GUIDELINES FOR ANTIRETROVIRAL THERAPY IN CHILDREN – NOVEMBER 2009 VERSION GUIDELINES

Since HIV is usually a disease occurring within families, the following are important: n Always enquire about the health and HIV status of the caregivers and other family members. n Encourage and assist caregivers to start ART if required; ideally families should receive treatment simultaneously in the same facility to avoid inconvenience and unnecessary expense for patients. n HIV testing should be offered and recommended for other family members if their status is unknown. n Ascertain and encourage HIV disclosure status of caregivers themselves, the child and other family members.


GOALS OF THERAPY
n Durable suppression of viral load (VL) (undetectable VL using an ultrasensitive assay) n Restoration or preservation of immunological function (CD4+ count) n Sustained improvement in clinical symptoms and quality of life n Reduction in morbidity and mortality.

FAMILY TREATMENT
Since HIV is usually a disease occurring within families, the following are important: n Always enquire about the health and HIV status of the caregivers and other family members.n Encourage and assist caregivers to start ART if required; ideally families should receive treatment simultaneously in the same facility to avoid inconvenience and unnecessary expense for patients.n HIV testing should be offered and recommended for other family members if their status is unknown.n Ascertain and encourage HIV disclosure status of caregivers themselves, the child and other family members.

ADHERENCE
High levels of adherence to antiretroviral therapy (ART) are vital for treatment success.The goal is for the patient to receive 100% of scheduled doses.Factors that impact on adherence include: n Parental/caregiver education: they must understand that poor adherence is the single most important factor for drug failure and resistance, leading to loss of future therapeutic options.n A good health care provider-patient relationship underpins adherence.n Motivation and commitment of caregiver/parent to the child's lifelong therapy.n Address any social issues as appropriate.
n Although unpredictable events can acutely impact on adherence (e.g.severe illness or death of a parent), frequent visits and good communication may help to anticipate and pro-actively plan for such events

TALKING ABOUT ADHERENCE Working with the client
A short checklist of points should include: n Checking caregiver's capacity to understand treatment plan/adherence (intellectual/developmental level, literacy) n Checking the basic facts about ART n Explaining adherence and why it is important n Explaining common ART side-effects and likely course n Explaining that symptoms associated with other illnesses (i.e.vomiting, diarrhoea, cough, fever, rash) overlap with drug toxicity and are not a reason to stop therapy.However, if an acute illness (acute gastro-enteritis) occurs and the child is unable to tolerate medications, it is permissible to stop all meds for a short period of time n Exploring the caregiver's readiness to start the child on antiretroviral therapy n Assessing the level of commitment to ART adherence n Assessing the caregiver's perception of the advantages and disadvantages of being on ART.
Discussion should include an assessment of the caregiver's psychosocial situation.This covers: n Exploration of the caregiver's lifestyle (e.g.work, daily routine, sleep, other responsibilities) n Exploration of the caregiver's personality traits (e.g.sense of organisation, self-discipline and responsibility) n Assessment of the caregiver's own HIV status and health and lifestyle choices (use of alcohol and drugs) (remember -HIV infection in adults not yet on ART can cause cognitive impairment) n Possible use of alternative/complementary medicine n Exploration of the caregiver's financial and material resources.
It is also necessary to explore possible barriers to adherence as well as sources of support, including: n Discussion around disclosure (e.g.how much the child knows about own status/how much other household members know about child's status/reasons for not wanting to disclose to child/others if applicable).Disclosure is an evolving process requiring an active plan and involvement of the parent/caregiver n Exploration of the current and potential sources of support n Problem solving with regard to barriers n Anticipation of events that might present an obstacle to adherence, e.g.school trips, visits to grandparents.
Finally, a specific adherence plan is developed in collaboration with the client (and child where appropriate).The plan should specify: n The treatment regimen (specifics of medication, doses and the intervals at which the medication should be given).Remember that the same drug may have many names (formula, generic, trade, fixed-dose combinations), which may be confusing to patients and families n Possible side-effects, what to do and who to contact in the case of serious side-effects n Ways of integrating treatment into the daily routine of the caregiver/child, especially the specific times the medication will be given.
The plan should be individualised and the health care professional is encouraged to provide practical aids and supportive information sheets.Demonstration of dosage and method of administration by the counsellor as well as by the caregiver is important.
Social disruption or catastrophic events can happen at any time and could affect adherence.Events such as loss of a caregiver or severe illness in a caregiver should be mentioned, with possible solutions.

Tips
In the case of school-age children and adolescents, it is important that adult caregivers are available to supervise.Routine is reassuring: caregivers should try to give medication in the same way, at the same time and in the same place every day.Caregivers should be encouraged to: Additional factors enhancing adherence include: n Children should be taught to swallow pills/capsules as early as possible (from about 4 years).This can be done using appropriately sized sweets.n Medications should fit into the patient's lifestyle.For example, twice-daily medication does not have to be given strictly 12-hourly, rather at a convenient time.
It is far better to give a dose later than usual than not to give the medication at all.n Too many caregivers involved in administering medicines can be an obstacle to good adherence.
A different caregiver accompanying the child to n Remind the child that medicines are important and will help to keep him or her from getting sick.
n Be positive and consistent when it comes to giving the child medicine.
n Always say something positive when the child has taken his/her medication.
n Reward the child with a sticker or a star on a record chart or calendar or other age-appropriate token.
n Allow the child to earn a special treat for sticking to his/her schedule (e.g. a small weekly treat and a bigger monthly treat.Avoid monetary rewards; a story or a favourite meal is more than adequate).n Get other people who care about the child to encourage and reward him/her for taking medication.n Anticipate and talk about possible problems before they arise.
n Be flexible with the treatment plan.Accommodate change (e.g. in the scheduled time of doses) if this would result in better adherence.n Think of possible simplification of the regimen.
n Ask about any side-effects.Suggest ways to manage less serious side-effects and indicate the likelihood of relatively short duration.n Ask about other medication that the child may be taking in order to avoid possible drug interactions and better co-ordinate dosing of all medications.n Anticipate possible adherence fall-off during times of increased stress.Make time to discuss and deal with problems and feelings.n Vomiting after taking medication: make sure that the caregiver knows that if a child vomits within 30 minutes of taking a medication the dose should be repeated.each appointment is a warning sign, requiring exploration.n Emphasise good adherence at each visit.It is useful to compare ART with therapy for diabetes and hypertension, both conditions requiring lifelong therapy and in which poor adherence is associated with disease progression.HIV is a chronic, manageable condition, with minimal morbidity, if the correct approach is taken.n It is useful to monitor whether treatment is being collected.

INDICATIONS FOR STARTING ART IN CHILDREN
First assess the child clinically and stage the child according to the World Health Organization (WHO) Staging System (Table I) to determine whether the child needs ART or not (note: all infants diagnosed <12 months of age should be started on ART regardless of clinical or immunological staging).If the child is clinically well, CD4 testing will further ascertain whether the child needs ART.
The CHER Study

NEXT VISIT
If therapy is indicated and if the family is adequately counselled and able to continue to maintain adherence, dispense drugs.Graphically illustrate the drugs and how and when to take them, preferably with actual drugs or samples.Consider observing initial administration of the drugs.

DAY 2 OF TREATMENT
If possible, a quick phone call to make sure that everything is in order is a good idea.

1 -2 WEEKS LATER
A phone call to the caregiver/parent is recommended to discuss tolerance and adherence issues.The government roll-out programme recommends a 2-week visit where adherence is discussed and medication technique is checked.

ONE MONTH AFTER STARTING TREATMENT
The clinician should conduct a general examination and draw blood to monitor drug toxicity (in national Department of Health (NDoH) guidelines, only if on tuberculosis (TB) treatment or on zidovudine (AZT)).
Tolerance and adherence issues should be discussed.It may be useful to ask how many doses have been missed in the last 3 days, and how many in the last month.
In young children weight gain can be surprisingly rapid.Check whether doses need to be increased.

THREE MONTHS AFTER STARTING TREATMENT
The clinician should conduct a general examination and draw blood to monitor drug toxicity.Check weight and alter doses accordingly.
Bloods should also be taken for HIV VL and CD4+ count.
In the NDoH guidelines, bloods would only be drawn if clinically indicated for suspected toxicity, if on AZT or if co-treated for TB.
Adverse effects, tolerance and adherence issues should be discussed with the caregiver.

THREE-MONTHLY THEREAFTER
The clinician should conduct a general examination and draw blood for drug toxicity, HIV VL and CD4+ count.Although there is no consensus, a growing number of international experts advise aggressively achieving and maintaining viral suppression.

Note:
n A repeat test is recommended whenever a routine measurement yields an unexpected result.It is usually not worth doing routine plasma HIV RNA levels during an intercurrent infection.Additional non-routine testing may be indicated if the clinical condition changes.n Two measurements should be performed 1 month apart before instituting changes.n VLs can be temporarily raised for up to a month after intercurrent infection or vaccination.
n Patients should be sequentially tested using the same method and the same laboratory.n The NDoH has decided to omit the baseline VL in order to save costs.Since the baseline VL doubles as a confirmatory test for infants diagnosed by PCR, it is strongly recommended that the baseline VL still be done in infants diagnosed by PCR.

CD4+ LYMPHOCYTE COUNTS AND PERCENTAGES
The CD4+ count should be measured with the VL, except when the VL is repeated for an unexpected result.Absolute CD4+ lymphocyte counts are much higher in infancy than adulthood, but the CD4+ percentage is more constant, although also higher in children <2 years.CD4+ percentages may be easier to work with, but CD4+ counts should also be used.Over the age of 5 years, adult cut-offs using CD4 counts can be used for therapeutic decision making.Lymphopenia and lymphocytosis may over-or understate CD4 percentages or counts.
CD4+ counts/percentages are useful for monitoring response to ARVs.VL changes will typically precede changes in CD4 counts.CD4+ counts can be temporarily lowered by intercurrent infections or vaccinations, taking up to a month to recover.
Although there is a strong association between CD4+ depletion and opportunistic diseases, Pneumocystis jirovecii pneumonia (PCP) may occur in the first year of life despite 'normal' counts for age.

HEIGHT AND WEIGHT
The 'Road to Health' chart is a valuable tool for monitoring the well-being of children.Failure to maintain growth is suggestive of progressive HIV disease or superimposed infection such as TB.
*NDoH guidelines recommend 6-monthly monitoring.† NDoH guidelines recommend not to do a baseline VL as a cost-saving practice.It is imperative that a baseline VL be done in all infants diagnosed on PCR as this doubles as a confirmatory test.Do not delay initiation of HAART while awaiting the confirmatory test result.FBC = full blood count; ALT = alanine transaminase.

TABLE III. ROUTINE MONITORING 6. RECOMMENDED ARV REGIMENS
ART drugs are listed in Table IV, and dosages in Table V. Simplified weight-based dosing is set out in Fig. 1.
There are major concerns about d4T toxicity, especially lipodystrophy.Stavudine should be changed to ABC at the first sign of lipodystrophy.In addition, zidovudine as part of second-line therapy will be compromised by resistance to stavudine.
Consider a boosted PI as the third drug in a child over 3 years exposed to SD-NVP or where there are concerns about adherence.

Rationale for choice of regimen
3TC and ABC backbone: n Very good long-term data from PENTA 5.    and to compensate for any possible reduction in the effectiveness of the hormonal contraceptive.n LPV/r co-administration can increase tenofovir levels by 30%, and may result in increased renal and bone toxicity.
The following website may be of assistance in assessing potential interactions: http://www.hiv-druginteractions.org/frames.asp?drug/ drg_main.asp

PRACTICAL DOSING
Although paediatric dosages are calculated using the child's weight or surface area, one must consider the practicalities of the dose.For example, 1.75 ml is very difficult to measure accurately, so a more practical dose is 2 ml (generally round upwards).Certain ARV solutions, e.g.LPV/RTV (Kaletra) or RTV (Norvir) are highly concentrated, so dosages do need to be calculated to the nearest 1/10th of a ml (but it is not necessary to calculate to the nearest 1/100th of a ml).Others, e.g AZT, 3TC, NVP (Viramune) or ABC (Ziagen) solutions, can quite safely be rounded up to the nearest ml.The volume of 3TC and ABC should always be the same, which makes dosing easier for caregivers.When using d4T capsules dissolved in water, dosages can be rounded up to the nearest 5 mg.Every effort should be made to switch to tablets or capsules as soon as possible.Certain drugs should still rather be dosed according to surface area, but where this is difficult the weight-based chart (Fig. 1) can be used.

Kivexa
Kivexa is a fixed-dose combination tablet containing 300 mg 3TC and 600 mg ABC.It is dosed as 1 tablet once a day and can be given to children >25 kg who can swallow this large tablet.It is particularly useful in older children to facilitate adherence.

Atazanavir (Reyataz)
ATV is a useful PI.

TIMING OF DOSING
There is a common misconception that ARVs need to be given exactly 12 hours or 24 hours apart.This is because older drugs with very short half-lives needed to be dosed exactly on time.However, there is much more flexibility with the drugs in current use.Drugs with twice-daily doses can generally be given between 10 and 14 hours apart.For drugs that are dosed with meals, the best approach is to give them strictly twice daily with breakfast and supper.It is clearly much more important to fit the drugs into our patients' lifestyles than vice versa.

HAART AFTER FAILED MTCT PROPHYLAXIS
n Where nevirapine was used as a single dose in prevention of mother-to-child (PMTCT) prophylaxis.In the HIVNET 012 study, up to 45% of HIV-infected infants had NNRTI-associated resistance mutations after 1 dose of NVP to the mother and the infant.There are good data in adults and infants suggesting reduced efficacy of future NNRTI-containing highly active antiretroviral therapy (HAART) regimens.Results from P1060 also indicate that in children who have been exposed to NNRTIs for PMTCT, there is an increased risk of virological failure when NVP is used subsequently for treatment. 6It is therefore advisable to avoid nevirapine and efavirenz as part of first-line therapy in this situation.
n If AZT monotherapy was used in MTCT prophylaxis.Data support its use in combination therapy for infected infants.Resistance has, however, been described.n If the mother was on triple combination therapy.
In this situation, do genotyping on the baby and design a regimen accordingly.If unable to do genotyping, avoid the drugs the mother was taking, especially if she had a detectable VL.If the mother had an undetectable VL, it is probably acceptable to use the same agents in her HIV-infected baby.

TUBERCULOSIS TREATMENT AND HAART IN CO-INFECTED CHILDREN
Rifampicin increases the breakdown of PIs and NNRTIs.Also, there are overlapping toxicities between TB drugs and ARVs.The immune reconstitution inflammatory syndrome (IRIS) causes morbidity and higher risk of mortality.IRIS can be misinterpreted as progression of TB or medication side-effects.In addition, the increased pill burden can impact on adherence.

Options
When to start ARVs: n Since TB is a clinical stage 3 disease, most children will need to be started on ART.ART should be initiated 2 -4 weeks after starting TB treatment.This may reduce the likelihood of immune reconstitution disease and will allow time to identify early adverse events from anti-TB drugs.The efficacy and toxic side-effects of this approach are unknown.Recent pharmacokinetic data show that super-boosted LPV/r yields good levels of LPV whereas simply doubling the dose yields suboptimal levels.

CHANGING THERAPY
For toxicity or intolerance, a simple substitution can be made, being mindful of previous therapies that may have failed.Do not reduce dosage unless the reduced dose is still in the therapeutic range.
For failure of a regimen, proceed as outlined below.

Failure of first-line therapy
If viraemia occurs, even at a low level, check and encourage adherence.Also check dosages or other 'technical problems' .These include vomiting or spitting out medications and not receiving meds on time.
If the VL is persistently >5 000 copies/ml on two or three occasions despite good adherence and technical problems having been resolved, consider changing regimens.Be sure to resolve the adherence problems before changing therapy, otherwise the second regimen will fail.On the other hand, continuing with a failing regimen results in ongoing viral replication with the development of new mutations and cross-resistance, thus limiting future options.
Resolving adherence issues is paramount for any child failing ART.In children on a PI-based first-line regimen, adherence interventions may be sufficient.On the other hand, failing an NNRTI-based regimen invariably requires a regimen change after resolving adherence issues.See below for choice of second-line regimen.
Since virological failure usually precedes immunological and clinical failure, by changing on virological criteria, one can hopefully prevent clinical and immunological deterioration.
When failure is due to viral resistance, at least two new active drugs should be used.Previous drug history and genotyping (see below) are helpful in deciding on a new regimen.

In the case of NNRTI resistance
n There is no place for maintaining patients failing an NNRTI regimen on the same regimen; the longer it is maintained, the more resistance mutations are likely to occur.n The regimen should be changed to a boosted PI with 2 active NRTIs (based on genotyping if possible).
In the case of PI resistance n Patients on a boosted PI regimen not suppressing may have no PI and minimal NRTI mutations, in which case the original regimen may be resumed after addressing the adherence issues.n In NNRTI-naïve patients with no NNRTI and at least 2 fully active NRTIs on genotyping, a simple switch to 2 NRTIs + NNRTI may be appropriate.n Patients with multiple PI mutations may achieve viral control when some of the newer agents not yet registered in South Africa are used.Consult an expert.

Failure of second-line or subsequent regimens
In this situation, consult an expert.

Nucleoside analogues
Resistance is slow to develop, except for 3TC.Resistance to 3TC occurs within weeks on a non-suppressive regimen.Useful benefits of 3TC resistance are the partial reversal of AZT, d4T and TDF resistance and rendering HIV less pathogenic (M184V mutation).

Non-nucleoside reverse transcriptase inhibitors
There is complete cross-resistance between the currently available NNRTIs.A patient resistant to NVP will also have resistance to efavirenz (despite what the genotyping indicates).This does not apply to the new second-generation NNRTI (not yet available in South Africa) etravirine, which needs a few NNRTI mutations for high-level resistance.For this reason, a patient failing an NNRTI should change regimens soon to prevent compromising this future option.

Protease inhibitors
The boosted PIs are very slow to develop resistance and need several mutations before high-level resistance occurs.In a PI-naïve patient who fails a boosted PI, it is generally accepted that resistance mutations do not occur over a short period of time.However, if a patient has PI mutations from previous PI failure, new mutations can occur even with a boosted PI.

Resistance testing
At present only genotypic resistance testing is available in South Africa.Genotyping is still expensive (±R4 400).
Genotyping will only provide information about resistance to the current regimen, and not necessarily about previous ART the child may have been exposed to.For this reason genotyping needs to be interpreted in conjunction with a detailed ART history.The interpretation is complicated and should be done in conjunction with an expert.Ideally genotyping should be done in any child whose VL is persistently above 5 000 copies/ml despite good adherence.Genotyping is also indicated for infants infected despite maternal HAART, before starting ART.Contact the South African HIV Clinicians Society for further information on when to perform and interpreting genotyping.
Patient failing ABC/3TC/LPV/r or d4T/3TC/LPV/r Current NDoH guidelines recommend AZT + ddI + NVP (<3 years) or EFV (>3 years).Some experts feel that this regimen is prone to failure.It is advisable to do resistance testing and /or discuss with an expert to devise a suitable second-line regimen.
After changing regimens, there should be frequent adherence and toxicity checks.

SWITCHING FROM A PI-TO AN NNRTI-CONTAINING REGIMEN
Numerous adult studies and one paediatric study have demonstrated the feasibility of switching from a PI to an NNRTI once VLs are <50 copies/ml.This approach will avoid some long-term adverse effects of the PIs.
Only consider if VLs are consistently <50 copies/ml and adherence is excellent.Where the mother and/or baby were given a single dose of NVP for PMTCT, switching should be avoided until further data are available.

INTERRUPTING THERAPY
Generally ART should not be stopped except on the advice of an expert.When it is necessary to stop or interrupt a regimen containing an NNRTI, be aware that the long half-life of the NNRTI will cause sub-therapeutic levels to persist for up to several weeks.Either continue the NRTIs for a week after stopping the NNRTI if feasible (for example if NNRTI-associated rash is suspected) or use a boosted PI for a week to avoid developing resistance to the NNRTI.

IMMUNE RECONSTITUTION INFLAMMATORY SYNDROME
IRIS is characterised by a paradoxical clinical deterioration after starting HAART.This results from rapid restoration of pathogen-specific immunity to opportunistic infections (OIs) and causes deterioration of an existing infection (paradoxical IRIS) or new clinical manifestations of a previously unrecognised subclinical infection (unmasking IRIS) during the early stages of ART.IRIS is usually associated with improvements in surrogate markers of HIV infection (virological, immunological, clinical).It may have distinct clinical presentations with pronounced inflammatory response.IRIS usually occurs within 6 months of starting HAART and in patients with a low starting CD4 count.The most common presentations in South African children include BCG adenitis, TB and herpes zoster.

SELECTED ADVERSE EFFECTS OF ANTIRETROVIRAL DRUGS IN CHILDREN (TABLE VI)
ARVs are generally well tolerated in children.A few more serious adverse effects are mentioned here.

LACTIC ACIDOSIS
Lactic acidosis is a rare but serious, life-threatening complication of NRTI therapy, especially when ddI and d4T are used together.Symptoms include nausea and vomiting, abdominal pain, tachypnoea and dyspnoea, weight loss and fatigue.It may also cause neurological symptoms including a Guillain-Barré-like picture.There is no value in screening for lactic acidosis in asymptomatic children.Clinicians should be aware of the symptoms and diagnose the condition timeously.Diagnosis is confirmed with a serum lactate level >5 mmol/l, metabolic acidosis and a raised anion gap.Liver enzymes may be increased.
In patients with a lactate level >10 mmol/l or >5 mmol/l with metabolic acidosis, ART should be discontinued and supportive therapy instituted.Treatment (usually in an ICU) consists of intravenous fluids and ensuring oxygenation.Some reports suggest that alkalinising the blood with bicarbonate might improve prognosis, but this remains controversial.Other controversial treatments include thiamine (vitamin B 1 ), riboflavin (vitamin B 2 ) and L-carnitine (no data to show efficacy).
Following an episode of lactic acidosis, it may take several months for lactate levels and liver enzymes to normalise.Contact the HIV Clinicians Society for assistance in designing a new regimen after lactic acidosis.

HAEMATOLOGICAL TOXICITY
The two major agents are AZT and co-trimoxazole (usually only high-dose co-trimoxazole for treating PCP, but occasionally with prophylactic doses, and this is reversible with folinic acid -not folic acid).
Patients on AZT should have full blood counts (FBCs) monitored monthly for the first 3 months and 3-monthly thereafter.The main bone marrow toxicities from AZT are anaemia and neutropenia.
Anaemia may be due to HIV infection itself, or to AIDSrelated conditions such as disseminated MAC, CMV or lymphoma.It may also be nutritional (e.g.iron or folate deficiency) or drug-related.Management depends on the underlying cause of anaemia, available options and the extent of the problem.It is reasonable to switch to a drug that causes fewer haematological side-effects, e.g.switch from ZDV to d4T or ABC.A haemoglobin level below 7 -8 g/dl warrants investigation and treatment.Nutritional deficiencies, especially iron, should be addressed.
Neutropenia is quite common before or on HAART.Unless severe, <0.25×10 9 /l, neutropenia often resolves spontaneously (providing there are no associated signs such as persistent fever or localised infection) and a repeat FBC should be done a week later.If neutropenia is severe, <0.25×10 9 /l, the offending agent should be replaced if feasible.

RASHES
Most rashes following ARVs are mild to moderate and resolve spontaneously with drug continuation.Most rashes are either maculopapular or urticarial.The most severe rashes include Stevens-Johnson syndrome, toxic epidermal necrolysis, ABC hypersensitivity, and the drug rash with eosinophilia and systemic symptoms (DRESS) reported with NNRTIs.
The highest prevalence of drug rashes occurs with the NNRTIs (more severe and more frequent with NVP).Rash usually occurs in the first 2 -4 weeks of treatment.The rash is usually maculopapular and erythematous.
NVP is given daily for the first 2 weeks and only increased to twice daily once the rash has resolved.Mild to moderate rashes will often resolve spontaneously but must be closely monitored.Oral antihistamines can be used in mild to moderate cases.
In children who develop severe rash, cutaneous bullae or target lesions, mucosal lesions or systemic symptoms, NVP  If NVP is discontinued for mild or moderate rash, restarting NVP after the rash has resolved may be considered with close monitoring.
Cross-reactivity among NNRTIs may occur.Therefore avoid EFV after a severe rash.However, in children with mild or moderate rash without mucosal involvement or systemic symptoms, EFV may be substituted with caution.
Rashes may occur in children receiving EFV.These rashes are usually less severe than those with NVP, and resolution during treatment continuation is common.However, if EFV-associated rash is severe, or is accompanied by mucosal or systemic symptoms, EFV should be permanently discontinued.

HYPERSENSITIVITY SYNDROME
ABC and NVP are most commonly implicated.ABC hypersensitivity reaction occurs in 4 -8% of patients but is less common in black Africans.There is a 100% correlation between skin patch test-positive reactions and HLA B*5701.HLA B*5701 is rare in black Africans.Hypersensitivity reaction usually occurs in the first 6 weeks of ABC.ABC hypersensitivity is multisystemic.Fever and rash occur commonly and may be associated with nausea, vomiting, diarrhoea, fatigue, myalgia and arthralgia.Respiratory symptoms, such as pharyngitis, cough or dyspnoea, may also be present.
The skin rash, usually maculopapular or urticarial, occurs in about 70% of cases.Symptoms worsen with each dose.ABC hypersensitivity reaction is fully reversible on discontinuing ABC, and fatalities have not been reported on first exposure to the drug.Patients must however never be rechallenged with ABC after a hypersensitivity reaction, as deaths have occurred due to hypotension.Parents need specific counselling to recognise the hypersensitivity reaction; they also require a letter to alert any health care worker who may be consulted and need the contact number of the prescribing doctor.
A hypersensitivity reaction has been described for NVP.Systemic symptoms such as fever, myalgia, arthralgia, hepatitis, and eosinophilia may occur.It usually occurs in the first 8 weeks of treatment.NVP should then be permanently discontinued and EFV should be avoided as well.

HEPATOTOXICITY
All three classes of ARV drugs currently in use in South Africa have been implicated.Liver dysfunction in HIV infection may be caused by HIV, co-infection with hepatitis B or C viruses, OIs, malignancies, drug interactions or drug-induced hepatotoxicity.NRTI-associated hepatotoxicity is primarily caused by mitochondrial toxicity.NNRTIs are associated with asymptomatic elevations in liver enzymes and hypersensitivity with hepatitis.NVP is associated with more hepatotoxicity than EFV.PI-associated elevations in liver enzymes can occur at any time during therapy.Patients with chronic hepatitis B or C may experience an increase in liver enzymes after starting HAART as part of IRIS.There may also be an increase in liver enzymes after discontinuing drugs such as 3TC or TDF (which are used to treat hepatitis B).Children do seem to get less hepatic dysfunction on HAART than adults.
Patients on NVP should have liver function tests (LFTs) done 2-weekly for the first 2 months, then 3-monthly thereafter.LFTs should be monitored routinely 3 -4monthly in patients on other HAART regimens.
If transaminases are elevated <10 times the upper limit of normal (ULN) there is no need to interrupt HAART.Patients with clinical hepatitis or severe hepatotoxicity (>10 × ULN) should have a work-up for other causes of hepatitis, e.g.hepatitis A, B or C, and interruption of HAART.Patients on NVP with clinical hepatitis should discontinue NVP and have their HAART regimen changed.Rechallenge with NVP or ABC after acute hepatitis is not recommended.Patients with hepatitis B co-infection may need to continue with 3TC if their HAART regimen is changed to prevent a flare-up in hepatitis B.

LIPODYSTROPHY (LIPO-HYPERTROPHY/LIPO-ATROPHY)
Lipodystrophy typically involves accumulation of visceral fat in the abdomen (central obesity), dorsocervical area (buffalo hump) and breasts (visceral fat accumulation) and/or loss of subcutaneous fat in the face, extremities and buttocks (lipo-atrophy (LA)).PIs have been implicated in fat accumulation, whereas the NRTIs, especially stavudine, have been implicated in LA.
EFV may be implicated in breast enlargement.There are no data in children, but adult data suggest that switching from d4T or ZDV to ABC will at least arrest and may partially reverse LA but not the visceral fat accumulation.Switching early, when the LA is mild, is advisable as LA may be irreversible.There are also limited data indicating that switching to a regimen containing a PI and an NNRTI only will also reverse LA.

HYPERLIPIDAEMIA
PIs (especially RTV and LPV/r) are implicated in hyperlipidaemia.However, both d4T and EFV have also been implicated.While PI therapy in adults is associated with an increased risk of cardiovascular disease, there is currently no evidence of an association between elevated cholesterol levels in children and an increased risk of premature death.As a result, there is no consensus Indications for co-trimoxazole prophylaxis and when to start and stop it are set out in Table VII.
Re-institute co-trimoxazole prophylaxis if the CD4 count or percentage subsequently drops and the criteria in Table VII for starting prophylaxis are reached.

INH PROPHYLAXIS
The following children should receive INH prophylaxis: n HIV-infected infants and children with a positive PPD test (>5 mm) n HIV-infected infants and children exposed to a person who has contagious TB.
Active TB disease first needs to be excluded.Stop once ART-associated immune reconstitution has occurred for ≥6 months: CD4 ≥15% or ≥200 cells/µl on ≥2 occasions, 3 -6 months apart Any HIV-infected child with high risk for bacterial infections, e.g.severe malnutrition, on oncological drugs or corticosteroids or at risk of malaria Start co-trimoxazole prophylaxis even with ART immune reconstitution Do not stop until risk has been eliminated and all CD4 cell percentage or CD4 cell count criteria listed above have been met

HIV-infected child with previous PCP infection
Start as soon as first PCP episode has been treated Stop once ART-associated immune reconstitution has occurred for ≥6 months in children over 1 year of age: CD4 ≥15% or ≥500 cells/µl (1 -5 years) or ≥200 cells/µl (>6 years) on ≥2 occasions, 3 -6 months apart * Note: any one of the criteria could be used for starting therapy.

TABLE VII. CO-TRIMOXAZOLE PROPHYLAXIS 10.3 MYCOBACTERIUM AVIUM COMPLEX
MAC is a true OI.Disseminated MAC only occurs in patients with extremely low CD4 counts, although it is unusual in very young children.The best prophylaxis against MAC is ART and immune recovery.Where resources allow, there is a role for azithromycin prophylaxis against disseminated MAC in patients with extremely low CD4 counts.Before prophylaxis is instituted a mycobacterial blood culture should be done to exclude disseminated MAC.Children aged 2 -5 years with a CD4 count <75 cells/µl and >6 years with a CD4 count <50 should be offered azithromycin prophylaxis.The dosage of azithromycin is 20 mg/kg body weight (max. 1 200 mg) orally once weekly.Discontinue once the CD4 count has been >200 cells/µl for children aged 2 -5 years and >100 cells/µl for children aged ≥6 years for >6 months in children on stable ART.

n
Setting an alarm on an alarm clock n Setting a cell phone alarm or reminder n Using a pillbox n Using a diary card n Using a wall calendar n Keeping a treatment diary n Sending SMS reminders to the caregiver n Using daily TV or radio programmes as cues n Using mealtime (breakfast and supper) as a cue n Having a treatment supporter n Having a treatment buddy (another child, also on treatment) n Keeping medication in a familiar place and not hidden or locked up n Using directly observed treatment support (DOTS) as for TB if needed.

7 8. 5
SPECIFIC ISSUES FOR ADOLESCENTSThese issues apply to both vertically and sexually transmitted HIV.n Non-adherence is often a problem, and strategies should be introduced to promote adherence, including more frequent visits and intensive counselling.n Adult supervision of treatment should continue throughout adolescence and includes verification that the medicine has been swallowed.n Disclosure of HIV status must have occurred before onset of sexual activity.n Adolescent-friendly services include: n A specific convenient day set aside for adolescent clinics n Adolescent groups and peer support groups n Access to family planning, sexually transmitted infection (STI) treatment, cervical cancer prevention and screening and gynaecological services n Human papillomavirus vaccination.
Each liquid medicine and its syringe should be colourcoded to prevent confusing medicines and dosages.n Ensure that the caregiver's eyesight is adequate to administer medication accurately.n Teach caregivers to open childproof containers.
n Dosages of liquid formulations should be rounded up to a convenient volume.n Syringes for liquid formulations should be marked at the correct dosage with a blade or permanent marker.Show the caregiver how to draw up the correct volume and expel excess air.Make sure that the syringes are appropriately cleaned.n

INITIATION OF THERAPY Note: For young infants initiation of treatment should be rapid, with ongoing counselling while on ARVs. 4.1 FIRST 1 -2 VISITS
1demonstrated that:

TABLE II . CRITERIA FOR ART INITIATION 5. MONITORING: SPECIAL CONSIDERATIONS FOR CHILDREN (TABLE III) 5.1 VIRAL LOAD
Efavirenz causes reduced levels of clarithromycin, but not azithromycin.nRitonavir should not be given with numerous drugs.nOf the anti-epileptic drugs, sodium valproate is the safest to use with antiretrovirals.
5n Spares thymidine analogue for next regimen.Lopinavir/ritonavir in children <3 yearsData show that young children have far better viral suppression on a boosted PI regimen than on an NNRTI regimen5(irrespective of single-dose NVP).In addition the IMPAACT P1060 study indicates that in SD-NVPexposed infants, those starting NVP-based regimens have poorer virological outcomes than those starting a boosted PI regimen.6 7. DRUG INTERACTIONS There are multiple opportunities for serious drug interactions.Treaters are advised to scrutinise package information and seek advice if uncertain.n Rifampicin reduces levels of lopinavir, indinavir, saquinavir, atazanavir, fosamprenavir (PIs) and nevirapine and should not be used with any of these drugs.n n Oral contraceptives.There are limited data available on potential drug interactions between many ARVs (particularly some NNRTIs and RTV-boosted PIs) and hormonal contraceptives, which may modify their safety and effectiveness.RTV-boosted PIs are not recommended with combined or ‡ Not available in paediatric formulation.¶ EFV is only available in capsule form and tablet form.There are no data for children under 3 years of age or <10 kg.§ Paediatric dosage still uncertain.Requires Section 21 authorisation from the Medicines Control Council.NRTI = nucleoside reverse transcriptase inhibitor; NtRTI = nucleotide reverse transcriptase inhibitor; NNRTI = non-nucleoside reverse transcriptase inhibitor; PI = protease inhibitor.

TABLE V . DOSAGE AND FREQUENCY OF ARVs IN CHILDREN progesterone
-only oral contraceptives, while NNRTIs can be used.A combined oral contraceptive containing at least 30 µg of ethinyl oestradiol should be used.Progesterone-only injectables can be used with all ARVs.Concomitant consistent condom use is recommended for preventing HIV transmission

TABLE V . DOSAGE AND FREQUENCY OF ARVs IN CHILDREN (CONTINUED)
It has the advantage of minimal lipid disturbances (although RTV boosting will cause some elevations of cholesterol and triglycerides).It should generally always be given with RTV boosting.Its advantages include once-daily dosing, a low pill burden and a good safety and tolerability profile.For this reason ATV may be a preferable alternative to Aluvia in PI-naïve older children in the private sector with adherence issues.It is best not to use ATV in PI-experienced patients unless one knows that no or limited PI mutations are present.*Awaiting MCC approval.Available with Section 21 authorisation.Body surface area (m 2 ) = √ (height (cm) × weight (kg) ÷ 3 600).

TABLE VI . ADVERSE EFFECTS OF ARVs IN CHILDREN* should
be permanently discontinued and hospitalisation is required.
or experience in lipid-lowering agents in children.Cholesterol and triglycerides should be measured 12monthly in children on PIs.A random cholesterol and triglyceride is probably adequate, but if these are raised, a fasting level should be done.Referral to a dietician and encouraging exercise are the first interventions.If these are unsuccessful, consult the HIV Clinicians Society.Options available include observation, ARV agent switching (e.g. from a PI to an NNRTI or to ATV), or lipidlowering agents.Statins are metabolised by cytochrome P450 resulting in either toxicity or diminished effect with RTV, so use with caution and only on the advice of an expert.
The dosage of INH is 10 -15 mg/kg/day and it should be continued for 6 months.Where the source case has INH-resistant TB, give rifampicin 15 mg/kg/d for 4 -6 months.For MDR and extensively drug-resistant (XDR) contacts an expert should be consulted.