By ULY CLINIC

Laboratory monitoring of patients on second line drugs

The following laboratory tests are recommended for Monitoring of patients on second line drugs:

CD4, baseline, if less than 350 cells/ml after every 6 months until more than 350cells/ml
FBC, baseline, then monthly for 3 months, then after every 6 months (with CD4 and viral load)
Fasting cholesterol and triglyceride, baseline, 6 months and thereafter every 12 months
Liver function tests, (ALT) 6 monthly
Fasting glucose, every 12 months
Urinalysis at baseline and after every 3 months
Serum creatinine at baseline and once a year.

When changing treatment, the following should be observed:

Never change a single drug in the combination if the reason for changing is treatment failure. Change at least two drugs, preferably change all three drugs
If changing due to toxicity, change only the drug suspected to be causing the problem.
Never change to monotherapy (i.e. single drug)
When selecting drugs, choose drugs that have not been used before, drugs which do not have cross-resistance/or no overlapping toxicities or drug-drug interactions.
Lamivudine has advantage of decreasing viral fitness therefore it may be retained when changing the failing regimen

IMMUNE RECONSTITUTION INFLAMMATORY SYNDROME (IRIS)

IRIS is a phenomenon associated with the occurrence or worsening of opportunistic infections/malignancies which can occur early after initiation of ART or at later (several months) during the course of ART.

There is an increased risk for occurrence of IRIS in the following situations:

Treatment naïve patients
Patients with advanced HIV disease with CD4 cell count < 50 cells/mm3
Patients with undiagnosed and untreated opportunistic conditions
Patients who have been introduced on ART before or shortly after initiation of treatment of opportunistic infection/malignancy

NB: Any OI may present as IRIS

Treatment of IRIS

Mild to moderate forms:

Reassure the patient and do not stop ART
Provide specific treatment for the opportunistic infections/malignancies or other diseases

Severe life threatening IRIS

Reassure the patient and Stop ART temporarily
Provide high doses of prednisolone 1mg/kg for 4 weeks then taper down the dose.
Provide other appropriate supportive measures such as management of fever, oxygen therapy, i.e. fluids
Restart ART when the patient stabilizes.

Immune Reconstitution Inflammatory Syndrome

Diagnosis of IRIS would require:

Both major (A plus B) criteria or criterion A plus 2 minor criteria

Major criteria

A typical presentation of “opportunistic infections or tumours” in patients responding to anti-retroviral therapy (ART) includes:

Localized disease e.g. lymph nodes, liver, spleen
Exaggerated inflammatory reaction e.g. severe fever, with exclusion of other causes of painful lesions
Atypical inflammatory response in affected tissues e.g. granulomas, suppuration, necrosis, perivascular lymphocytic inflammatory cell infiltrate
Progression of organ dysfunction or enlargement of pre-existing lesions after definite, clinical improvement with pathogen specific therapy prior to commencement of ART and exclusion of treatment toxicity and new diagnoses
Development or enlargement of cerebral space occupying lesions after treatment for cerebral cryptococcus or toxoplasmosis
Progressive pneumonitis or the development of organizing pneumonia after treatment of pulmonary-TB or PCP
New onset or worsening of uveitis/vitritis after resolution of CMV retinitis
Fever and cytopenia after treatment for disseminated Mycobacterium avium complex (MAC) disease
Enlargement of Kaposi’s sarcoma lesions and subsequent resolution or partial regression without
Commencement of radiotherapy, systemic chemotherapy or intralesional therapy

Decrease in plasma HIV-RNA level by > 1 log base ten copies/ml (1 log drop = 9/10 of Baseline VL copies). This applies in settings where baseline VL is performed.

Minor criteria

Increased blood CD4+ cell count after initiation of ART
Increase in immune response specific to the relevant pathogen e.g. delayed type hypersensitivity to mycobacterial antigens (PPD conversion)
Spontaneous resolution of disease without specific antimicrobial therapy or tumour chemotherapy with continuation of anti-retroviral therapy.

ANTIRETROVIRAL THERAPY IN CHILDREN AND ADOLESCENTS BELOW 15 YEARS

ART in children has been proven to increase survival and decrease HIV-related morbidity and mortality. Children should be started on ART as soon they are diagnosed including those who are presumably diagnosed.

Diagnostic Criteria

There are 2 groups for eligibility to begin treatment:

All children who have a confirmed diagnosis of HIV, regardless of WHO clinical stage or CD4 cell count
All HIV exposed children below 18 months old with a presumptive HIV infection.

When to start ART in children under 15 years

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

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

NOTE: Children > 2 years with weight above 35kg can use TDF

Special Considerations for LPV/r syrup 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 tablet is heat stable but must be swallowed whole and should not be split or crushed as it loses effectiveness
LPV/r has shown protection benefit against malaria2.

CHANGING ARV THERAPY IN CHILDREN UNDER 15 YEARS

Drug toxicity

The principles for changing ARVs and the managing drug toxicity in children are similar to 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:

CD4 criteria suggesting immunological failure

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.

Laboratory parameters for monitoring infants and children under 15 years at baseline, before and during ART

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).

Recommended Second-line ART regimens for children under 15 years

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 Counseling

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.

Third-line Regimens for Paediatrics and Adolescents

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.

Major Types of ARV Toxicity in Children

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.

Suggested ARV Substitutions

updated on, 31.10.2020

References

1. STG

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