Ped hiv

Asian Biomedicine Vol. 4 No. 4 August 2010; 505-513

Practice Guidelines

Thai national guidelines for the use of antiretroviraltherapy in pediatric HIV infection in 2010

Thanyawee Puthanakita, Auchara Tangsathapornpongb, Jintanat Ananworanichc, Jurai Wongsawatd, PiyaratSuntrattiwonge, Orasri Wittawatmongkolf, Jutarat Mekmullicag, Woraman Waidabh, Sorakij Bhakeecheepi,Kulkanya Chokephaibulkitf, for the Thai National HIV Guidelines Working GroupaDepartment of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok 10330;bDepartment of Pediatrics, Faculty of Medicine, Thammasat University Hospital, Pathumthani 12120;cThe Thai Red Cross AIDS Research Center, Bangkok 10330; dBamrasnaradura Institute, Ministry ofPublic Health, Bangkok; eQueen Sirikit National Institute of Child Health, Bangkok 10400; fDepartmentof Pediatrics, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700; gDepartmentof Pediatrics, Bhumibol Adulyadej Hospital, Royal Thai Air Force, Bangkok 10220; hCharoenkrungPracharak Hospital, Bangkok 10120; iNational Health Security Office, Bangkok 10120, Thailand

With better knowledge and availability of antiretroviral treatments, the Thai National HIV Guidelines WorkingGroup has issued treatment guidelines for children in Thailand in March 2010. The most important aspects ofthese new guidelines are detailed below.

ART should be initiated in infants less than 12 months of age at any CD4 level regardless of symptoms andin all children at CDC clinical stage B and C or WHO clinical stages 3 and 4. For children with no or mild symptomsconsider CD4-guided thresholds of CD4 <25% (children aged one to five years) or CD4 <350 cells/mm3 (children5 years or older). The preferred first-line regimen in children aged < 3 years is AZT+3TC+NVP. For children >3years of age the preferred regimen is AZT+3TC+EFV. If an infant has previously been exposed to NVP perinatally,use AZT+3TC+LPV/r as empirical first regimen. In adolescents, consider TDF+3TC+EFV.

The preferred ARV treatment in children who failed first line regimens of 2NRTI+NNRTI (Salvage treatment)comprises 2NRTI (guided by genotype) +LPV/r, and an alternative regimen is 2NRTI (guided by genotype) +ATV/r (use in cases with dyslipidemia who are six years or older). In cases with extensive NRTI resistance with noeffective NRTI option available, double boosted PI with LPV/r+SQV or LPV/r+IDV can be considered. Consultationwith an expert is recommended.

Laboratory monitoring is recommended for CD4 and every six months. Viral load at least at 6 and 12 monthsafter initiation or change of regimen, then yearly thereafter. More frequent viral load monitoring is advised forcases with unsuccessful virologic response, infants, children with imperfect adherence, or those using of thirdline regimens. Toxicity monitoring depends on the drug received, at least every six months, and more often asclinically indicated. These include, but are not limited to, complete blood count, renal function tests, liver functiontests, urinanalysis, and lipid profiles. Therapeutic drug monitoring is recommended in cases that have ARV-relatedtoxicity, receiving non-standard dosing or regimens, using double boosted PI, and in those with renal or hepaticimpairment.

Keywords: HIV, pediatrics, Thai guidelines

The systematic treatment program for humanimmune deficiency virus (HIV)/acquired immunedeficiency syndrome (AIDS) is continuously evolving

in the Thai medical community. The Ministry of PublicHealth, and later on, the National Health SecurityOrganization (NHSO) has been providing free access

Correspondence to: Kulkanya Chokephaibulkit, MD. Department of Pediatrics, Faculty of Medicine Siriraj Hospital, Mahidol University,2 Prannok Road, Bangkok-noi, Bangkok 10700, Thailand. E-mail: [email protected]

506 T. Puthanakit, et al.

to antiretroviral therapy (ART) and monitoring formore than 10 years. The National Guidelines havebeen updated as knowledge and availability oftreatment and care have improved. The Thai NationalHIV Guidelines Working Group is composed ofpediatricians, academicians, researchers, andnongovernment organizations (NGOs) with expertisein HIV and AIDS, and is supported by the Bureau ofAIDS, TB, and STD, and Ministry of Public Health(MOPH). Representatives from the NHSO and theMOPH have joined the Working Group. The guidelineswere issued in March 2010.

The treatment guidelines presented here aimto provide a summary of recommendations fortreating HIV-infected children and adolescents inThailand. The Working Group reviewed and maderecommendations based upon data from Thai childrenand from recently published WHO [1], PENTA [2]and US guidelines [3].

Current situation of Pediatric HIV/AIDS inThailand

The major route of HIV infection in Thai childrenis mother to child transmission. The cumulativenumbers of perinatally HIV-infected Thai children areestimated to be 15,000 to 20,000, of which more than8,000 children have received antiretroviral therapythrough the National program. HIV prevalence amongpregnant women at antenatal care clinics has beenreduced from about 2% in 1999 to 0.74% in 2009.There are about 6,000 infants born to HIV-positivemothers each year, leading to 200-400 newly HIV-infected infants annually.

Diagnosis of HIV in children younger than 18months of age

HIV infection should be diagnosed early in life toprovide appropriate treatment and care. The diagnosiscan be made by positive HIV RNA or DNApolymerase chain reaction (PCR) as early as onemonth of age.

HIV infection can be excluded if a child had either1) two negative HIV PCR tests, of which the firsttest is performed at > one month of age and thesecond test is performed at > four months of age; 2)two negative HIV antibody test after six months ofage; or 3) one negative PCR at > four months of ageand one negative HIV antibody test after six monthsof age plus no clinical signs or symptoms compatiblewith HIV infection [4].

In the clinical care for infants born from HIV-positive mother in Thailand, it is recommended to haveat least one HIV antibody test preferable at 18 monthsto definitely exclude HIV infection. At 12 months, themajority of infants who are not infected have negativeHIV antibody tests. However, 5-10% of HIVuninfected infants may have persistent maternalantibodies. The infants with positive HIV antibody testsat 12 months should have the test repeated at 18months. It is noted that combination serologic tests(antigen-antibody combined tests) may be able todetect very low levels of HIV antibodies and reportpositive results in some HIV-uninfected children at 18months of age. Therefore, it is recommended not touse the combination test for diagnosis of perinatalinfection.

Baseline evaluations before the initiation of ARTA detailed history of any possible previous

exposure to ART in a child should be documented.Children should be examined and evaluated foropportunistic infections (OI), especially tuberculosis.Cotrimoxazole (TMP/SMX), is recommended in allHIV-exposed infants until HIV infection is excludedand in all HIV-infected infants regardless of CD4levels. TMP/SMX is also recommended in HIV-infected children younger than five years of age whohave CD4 percentage lower than 15%, and in olderthan five years who have CD4 count less than 200cells/mm3. The common side effects of TMP/SMXare rash or cytopenia, which might be confused withART toxicity if started at the same time. Baseline pre-ART evaluations should include CD4 cell count andpercentage, hematology, biochemistry, (e.g. AST, ALT),and profile testing for other blood-borne infections,especially hepatitis B. Moreover, the evaluation ofpsychosocial aspects including whether the child hasbeen informed about their HIV status and theirreadiness to take antiretroviral therapy are crucial.Clinical monitoring and measurements of CD4 levelshould be repeated every six months in well childrenwho do not need to start ART, and more frequently ininfants and in older children approaching treatmentthresholds.

When to start antiretroviral therapy (ART)Because disease progression among HIV-infected

infants is unpredictable and has high morbidity andmortality, ART should be started urgently in all infants,as soon as the diagnosis of infection is confirmed

507Thai national pediatrics HIV guidelinesVol. 4 No. 4August 2010

irrespective of the clinical or immunological stage [5].ART should be initiated in all children with symptomaticdiseases (CDC clinical stage B or C or WHO stage 3or 4) who are > one year of age. For children whohave minor symptoms, ART initiation should be basedon age-specific CD4 thresholds (Table 1). Baselineviral load is not recommended as criteria to initiateART. Importantly, issues likely to affect adherenceshould always be considered and addressed beforestarting therapy.

What antiretroviral regimens to start withThe current preferred first-line ART regimen for

previously untreated children comprises twonucleoside reverse transcriptase inhibitors (NRTIs)with a non-nucleoside reverse transcriptase inhibitor(NNRTI).

The preferred NRTI combination is zidovudine(ZDV) and lamivudine (3TC) and the alternativecombination is stavudine (d4T) and lamivudine(3TC). AZT is preferred because it has less long-term toxicities, such as lipodystrophy, compared tostavudine. However, children with low baselinehemoglobin <8 g/dL should start with d4T and switchto AZT after 6-12 months of treatment. In adolescentswho weigh > 40 kg or with Tanner stage IV, tenofovir(TDF) and 3TC is a preferred because the dosing isonce daily, which may improve adherence (Table 2).

The preferred NNRTI is nevirapine (NVP) forchildren age < 3 years, and efavirenz (EFV) for olderchildren. NVP has benefits over EFV in terms offormulations available, i.e. syrup, tablet, and fixed dosecombination GPOvir (d4T/3TC/NVP) or GPOvir-Z(AZT/3TC/NVP). However, NVP has more sideeffects such as rash and hepatotoxicity [6]. Somereports showed better virological efficacy of EFV overNVP [7].

Infants who are exposed to NVP as part ofprevention of mother to child transmission have20-57% risk of harboring NVP resistance [8, 9].Therefore, the first line regimen should be two NRTIsand boosted lopinavir (LPV/r), the only proteaseinhibitor (PI) available for infants [10]. Genotypictesting for drug resistance prior to initiating ARV isrecommended. After the first six months of treatmentwith a PI-based regimen, if the patient has viralsuppression and the genotypic testing of the sampleprior to ARV initiation has no evidence of NVPresistance, the regimen can be switched to NNRTI-based regimen.

For children who had recent opportunisticinfections, there are some special considerations suchas timing of the start of antiretroviral drugs, druginteractions, and the risk of developing immunereconstitution inflammatory syndrome (IRIS). Ingeneral, antiretroviral therapy should be initiated within

Table 1. Criteria for initiation of antiretroviral therapy among HIV-infected children.

Age <1 year Age 1-5 years Age > 5 years

Clinical staging criteria All CDC category B, C CDC category B, Cor WHO stage 3, 4 or WHO stage 3, 4

Immunological criteria All %CD4 <25 CD4 <350 cells/mm3

%CD4 or CD4 cell count

Table 2. The recommended first line regimen in Thai children.

Preferred regimens AZT+3TC+NVP AZT+3TC+EFVPreferred regimens foradolescents (weight >40 kg - TDF+3TC+EFVor Tanner stage IV)

AZT+3TC+NVPAlternative regimens d4T+3TC+NVP d4T+3TC+EFV

d4T+3TC+NVP

Age <3 years Age >3 years


two to eight weeks after starting treatment for OI.Among children who have a low baseline CD4 level,the risk of developing IRIS is about 20% [11].However, this should not be a reason to delay initiationof antiretroviral treatment when indicated. The mostproblematic drug interactions with ART are withrifampicin in children with tuberculosis (TB) co-infections. Rifampicin reduces EFV levels by 25%,however data from Thai HIV-infected adult patientsshowed that the standard dose of EFV provideadequate plasma levels [12]. Recent data also showedthat despite drug interactions between rifampicin andNVP, the standard dose of NVP could be used [13].However, rifampicin significantly reduces PI levelsand these drugs must not be used together. In casepatients need PI, the treatment option depends onimmune status. If a patient has a low CD4 leveland needs a PI-containing salvage regimen, theantiretroviral drug has a higher priority. Therefore,one should avoid rifampicin and modify anti-tuberculous drugs using quinolones oraminoglycosides. If a patient has a high CD4 level,PI-based antiretroviral treament initiation should bepostponed until the completion of a two-monthintensive anti-tuberculous treatment with rifampicin.The maintenance phase without rifampicin should beused with PI containing regimens.

Monitoring while on ARTThe first six months after initiation of treatment

is a vulnerable period due to potential drug toxicity,IRIS, or poor adherence. It is crucial to monitor forclinical response, which would include confirminggeneral well being, changes in body weight, andproblems related to ART or IRIS. Follow-up visitsshould be scheduled every month until stable, thenextended to every two to three months. It is importantto specifically check for adherence to therapy at everyclinic visit.

The CD4 cell count should be monitored everysix months. Plasma HIV viral load should be monitoredat least at 6 months and 12 months after treatmentinitiation and yearly thereafter. In cases where thevirologic response is not as successful as expected,more frequent virologic monitoring is required. Morefrequent clinical and laboratory monitoring arerequired in infants, as well as in cases of imperfectadherence, especially at the start or change of therapy.

Serum testing for drug toxicity should be doneroutinely every six months. It should include completeblood count, liver function tests, renal function tests,

and lipid profile. Some antiretroviral drugs have specificdrug toxicities which require monitoring, such as NVP(alanine aminotransferase, ALT, at two to four weeksafter initiation), AZT (complete blood count after threemonths after initiation), indinavir (IDV), and TDF(urinalysis and creatinine every three months).

Diagnosis of treatment failureTreatment failure can be detected through

virologic, immunologic, or clinical criteria [3]. Virologicfailure is usually detected earlier than immunologicfailure. However, the lapsed time differs in eachindividual ranging from few months to few years.Clinical failure usually occurs after a period ofimmunologic failure. Immunologic failure or clinicalfailure must concur with virologic failure in order toindicate treatment failure.1) Clinical failure is defined as one of the following:• Abnormal or regression of developmentalmilestones.• Poor growth without other causes.• Appearance of new, or progression of, HIV-related conditions or opportunistic infections. Due tothe high prevalence of tuberculosis in Thailand,tuberculosis of the lung or lymph node does notnecessarily indicate clinical failure, especially if thereis an otherwise good response to treatment.2) Immunologic failure is determined based on at leasttwo measurements of CD4, at least one week apart.Some acute conditions or infections may cause atransient drop in CD4. Immunologic failure is definedas one of the following:• Inadequate immunologic response to treatment:

- For children younger than five years withbaseline CD4<15%, an increase of CD4 percentageof less than five after one year of treatment

- For children five years or older with baselineCD4 <200 cells/mm3, an increase of CD4 of less than50 cells/mm3 after one year of treatment.• Decrease of CD4 levels:

- For those with baseline CD4 percentage <15%,a sustained decrease of at least 5% after treatmentinitiation, i.e., decrease from 15% to 10%.

- Any decrease in CD4 percentage or count ofmore than 30% over a six-month period.3) Virologic failure is defined as one of the following:

Inadequate virologic response to treatment• In infants younger than 12 months of age, the HIVRNA level (viral load) is >50 copies/mL after one yearof treatment.


• In children older than one year of age, the viralload is >50 copies/mL after six months of treatment• Increase of viral load to >1,000 copies/mL in thosewho previously had good viral suppression. The viralload of 50-1,000 copies/mL may be a transient viralblip from imperfect adherence or other temporaryeffects. In such cases, the viral load measurementshould be repeated at one to three months afteradherence counseling.

Antiretroviral treatment in children withtreatment failure

Most treatment failures are caused by pooradherence. Therefore, adherence must be evaluatedand counseling must be provided to patients and theirfamilies. Treatment failure may be from inappropriatetreatment regimens, e.g., dual NRTI that wascommonly used when antiretroviral drugs were notwidely available. Some children may acquire resistantvirus from the beginning, such as infants exposed toperinatal single dose NVP. These children are at riskfor treatment failure with NNRTI regimens. A baselinegenotypic assay is a useful guide to treatment in suchcases.

The new treatment regimen should be guidedby genotypic assay results. In Thailand, it isrecommended to perform a genotypic assay when theviral load is >2,000 copies/mL and the child has beenreceiving treatment or discontinued treatment nolonger than one month.

It is important that the new treatment or salvageregimen be started soon after virologic failure toprevent accumulation of resistance mutations.Prolonged use of failing regimens causes selectivepressures that result in more resistance mutations andmay jeopardize future options. For example, prolongeduse of NRTI in patients with thymidine analoguemutations (TAMs) will cause accumulation of moreTAMs; and prolonged use of NNRTI in patients whohave NNRTI resistance mutations may cause furtherresistance to etravirine, (a new NNRTI drug) [14].However, the new treatment regimen should not bestarted until good adherence is ensured.

Choosing the new regimen in children who fail2NRTI+1NNRTI regimens (Fig. 1)• Preferred regimen: 2NRTI plus LPV/r[15](selection of NRTI guided by genotype)• Alternative regimens: 2NRTI plus boostedatazanavir (ATV/r). Selection of NRTI is guided by

genotype (see below). ATV is approved in childrensix years or older. This regimen is most appropriate inthose with dyslipidemia [16].

Double boosted PI with boosted lopinavir andsaquinavir (LPV/r+SQV) [17] or boosted lopinavir andindinavir (LPV/r+IDV) [18], with or without NRTI.These regimens are considered only in children whohave no effective NRTI available, i.e., with extensiveNRTI resistance mutations and cannot use TDF orABC. Initiating these regimens requires expertconsultation. Children receiving double boosted PImust be closely monitored for toxicities, especiallymetabolic and renal. Children who receive theseregimens and had complete viral suppression for morethan one year should be considered to switch to aregimen comprising a single boosted PI plus NRTI(s).

Selection of NRTI for the new regimen guidedby genotypic assay

The genotypic resistance testing reports includethe gene mutations and the interpretation of ARV drugsusceptibility. The principles of interpreting genotypicassay in order to select NRTI in the new regimen areas follows [19]:• Resistance mutations in reverse transcriptase (RT)genes that confer resistance to most NRTIs, except3TC and FTC, are called TAMs. When number ofTAMs is >4, most of the NRTIs will not be effectiveexcept that TDF, ABC, and ddI may still be useful ifwithout K65R.• The other multi-NRTI mutations are T69i andQ151M. They confer resistance to all NRTIs. Theexception is that virus with Q151M are still susceptibleto TDF.• The K65R mutation confers resistance to TDF,ABC, and ddI, but is susceptible to AZT.• The L74V and K65R mutations confer resistanceto ddI and ABC.• The M184V mutation confers resistance to 3TCand FTC. However, the virus with M184V is a less fitvirus, and therefore keeping the patient on 3TC orFTC to sustain this mutation may have clinical benefits.The M184 mutation also causes hyper-susceptibilityto AZT or TDF.

The guide to selecting NRTIs in the new regimenin combination with LPV/r or ATV/r is as follows(Fig. 1):

a) When there are < 4 TAMs and without Q151Mor T69i.


The 2NRTI selected for new regimens afterfailing AZT/d4T+3TC may be ddI+3TC, ddI+AZT,ABC+3TC or ABC+ddI.

b) When there are >4 TAMs or with Q151M orT69i, but without K65R.

The new regimen may be TDF+3TC orTDF+ABC or TDF+AZT. Some experts recommendTDF+AZT+3TC because AZT may preventdevelopment of K65R, and 3TC may decrease viralfitness. TDF should only be used for salvage treatment

in children >30 kg or with Tanner stage IV. TDF shouldnot be used with ddI.

c) When there are >4 TAMs and with K65R butunable to use TDF (e.g. too young)There will be no effective NRTI available. In this case,the regimens with double boosted PI should beconsidered. 3TC may be added to reduce viral fitness.However, some experts may consider the 2NRTIs asin a) plus single boosted PI (LPV/r, ATV/r) with closelyviral load monitoring.

Fig. 1 Formulating a new or salvage regimen in children failing 2NRTI+NNRTI regimens.


Salvage regimens in children who are infectedwith three classes of resistance mutations [20]

Children experiencing extensive antiretroviraltherapy and have resistance mutations to NRTIs,NNRTIs, and PIs, have been identified more often inolder children. The principle in designing the salvageregimen is to use at least two active drugs plus recycleNRTIs because NRTIs may still be useful even withresistance mutations. The aim is to achieve completeviral suppression. New drugs, such as darunavir,maraviroc, etravirine, or raltegravir, may be neededin compassionate programs or study trials. Expertconsultation is recommended.

In case new effective regimens are not availablein the near future, and the patient has a high CD4level (e.g. over than 200 cells/mm3), 3TC monotherapymay be considered to slow the disease progression,yet not select further resistance mutations that mayjeopardize future options. The salvage regimen shouldbe initiated as soon as possible.

Salvage regimens in children who fail dual NRTIregimens

Dual NRTI regimens (AZT or d4T + 3TC or ddI)were often used in the past when ART availabilitywas limited. Children receiving dual NRTI regimenswill have virologic failures at some points. However,there are many children who have been receiving dualNRTIs with stable CD4 and clinical status. Thesechildren should be tested for viral load and viralresistance. Whenever possible, the treatment regimenshould be switched to highly active antiretroviraltherapy (HAART) to prevent emerging of resistanceeven though their viral load is suppressed. For childrenwho had incomplete viral suppression, the genotypicassay should be used to guide the design of the newregimen. The following points are guides to formulatethe new regimen- If the RT mutations are not extensive, TAMs <4(please see above for NRTI selection), the preferrednew regimen is 2NRTIs+LPV/r.- If there are >4 TAMs especially with K65R or unableto use TDF, the preferred regimen is NNRTI (preferEFV) +LPV/r with or without NRTI.

Monitoring in children receiving salvageregimensMonitoring for efficacy and safety of treatment

During the early phases of the new treatmentregimen, patients should be closely monitored foradherence and potential side effects. The CD4 and

viral load should be monitored at least at six monthsand 12 months after switching to the new regimens.The salvage regimens containing PI that may causemetabolic side effects should be monitored for fastingglucose and lipid levels. Children who receive TDFand IDV should be monitored for renal function(electrolytes, BUN, creatinine, and urinalysis). Thetests for safety monitoring should be performed everythree to six months or as clinically indicated.

Therapeutic drug monitoring (TDM)Therapeutic drug monitoring is useful for patients

who receive IDV, double boosted PI regimens, or drugsthat may have interact with each other. Moreover,patients using drugs at dosages different from what isrecommended, and patients with underlying kidney orliver diseases should receive TDM. The drug levelmonitored is the trough level after at least two weeksof treatment. However, TDM in the patients receivingIDV should also include the peak level at two to fourhours after drug administration, which correlates withkidney toxicity. Expert consultation is required for drugor dose adjustments.

AcknowledgementThe Thai National HIV Guidelines Working Group

thankfully acknowledges the participation of thefollowing colleagues in preparing these guidelines:

The Pediatric Committee of The Thai NationalHIV Guidelines Working Group:

Auchara Tangsathapornpong, Benjawan Raluek,Boonyarat Warachit, Boripat Donmon, ChitsanuPancharon, Chuenkamol Sethaputra, JintanatAnanworanich, Jurai Wongsawat, Jutarat Mekmullica,Kulkanya Chokephaibulkit, Orasri Wittawatmongkol,Peeramon Ningsanond, Peninnah Oberdorfer, PiyaratSuntrattiwong, Pope Kosalaraksa, Pramot Srisamang,Rangsima Lolekha, Rawiwan Hansudewechakul,Rudiwilai Samakoses, Siriporn Pongjitsiri, SiriratKasisedapan, Sorakij Bhakeecheep, SupichayaNetsawang, Thanyawee Puthanakit, VeerachaiWatanaveeradej, Virat Sirisanthana, WasanaPrasitsuebsai, Wittaya Petdachai, Woraman Waidab.The Steering Committee of The Thai National HIVGuidelines Working Group:

Achara Teeraratkul, Aree Kumpitak, KulkanyaChokephaibulkit, Manoon Leechawengwong, MichalleMcConnell, Peeramon Ningsanond, PraphanPhanuphak, Sanchai Chasombat, SomnuekSungkanuparph, Taweesap Siraprapasiri, WasunChantratita, Wichai Techasathit.


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