentage decreased to less than20% or clinical criteria were met (the deferred ART group) orto immediate initiation of limited ART until 1 year of age or 2years of age (the early ART groups). Early ART reduced infantmortality by 76% and HIV progression by 75% [41]. Of interest,a considerable number of children could not enroll in themain CHER trial (Part A) due to severity of illness or low CD4that emphasizes the rapid progression of HIV infection andstrengthens the argument for moving the therapy start timeearlier. It should be noted that infants in the CHER trial startedART at 6–12 weeks of age; whether there would be additionalbenefit to very early initiation of ART (close to birth) remainsunclear.
Early effective ART in perinatal HIV infection appears tolimit the size of the viral reservoir, which is considered onestep in the pathway toward HIV cure [42,43]. In a recentretrospective study including 23 perinatally HIV-infectedchildren, there was a strong positive correlation between thetime to initiation of ART and the size of the proviral reservoir[44]. Children who initiated ART within the first 12 weeks of lifeshowed a proviral reservoir 6-fold smaller than children initiat-ing ART beyond this time [44]. The relationship between earlyeffective ART and smaller reservoir size has also been noted inHIV-infected adults treated during acute infection [42,43],highlighting the potential of very early ART initiation to restrictreplication-competent reservoirs.
Initiation of early effective ART during infancy may alsorestrict replication-competent HIV and promote continuousdecay of viral reservoirs during long-term effective ART. Infour perinatally HIV-infected adolescents who initiated effec-tive treatment prior to 3 months of age, the median proviralburden was extremely low and considerably smaller than in
other four youth who achieved virologic control at a medianof 12.9 years of age (7 vs. 181 copies/106 peripheral bloodmononuclear cells [PBMCs]) [45]. Replication-competent viruswas recovered from all the four youth starting ART late butonly in one of the four achieving virologic control early in life.Decay in proviral DNA was noted in all four early treatedyouth in association with limited T-cell activation and withabsent-to-minimal HIV-specific immune responses [45]. In across-sectional study including 144 perinatally HIV-infectedadolescents receiving durable (median duration, 10.2 years)effective ART, proviral reservoir size was markedly reduced inthose who achieved virologic control before 1 year ofage (4.2 [interquartile range, 2.6–8.6] copies per 1 millionPBMCs) compared with those who achieved virologic controlat 1–5 years of age (19.4 [interquartile range, 5.5–99.8] copiesper 1 million PBMCs) or after 5 years of age (70.7 [interquar-tile range, 23.2–209.4] copies per 1 million PBMCs; P < .001)[46]. In addition 46% of adolescents with virologic controlbefore 1 year of age had proviral DNA concentrations belowthe limit of detection compared with only 11% of 101 ado-lescents with virologic control at older ages [46].
Altogether, these studies highlight the likely impact oftiming of initiation of ART on the latent reservoir in perinatalHIV infection and suggest that achieving virologic controlvery early in infancy can be associated with a low proviralreservoir size that may be maintained for over a decade onlong-term effective ART. However, it should also be notedthat the clinical benefits of reducing viral reservoir remainspeculative and, to date, the only proven benefit of veryearly treatment is the reduction in early mortality and pro-gression found in the CHER trial [41]. The benefit of a veryearly treatment for children with less severe illness not at riskof early mortality is less obvious. In addition, there are nogood predictors of progression in young children. Theso-called “Mississippi Child,” who received ART between 30h of life and 18 months of age and remained free of replicat-ing HIV without treatment for more than 2 years, has gener-ated hope on the potential long-term benefits of very earlyART in perinatally infected infants [19].
4.2. Initiating ART in neonates
While there is considerable interest in moving treatment initia-tion closer to birth, there are challenges to start ART in earlylife, including a paucity of drug choices, uncertain dosing forsome medications, concerns about toxicities, and adherence.In addition, the poor palatability of many of the existingformulations often leads the children to refuse taking them.Compared to older children, neonates and young infants havedelayed absorption, reduced liver metabolism, and reducedrenal elimination of drugs; therefore, it is important to obtaindata on PK and safety of antiretroviral drugs in this particularpopulation. Changing PK as a result of rapid growth andcontinuous development and maturation of the organsinvolved in drug metabolism, and in the activity of the iso-forms of drug metabolizing enzymes, makes dosing evenmore complex. Although routine evaluation of plasma con-centrations of antiretroviral drugs is not generally recom-mended for managing infants with HIV infection, targeted
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therapeutic drug monitoring can be considered when usingdrugs with limited PK data and/or therapeutic experience, incases of significant drug–drug and food–drug interactions, orwhen suspecting suboptimal absorption, distribution, metabo-lism, or elimination of the drug.
4.2.1. Antiretroviral drugs that can be used safely inneonatesUnfortunately, dosing and safety data to provide appropriaterecommendations for the treatment of HIV infection in neo-nates have been generated only for a few antiretroviral drugs.Data on which to base a firm recommendation for treatmentdoses from birth in full term neonates exist only for fourantiretroviral drugs: zidovudine, lamivudine, emtricitabine,and stavudine; in preterm infants, data are available only forzidovudine. From age 2 weeks in full-term neonates, there aredata to allow recommendations for safe doses for anotherthree antiretroviral drugs: didanosine, nevirapine, and lopina-vir-ritonavir [12]. Two (stavudine and didanosine) of the sevenantiretroviral drugs are rarely used in adults due to the highrisk of mitochondrial toxicity. The use of other nucleosidereverse transcriptase inhibitors like abacavir or tenofovir isnot recommended due to the lack of data in neonates. Evenwith the considered “safe medications,” close monitoring isneeded when ART is initiated very early after birth. The experi-ence with the use of lopinavir-ritonavir oral solution in infantshighlights the risk of using antiretroviral drugs during the firstweeks of life without neonatal PK and safety data. Life-threa-tening toxicity, including cardiovascular, renal, and centralnervous system severe adverse events, has been reported in10 infants (8 preterm) receiving lopinavir-ritonavir oral solu-tion during the first weeks of life [47]. After this report, the useof lopinavir-ritonavir oral solution is only recommended in full-term neonates of 2 weeks or older [47].
Integrase strand transfer inhibitors have become a cor-nerstone of antiretroviral combination regimens in adults[11] and there is considerable interest in the use of thesedrugs in children and neonates, especially after the recentapproval of an oral granule raltegravir formulation which issuitable for use in young infants. After preliminary datafrom a cohort of 15 infants receiving two single doses ofraltegravir during the first week of life [48], PK results and 6-week safety data from 25 newborns (full-term infants aged≤48 h of age; gestational age at birth at least 37 weeks &weight ≥2 kg) have been recently reported [49]. In thisstudy, daily raltegravir given at the study-specified dosingregimen (as described in Table 1) was safe and well toler-ated during the first 6 weeks of life, meeting the PK targetsand the safety guidelines [49]. As raltegravir is primarilymetabolized by the UGT1A1 enzyme, it may compete withbilirubin for elimination through glucuronidation. Indeed,in vitro data suggest that raltegravir plasma concentrations50–100 times greater than typical peak concentrations(~5000 ng/mL) may lead to increased plasma concentrationsof free unconjugated bilirubin, leading to an increase risk ofbilirubin encephalopathy and kernicterus [52]. Therefore,
caution should be taken in neonates with elevated bilirubin,particularly in preterm infants.
4.2.2. Summary of antiretroviral drugs recommended forinitial therapy in neonates4.2.2.1. Zidovudine. Therapeutic indication and usage:recommended for HIV treatment from the first day of life.Zidovudine is the only antiretroviral drug currently recom-mended for premature infants.
Pharmaceutical form: it is available in syrup form withconcentration of 10 mg/ml [12].
Metabolism: zidovudine is metabolized in the liver to zido-vudine glucuronide and then renally excreted. The enzymesresponsible for glucuronidation increase dramatically duringthe first 4–6 weeks of life in full-term neonates, and hencedose adjustment after this age is required.
Dose: an initial dose of 4 mg/kg orally twice a day duringthe first 4 weeks of life is recommended in infants with at least35 weeks of gestation, and this dose has to be increased to 12mg/kg twice daily after the fourth week of life. In prematureinfants, the clearance of zidovudine is reduced, and adjust-ments should therefore be done [53]. In neonates with gesta-tional age between 30 and 35 weeks, the initial recommendeddose is 2 mg/kg twice a day, increasing to 3 mg/kg twice a dayafter 2 weeks of life and then to 12 mg/kg twice a day from 6to 8 weeks of life. In case of premature infants born before the30th week of gestation, an initial dose of 2 mg/kg twice a dayis recommended for the first 4 weeks of age, increasing to 3mg/kg twice a day from 4th to 8th or 10th week of life, andthereafter to 12 mg/kg twice a day [54].
For infants unable to tolerate oral agents, intravenous zido-vudine, at a concentration of 10 mg/mL, may be used, althoughthis formulation is not available in many settings. If the intrave-nous formulation is used, the dose of zidovudine should bereduced by 25%, maintaining the same dose interval [53].
Recommendations for administration: this drug can begiven without regard to food, and it is recommended to bediscontinued in case of substantial granulocytopenia or anemiadue to its association with both hematologic side effects [12].
Adverse events are shown in Table 1. Treatment-limitingadverse events with zidovudine has been described in <10%of the children receiving this drug in Europa and Thailand [54].
4.2.2.2. Lamivudine. Therapeutic indication and usage:lamivudine is recommended for HIV treatment from the firstday of life in full term infants.
Pharmaceutical form: it is available in oral solution inconcentration of 10 mg/mL [11].
Metabolism: this drug is eliminated by renal excretion. It isrecommended to double the starting dose after the fourth weekof life for infants with normal maturation of renal function.
Dose: Studies made with oral solution of lamivudine set therecommended dose at 2 mg/kg twice a day for neonates, increas-ing to 4 mg/kg twice a day from the fourth week of life [55].Bioavailability of oral solution is lower than tablets of lamivudine,and this is reflected in the differences in the response rate between
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pediatric patients treated with oral solution compared with pedia-tric patients treated with tablets at the same dose. There are noidentified causes to justify this, and further research is needed [56].
Recommendations for administration: lamivudine oralsolution can be given without regard to food and can bekept at room temperature.
Adverse events are shown in Table 1.
4.2.2.3. Emtricitabine. Therapeutic indication and usage:as well as lamivudine, emtricitabine is recommended for HIVtreatment in full-term neonates since birth.
Pharmaceutical form: it is available in oral solution atconcentration of 10 mg/mL [12].
Metabolism: emtricitabine is excreted 86% throughurine [57].
Table 1. Antiretroviral drugs recommended for initial therapy in neonates.
Drug Presentation for neonate Dose Adverse events
Zidovudine Syrup 10 mg/mLIntravenous 10 mg/mL
≥35 weeks of gestational age– Birth to age 4 weeks:∘ 4 mg/kg twice a day
– Aged >4 weeks:∘ 12mg/kg twice a day
≥ 30 to <35 weeks of gestational age– Birth – age 2 weeks:∘ 2 mg/kg twice a day
– Aged 2 weeks to 6–8 weeks∘ 3 mg/kg twice a day
– Aged >6–8 weeks∘ 12 mg/kg twice a day
<30 weeks of gestational age– Birth – age 4 weeks:∘ 2 mg/kg twice a day
– Aged 4 weeks to 8–10 weeks:∘ 3 mg/kg twice a day
– Aged >8–10 weeks:∘ 12 mg/kg twice a day
- Frequent: headache, bone marrowsuppression [50,51], nausea, vomiting.
- Rare: hepatic toxicity, lactic acidosis,hepatic steatosis, myopathy, myositis,lipoatrophy, cardiomyopathy
Lamivudine Oral solution 10 mg/mL Birth to age 4 weeks– 2 mg/kg twice a day
Aged >4 weeks– 4 mg/kg twice a day
- Frequent: headache, nausea- Rare: hepatic steatosis, lipoatrophy,
pancreatitis, neutropenia
Emtricitabine Oral solution 10 mg/mL Birth to age 3 months– 3 mg/kg once a day
Aged ≥3 months– 6 mg/kg once a day (maximum dose 240 mg)
- Frequent: headache, insomnia, nausea,hyperpigmentation/skin discolorationon palms, and/or soles.
- Rare: lactic acidosis with hepaticsteatosis, neutropenia
Stavudine Powder for oral solution:1 mg/mL
Birth to age 13 days:– 0.5 mg/kg twice a day
Aged ≥ 14 days– 1 mg/kg twice a day
- Frequent: headache, hyperlipidemia,nausea, lipoatrophy, skin rashes
- Rare: pancreatitis, hepatic steatosis,peripheral neuropathy, lactic acidosis,hepatomegaly
Didanosine Powder for oral solution:10 mg/mL
Aged ≥ 2 weeks to <3 months– 50 mg/m2 twice a day
Aged ≥ 3 months to 8 months– 100 mg/m2 twice a day
- Frequent: diarrhea, abdominal pain,nausea, vomiting.
- Rare: pancreatitis, hepatomegaly withhepatic steatosis, peripheralneuropathy, lactic acidosis, retinalchanges, optic neuritis, hyperuricemia
Nevirapine Suspension 10 mg/mL Aged <14 days:– Term infant: 6 mg/kg twice a day. No lead-in– Preterm infant(*):– 1st week: 4 mg/kg twice a day– Aged >7 days: 6 mg/kg twice a day. No
lead-inAged >14 days (or >14 days of adjusted gestational
age) to 8 years:– Term infant: 200 mg/m2 twice a day
Body weight < 2 kg– First two weeks: 2 mg/Kg once a day– Older than two weeks: 4 mg/Kg once a day
- Frequent: skin rash, fever, nausea,headache
- Rare: hepatic toxicity, hypersensitivitysyndrome with potential formultisystem organ involvement andshock
Ritonavir boosted lopinavir(LPV/r)
Oral solution:80 mg LPV /20 mgritonavir /mL
Aged ≥ 14 days to 6 months– 300mg/m2 LPV/75 mg/m2 ritonavir twice a day
1–2 Kg: 40 mg every 12 h2–6 Kg: 80 mg every 12 h6–10 Kg: 120 mg every 12 h
- Frequent: hyperlipidemia, headache,diarrhea, nausea, vomiting, skin rash
- Rare: pancreatitis, diabetes, hepatitis
Raltegravir Granules: 100 mg Birth – age 7 days(**)– 1.5 mg/kg once a day
Aged 8 –28 days(**)– 3 mg/kg twice a day
Aged ≥ 4 weeks(**)– 6 mg/kg twice a day
- Frequent: dizziness, fatigue, diarrhea,itching, nausea, headache, insomnia
- Rare: abdominal pain, vomiting, skinrash, creatine phosphokinaseelevation, myopathy, andrhabdomyolysis
* 34–37 weeks of gestational age.**Investigational dose, not FDA-approved.
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Dose: recommended dose is 3 mg/kg once a day for thefirst three months of life, increasing to 6 mg/kg once a dayfrom then on, to a maximum dose of 240 mg per day until thechild’s weight is over 33 Kg. It is recommended to escalate thedose after the third month of life because of the increasingclearance of the drug with increasing age.
Recommendations for administration: oral solution canbe given regardless of food intake and it can be kept at roomtemperature if used within 3 months after opening [12].
Adverse events are shown in Table 1.
4.2.2.4. Stavudine. Therapeutic indication and usage: sta-vudine is no longer a drug of choice and its use is limited inadults and children because of the risk of serious adverseevents associated with mitochondrial toxicity. It could excep-tionally be considered in selected cases of full-term neonatesfrom the first day of life, and only for a short period of time.
Pharmaceutical form: it is available for neonates in pow-der for oral solution to get a concentration of 1 mg/mL.
Metabolism: This drug is eliminated by renal excretion toabout 50%, so it is recommended to reduce the dose in caseof renal dysfunction.
Dose: in the first two weeks of life, the recommended doseis 0.5 mg/kg twice a day, and it must be increased to 1 mg/kgtwice a day from the 14th day of life [58].
Recommendations for administration: this solution mustbe shaken before use and kept refrigerated [12].
Adverse events are shown in Table 1. The combination ofstavudine with didanosine should never be used due to ahigher risk of hepatotoxicity, pancreatitis, or lactic acidosis[59]. Combination of antiretroviral drugs with stavudineshowed higher risk of clinical and analytical toxicity thancombinations with zidovudine [60].
4.2.2.5. Didanosine. Therapeutic indication and usage:didanosine is no longer a drug of choice and its use is limitedin adults and children because of the risk of serious adverseevents associated with mitochondrial toxicity. It could excep-tionally be considered in selected cases of neonates from twoweeks of life and only for a short period of time.
Pharmaceutical form: it is available in powder for oralsolution, at concentration of 10 mg/mL when reconstituted[12]. This solution contains antacids that may interfere withthe absorption of other drugs.
Metabolism: like other antiretroviral drugs, didanosine ispartially excreted through the kidneys, and that justifiesincreasing the dose according to maturation of renal function.
Dose: from 2 weeks of life to 3 months of age, the recom-mended dose is 50 mg/m2 twice a day, and from 3 months,dose should be doubled to 100 mg/m2.
Recommendations for administration: didanosineabsorption is decreased when given with food, and that iswhy it is recommended to be given 30 min before or 2 h aftera meal. In neonates, it is impractical due to the need offrequent oral intake. The effect of food on didanosine wasstudied in adults, showing that the administration of fooddid not interfere with the antiviral activity of didanosine [61].
Adverse events are shown in Table 1:
4.2.2.6. Nevirapine. Therapeutic indication andusage: nevir-apine is approved by the Food and Drug Administration (FDA) ofUS for HIV treatment in full-term neonates aged >1 month.
Pharmaceutical form: nevirapine is available in suspensionat concentration of 10 mg/ml.
Metabolism: nevirapine is metabolized by cytochromeP450 and 80% excreted in urine. Prematurity is associatedwith immature drug metabolism and nevirapine safety; effi-cacy and PK data in preterm and low-birth weight infants arelimited. Nevirapine auto-induces its metabolism and it is tra-ditionally initiated at a lower dose and increased after 2 weeksto allow induction of cytochrome P450 metabolizing enzymes.This stepwise fashion results in increased drug clearance and itis believed that it may reduce drug toxicity, but has thepotential for under-dosing with an increased risk of resistance.The extent of autoinduction on immature enzyme systems isunknown, and preliminary data suggest that full-dose nevira-pine at ART initiation should be considered in infants andyounger children [62–65]. No dose adjustment is required inrenal insufficiency. When given with ritonavir-boosted lopina-vir, higher dose of lopinavir may be needed because of theincrease of lopinavir metabolism caused by nevirapine.
Dose: based on PK modeling for full-term newborns diag-nosed as infected in the first few days of life, a nevirapineinvestigational (not FDA-approved) dose of 6 mg/kg adminis-tered twice daily (without lead-in dose) is recommended forfull-term newborns [66]. For late preterm newborns between34 and 37 weeks of gestational age, the traditional stepwisefashion of administering the drug is still recommended withan initial dose if 4 mg/kg twice a day for the first week of life,followed by an increase to 6 mg/kg twice day after the firstweek, which have shown to get an adequate therapeuticplasma concentration of nevirapine (3 µg/mL) [62]. For infants<2 kg, the Health Organization guidelines recommend nevir-apine 2 mg/kg/day, but in a recent study carried out in low-birth-weight infants, doubling the dose to 4 mg/kg/day at 2weeks achieved adequate plasma concentrations without sig-nificant toxicity [67]. Single nevirapine dose of 2 mg/kg within72 h of birth to prevent mother-to-child transmission is nolonger recommended due to the potential risk for resistancewith single-dose nevirapine.
Recommendations for administration: this suspensionmust be shaken before use and can be given without regardto food [12].
Adverse events are shown in Table 1. Skin rash has beenobserved in between 7.5% and 20% of the children receivingnevirapine as part of first-line antiretroviral regimen; it canoccasionally be severe, needing hospitalization [68]. Hepatictoxicity, including fatal hepatic necrosis, or severe hypersensi-tivity syndrome with potential for multisystem organ involve-ment and shock, are less common. Severe nevirapine-relatedtoxicity, according to the criteria of the Division of AIDS (DAIDS)of the National Institute of Allergy and Infectious Diseases [69]when given as treatment, occurred in 6.8% of the children [70].In the HPTN 046, a randomized, double-blind, placebo-con-trolled trial, comparing three different regimens with once-daily infant nevirapine for prevention of postnatal HIV transmis-sion, 16% of the children had a serious adverse events [71].
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Most cases of nevirapine-associated toxicity occur during thefirst 6–12 weeks of therapy; frequent clinical and laboratorymonitoring, including liver function tests, is important duringthis period.
4.2.2.7. Lopinavir/ritonavir. Therapeutic indication andusage: lopinavir/ritonavir is indicated to treat HIV infection infull-term neonates aged 2 weeks or older. Lopinavir/ritonavirhas demonstrated being superior to nevirapine, reducing mor-tality and achieving higher degree of virological suppression[70,72].
Pharmaceutical form: lopinavir/ritonavir oral solution isavailable at concentration of 80 mg of lopinavir and 20 mgof ritonavir per milliliter. Oral solution contains 42% of alcoholand 15% of propylene glycol [12].
Metabolism: lopinavir/ritonavir is primarily metabolized bythe liver and it is a cytochrome P 3A4 inhibitor and substrate.Newborn immature hepatic metabolism and renal excretioncan lead to an accumulation of lopinavir, alcohol, and propy-lene glycol. Adverse events, including cardiac, renal, meta-bolic, or respiratory problems, have been described inneonates receiving lopinavir and have been related to accu-mulation of the drug or the inactive ingredients. Adrenaldysfunction was also observed in newborns treated with lopi-navir/ritonavir, but life-threatening symptoms compatible withadrenal insufficiency were only present in prematureinfants [73].
Dose: dose recommended for infants from 14 days to 6months of age is 300 mg/m2 of lopinavir and 75 mg/m2 ofritonavir twice a day, this approximates 16 mg of lopinavirand 4 mg of ritonavir per kg body weight twice daily.Lopinavir/ritonavir population PK in 96 neonates and infantsfrom birth to less than 2 years (1.16–10.4 kg) showed thatclearance and distribution volume were dependent on bodyweight on an allometric basis and post-menstrual age [70].According to this model, optimal dosing regimens would be40 mg every 12 h for children from 1 to 2 kg, 80 mg every 12 hfor children from 2 to 6 kg, and 120 mg every 12 h to childrenfrom 6 to 10 kg [74].
Recommendations for administration: lopinavir/ritonavirshould be taken with food. The poor palatability of oral solu-tion lopinavir/ritonavir is a problem, and it is difficult to mask.Future studies with pellets of lopinavir/ritonavir mightincrease adherence in infants younger than 12 months [75].
Adverse events are shown in Table 1.
4.2.2.8. Raltegravir. Therapeutic indication and usage:raltegravir is at present not approved for neonates [12].Recent data from IMPAACT P1110 study support that raltegra-vir could be an alternative to lopinavir/ritonavir or nevirapinefor full-term neonates providing elevated bilirubin requiringphototherapy and low-weight infants are excluded [48].
Pharmaceutical form: raltegravir is available in granulesfor oral suspension as a single use package of 100 mg.
Metabolism: the same as bilirubin, raltegravir is metabo-lized through glucuronidation by UGT1A1 (uridine dipho-sphate gluronosyl transferase), and hence both of themcompete for albumin-binding sites. UGT enzyme activity islow at birth, which diminishes raltegravir metabolism. In
addition, in neonates, because of the physiologic immaturebilirubin elimination, raltegravir can lead to an increase of freeunconjugated bilirubin, which is directly related to bilirubintoxicity and kernicterus [52].
Dose: in the MPAACT P1110 study, a dose of 1.5 mg/kgonce a day in the first week; 3 mg/kg twice a day from the 8th
to the 28th day of life; and 6 mg/kg twice a day from thefourth week of life seemed to be secure without seriousadverse events and with good suppression rates [48].
Recommendations for administration: raltegravir can begiven without regard to food. Raltegravir granules must bemixed with water, dose should be administered within 30 minof mixing, and unused solution should be discarded.
Adverse events are shown in Table 1.
4.2.2.9. Novel drugs and strategies under investigation.Clinical studies in neonates are characterized by ethical andlogistic barriers complicating the development of new antire-troviral agents and strategies. Fixed-dose combinations andonce-a-day medications have solved many issues of adherencein older children and adolescents who are able to swallowpills. Developing child-friendly pediatric drug formulationsremains a challenge to improve ART in neonates. One of themost rapidly changing fields is the formulation of poorlywater-soluble drugs in flexible solid dosage forms. A noveltechnology that produces in situ self-assembly nanoparticlesis a promising platform to manufacture palatable and flexiblepediatric granules of ritonavir [76] and fixed-dose combina-tions of lopinavir/ritonavir that can be used as sachets andsprinkles [77]. In addition to fixed-dose combinations, once-a-day formulations of extended-release nevirapine show pro-mise as a way to simplify ART administration, decrease pillburden, and improve adherence in children [78]. Another areaof innovation is the development of injectable long-actingformulations of antiretrovirals. These formulations may be apharmacological alternative to oral drugs and an innovativeclinical option to address adherence. Long-acting injectablenanosuspension formulations of cabotegravir and rilpivirineare in clinical development in adults [79] and could representa paradigm shift in the treatment of HIV infection.
4.2.3. Recommended antiretroviral regimen options forneonatesDecisions around which ART regimen to start with in neo-nates are complicated by the lack of clinical trials in thisparticular setting, few drug choices, and potential toxicities.Despite lack of scientific evidence and concerns associatedwith initiation of effective ART within the first days of life,clinicians seems to be moving toward effective combinationtreatment from birth. Most information on trends in ARTusage in newborns comes from drug prophylaxis of infantsat high risk of HIV infection. Among 1105 infants at high riskof HIV infection receiving prophylaxis in eight Europeancohorts between 1996 and 2010, 13.5% received zidovudineplus lamivudine, 22.7% received zidovudine plus single-dosenevirapine, 55.8% received zidovudine plus single dosenevirapine plus lamivudine, and 4.4% received a regimenincluding a protease inhibitor [80].
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An standard three-drug antiretroviral regimen generally con-sists of two nucleoside reverse transcriptase inhibitors in combina-tion with a third active drug from one of three drug classes: a non-nucleoside reverse transcriptase inhibitor, a boosted protease inhi-bitor, or an integrase strand transfer inhibitor. With regard to thethird active drug, as mentioned earlier, PK and dosing data inneonates only exist for nevirapine and lopinavir/ritonavir and, toa lesser extent, for raltegravir, and sufficient safety data as toprescribe a complete three-drug regimen are only available forfull-term newborns from 2 weeks of life onwards. Available evi-dence from clinical studies favor triple-drug combinations includ-ing lopinavir/ritonavir, recommendation supported by dataobtained in older children showing that a lopinavir/ritonavir-based first-line regimen is more efficacious than a nevirapine-based regimen, regardless of PMTCT exposure status [70].
Table 2 provides guidance on choosing an antiretroviral regi-men based upon length of gestation and age. Given the optionsfor initial therapy, in full-termneonates from age 2weeks onwards,a regimen consisting of zidovudine and lamivudine (or emtricita-bine) in combination with lopinavir/ritonavir is recommended.Regimens using nevirapine or raltegravir as third active drugsmay be alternative options for infants who cannot tolerate lopina-vir-ritonavir. In term infants younger than 2 weeks, a regimenconsisting of zidovudine and lamivudine (or emtricitabine) plusnevirapine is recommended, although there are no clinical trialdata supporting that initiating treatment before 2 weeks improvesoutcome compared to starting after 14days of age. Switching fromnevirapine to lopinavir/ritonavir should be considered after 14days of life based on the better outcomes of lopinavir/ritonavir inchildren aged <3 years. Existing safety information is insufficientfor recommending ART in preterm infants, with PK data onlyavailable for zidovudine. If ART is considered in this setting, anindividual case assessment of the risk/benefit ratio of treatmentshould be made, and the latest information on neonatal drugdoses of the candidate drugs to be used thoroughly reviewed.
4.2.4. Challenges and needs for early initiation of therapyin neonatesDespite global recommendation to initiate ART in HIV-infectednewborns as soon as possible, implementation of earlytreatments remains complex. An important barrier for earlyinitiation of ART is the complexity of early infant diagnosis in
low-resource settings. Conventional virological diagnosisrequires sophisticated technology that is typically only availablein urban, centralized laboratories. As a result, in resource-limit-ing settings, access to early diagnosis may be difficult and thelogistic challenges may lead to long turnaround times, therebydelaying the diagnosis. Point of care (POC) diagnostic technol-ogy has the potential to increase access to virological tests forearly infant HIV diagnosis. Available data indicate that somePOC assays perform well showing high specificity and positivepredictive value, thus suggesting that a positive POC result maybe adequate for immediate infant ART initiation [81,82]. Largeclinical studies are under way to provide evidence for theincremental benefit of implementing a POC strategy in low-resource settings where only off-site services for virologicalearly infant HIV diagnosis are currently available [83].
Additional challenges associated with early ART in neonatesinclude concerns on the risk of emergence of early viral resis-tance and virological failure [84,85]. Antiretroviral drug-resistantvirus can develop during ART due to ongoing viral replication inthe presence of subtherapeutic drug concentrations caused bylimited pediatric drug formulations, poor adherence, poorabsorption, variable PK, a regimen that is not potent, or a com-bination of these factors. Concerns related to drug adherenceshould be addressed before initiating therapy and suboptimalregimens should be avoided particularly in those with high pre-ART viral loads. In settings where technology is available, anynewly diagnosed infant should undergo viral resistance testingby genotype and/or phenotype to assess for susceptibility toART. In addition, frequent monitoring of plasma viral load isneeded to assess virologic response to therapy.
5. Conclusion
Early diagnosis and prompt initiation of ART in every infantinfected with HIV should now be considered the standard ofcare. There is considerable interest in moving treatmentinitiation closer to birth, since very early ART appears tolimit the size of the viral reservoir. However, there are chal-lenges to start ART in early life, including a paucity of drugchoices, uncertain dosing for some medications, and con-cerns about toxicities. Safety data and available evidencefrom clinical studies favor triple drug combinations in full-
Table 2. Recommended antiretroviral regimens in newborns.
Length of gestation and ageRecommended regimen
options Alternative regimen options Comments
Preterm neonates Individual case assessmentweighing the risks andbenefits of treatment
PK and safety data available only for zidovudine
Full-term neonates First 2 weeks of life Zidovudine plus lamivudine(or emtricitabine) plusnevirapine
Zidovudine plus lamivudine(or emtricitabine) plusraltegravir
Limited PK and safety datawith raltegravir*
From 2 weeks of life onwards Zidovudine plus lamivudine(or emtricitabine) pluslopinavir-ritonavir
Zidovudine plus lamivudine(or emtricitabine) plusnevirapineZidovudine plus lamivudine(or emtricitabine) plusraltegravir
Nevirapine-based regimenless effective thanlopinavir-ritonavir-basedin a clinical trial in olderchildrenLimited PK and safety datawith raltegravir*
*Pharmacokinetic and 6-week safety data from 25 full-term infants (aged ≤48 h of age; gestational age at birth at least 37 weeks & weight ≥2 kg). There are no datain infants born to mothers who received raltegravir during pregnancy, nor in low-birth-weight infants and in those with elevated bilirubin requiring phototherapy.
PK, pharmacokinetic.
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term neonates. The risks associated with use of different ARTregimens as well as the potential benefits of very early treat-ment within days of birth, including the possibility of pro-longed remission in infected neonates, require furtherinvestigations before firm recommendations can be made.
6. Expert opinion
Although available data on the risks and benefits of immedi-ate therapy in asymptomatic HIV-infected children are weakerthan in adults, there is general consensus in initiating ART asearly as possible in HIV-infected infants. In order for HIV-infected neonates to receive prompt treatment, accurateearly infant diagnosis is crucial. Advances in HIV virologictesting have improved accuracy and reduced turnaroundtime, allowing diagnosis of HIV infection soon after birth.
The recommendation for early onset of treatment in HIV-infected children is justified by the rapid progression of HIV diseasereported in younger children and supported by data from cohortstudies and clinical trials suggesting that earlier initiation of ARTmay reduce the risk of mortality and progression to AIDS. Theprecise timing of initiation of ART in neonates remains undeter-mined. Whereas the benefit of starting therapy between 6 and 12weeks of age has been clearly demonstrated in the CHER trial, it isnot known whether initiating ART earlier (close to birth) wouldcarry additional benefits. Very early effective ART in perinatal HIVinfection appears to limit the size of the viral reservoir, which isconsidered one step in the pathway toward HIV cure. Initiation oftherapy very early may also restrict replication-competent HIV andpromote continuous decay of viral reservoirs during long-termeffective ART.
Barriers to use ART in neonates include lack of access tovirologic testing, insufficient data on which to base a firm recom-mendation for treatment doses, and safety concerns by pediatri-cians arising from limited knowledge and experience regardingthe use of antiretroviral drugs in this setting. Compared to olderchildren, neonates and young infants have delayed absorption,reduced liver metabolism, and reduced renal elimination ofdrugs; therefore, it is important to obtain data on PK and safetyof antiretroviral drugs in this particular population. In addition,the poor palatability of many of the existing formulations oftenleads the children to refuse taking them.
Unfortunately, reliable dosing and safety data to provideappropriate recommendations for neonates have been generatedfor a few antiretroviral drugs, most of them old agents. In full-termneonates, reliable data exist only for seven drugs. Two (stavudineand didanosine) of the seven antiretroviral drugs are rarely used inadults due to the high risk of mitochondrial toxicity. In preterminfants, data are available only for zidovudine. Ethical and logisticbarriers complicate the development of new antiretroviral agentsand strategies to treat HIV infection in neonates. Developing child-friendly pediatric drug formulations remains a challenge toimprove ART in neonates. There is growing interest in the use ofintegrase strand transfer inhibitors in children and neonates, espe-cially after the recent approval of an oral granule raltegravirformulation which is suitable for use in young infants.Preliminary PK results and 6-week safety data in full-term new-borns aged ≤48 h of age (gestational age at birth at least 37 weeks
& weight ≥2 kg) suggest that this drug may provide a significanttherapeutic advance.
Decisions around which ART regimen to start in neonates arecomplicated by the lack of clinical trials in this particular setting.Available data favor triple drug combinations including lopinavir/ritonavir, recommendation supported by a clinical trial in olderchildren showing that a lopinavir/ritonavir-based first-line regimenis more efficacious than a nevirapine-based regimen. Among thecurrent options for initial therapy, in full-term neonates, a regimenconsisting of zidovudine and lamivudine in combination withlopinavir/ritonavir is recommended. Regimens using nevirapineor raltegravir as third active drugs may be alternative options forinfants who cannot tolerate lopinavir-ritonavir. In term infantsyounger than 2 weeks, a regimen consisting of zidovudine andlamivudine (or emtricitabine) plus nevirapine is recommended,although there are not clinical trial data suggesting that initiatingtreatment before 2weeks improves outcome compared to startingafterwards.
There is still an important lack of evidence to support theuse of antiretroviral drugs in special situations in the neonatalperiod like prematurity or low birth weight. These situationsare more frequent in neonates born to mothers with HIVinfection, and currently PK and safely data in preterm new-borns are only available for zidovudine. If ART is considered inpreterm infants, an individual case assessment of risks andpotential benefits should be made.
Improvement on palatability of antiretroviral drugs is anotherneglected field. Due to the impossibility to swallow pills, oralsolutions have to be given and poor palatability can make theneonate reject the medication and affect to the treatmentadherence.
Funding
This paper was not funded
Declaration of interest
The authors have no relevant affiliations or financial involvement with anyorganization or entity with a financial interest in or financial conflict withthe subject matter or materials discussed in the manuscript. This includesemployment, consultancies, honoraria, stock ownership or options, experttestimony, grants or patents received or pending, or royalties.
ORCID
Mar Masiá http://orcid.org/0000-0001-9878-2458
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