5 Management of children with antiretroviral treatment

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Contents

• Objectives
• Criteria for antiretroviral treatment
• Patient readiness
• Preparation for antiretroviral treatment
• Managing antiretroviral treatment
• Problems with antiretroviral treatment
• Adherence
• Inadequate dosage
• Drug resistance
• Unsuppressed viral load and treatment failure
• Drug interactions
• Drug interruptions
• Side effects of antiretroviral agents
• Immune reconstitution inflammatory syndrome (IRIS)
• Case studies

Objectives

When you have completed this chapter you should be able to:

1. Understand the importance of antiretroviral treatment.
2. List the criteria for starting antiretroviral treatment.
3. Prepare a child and family for antiretroviral treatment.
4. Describe what is done at the first few treatment visits.
5. Care for a child on antiretroviral treatment.
6. Monitor the clinical and immunological response to treatment.
7. Promote excellent adherence.
8. Detect and manage problems with treatment.

5-1 What are the benefits of antiretroviral treatment?

Once the immune system has been severely damaged by HIV infection, and the disease has reached stage 3 or 4, only antiretroviral treatment can control and partially reverse the disease process. Without antiretroviral treatment most of these children will die within infancy or early childhood. Starting treatment early in HIV infected infants, before clinical signs appear, reduces mortality by 75%.

Antiretroviral treatment can change HIV infection from a rapidly fatal disease to a manageable, chronic illness.

Only antiretroviral treatment can change AIDS from a rapidly fatal disease to a manageable chronic illness.

5-2 What can antiretroviral treatment achieve?

• The child should feel well again and have few HIV-related illnesses. Growth and mental development should improve or be normal.
• The CD4 percentage should increase and remain above the baseline level.
• The viral load should become undetectable and remain undetectable.

With antiretroviral treatment the child should feel well again.

5-3 For how long will these children need to remain on antiretroviral treatment?

For life. Antiretroviral treatment can control HIV infection but not cure it.

Criteria for antiretroviral treatment

5-4 What are the criteria for starting antiretroviral treatment?

All children, irrespective of CD4 count or clinical stage should be started on antiretroviral treatment as soon as their parents or caregivers have been adequately counselled. For all HIV-infected children without contra-indications, ART should be commenced within 7 days of diagnosis.

Infants and children less than 5 years old and those with advanced HIV infection should be prioritised for rapid ART initiation, i.e.

• All children less than 5 years of age
• Children with a CD4 count less than 200 cells/μl or less than 15%
• Children with WHO stage 4 disease

Unless ART initiation within 7 days is contra-indicated, all children who are infected with HIV must be started on antiretroviral treatment as soon as possible.

5-5 What are the social criteria?

• It is essential that there is at least one responsible adult (parent or care giver) who can administer the antiretroviral medication.
• The responsible parent or care giver must be ‘treatment ready’.
• It is strongly recommended that the responsible parent or caregiver reveal the child’s HIV status to at least one other family member or friend who can give support. It is best to have a treatment supporter in the home.
• The child and responsible parent or care giver must be able to attend an antiretroviral centre on a regular basis. It may be necessary to arrange transport.

The social criteria should be met before starting antiretroviral treatment.

If the social criteria are not met, there is little chance that medication will be given regularly. As a result antiretroviral treatment is likely to fail. A social worker should help if the social criteria cannot be met.

5-6 What are the indications for delaying the start of antiretroviral treatment?

Indications are:

• Children with symptoms of tuberculosis (TB) (cough, fever, weight loss, reduced playfulness, night sweats): Investigate these children for TB before initiating ART. If TB is excluded proceed with ART initiation. If TB is diagnosed, initiate TB treatment and defer the timing of ART.
• Children with drug-susceptible TB at a non-neurological site e.g. pulmonary TB or abdominal TB: If the baseline CD4 is less than 15% or 200 cells/μL start ART within 2 weeks of starting TB treatment. However, if the baseline CD4 count is more than 15% or 200 cells/μL start ART within 2 to 8 weeks of commencing TB treatment.
• Children with drug-resistant TB at a non-neurological site: Start ART 2 weeks after starting TB treatment when the symptoms are improving and the TB treatment is tolerated.
• Children with drug-susceptible or drug-resistant TB at a neurological site: Defer the start of ART until 4-8 weeks after staring TB treatment.
• Children with symptoms or signs of meningitis: Investigate for meningitis before starting ART.
• Children with cryptococcal meningitis: Defer the start of ART until 4-6 weeks of antifungal treatment has been completed
• Children with symptoms and signs of liver disease: Confirm liver disease using ALT (alanine transaminase) and bilirubin levels. If hepatitis is present investigate and treat the possible causes, including hepatitis B and drug-induced liver injury.

Patient readiness

5-7 Who usually refers a child for antiretroviral treatment?

The staff at a primary-care clinic or HIV clinic where the child has been followed up. The child should be referred when the criteria for antiretroviral treatment have been met. Many children with HIV infection are admitted to hospital with HIV-associated infections such as diarrhoea and pneumonia. These children should be assessed and, if necessary, also referred for antiretroviral treatment.

5-8 Where should antiretroviral treatment be started?

Ideally at a local antiretroviral clinic. However, some children who have been admitted to hospital need to start antiretroviral therapy during their admission. Children should be referred to an antiretroviral clinic when they are ready for discharge from hospital. An antiretroviral clinic is staffed by nurses and doctors who have had special training in the correct use of antiretroviral drugs and the correct management of children receiving these drugs.

Note

Children below the age of six months, or with a weight below 3 kg should ideally be started on antiretroviral therapy by an experienced doctor or nurse.

5-9 What is patient readiness?

Patient readiness means that the child’s parent or caregiver has been fully prepared for antiretroviral treatment to start. If this preparation is not correctly planned and done properly, then antiretroviral treatment is unlikely to be successful due to poor adherence (compliance). Therefore, patient readiness is very important and is needed before antiretroviral treatment can be started. With a family-oriented approach to HIV infection, the whole family should become involved with patient readiness.

Correct preparation for antiretroviral treatment is very important.

5-10 What are the aims of preparing for antiretroviral treatment?

Aims are:

• The parent (or care giver) must have a good understanding of HIV infection.
• The importance of excellent adherence must be understood and accepted.
• The names, dosing and timing of the antiretroviral agents must be learned.
• The risk and symptoms of possible side effects must be known.
• Disclosure to a family member or friend is needed.
• The importance of regular follow-up care must be accepted.

5-11 How long does it usually take to prepare for antiretroviral treatment?

It usually takes about two clinical and counselling sessions. If the parents are not yet ‘treatment ready’ the start of antiretroviral treatment may have to be postponed. However, children without contra-indications should be prepared and started on antiretroviral treatment within 7 days of diagnosis.

5-12 What visits are needed before antiretroviral treatment is started?

Usually two visits to the antiretroviral clinic are needed before treatment can be started:

• The first screening visit. This visit is usually the parent and child’s first contact with the staff of the antiretroviral clinic.
• The second screening visit. The first and second visits are used to prepare and assess whether the parent/care giver is ready for the treatment to start.

Following the two screening visits, the ‘start of treatment’ visit can be planned (often called the week 0 visit).

Usually two screening visits are needed to assess the home and plan for antiretroviral treatment.

For children without contra-indications, the interval between preparatory visits should be short so that antiretroviral treatment is started within 7 days of HIV diagnosis.

Preparation for antiretroviral treatment

5-13 What should be done at the first screening visit?

The child and parents (or caregiver) are usually referred to the antiretroviral clinic with a referral letter from the primary-care clinic. They should be seen by a doctor at the first screening visit.

• Check that the diagnosis of HIV infection is correct by reviewing the HIV test results.
• Take a careful history and perform a physical examination of the child.
• Measure and plot the child’s weight, height (or length) and head circumference, and assess the developmental level.
• Complete the information record form.
• Speak to the parents or the person who will be responsible for giving the medicine and bringing the child for follow-up visits.
• Arrange for readiness education and counselling. This is often done in a group session. Ideally the parents and child should meet the multidisciplinary team of doctors, nurses and counsellors.
• Exclude tuberculosis. This requires a careful history including TB contacts, a chest X-ray, sputum examination for Xpert Ultra and TB culture, and Mantoux skin test.
• Commence cotrimoxazole prophylaxis if this has not already been started.
• Take blood for baseline investigations: CD4 count and percentage if not already done, a haemoglobin or full blood count on all children, serum ALT and bilirubin levels should be measured if the child is jaundiced, serum ALT if the child is on TB treatment, serum creatinine and estimated glomerular filtration rate (eGFR) if TDF is to be used, and a hepatitis B surface antigen in adolescents.
• In adolescent girls in whom DTG is to be used, screen for pregnancy and screen for sexually transmitted infections in adolescent patients.
• Make an appointment for the second screening visit.
• Following the first screening visit, a home visit by a counsellor is recommended before starting antiretroviral treatment. Unfortunately this may not be possible due to limited counsellor support. Home visits may be difficult if hospital-based programmes are far from the child’s home.

Note

Before initiating a TDF-containing regimen the eGFR is measured in children aged 10 to 16 years using the Counahan-Barratt formula. An eGFR of greater than 80 mL/minute/1.73 m2 is considered an acceptable level for TDF use.

5-14 What should be looked for during the physical examination?

• Assess the child’s general health.
• Determine the nutritional status.
• Assess the child’s neurodevelopmental status and look for neurological signs.
• Confirm the clinical stage.
• Look for signs of HIV-associated conditions, especially tuberculosis.

5-15 What is the importance of a home visit?

If possible, a home visit by a counsellor should be done to:

• Make sure that the contact address is correct.
• Assess the home circumstances.
• Determine what support there is at home and whether there has been disclosure.
• Find out where the medicines will be stored.

A home visit is an important part of preparing for antiretroviral treatment.

5-16 What education is needed?

It is essential that the parents (or guardians) fully understand HIV infection as well as why the child needs treatment and how the treatment should be correctly given. The same applies to older children.

The parent needs to:

• Understand what HIV infection is.
• Understand what antiretroviral treatment is.
• Know the names and appearance of the antiretroviral drugs to be used.
• Know the dose and how to give these drugs correctly.
• Know the symptoms and signs of the possible side effects.
• Know about the common HIV-associated infections.
• Know that a good diet is important.
• Know to store the drugs safely in a place where young children cannot reach.

It is particularly important that the parents accept that excellent adherence is essential, resistance is dangerous, and that failure of treatment and development of resistance are usually due to poor adherence.

Parents need to know about the drugs that their child will be taking.

5-17 How is education provided?

• During individual counselling sessions
• In group education classes
• With pamphlets on HIV infection and antiretroviral treatment
• Posters and videos are helpful
• A treatment chart illustrating the drugs, timing of doses and possible side effects

Usually two education classes are attended before the second screening visit.

5-18 What counselling is needed?

Counselling is important so that parents (and older children) are emotionally ready for antiretroviral treatment and have the home and social support needed for successful management. The parents may need help in accepting the family’s HIV status and the importance of antiretroviral treatment. They may also have difficulty disclosing the HIV status and finding someone who can support them. All parents preparing for antiretroviral treatment should be encouraged to join a support group. They often need an opportunity to talk about their fears and concerns. Counselling empowers parents to make the best decisions for themselves and their child. It helps them understand, accept and make choices. Trained lay counsellors are very important members of the treatment team and play an important role in parent counselling.

Disclosure and support are needed for successful treatment.

5-19 What baseline blood tests are needed?

• The baseline CD4 count and percentage is usually done before the patient is referred for treatment consideration and, therefore, need not be repeated. If the CD4 count and percentage were not measured, this should be done.
• Blood should be taken for baseline haemoglobin or full blood count, serum ALT and bilirubin levels if the child is jaundiced, serum ALT if the child is on TB treatment, serum creatinine and eGFR if TDF is to be used, and a hepatitis B surface antigen in adolescents.

A baseline CD4 count is needed before antiretroviral treatment is started.

5-20 What should be done at the second screening visit?

• The clinical assessment should be repeated.
• Get the baseline blood results and screen for TB: careful history for household/close TB contacts, and TB symptoms (persistent cough and night sweats, growth faltering or loss-of-weight), a chest X-ray, sputum examination and Mantoux skin test.
• Consider the counsellor’s feedback report plus the report of the home visit, if these have been done.
• The important of adherence and regular attendance is stressed.
• Assess whether the cotrimoxazole medication has been taken correctly.
• Make sure that education has been provided.

Following the second visit the details of the child should be discussed by the multidisciplinary team to decide whether treatment readiness has been achieved.

Managing antiretroviral treatment

5-21 Who are the members of the multidisciplinary team at the antiretroviral clinic?

• The doctor or nurse practitioner, who should take a history and perform a general examination at the first treatment visit and again at the follow-up visits.
• The nurse, who should see the patient to complete the treatment register and take the necessary blood samples. The nurse should also check adherence at every visit.
• The counsellor/educator, who should see the patient at every visit. Trained lay educators and counsellors often help at the clinic.
• The pharmacist, who should provide the antiretroviral drugs and advise the patient on how to take them every time medicines are dispensed.

The role of each member of the multidisciplinary team may vary between different clinics.

5-22 What should be done at the starting visit?

This is the visit when antiretroviral treatment is started (i.e. the starting or commencement visit). The child and parents (or carer) should already have been prepared for antiretroviral treatment at two screening visits. A decision would already have been made that the child and parents are ‘treatment ready’ and baseline blood tests done. A final check is made that the parents are fully prepared for treatment. At the starting visit the following should be done:

• The importance of excellent adherence is again stressed by the counsellor.
• The child and parent see the doctor or nurse for the final instructions and support. A detailed description of the drugs and their doses are given by the doctor or nurse using a treatment chart. A graphic treatment chart is very useful and should be given to the parents.
• The child’s details are entered into the antiretroviral treatment register.
• An HIV summary record is started which will be kept by the clinic and updated on the child’s notes at each visit. Examination notes from the two screening visits should be included.
• The instructions and dosing are reinforced by the nurse. The instructions must be clearly written on the pill container or medicine bottle with a permanent marker.
• The parent is given a two-week supply of drugs by the pharmacist.

Each person in the team makes sure that the parents understand which medicines are to be given, how much and when. They also check that the parent knows the side effects of the drugs to be taken and the importance of excellent adherence.

In some services, parents or caregivers are given a patient-carried HIV treatment card.

5-23 When should the first follow-up visit be planned?

The child should be brought back after two weeks. If there are any problems the child should be brought back earlier.

5-24 What should be done at the first follow-up visit?

The most important reasons for the child attending this visit are to assess adherence and check for side effects.

• Repeat the history and examination. Be aware of symptoms and signs of side effects of the medication.
• Measure and plot the child’s weight.
• Check the drug doses and assess how much medication has been taken. This is important to determine adherence. Make sure that the medication schedule is understood and that all the drugs are being given in the correct dose and at the correct time.
• The importance of excellent adherence must be stressed.
• Treat any infections or other medical problems.
• Provide medication and make an appointment for four weeks later.

5-25 What should be done at the second follow-up visit?

The second follow-up visit should take place four weeks after starting antiretroviral treatment. Again adherence and side effects must be assessed.

• Repeat the history and examination. Be aware of symptoms and signs of side effects of the medication.
• Measure and plot the child’s weight.
• Check the drug doses and assess how much medication has been taken.
• Stress the importance of excellent adherence.
• Manage any new medical problem.

5-26 What further follow-up visits are needed?

• Older children should be seen again at eight weeks (two months) and then 12 weeks (three months) after starting treatment.
• The next visit usually is at six months after starting treatment. However, more frequent visits (monthly or every three months) may be needed for some children who are still unwell.
• Young children under one year should be assessed monthly for the first 6 months as they are growing rapidly. Thereafter they can be seen at two and later three monthly intervals.
• Viral load should be done at 6 months and 1 year, and if virally suppressed (viral load less than 50 copies/ml) then repeat viral load annually
• CD4 count should done at 12 months. Thereafter, repeat CD4 count every 6 months until the criteria are met for stopping cotrimoxazole prophylaxis. Stop CD4 count monitoring if the viral load remains below 1000 copies/ml. If the viral load remains above 1000 copies/ml, continue CD4 count monitoring every 6 months.
• If the child is treated with a PI-containing regimen, check the total cholesterol and triglyceride concentrations at 3 months after starting ART. If the results are above the normal age-related ranges measure the fasting total cholesterol and triglyceride concentrations and if they remain above the normal age-related ranges obtain expert advice.
• For children on AZT do a full blood count and differential count at months 3 and 6. Thereafter, repeat if clinically indicated.
• If on a TDF-containing regimen, measure serum creatinine and calculate the eGFR at months 3, 6 and 12. Thereafter, repeat these measurements every 12 months.
• Neurodevelopmental screening should be performed at 14 weeks, 6 months, 9 months, 18 months, 3 years and 5 to 6 years of age using the guideline in the Road-to-Health booklet.
• Ask about side effects at each clinic visit.

5-27 How often should medication be collected?

Medicines still need to be collected every month. A careful record in the antiretroviral treatment register must be kept of all medication given. Excellent adherence must be stressed every time medication is collected. It is important to check how much medication has been returned and not taken. A missed medication visit suggests poor adherence.

5-28 What should be done at the six month visit?

In addition to the routine checks (history, examination, weight), it is very important to make a formal assessment of treatment success or failure.

• Assess growth by measuring and plotting weight, height and head circumference.
• Grade the clinical stage of HIV infection and assess whether the child is clinically well.
• Assess neurological development.
• Take blood for viral load and other monitoring bloods as advised in 5-26.

5-29 What is the expected clinical response to antiretroviral treatment?

With successful treatment children should start to feel and look well again. Most children will develop a good appetite and gain weight. Associated infections such as thrush and diarrhoea disappear and skin rashes clear up. The clinical response follows the gradual recovery of the immune system. By three months there should be a big difference in their general health.

5-30 What should the viral load be by six months?

If the response to antiretroviral treatment is good, the viral load is usually less than 50 copies/ml (i.e. an undetectable viral load) by six months.

Note

One of the aims of antiretroviral treatment is to achieve and maintain full virological suppression. At the end of the first six months of treatment this may not be possible in some children because of a very high baseline viral load. However a drop in viral load should be at least 2 log values (factors of 100) which at this stage is considered satisfactory.

5-31 What is the best indicator of treatment success?

An undetectable viral load. This is the best indicator of successful treatment.

Note

An undetectable viral load is less than 50 cells/ml on the currently used sensitive assay. The viral load is a measure of the number of virus particles per ml blood. The higher the viral load the more rapidly the disease is progressing while an undetectable viral load indicates very little viral production.

An undetectable viral load is the best indicator of successful treatment.

5-32 When can the child be transferred to the local community clinic?

If the child is relatively well, antiretroviral treatment can usually be managed at a clinic in the community in which the child lives. Sick children who are started on antiretroviral treatment in hospital should be referred to their community clinic for ongoing care as soon as they are clinically stable, usually within six months after starting treatment. A small proportion of children have complex problems or severe HIV-related complications. These children are best managed by an experienced paediatrician, usually at a hospital-based antiretroviral clinic.

Antiretroviral management is being offered at more and more community clinics as the ‘roll-out’ programme continues. Most of the children can be managed by nurses trained in antiretroviral care.

5-33 For how long can treatment remain successful?

Children who achieve an undetectable viral load and who maintain excellent adherence should remain well for many years. However, the average time before treatment fails has not yet been established in resource-poor settings.

Note

Clinical trials in children have shown that between 63 and 87% achieve undetectable viral loads under optimal care conditions. Therefore, some children will never become fully virologically suppressed and they are likely to fail antiretroviral treatment much sooner.

Antiretroviral treatment can be successful for many years.

5-34 What additional visits are needed?

The child should be seen at nine and 12 months (one year) after starting treatment. If the child is well and the blood tests are normal, the child can be seen every three months.

• At the one year visit a CD4 percentage or count and viral load should be measured.
• If the patient is on a TDF-containing regimen, serum creatinine should be measured and eGFR calculated at the one-year visit.

5-35 When can cotrimoxazole prophylaxis be stopped?

The prophylaxis in children on antiretroviral treatment should only be stopped when there is good evidence that the immune function is recovering well. It is suggested that cotrimoxazole in children be stopped when antiretroviral treatment has provided the following improvement in CD4 percentage:

• Children aged one to five years if the CD4 is more than 25% regardless of the clinical stage.
• Children aged six years or more if the CD4 is more than 200 cells/μl regardless of the clinical stage.

Problems with antiretroviral treatment

5-36 What are the main problems with antiretroviral treatment?

• Poor adherence
• Inadequate dosage
• Drug resistance
• Treatment failure
• Drug interactions
• Drug interruptions
• Side effects
• Immune reconstitution inflammatory syndrome

The main problem with antiretroviral treatment is poor adherence.

Poor adherence is the main problem with antiretroviral treatment.

Adherence

5-37 What is adherence?

Adherence (or compliance) is the degree to which patients take their antiretroviral drugs correctly.

5-38 What is excellent adherence?

Excellent adherence is taking all the medication correctly every day. With excellent adherence, 95% of all doses must be taken (i.e. 19 out of 20 doses) in children on twice daily dosage. This means that for children taking antiretroviral treatment twice a day not more than three doses can be missed in a month. It is also important that the doses are taken at the same time each day. Taking all the drugs at the correct dose and at the correct time each day is very important if antiretroviral treatment is going to be successful. Antiretroviral treatment can suppress the viral load reliably only if adherence is excellent.

Not more than three doses a month should be missed by children taking twice a day treatment.

Note

Due to the short half-life of antiretroviral drugs, blood levels fall rapidly if a single dose is missed. The correct dose must be taken at the correct time in the correct way.

Excellent adherence is the key to treatment success.

5-39 What is poor adherence?

Poor adherence is missing doses or taking doses at the wrong time. Any adherence of less than 95% is not good enough (i.e. poor). Even adherence of 80 to 95% may be inadequate.

5-40 What are the dangers of poor adherence?

• Drug resistance
• Treatment failure
• Increased morbidity and mortality

Every effort must be made to ensure excellent adherence. Without excellent adherence the progression of HIV will not be stopped.

Poor adherence increases the risk of drug resistance and treatment failure.

5-41 How is adherence measured?

The history given by the parent or guardian may be an unreliable method of assessing adherence. Better methods include:

• Counting tablets that have not been taken (pill count) or measuring the amount of medication remaining in the bottle. Parents should be asked to bring all the medication back to the clinic at every visit.
• Daily record cards or dosing diaries.
• Unannounced home visits with pill counts.

A simple card for recording each dose on a daily basis helps promote and assess excellent adherence.

A home record card of medication is important to maintain excellent adherence.

5-42 What factors are associated with poor adherence?

• Poor parent preparation for antiretroviral treatment.
• Inadequate home support. This is often due to non-disclosure of the child’s HIV status.
• A change in the caregiver, e.g. from the mother to a friend or relative.
• Poor relationship with the clinic staff.
• Alcohol, drug abuse, depression or other emotional problems in the care giver or among other household members.
• Side effects to antiretroviral treatment.
• Complicated regimens, e.g. many pills, having to take some medicines on an empty stomach, having to prepare the medication before it is administered, such as dissolving or crushing tablets.

Note that excellent adherence is not related to the race, gender, education level, socioeconomic class or cultural background of the parent or caregiver. Adherence can be excellent even in poor, underdeveloped communities.

5-43 How can adherence be improved?

Excellent adherence must be promoted before treatment is started and then promoted continually during treatment. Discuss excellent adherence at every clinic visit. Parents and older children must be encouraged to take an active and responsible role in the treatment.

• Before starting antiretroviral treatment, parents and older children must make a firm decision to take medication at the correct time every day for life. A clearly understood treatment plan must be negotiated with the parents.
• Parents must understand why adherence is important and know about the dangers of poor adherence. Education and counselling about adherence should be provided in the parents’ home language. A supportive and non-judgemental approach is needed.
• The clinic should check on adherence at every visit. A pill or medication count should be done. If adherence is poor, ask the parent why doses have been missed and re-educate them about the importance of adhering to treatment.
• Suggest practical reminders such as an alarm clock, or link the time of taking medication to a particular radio or TV programme or cleaning teeth. A cellphone message or pager call can be arranged. Get the parent to use a pill box where tablets for the day can be counted out beforehand in children and adolescents who are receiving capsules or tablets. Counsellors who know the community well can often offer the best adherence advice that will be suitable to the family’s lifestyle.
• Regular support groups of other parents with children on antiretroviral treatment are very helpful.
• Side effects must be promptly and correctly managed.
• Provide a more caring service.

Parents often need constant monitoring, education, encouragement and support. Good preparation and long-term support are essential for excellent adherence.

5-44 How can health workers provide a more caring service?

• Healthcare providers must make every effort to establish a trusting relationship with each patient. If possible the parents should see the same dedicated carer at each visit.
• Parents should feel they are welcome to come to the clinic with a problem on any day, not just on their appointment day.
• Remember that acceptance and emotional support by the clinic staff are very important parts of good care. Regular updating of education and an evaluation of the quality of advice being given by health workers are important.
• A patient should never be without the required medication. It is unacceptable for the clinic to run out of drugs.

A good, caring service by the clinic improves adherence.

5-45 What are the commonest reasons for missing a dose?

• Forgot
• Too busy or away from home
• Too ill
• Side effects
• Parents angry or depressed
• Other urgent family matters such as another sick child or death of a relation
• Poor support due to non-disclosure

It is very important to find out why doses have been missed. Reasons for missing doses must be addressed by the clinic staff.

It is important to find out why doses are missed.

5-46 Can a dose be taken late?

If a dose is not taken at the correct time, it can still be safely taken up to six hours late. It is better to take the dose late than not at all.

5-47 What should be done if adherence remains poor?

If adherence remains very poor (below 80%), it may be necessary to attempt directly observed treatment (DOT) using a community clinic counsellor or a treatment buddy, i.e. an adult who can support the primary caregiver. In exceptional circumstances it may be necessary to discontinue the child’s antiretroviral therapy temporarily until such time that the caregiver is re-counselled and prepared to administer the medication optimally.

Inadequate dosage

5-48 What are the dangers of inadequate dosage?

Besides poor adherence, prescribing lower than the recommended doses of antiretroviral drugs may also lead to treatment failure. The dosing requirements increase as the child grows. Therefore doctors and nurses treating HIV-infected children must check the doses of all antiretroviral drugs at each clinic appointment to ensure that the doses remain adequate.

The use of weight bands has made it easier to decide on the correct dose of antiretroviral drug.

Drug doses must be increased as the child grows.

5-49 Does it matter if the medication is vomited?

Yes. If the child vomits up the medication, the dose should be given again immediately. Vomiting a few hours after the medication is probably not important.

5-50 What factor may reduce the effectiveness of antiretroviral drugs?

Antiretroviral drugs should be taken according to the manufacturer’s instructions. For example, lopinavir / ritonavir film-coated tablets (Aluvia) should be swallowed whole. If these tablets are crushed and mixed with food or water before taking them, the bioavailability of these tablets will be reduced by more than 50%, resulting in an ineffective antiretroviral response.

Note

Measuring serum levels of antiretroviral drugs is rarely done in developing countries. However, in resource-rich settings drug levels are part of standard clinical practice.

Drug resistance

5-51 What is drug resistance?

Drug resistance in HIV develops when the multiplication of HIV is not blocked by a particular triple antiretroviral combination. Drug resistance will lead to treatment failure. The development of resistance to one or more antiretroviral drugs is important as it will reduce the chance of successful treatment and shorten the effectiveness of antiretroviral therapy.

Drug resistance may be due to:

• Infection with HIV that is already resistant to one or more drugs (primary drug resistance). This is still uncommon in South Africa.
• Resistance only developing some time after treatment had started (secondary drug resistance). Every effort must be made to avoid this form of drug resistance, which is mainly caused by poor adherence.

Every effort must be made to avoid drug resistance as this may lead to treatment failure.

Note

Resistance is most common with ‘non-nucs’ and 3TC as resistance occurs after a single mutation. Resistance only develops slowly with AZT and d4T. Resistance to lopinavir/ritonavir is less common but will develop after prolonged periods of poor adherence.

5-52 How can the development of drug resistance be avoided?

• By always using a combination of three drugs from two different drug classes to treat patients. This is the basis of standardised regimens. If one drug runs out, all drugs should be stopped until a new supply is obtained.
• By excellent adherence. The more frequently doses are missed, the greater is the risk of resistance to those drugs.
• By making sure that the weight and length of the child are measured, and the doses of the antiretroviral drugs are checked at each clinic visit.

Excellent adherence to antiretroviral treatment is the best way of avoiding the development of drug resistance.

5-53 May resistance be caused by previous drug exposure?

• There is concern that NVP used in the prevention of mother-to-child transmission (PMTCT) may cause drug resistance to both NVP and EFV in mother or infant. This may limit the success of future antiretroviral treatment.
• Children who have previously been given antiretroviral drugs (‘non-naive patients’) must be carefully assessed by an antiretroviral expert before one of the standard drug combinations is started.

5-54 What is cross-resistance?

If HIV becomes resistant to one drug in a class it is often also resistant to some or all the drugs in the same class. This is called cross-resistance (i.e. HIV is resistant to drugs within a drug class). This is particularly common for ‘non-nucs’. If patients are resistant to NVP there is a high chance that they will also be resistant to EFV. Drug resistance between classes is uncommon.

Note

Genotyping can be done to identify mutations associated with drug resistance. It is expensive.

Unsuppressed viral load and treatment failure

5-55 What is an unsuppressed viral load?

A suppressed viral load is one that is less than 50 copies/ml. A suppressed viral load means that the antiretroviral treatment is given at the correct doses, absorption and bioavailability of the drugs are good, and the adherence to treatment is excellent (more than 95%).

By contrast, an unsuppressed viral load is when the viral load is more than 50 copies/ml. This suggests that there is one or more problems with the administration of the antiretroviral drugs.

With an unsuppressed viral load there are more than 50 copies/ml.

5-56 What are the causes of an unsuppressed viral load?

There are a number of causes:

• Infection e.g. an upper respiratory tract may cause a temporary increase in viral load. Thus viral load should not be measured within a month of an infection.
• Poor adherence is an important cause of an unsuppressed viral load and results in treatment failure. Therefore excellent adherence must be stressed at every clinic visit to the HIV clinic.
• Incorrect dosing
• Poor absorption and reduced bioavailability of antiretroviral drugs
• Adverse drug interactions e.g. during TB treatment with a rifampicin-containing TB drug regimen. Rifampicin induces the metabolism of ‘PIs’ such as lopinavir, ‘IIs’ such as DTG and ‘non-nucs’ such as NVP.
• Drug resistance i.e. the development of mutations in the virus that resists the action of the antiretroviral drugs. Poor adherence, incorrect dosing, poor absorption, reduced bioavailability and adverse drug interactions may all promote the emergence of drug resistance.

Poor adherence is a common cause of an unsuppressed viral load and treatment failure.

5-57 How should an unsuppressed viral load be managed?

• If the viral load is more than 50 copies/mL, do a thorough assessment for the cause of the elevated viral load (refer 5-56). Implement interventions to lower the viral load including intensified adherence support and re-measure the viral load after 3 months.
• If the repeat viral load is less than 50 copies/ml return to routine viral load monitoring (refer 5-26).
• If the repeat viral load in between 50 and 1000 copies/ml, continue intensified adherence support and repeat the viral load after 6 months. If low grade viraemia persists (viral load between 50 and 1000 copies/ml) discuss further treatment with an experienced clinician. For example, if the patient is on an EFV-containing regimen a single drug switch to DTG can be considered if the child weighs 20 kg or more.
• If the repeat viral load is more than 1000 copies/ml:
  • For children on an EFV-based regimen consider changing to second-line regimen if virological failure is confirmed i.e. the viral load is greater than 1000 copies/ml on two consecutive occasions and adherence problems have been addressed.
  • For children on a PI- or DTG-containing regimen consider switching to a second-line regimen if virological failure is confirmed i.e. the viral load is greater than 1000 copies/ml on at least three occasions over the course of two years, or the viral load is greater than 1000 copies/ml with signs of immunological or clinical failure i.e. a declining CD4 count and/or the development of opportunistic infection.

5-58 What should be done if first-line treatment failure occurs despite excellent adherence?

For a child on a ‘non-nuc’-containing regimen, treatment failure should be diagnosed if the viral load is greater than 1000 copies/ml on two consecutive occasions and adherence problems have been addressed. The case should be discussed with an experienced clinician about a new regimen.

If the child is on a PI- or DTG-containing regimen treatment failure should be diagnosed if the viral load is greater than 1000 copies/ml on at least three occasions over the course of two years, or the viral load is greater than 1000 copies/ml with signs of immunological or clinical failure i.e. a declining CD4 count and/or the development of opportunistic infection, while the child is adherent on the failing regimen. An application for viral resistance testing and a new regimen should be lodged with the national or provincial 3^rd line committee. Before the antiretroviral drugs are chosen for the new regimen, viral resistance testing should be done. The viral resistance test results will be used by the national or provincial third-line committee, to decide which drugs to include in the new second-line regimen.

5-59 What should be done if the second-line of treatment fails?

Patients who have failed both first- and second-line combinations, despite good adherence, may be considered for a 3^rd line regimen with new drugs. The decision is dependent on viral resistance testing and the patient’s prior treatment history. An application for 3^rd line therapy should be lodged with the national or provincial 3^rd line committee. The final decision to start 3^rd line therapy rests with an experienced national or provincial committee that also decides which antiretroviral drugs to include in the child’s 3^rd line regimen.

Note

Additional antiretroviral drugs can be used in new combinations in an attempt to control viral replication in patients who have failed on both first- and second-line treatment. While waiting for new antiretroviral drugs the child may be placed on a holding regimen or 3TC monotherapy. This is a complex problem that must only be addressed by an antiretroviral specialist.

Drug interactions

5-60 What is a drug interaction?

This is the interference of one drug with another drug. Common examples of drug interaction are:

• Two similar drugs compete with each other at their site of action. For example, NVP and EFV should not be used together.
• One drug alters the rate at which another drug is broken down in the body. This may result in the blood level of either the drug being too high or too low. For example rifampicin can decrease the blood concentrations of some antiretroviral drugs.
• If two drugs have similar side effects, these side effects are more likely to occur and be severe if the two drugs are used together. For example, both NVP and cotrimoxazole may cause skin rashes.

5-61 Which antiretroviral agents should not be used together?

Using either the first- or second-line combinations for antiretroviral treatment avoids drug combinations which compete with each other.

Note

AZT should not be used together with d4T due to their competing sites of action. Similarly, 3TC should not be used with FTC.

5-62 What is the effect of rifampicin on antiretroviral drugs?

Rifampicin, used in the treatment of TB, increases the rate at which some antiretroviral drugs are broken down by the liver. As a result these drugs may not act adequately because their blood levels are too low:

• Rifampicin causes no problems with ‘nucs’.
• Rifampicin causes some problems with ‘non-nucs’ and lowers blood level of these drugs, especially NVP. EFV is less affected than NVP, therefore NVP is often changed to EFV when first-line antiretroviral treatment is being given at the same time as anti-TB treatment. The dose of EFV need not be changed.
• Rifampicin causes serious problems with ‘PIs’ as it lowers blood levels of most of these drugs by about 80%. Therefore higher doses of ‘PIs’ are needed when they are used with rifampicin. An exception is the PI ritonavir which stops rifampicin from lowering the blood level of lopinavir. Therefore a good approach is to boost the normal daily dose of lopinavir/ritonavir with additional ritonavir. This has been shown to maintain blood concentrations of lopinavir, the active antiviral, in children treated with rifampicin-based TB treatment.
• Rifampicn also decreases the blood levels of DTG significantly. Twice daily dosing of DTG i.e. 50 mg twice daily overcomes this effect during rifampicin co-administration.
• Because rifampicin does not affect the blood levels of the ‘nucs’, an alternative approach during TB treatment is to switch to an antiretroviral regimen containing three ‘nucs’.

Note

Boosted lopinavir/ritonavir means that the total amount (dose) of lopinavir in mg is equivalent to the total amount (dose) of ritonavir in mg administered to the patient.

Higher than normal doses of ‘PIs’ drugs and DTG are needed if used together with rifampicin.

Note

Ritonavir, a protease inhibitor alters the metabolism of many drugs by inhibiting the P450 enzyme system (especially CYP3A4), which is used to break down these drugs. Therefore, by increasing the dose of ritonavir during rifampicin-based TB treatment the effect of rifampicin on the P450 enzyme system can be overcome.

5-63 What is the risk of using INH together with antiretroviral therapy?

Peripheral neuropathy is a side effect of INH as well as d4T. Therefore, the risk of peripheral neuropathy is greater if d4T is used together with INH.

Drug interruptions

5-64 What is a drug interruption?

This is when antiretroviral treatment is stopped for a short period (a temporary interruption). Drug interruptions must be avoided. The cause of drug interruptions may be intolerable side effects or poor adherence. These children should be reviewed by an experienced clinician and the cause for the interruption established. If the cause is intolerable side effects then further investigation and/or treatment modification may be required. Lack of drugs at the clinic (stock-outs) should never be the cause of a drug interruption.

5-65 What is the danger of drug interruption?

If only one antiretroviral drug is stopped for a while there is a danger that resistance may develop to the remaining drugs. Therefore, it is best to stop all the antiretroviral drugs if drug interruption cannot be avoided.

It is better to stop all drugs rather than the one drug believed to be causing a problem.

Note

Planned drug interruptions at regular intervals are not being used in the treatment of HIV.

Side effects of antiretroviral agents

5-66 What should be done if the patient has a severe reaction to a drug?

All drugs must be stopped immediately. Never only stop one drug. The whole drug combination must be assessed by an expert. A common and important side effect of d4T and lopinavir/ritonavir is wasting of the face, buttocks and limbs (lipoatrophy). This should be recognised early, as the wasting may be permanent.

Immune reconstitution inflammatory syndrome (IRIS)

5-67 What is the immune reconstitution inflammatory syndrome?

This is an unexpected clinical deterioration which occurs soon (usually within four to 12 weeks) after antiretroviral treatment is begun. After initially improving, the child becomes ill once again.

Functional immune recovery starts within weeks of beginning antiretroviral treatment. An inflammatory response to an HIV-associated infection (such as BCG vaccination or TB) was not possible before antiretroviral treatment was started as the immune system was too suppressed. As the immune system recovers, the body may develop an inflammatory response to any of the following:

• Hidden or mild infections which have been missed clinically at the start of ART but start to produce clinical symptoms a few weeks after starting antiretroviral treatment (unmasking IRIS). An example would be silent TB.
• Worsening of existing infections after starting antiretroviral treatment(paradoxical IRIS). An example would be TB which has only been treated for a few weeks.

BCG-associated lymphadenitis is the commonest form of IRIS in children in South Africa. TB is another important cause.

Note

During the initial stages of antiretroviral therapy many children with advanced HIV infection are still severely immunosuppressed and are thus susceptible to new opportunistic infections. Therefore differentiating classic IRIS from new infection associated with ongoing immune suppression during the first six months of antiretroviral treatment may be difficult.

TB may present for the first time (previously missed clinically) or partially treated TB (dead bacteria still present) may flare up with an acute inflammatory reaction such as suddenly enlarged paratracheal nodes, pleural effusions or parenchymal lung disease which may be seen on chest X-ray.

5-68 How many patients develop the immune reconstitution inflammatory syndrome?

About a third of adults starting antiretroviral treatment develop mild IRIS. The frequency has not been established in children, but at least 20% of children with advanced HIV infection experience serious infections during the first six months of antiretroviral treatment, requiring admission. Many of these infections may be due to IRIS, which can be serious, but rarely life threatening. It usually presents 2 to 6 weeks after starting antiretroviral therapy. Children who start antiretroviral treatment with a very low CD4 percentage have the greatest risk of developing IRIS.

5-69 How does the immune reconstitution inflammatory syndrome present clinically?

It usually presents with fever and a worsening of the patient’s symptoms after starting antiretroviral treatment. The clinical features vary and depend on the anatomical site. For example, children may develop a reaction at their BCG site or axillary adenitis with or without the formation of a fistula as a result of previous BCG vaccination. Lymphadenopathy or the appearance of the chest X-ray may become worse in children whose lungs are colonised with the TB organism. Children whose liver is colonised with hepatitis B or C will present with features of acute hepatitis or liver failure. All children with severe IRIS must be referred to an experienced clinician for assessment and appropriate investigations. Consider IRIS in anyone who is not improving within the first few months of antiretroviral treatment.

The immune reconstitution inflammatory syndrome presents suddenly and unexpectedly with the clinical deterioration soon after antiretroviral treatment is started.

Case study 1

A 7 year old child is referred for antiretroviral treatment. His HIV infection is graded at stage 2 and his CD4 count is is less than 200 cells/µl. He is brought by a neighbour as his mother died a year before.

1. Does this child qualify for antiretroviral treatment?

Yes, all HIV-infected children should be treated with antiretroviral treatment irrespective of CD4 count or clinical stage.

2. How soon should antiretroviral treatment be started?

Unless contra-indicated, antiretroviral treatment should be started within 7 days of diagnosing HIV infection. Because his CD4 count is below 200 cells/μl he should be prioritised for rapid initiation onto antiretroviral treatment. Therefore, the baseline investigations and pre-antiretroviral treatment counselling should be completed as soon as possible and the child commenced on antiretroviral treatment.

3. Should this child be asked if he agrees with the decision to treat him?

Yes. Whenever possible older children should agree with their carer’s or parent’s decision to give consent for treatment. This plays an important part in adherence to treatment.

4. What are the social criteria for treatment?

At least one adult must be responsible for giving the treatment, they should be ‘treatment ready’, and they should be able to bring the child to the clinic for the scheduled visits. Treatment is unlikely to succeed if all these criteria are not met.

5. Does this child meet the social criteria?

No. A home visit is needed to identify the best person to take responsibility for giving this child’s antiretroviral treatment.

Case study 2

The parents of an 8 year old child with stage 4 HIV infection are referred for education and counselling in preparation for the child’s antiretroviral treatment. They are anxious that the treatment is started as soon as possible and are willing to be actively involved in the care needed.

1. What parent education is needed?

The parents need to understand what HIV infection is and what treatment is needed. They must be able to recognise the drugs to be used and know how to give them correctly. They should also know what side effects to look for and what common HIV-associated infections may occur. They must understand the importance of excellent adherence.

2. Who should provide this education?

Usually a counsellor in individual sessions or in group education classes. Often trained lay counsellors are used to provide the education needed. Pamphlets, videos and posters are also useful.

3. What parent counselling is needed?

It is important that the parents are able to accept the child’s HIV status (and often that of the family), are able to disclose the status to close family members and friends, and are emotionally ready for the start of the child’s antiretroviral treatment.

4. How may the parents be emotionally supported?

It is important that their family and close friends support them. It is often very helpful if they join a support group.

5. How long does it take to become ‘treatment ready’?

Usually two counselling sessions. In HIV-infected children treatment counselling should be completed rapidly to ensure that treatment starts as soon as possible. It is very important that the parents or caretakers are well prepared before treatment is started.

6. Should the child be involved in the education and counselling?

Yes. Older children should be involved in the decisions and management of their illness.

Case study 3

A mother brings her daughter to the first screening visit. She is examined by the doctor who says that she has the criteria for starting antiretroviral treatment.

1. What needs to be done at the first screening visit other than checking the criteria for antiretroviral treatment?

• A history is taken and general examination done.
• The child is weighed and measured.
• Readiness education and counselling are arranged.
• A home visit is planned if possible.
• The management is discussed with the parents.

2. What infection should be screened for?

Tuberculosis. A history of TB in the family is taken, sputum sample collected for examination and Mantoux skin test performed. It is very important to exclude TB before starting antiretroviral treatment.

3. Can adherence to treatment be assessed at the first visit?

Yes, if the child is receiving cotrimoxazole prophylaxis. Good adherence to prophylaxis suggests that there will be excellent adherence to antiretroviral treatment.

4. Why is a home visit important?

It is important to confirm the correct home address and assess the home circumstances where support and disclosure can be determined.

5. What baseline blood tests should be done at the first screening visit?

Take blood for CD4 count and percentage if not already done, a haemoglobin or full blood count, serum ALT and bilirubin levels should be measured if the child is jaundiced, serum ALT if the child is on TB treatment, serum creatinine and calculate the estimated glomerular filtration rate (eGFR) if TDF is to be used, and a hepatitis B surface antigen in adolescents.

6. When is it decided whether the parents are ‘treatment ready’?

This decision is made by the multidisciplinary team at the second screening visit.

Case study 4

A child who is started on antiretroviral treatment attends the first follow-up visit. His father asks what the chances of drug failure are. He has read about antiretroviral treatment and wants to know about ‘IRIS’.

1. What is the schedule of visits once antiretroviral treatment is started?

The child is usually seen at two, four, eight and 12 weeks after starting treatment. Thereafter visits are at three- or six-month intervals if progress is satisfactory. Infants should be seen monthly for the first 6 months.

2. What is the expected response to antiretroviral treatment?

The child gradually feels better and gains weight. HIV-associated infections become less frequent and severe. By six months the CD4 percentage should be above baseline. In most children the viral load is undetectable. This is the best indicator of successful treatment.

3. What is the main cause of drug failure?

Poor adherence. With excellent adherence this child has a good chance of steady improvement. Excellent adherence means that no more than one in 20 doses should be missed. That is one mistake in 10 days in children taking twice daily antiretroviral treatment.

4. What are a few ways of improving adherence?

• The parents must be well prepared before treatment is started. They must understand the importance of excellent adherence.
• Practical reminders are important. An alarm clock, radio or TV programme or cellphone message may be helpful.
• Side effects must be correctly managed.

5. Can previous exposure to antiretroviral drugs lead to treatment failure?

Yes. The commonest cause is exposure to prophylactic NVP at the time of delivery. Therefore NVP is usually not used for first-line antiretroviral treatment in children younger than three years.

6. What is ‘IRIS’?

The immune reconstitution inflammatory syndrome (IRIS) is an unexpected clinical deterioration after starting antiretroviral treatment. It is due to an immune response to an HIV-associated infection, such as BCG infection following immunisation or TB.