6.6 Changing ARV Therapy In Children Under 15 Years

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	CD4 count of <200 cells/mm3 or CD4 <10%
≥5 years of age	CD4 count of <100 cells/mm3
a 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 6^th 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 2^nd 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 2^nd 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 2^nd line regimens
• Documented virologic failure (VL > 1000) on a PI regimen; except children below 3 years

Steps to refer client to 3^rd line review committee

• Client suspected to have 2^nd 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 reactions: Substitute the offending drug without stopping ART

Moderate reactions: Consider 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