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6.6 Changing ARV Therapy In Children Under 15 Years

Table of Contents

i) Drug toxicity

The principles for changing ARVs and the managing drug toxicity in children are similar to those applied to adults.

ii) Treatment failure

  • Virological treatment failure: Viral load is the most reliable method to detect early treatment failure. Virological treatment failure is recognized if the child is adherent to the current ART regimen, for 6 months or more and has two consecutive viral load measurements over 1000 copies/ml at 3 months apart.

Immunological treatment failure: If adherence is good, immunological criteria indicating that a change to second-line therapy is warranted where/when HVL test is not available includes the following:

Table 6.12: CD4 criteria suggesting immunological failure a

Immunological failure is recognized as developing or returning to the following agerelated immunological thresholds after at least 6 months on ART, in a treatmentadherent child:
<5 years of age CDcount of <200 cells/mm3 or CD4 <10%
≥5 years of age CD4 count of <100 cells/mm3
Preferably, at least two CD4 measurements should be available

Use of CD4 in children <5 years and absolute CD4 cell counts in those ≥5 years of age is preferred.

If serial CD4 values are available, the rate of CD4 cell count declines from the peak, CD4 cell count reached should be taken into consideration.

NOTE: CD4 cell percent should not be measured during an inter-current infection but can be determined when the child has recovered.

If there is a modest decline in CD4 cell count or percent (< 5%); and if there is no failure to thrive do not change medication, instead maintain close monitoring.

Clinical Treatment Failure:

Clinical conditions indicating that a change to second-line therapy is warranted include:

  • Poor growth (failure to gain weight, declining or stagnant weight) over a 6month period, after excluding other causes, such as TB, feeding problems and food insecurity
  • No improvement of neuro-developmental milestones
  • Development of HIV encephalopathy
  • Recurrent infections, such as oral candidiasis, persistent diarrhoea, recurrent severe bacterial pneumonia
  • Advancement from one clinical stage to another or new evidence of new WHO stage 3 or 4 disease (see Annex 2 Pediatrics WHO Clinical Staging)

Note:

  • Short inter-current episodes of pneumonia, LRTI and gastroenteritis should not be regarded as clinical failure
  • Pulmonary or lymph node TB, which are clinical stage 3 conditions, are not indications of treatment failure, and thus may not require consideration of second-line therapy
  • The response to TB therapy should be used to evaluate the need for switching therapy
  • Before an ARV regimen is thought to be failing based on clinical criteria, the child should have received the regimen for at least 6 months.

Table 6.13: Laboratory parameters for monitoring infants and children under

15 years at baseline, before and during ART

Laboratory tests for diagnosis and monitoring Baseline (at entry into care) At initiation of 1st or 2nd -line ART regimen Every 6 months As required or

symptom-

directed

HIV diagnostic testing
Haemoglobina
WBC and differential count
%CD4+ or absolute CD4 cell count e
Pregnancy testing in adolescent girls c
Full chemistry (including, but not restricted to, liver enzymes, renal function, glucose, lipids, amylase, lipase and serum electrolytes)e
HIV VL measurement d
OI screening (where possible)

Routine monitoring (every six months) of full chemistry, particularly lipid levels, liver enzymes and renal functions, should be considered for infants and children on secondline drugs

eCD4 cell count should be taken on emergence of WHO stage 3 or 4 disease

dViral load monitoring is annual if the first two successful VL results 6th month apart are <1000 copies/Ml

Assessment of Infants and Children Receiving ARV Therapy

Important clinical signs of response to ARV therapy in children include improvement in growth and development and decreased frequency of infections (bacterial infections, oral thrush, and/or other opportunistic infections).

Clinical monitoring of ARV treatment in children should include:

  • Feeding practice and nutritional status
  • Growth monitoring: weight, height, MUAC (mid-upper arm circumference)
  • Head circumference should be monitored in children under 3 years old
  • Neurologic symptoms and developmental milestones
  • Cotrimoxazole prophylaxis taken daily
  • Adjustment of ARV dose based on weight
  • WHO disease clinical staging
  • Immunization status  Other medical conditions  Screening for malaria and TB.

Recommended Second-Line ARV Therapy for Infants and Children under 15 years

  • After failure of a first line LPV/r-based regimen, children younger than 3 years should remain on their first-line regimen, and measures to improve adherence should be taken. (PI based regimen have high genetic barrier for mutation and virological suppression can still be achieved.)
  • After failure of a first line LPV/r based regimen, children of 3 years and above should switch to a second-line regimen containing an NNRTI plus two NRTIs; EFV is the preferred NNRTI
  • After failure of a first-line regimen of ABC or TDF + 3TC, the preferred NRTI backbone option for second-line ART is AZT + 3TC
  • After failure of a first-line regimen containing AZT + 3TC, the preferred NRTI backbone option for second line ART is ABC or TDF + 3TC

Note: Infant and children take longer time to attain adequate viral suppression. Before confirming treatment failure, calculate drop in VL (using 0.5 log 2 years and above, 0.7log below 2 years- for further details on how to convert VL into numbers see Annex 05).

Table 6.14: Recommended Second-line ART regimens for children under 15 years

Patient group If is on the following firstline Preferred 2L Justification
Children under 3 years ABC/3TC+LPV/r ABC/3TC+LPV/r

AZT/3TC+LPV/r

 

 For children who were on

PI based first-line regimen, maintain the same regimen

AZT/3TC/NVP  For children who were

not on PI-based first-line regimen

Children 3–15 years ABC/3TC+LPV/r AZT/3TC+EFV
ABC/3TC+EFV
TDF/3TC/EFV

For dosing of ARV regimens see Annex on Paediatric Antiretroviral Dosing

NOTE:

  • TDF may only be given to children > 2 years and above 35kg
  • ATV/r can be used as an alternative to LPV/r in children above 6 years old if paediatric formulation is available but adolescents >40kg can take adult formulation.

Third-Line ARV regimens in children under 15 year

Patients failing 2nd line regimen have extensive NRTI and NNRTIs associated resistance mutations which minimise their use in third-line regimens. Third-line regimen is constructed using new classes of drugs or second generation formulations, in order to have at least two or three effective drugs.

This guideline recommends the use of Integrase Inhibitors DTG and RAL, Second generation PIs (DRV/r), and an NNRTI (ETV).

Criteria for Change to Third-line Failing any 2nd line regimen

Referral to specialist care is recommended where third line regimen can be chosen according to genotype resistance testing and managed by an expert panel at tertiary care facilities.

The criteria for diagnosing second-line failure are the same as those used for diagnosing first-line failure.

Eligibility for Third Line Evaluation:

All clients should have undergone an Enhanced Adherence Counselling

  • Failing 2nd line regimens
  • Documented virologic failure (VL > 1000) on a PI regimen; except children below 3 years

Steps to refer client to 3rd line review committee

  • Client suspected to have 2nd line failure from dispensary or health centre is referred to a hospital.
  • At the hospital, the client is reviewed by clinicians working in CTC, the checklist is completed and only the checklist is sent to the review committee at the tertiary /zonal referral hospital
  • At the zonal level, the review committee reviews the checklist and recommends which clients should be referred for evaluation including genotype resistance testing and decision
  • Zonal level review committee communicates the decision back to the referring hospital within a month.

Third-line Regimens FOR Paediatrics and Adolescents

Selection of third-line regimen should consider genotype resistance test results as well as treatment history.

Table 6.15: Third-line Regimens for Paediatrics and Adolescents

Patient group

 

Third options

 

Justification
Children <12 years

 

S: RAL+DRV/r+ETV

S: RAL + 2 NRTIs

S: DRV/r + 2 NRTIs

S: DRV/r + RAL + 1-2 NRTIs

DRV/r

• High genetic barrier

• Effective for patients with resistance to LPVr and ATVr

• Cannot be used in children < 3

years of age

ETV

• Effective for patients with NNRTI resistance

RAL

• Can be used for children under 12 years

DTG

• Can be used for children > 12 years

 

Children 12 years and

above

 

S: DTG+DRV/r+ETV

S: DTG (or RAL) + 2 NRTIs

S: DRV/r + 2 NRTIs

S: DRV/r + DTG (or RAL) + 1-2 NRTIs


Adverse reactions in children

Drug-related adverse reactions while on ART can occur immediately (soon after a drug has been administered), early (within the first days or weeks of treatment) or later (after months of treatment). Adverse reactions can vary in severity from mild to severe to lifethreatening and may be specific to the drug or general to the class of drugs in use.

Table 6.16: Major Types of ARV Toxicity in Children

ABC

 

ABC is associated with hypersensitivity reactions. Patients may have severe skin rashes or other non-specific symptoms such as fever, arthralgias and lymph node enlargement.
AZT AZT is associated with risk of haematological toxicity which can include anemia neutropenia and thrombocytopenia. Measuring hemoglobin is recommended before initiating ART among children with low body weight, low CD4 cell counts and advanced HIV disease. Patients with severe anaemia at baseline (haemoglobin < 7.5 g/dL) should avoid AZT as first line therapy.
TDF

 

TDF is associated with nephrotoxicity. Nephrotoxicity is more common in elderly patients but it also occurs in children, especially if co-administered with PI based therapy. Monitoring of creatinine clearance is recommended.

 

EFV

 

EFV’s main type of toxicity is central nervous system side effects, which typically resolve after a few weeks. However, in some cases, they can persist for months or never resolve at all.

 

NVP

 

NVP’s major toxicities include severe skin rash and hypersensitivity reaction (Steven’s Johnson syndrome) and hepatotoxicity. Because of the risk of potentially life-threatening hepatotoxicity associated with NVP, hepatic dysfunction of any aetiology in a child on NVP requires careful consideration of whether NVP should be continued.
LPV/r

 

LPV/r’s major toxicity includes hepatotoxicity, pancreatitis, diarrhoea and lipoatrophy. The risk of hepatotoxicity is increased in patients with underlying hepatic disease and the risk of pancreatitis is increased in patients with advanced HIV disease. Electro-cardiac abnormalities are also possible; patients with pre-existing conduction system disease are at increased risk

 

ATV/r

 

Toxicities of ATV/r are similar to those of LPV/r. ATV/r can cause jaundice (indirect hyperbilirubinemia). Jaundice (indirect hyperbilirubinemia) is usually transient and ATV/r can be continued. If severe jaundice develops and there are significantly raised transaminases, then ATV/r should be replaced with LPV/r

 

DRV/r

 

DRV/r’s major toxicity is hepatotoxicity. Patients with underlying hepatic disease, hepatitis B or C co-infection or who are taking other hepatotoxic drugs are at higher risk. The other side effect is severe skin and hypersensitivity reactions. Patients with sulphonamide allergy are at higher risk

 

ETV

 

ETV’s potential toxicity has severe skin and hypersensitivity reactions

 

RAL

 

RAL’s potential toxicity includes rhabdomyolysis, myopathy and myalgia as well as hepatitis and hepatic failure and severe skin rash and hypersensitivity
DTG

 

reactions.

DTG major toxicity is hepatotoxicity and hypersensitivity reactions. Patients with underlying liver disease or hepatitis B or C co-infection are at higher risk.

Principles in the management of ARV drug toxicity

Severe life-threatening reactions: Immediately discontinue all ARV drugs, manage the medical event (i.e. provide symptomatic and supportive therapy) and reintroduce ARV drugs using a modified regimen (i.e. with an ARV substitution for the offending drug) when the patient is stabilized

Severe reactionsSubstitute the offending drug without stopping ART

Moderate reactionsConsider continuation of ART as long as it is feasible. If the patient does not improve on symptomatic therapy, consider single-drug substitution

Mild reactions: Reassure a child and caregiver that while the reaction may be bothersome, it does not require a change in therapy; provide counselling and support to mitigate adverse reactions.

Emphasize on the maintenance of adherence despite mild and moderate reactions.

Table 6.17: Suggested ARV Substitutions

Toxicity events Responsible ARV Suggested first-line ARV drug substitution
Acute symptomatic

hepatitis

NVP EFV

If the patient cannot tolerate either NNRTI, use boosted PI

Severe or lifethreatening rash

(Stevens-Johnson syndrome)

boosted PI
Hypersensitivity reaction ABC AZT
Lipoatrophy/metabolic syndrome LPV/r If LPV/r is used in first line ART for children, use an age appropriate NNRTI (NVP for children below 3 years and EFV for children with 3 years and above)

 

ATV/r can be used for children above 6 years

Severe anaemia or

neutropenia

AZT Substitute with ABC if < 35 kg

 

Substitute with TDF if > 35 kg

Severe gastrointestinal intolerance
Persistent and severe central nervous system toxicity EFV NVP
Tubular renal

dysfunction

TDF If TDF is being used in first line ART, substitute with AZT or ABC

If TDF is being used in second line ART, substitute with ABC

 

NOTE: Patients on third line ARV regimen who develop toxicities should be referred to next level facility with adequate expertise and facilities

The codes will be shown below

Seconds
First: 170598
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Second: 180198

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