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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 reverse the disease process. Without antiretroviral treatment most of these children will die within a few months. Starting treatment early in HIV infected infants, before clinical signs appear, reduces mortality by 75%.
Antiretroviral treatment (highly active antiretroviral treatment or HAART) 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.
With antiretroviral treatment the child should feel well again.
For life. Antiretroviral treatment can control HIV infection but not cure it.
All children of 5 years or younger with confirmed HIV infection should be started on antiretroviral treatment irrespective of their clinical or immunological stage, as they are at high risk of rapid progress of their disease and early death.
All HIV-infected children aged 5 years or less should be started on antiretroviral treatment.
The criteria for starting older children on antiretroviral treatment are:
Either the clinical or immunological criteria must be met before starting antiretroviral treatment in children more than five years of age. Every effort should also be made to meet the social criteria. If the clinical or immunological criteria are not yet met, the child should be carefully followed up with regular monitoring of the clinical stage and CD4 count.
Either clinical or immunological criteria can be used to indicate the need for antiretroviral treatment in children aged over 5 years of age.
In children with HIV infection it is better to start antiretroviral treatment earlier than later.
All children over five years of age with stage 3 or stage 4 disease should be started on antiretroviral treatment even if their CD4 count is not severely depressed or if a CD4 count is not available. Recurrent hospital admissions (more than two per year) or prolonged hospital admissions (more than four weeks) strongly suggest that the child needs antiretroviral treatment. It is important to follow the current national protocol for starting antiretroviral treatment.
Clinical stage 3 or 4 HIV infection alone is an indication for antiretroviral treatment in children age 5 years or more.
The development of age-related severe immunodeficiency i.e.:
The immunological criteria indicate how severely the immune system has been damaged by HIV. Therefore, it is a very useful measure of when best to start antiretroviral treatment.
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.
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.
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.
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.
It usually takes about two weeks. If the parents are not yet ‘treatment ready’ the start of antiretroviral treatment may have to be postponed. However, every effort must be made to speed up preparation, especially in young children, where the disease can progress rapidly.
Usually two visits to the antiretroviral clinic are needed before treatment can be started:
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.
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.
If possible, a home visit by a counsellor should be done to:
A home visit is an important part of preparing for antiretroviral treatment.
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:
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.
Usually two education classes are attended before the second screening visit
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.
A baseline CD4 count and viral load is needed before antiretroviral treatment is started.
Following the second visit the details of the child should be discussed by the multidisciplinary team to decide whether treatment readiness has been achieved.
The role of each member of the multidisciplinary team may vary between different clinics.
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:
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.
The child should be brought back after two weeks. If there are any problems the child should be brought back earlier.
The most important reasons for the child attending this visit are to assess adherence and check for side effects.
The second follow-up visit should take place four weeks after starting antiretroviral treatment. Again adherence and side effects must be assessed.
Parents must be able to bring their child back at any time if they are concerned or if a new problem appears. They must not wait until the next scheduled visit.
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.
In addition to the routine checks (history, examination, weight), it is very important to make a formal assessment of treatment success or failure.
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.
The CD4 percentage usually increases above the baseline level.
If the response to antiretroviral treatment is good, the viral load is usually less than 400 copies/ml (i.e. an undetectable viral load) by six months.
An undetectable viral load.
An undetectable viral load is the best indicator of successful treatment.
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.
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.
Antiretroviral treatment can be successful for many years.
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.
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 co-trimoxazole in children be stopped when antiretroviral treatment has provided the following improvement in CD4 percentage:
The main problem with antiretroviral treatment is poor adherence.
Poor adherence is the main problem with antiretroviral treatment.
Adherence (or compliance) is the degree to which patients take their antiretroviral drugs correctly.
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.
Excellent adherence is the key to treatment success.
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.
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.
The history given by the parent or guardian may be an unreliable method of assessing adherence. Better methods include:
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.
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.
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.
Parents often need constant monitoring, education, encouragement and support. Good preparation and long-term support are essential for excellent adherence.
A good, caring service by the clinic improves adherence.
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.
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.
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.
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.
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.
Taking ddI with meals results in poor absorption. Therefore ddI is always taken well before or well after a meal. Drug absorption may be low with chronic diarrhoea.
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:
Every effort must be made to avoid drug resistance as this may lead to treatment failure.
Excellent adherence to antiretroviral treatment is the best way of avoiding the development of drug 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 nevirapine there is a high chance that they will also be resistant to efavirenz. Drug resistance between classes is uncommon.
The features of treatment failure on antiretroviral therapy are:
Before diagnosing treatment failure on a high viral load measurement it is important to step up adherence counselling and then repeat the viral load after two to three months. The diagnosis of treatment failure is confirmed if the viral load remains high or increases further. Sometimes the viral load will be increased at the time of the first measurement but falls with the second measurement. Transient rises in the viral load are called ‘blips’. They are not uncommon and may be caused by a recent viral or bacterial infection, or an immunisation. Therefore, always repeat the viral load after two or three months before diagnosing treatment failure.
There are a number of causes:
Poor adherence is the commonest cause of treatment failure. These children usually respond to treatment at the beginning but later fail. Excellent adherence must be stressed at every visit to the HIV clinic.
Poor adherence is the commonest cause of treatment failure.
Further care, including decisions about second-line treatment and the selection of subsequent regimens should be guided by an experienced clinician. The cause of the treatment failure must be determined as far as possible. It is important that the treatment regimen should not be changed until a careful assessment is done and all the options considered. Remember that a second measurement of the viral load must be done before diagnosing treatment failure.
The treatment regimen should not be changed in haste.
If adherence has been poor, every effort must be made to improve adherence. If adherence has been good, a change to the second-line treatment regime should be considered.
Yes. If first-line treatment including nevirapine has failed, despite excellent adherence, make sure that the child was not given nevirapine for the prevention of mother-to-child transmission of HIV. In many countries, previous exposure to nevirapine is not considered a contraindication to standardised first-line treatment which includes nevirapine. However, treatment of children previously exposed to any antiretroviral drugs should be discussed with an antiretroviral expert before starting a new treatment regimen.
Change from first-line to second-line treatment. This decision must always be made by an expert in antiretroviral treatment as it is an important step. Do not rush into second-line therapy. Re-counsel the parent or caregiver.
Treatment is changed to three new drugs, from at least two antiretroviral classes. The second-line combination in children is usually AZT, ddI or 3Tc and lopinavir/ritonavir. Review all other medication for possible drug reactions.
If adherence is excellent and the patient becomes clinically worse on the second combination, a decision may be made to stop all antiretroviral treatment and start supportive care only. If failure is due to poor adherence every effort must be made to improve adherence.
This is the interference of one drug with another drug. Common examples of drug interaction are:
Using either the first- or second-line combinations for antiretroviral treatment avoids drug combinations which compete with each other.
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:
Higher than normal doses of ‘PIs’ drugs are needed if used together with rifampicin.
Peripheral neuropathy is a side effect of INH (isoniazid) as well as d4T and ddI. Therefore, the risk of peripheral neuropathy is greater if either d4T or ddI are used together with INH.
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 should never be the cause of a 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.
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.
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:
BCG-associated lymphadenitis is the commonest form of IRIS in children in South Africa. TB is another important cause.
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.
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 3 weeks after starting antiretroviral therapy. Children who start antiretroviral treatment with a very low CD4 percentage have the greatest risk of developing IRIS.
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 possible 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.
A 7 year-old child is referred for antiretroviral treatment. His HIV infection is graded at stage 2 and his CD4 count is 250 cells/µl. He is brought by a neighbour as his mother died a year before.
No, as he is assessed as only stage 2. Stage 3 and 4 are current clinical indicators for treatment in children over five years of age.
Yes, as his CD4 percentage is below 350 cells/µl. This is the indication for treatment in children above five years of age.
No. Either clinical or immunological criteria can be used on their own. However, both are often present in a child.
Yes. All HIV-infected children of 5 years or younger should receive antiretroviral treatment even if their clinical staging and CD4 count or percentage are normal.
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.
No. A home visit is needed to identify the best person to take responsibility for giving this child’s antiretroviral treatment.
The parents of an eight-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.
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.
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.
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.
It is important that their family and close friends support them. It is often very helpful if they join a support group.
Usually two weeks. 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.
Yes. Older children should be involved in the decisions and management of their illness.
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.
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.
Yes, if the child is receiving co-trimoxazole prophylaxis. Good adherence to prophylaxis suggests that there will be excellent adherence to antiretroviral treatment.
It is important to confirm the correct home address and assess the home circumstances where support and disclosure can be determined.
Usually a CD4 percentage has already been done for staging. A full blood count, and ALT if nevirapine is to be used, should be taken.
This decision is made by the multidisciplinary team at the second screening visit.
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’.
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.
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.
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.
Yes. The commonest cause is exposure to prophylactic nevirapine at the time of delivery. Therefore nevirapine is usually not used for first-line antiretroviral treatment in children younger than three years.
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, usually TB.