Antiretroviral Therapy in Children and Adolescents Living with HIV

First-Line ARV Regimens in Infants and Children under 15 years

Table 6.10: First-Line ARV Regimens in Infants and Children under 15 years

Patient Group	Preferred 1st Line Regimen	Justification	Alternatives	Comments
Infants and Children weighing <20kg	ABC+3TC+LPV/r	Higher genetic resistance barrier Avoids NNRTI transmitted resistance from mother during PMTCT Potential for malaria prevention Spares AZT for second line	AZT+3TC+LPV/r AZT/3TC+DTG (25mg or 10mg DTG if available)	LPV/r is available in three formulations (syrup, granules and tablets) LPV/r oral solutions for younger infants until they can take granules LPV/r granules for infants and younger children LPV/r 100mg/25mg heat stable tablets for children 10kg and above and able to swallow whole tablets
Children and adolescents weighing ≥20kg	ABC+3TC + DTG	Lowers HIV viral load very fast Has high genetic barriers to resistance compared to both PIs and NNRTIs Spares AZT for second line	ABC+3TC+LPV/r	ABC+3TC Dispensable Tablet 120/60mg plus DTG 50mg
Children and Adolescents weighing ≥30 kg	TDF+3TC+DTG	Higher genetic resistance barrier Avoids NNRTI transmitted resistance from mother during PMTCT Possibility of malaria prevention Spares AZT for second line	ABC+3TC+DTG TDF+3TC+EFV600 or EFV400	TLD Fixed Dose Combination
For TB and HIV co- infected children already on LPV/r-based regimen	ABC+3TC+LPV/r	Continue with ABC+3TC+LPV/r but the dose of LPV/r should be doubled due to the interaction between ritonavir and rifampicin		ABC+3TC+LPV/r in the morning and only LPV/r in the evening
For TB and HIV co- infected children already on DTG based regimen	ABC+3TC+DTG	For children 20-25 kg who get TB/HIV co-infection it is advisable to give them ABC+3TC+EFV for the time of the TB treatment then revert to ABC+3TC+DTG after completion of TB Treatment For children > 25 kg continue with ABC+3TC+DTG but the dose of DTG should be doubled due to the interaction between ritonavir and rifampicin		ABC+3TC+DTG in the morning and only DTG in the evening
For TB and HIV co- infected on TLD	TDF+3TC+DTG	For children 20-25 kg who get TB/HIV co-infection it is advisable to give them TDF+3TC+EFV for the time of the TB treatment then revert to TDF+3TC+DTG after completion of TB Treatment For children > 25 kg continue with the same regimen, Double dose of DTG		TLD in the morning and only DTG (50mg) in the evening

For dosing of ARV regimens see Annex 6, Paediatric Antiretroviral Dosing

Note: Children with weight above 30kg can use TDF as a fixed dose combination with 3TC.

Special Considerations for LPV/r syrup, granules and tablets

The LPV/r liquid requires a cold chain only during storage at the facility
After dispensing, the liquid is stable at room temperature for 1 month so patients should be given a maximum of 1-month supply
Patients do not have to refrigerate the LPV/r liquid
LPV/r granules for infants who can safely swallow LPV/r granules but who are unable to swallow LPV/r tablets whole
LPV/r tablet is heat stable but must be swallowed whole and should not be split or crushed as it loses effectiveness

Changing ART in Children Under 15 Years

Drug toxicity
- The principles for changing ARVs and the managing drug toxicity in children are like those applied to adults.
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 6.11: CD4 Criteria Suggesting Immunological Failure ^a

Immunological failure is recognized as developing or returning to the following age-related immunological thresholds after at least 6 months on ART, in a treatment-adherent child:
<5 years of age	CD₄count of <200 cells/mm³ or CD4 <10%
≥5 years of age	CD₄ count of <100 cells/mm³
^aPreferably, 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 6-month 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

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.
The condition must be differentiated from immune reconstitution inflammatory syndrome.

Table 6.12: 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 first-line or second-line ART regimen	Every six months	As required or symptom-directed
HIV diagnostic testing	√
Haemoglobin	√	√		√
WBC and differential count	√			√
%CD4+ or absolute CD4 cell count	√		√_b	√
Pregnancy testing in adolescent girls		√		√
Full chemistry (including, but not restricted to, liver enzymes, renal function, glucose, lipids, amylase, lipase and serum electrolytes)^e		√	√_e	√
HIV VL measurement			√^d	√
OI screening (where possible)	√	√	√	√
a. HIV re-testing for verification before ART initiation, re-testing is not indicated when switching to 2^ndor 3^rd line b. For children of <5years continue CD4 monitoring every six months c. CD4 cell count should be taken on emergence of WHO stage 3 or 4 disease d. Viral load monitoring is done annually if the first two VL results 6^th month apart are ≤ 1000 copies/mL e. Regular monitoring (every six months) of full chemistry, particularly lipid levels, liver enzymes and renal functions, should be considered for infants and children on ART.

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 regimens for children under 15 years

Table 6.13: Recommended Second-line ARV regimens for children under 15 years

Patient group	If is on the following first line	Preferred 2L	Comments
Children and adolescents <20kg whose 1^st regimen was EFV or NVP based, then transitioned to LPV/r based regimen	ABC/3TC+LPV/r AZT/3TC+LPV/r	Maintain PI AZT/3TC+LPV/r	Higher genetic resistance barrier Spare INSTI for third- line
Children and adolescents ≥20kg whose 1^stregimen was EFV or NVP based, then transitioned to DTG based regimen	ABC/3TC+DTG AZT/3TC+DTG	AZT/3TC+ATV/r AZT/3TC+DTG ABC/3TC+DTG (for those who cannot tolerate AZT)	Maintain DTG in the 2^nd line due to higher genetic barrier than PIs
Children and adolescents weighing ≥30kg	TDF/3TC/DTG	AZT+3TC+ATV/r ABC+3TC+ATV/r

Note:

Infant and children take longer time to attain adequate viral suppression. Before confirming treatment failure, calculate drop in VL (using 0.5 log two years and above, 0.7log below 2 years - for further details on how to convert VL into numbers.
ATV/r can be used as an alternative to LPV/r in children above 6 years old if paediatric formulation is available but adolescents >30kg can take adult formulation.

Third-Line ARV regimens in children under 15 years and adolescents

Clients 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. For examples, Darunavir (DRV) is a second-generation PI without cross resistance to Lopinavir/r used in the previous regimens.

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

Third-line Regimens for Children and Adolescents

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

Table 6.14: Third-line Regimens for Children and Adolescents

Patient Group

3L Options

Justification

Children <20kg

RAL + DRV/r + AZT+3TC

DRV/r - High genetic barrier, Effective for patients with resistance to LPVr and ATVr, cannot be used in children <3 years of age

RAL - Can be used for children <20 kg DTG - Can be used for children ≥ 20 kg

Children ≥ 20kg and above

DTG +DRV/r + AZT+3TC

Adverse reactions in children and adolescents

Adverse reactions in children and adolescents

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 life-threatening and may be specific to the drug or general to the class of drugs in use.

Table 6.15: Major Types of ARV Toxicity in Children and adolescents

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 anaemia, neutropenia and thrombocytopenia. Measuring haemoglobin 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 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 like 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.
RAL	RAL’s potential toxicity includes rhabdomyolysis, myopathy and myalgia as well as hepatitis and hepatic failure and severe skin rash and hypersensitivity reactions.
DTG	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 if 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 6.16: 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 life-threatening rash (Stevens-Johnson syndrome)	NVP	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	AZT
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

Age	When you start
Children 0-15 years	Treat all of them regardless of WHO clinical stage or CD4 cell count
Children below 18 months old who qualify for presumptive diagnosis	Start ART while awaiting for DNA-PCR confirmation test results
Children <18 months of age with a positive DNA/RNA PCR test	Start ART while waiting for the second DNA/RNA PCR test result