HIV & AIDS treatment for children

HIV develops very rapidly among infants and children, and, without treatment, a third of children with HIV will die of AIDS before their first birthday, with half dying before they are two.¹ In 2008, there were 280,000 deaths attributed to HIV in under-15s, most of which could have been prevented through early diagnosis and effective treatment.² Though the number of children receiving antiretroviral therapy (ART) has increased significantly in recent years, at the end of 2008 less than 40% of the 730,000 children needing ART in lower- and middle-income countries were receiving it.³

How effective is antiretroviral treatment for children with HIV?

The most effective treatment for children with HIV is antiretroviral therapy. This requires several antiretroviral drugs (ARVs) be taken every day.
Antiretroviral treatment reduces illness and mortality among children living with HIV in much the same way that it does among adults. In one study in Brazil, three-quarters of HIV-positive children receiving ART were alive after a four-year follow-up period.⁴ Positive outcomes were also seen in paediatric ART programmes in Thailand and Kenya.^{5 6} A study released in 2007, which monitored 586 HIV-positive children receiving antiretroviral treatment in 14 countries in Africa and Asia, found that 82% were still alive after two years.⁷
Some of the most compelling evidence that treatment works in children does not come from studies or statistics, but rather the stories of those who have witnessed HIV-positive children returning to health after starting treatment:

"You see scrawny, rashy, tired, lethargic kids come in, you start them on treatment and within weeks you’ve got bounding, podgy, gorgeous growing children. People often don’t believe, they’re often quite sceptical of the medications, and then you see this transformation and parents are like ‘The child’s got so much energy!’”Julie, UK nurse working with children living with HIV⁸

Identifying and testing children living with HIV

Providing treatment for children with HIV/AIDS essentially involves three stages: finding a child, testing a child and treating a child. Most children living with HIV become infected through mother-to-child transmission, and these children need to be tested as soon as possible after birth to find out if they are are infected with the virus. If a child living with HIV is only diagnosed once they are ill, it may be too late for antiretroviral treatment to be effective.

Collection of dried blood spots from an infant

In developed countries, children can be tested soon after birth (sometimes within 48 hours) using polymerase chain reaction (PCR) tests and other specialist techniques. Where this technology is available, the longest a mother will have to wait for an accurate result is usually around six weeks.
In resource-poor countries, where PCR testing is generally unaffordable or unavailable, a mother may have to wait up to 18 months after giving birth before antibody tests (which are used in adults, and are more commonly available) can be used to accurately diagnose her child. During this time the antenatal clinic, where the mother was probably diagnosed, is likely to lose contact with her.
In some resource-poor countries, ‘dried blood spot’ testing has been introduced in recent years. This is where a small sample of blood is taken from a child, dropped onto paper, and sent to a laboratory where it can be tested. Since these samples do not need to be refrigerated and are easy to transport, they can potentially be sent miles away to places where PCR is available. This means that even children living in resource-poor areas can be tested relatively quickly. However, dried blood spot testing can be expensive and it can take a long time for test results to return. There's also evidence that when the drug nevirapine is used to prevent mother-to-child transmission of HIV, dried blood spot testing doesn't always detect HIV in the first few days of the child's life.^{9 10}

Starting antiretroviral treatment in children with HIV

As with adult treatment, there is ongoing debate about when it is best to start antiretroviral treatment in HIV-positive children. There is a complex balance between the immediate benefits of providing treatment to children who are not showing any symptoms of AIDS-related illness, and concerns about long-term resistance and antiretroviral drug side effects if treatment is started too early.

CD4 counts in children

To judge whether an HIV-positive person requires treatment, a CD4 test is usually carried out. This measures the number of T-helper cells – white blood cells that are attacked by HIV – in an individual’s blood. It can either measure the absolute number of CD4 cells, or the percentage of white blood cells that are CD4 cells, in a sample of blood.
A falling CD4 count is a sign that HIV is progressing, and that the immune system is becoming weaker. In healthy, uninfected adults, absolute CD4 count is usually between 500 and 1500 cells per cubic millimetre of blood. When an HIV-positive adult’s CD4 count falls below 350 it is usually recommended (in economically developed countries) that they start receiving antiretroviral treatment.
For children below the age of five, though, these adult guidelines are generally irrelevant. Absolute CD4 counts vary with age, and younger children usually have a much higher CD4 count than adults. This makes it difficult to judge the health of a child's immune system based on CD4 count. Percentage CD4 count does not vary in the same way as absolute CD4 count, and is therefore recommended for children under five.
In some cases, viral load testing (which measures the amount of HIV in an individual’s blood) is used alongside CD4 testing to guide decisions about treatment.

Starting treatment based on clinical symptoms

In resource-poor communities, the technology needed for CD4 counts and viral load testing is not always available. In the absence of these facilities, healthcare workers sometimes have to make a presumption that a child should begin treatment based on their stage of HIV infection as defined by a range of cancers and infections that are present.

When to start treatment

Until recently it was generally agreed across guidelines that a child aged less than one year to 18 months with a percentage CD4 count below 20-25% should be started on treatment, whether symptomatic or not. However, the findings of one study prompted WHO to revise their guidelines and it now recommends that all diagnosed children under 12-months should begin antiretroviral therapy regardless of the infant’s clinical or immunological stage.¹¹ (Children under 12-months with clinically diagnosed presumptive severe HIV should also begin treatment, but confirmation of infection should be obtained as soon as possible.) The Children with HIV Early Antiretroviral Therapy (CHER) study of infants (aged six-to-twelve weeks) in South Africa compared the outcomes of those starting limited treatment immediately with those deferring treatment until CD4 percentage dropped below certain levels or if symptomatic and severe disease occurred. (The study's criteria for deferred treatment were only slightly different from South African or WHO guidelines.) It found the risk of death for infants who began treatment immediately was 76% lower than the deferred treatment group.¹²

Doctors at the Rixile HIV clinic treat an ill HIV positive child, Tintswalo, South Africa

The United States has followed the lead of the WHO and now recommends treatment, rather than the consideration of treatment, for all infants with HIV, regardless of CD4 percentage, clinical status or viral load.¹³ 2009 guidelines produced by the Paediatric European Network for Treatment of AIDS (PENTA) also advocate treatment for all infected children under 12 months regardless of clinical or immunological stage.¹⁴ Other countries’ guidelines may be revised to reflect the CHER study’s findings.
The effect of planned treatment interruptions at one and two years, on those infants who started immediate treatment, will be revealed after the trial is completed in 2011.¹⁵
While there is an emerging consensus on initiating therapy immediately in infected infants, there is an ongoing debate as to when treatment should begin in young children. Generally for children aged between one and five years, treatment is recommended if significant symptoms are evident or percentage CD4 count has decreased to below 20-25% with this indicator declining with age to around 15-20%.^16 17 18
Arguments for earlier treatment include: evidence that disease progression is faster in young children; that there is an association between severe HIV disease and persistent neurocognitive deficits in adolescent long-term survivors of perinatally acquired HIV;¹⁹ and that ART can reduce tuberculosis, encephalopathy and bacterial infections that occur even at high CD4 levels, as well as improve physical growth. Advocates for earlier treatment also point to studies showing that the risk of disease progression is identical between adults and over-5s so it follows that any argument for earlier initiation in adults should also apply to older children. Arguments for deferring treatment include a lack of information on the long term effect of doing so, and the additional cost and burden of adherence due to a longer overall period of treatment.²⁰

Which antiretroviral drugs should be used?

As with adults, antiretroviral therapy with at least three drugs is recommended for children as this prevents HIV from becoming resistant to any single drug. It is usually recommended that this therapy should consist of two nucleoside reverse transcriptase inhibitors (NRTIs) combined with either one non-nucleoside reverse transcriptase inhibitor (NNRTI) or a protease inhibitor (PI). ²¹
There are many factors that can influence the choice of drugs for children. Considerations about medications that the mother may have received during pregnancy, the toxicity of certain drugs, and whether the child is still breastfeeding, all need to be taken into account when choosing a regimen.

Dosing and drug formulations in children

The dose of antiretroviral drugs given to children is generally based on either weight or body surface area. Children have traditionally been thought of as being ‘mini adults’ but this is not the case. Children’s bodies are constantly changing and developing and often it is vital that drug doses are altered to ensure that a child is not given too much, or too little, of a drug. The study of how a child’s body reacts to medication is called pharmacokinetics (PK) but current paediatric PK studies mostly focus on 6-18 years old, which misses the early stages of development; a period when the human body changes the most. Pharmacokinetic properties such as absorption, distribution, metabolism and excretion of a drug all influence the efficacy, toxicity and dosing regimen required in a child.  As such, information is limited on PK for infants and drug manufacturers and expert guidelines use a variety of ways to calculate doses of paediatric ARVs, so there is no uniform dosing system to follow. ²²
Dosing is further complicated by the variety of forms that ARVs may take when provided to children, all of which require different measurements. Infants who are too young to swallow tablets ideally need to be provided with drugs that are more child friendly such as syrups, powders, sprinkles or ‘melts’ but these formulations are not widely available and are expensive. ^{23 24}.  Unfortunately, a lot of HIV medicine has an unpleasant taste, especially in syrups and powder form. This can make it difficult for children to take their ARVs every day, and increases the burden of HIV. In addition, it is critical that children’s medicine has clear and concise labelling to ensure that caregivers are able to give an appropriate dosing and ensure adherence.

Since there are still no available, easy-to-use triple drug combinations for children, I do what most doctors are doing: I try to show caregivers such as grandparents how to break adult tablets, hoping that the children will get the doses they need.

- Dr Fasineh Samura, Malawi

An encouraging development is the relatively recent availability of fixed-dose combination therapies (FDCs), which combine multiple ARVs into a single tablet, for children. Tablets consisting of lamivudine, stavudine and nevirapine have been supplied by the Clinton HIV/AIDS Initiative (CHAI), in conjunction with drug purchase facility, UNITAID, to children in 26 nations. In these countries CHAI’s monthly paediatric treatment formerly consisted of 12 bottles of liquid. For those children who can now access FDCs, only a small container of tablets is needed, making the therapy easier to store, transport and administer.²⁵
In areas where there is a lack of affordable paediatric ARV formulations, clinicians often have no choice but to divide adult fixed-dose combination drugs into measures appropriate for children. There is evidence that dividing tablets carries a risk of under- or over-dosing²⁶ but equally, a significant 2006 study of eight countries concluded that the use of divided adult FDCs can achieve successful and satisfactory results in children.²⁷ The World Health Organisation supports this practice in situations where no appropriate paediatric medications are available.²⁸

“Since there are still no available, easy-to-use triple drug combinations for children, I do what most doctors are doing: I try to show caregivers such as grandparents how to break adult tablets, hoping that the children will get the doses they need.” Dr Fasineh Samura, Malawi²⁹

Side effects of paediatric HIV treatment

Children receiving ARVs can suffer from the same drug side effects that adults experience. Because children’s bodies are still developing, and they are likely to be exposed to treatment for prolonged periods of time, they may be particularly vulnerable to some complications.³⁰ Side effects can occur at various stages of a child’s course of treatment, and may be acute (occurring directly after drug administration), sub-acute (within one or two days after administration), or late (after prolonged drug administration). It can be difficult to distinguish between adverse events caused by ARVs given to a child and complications caused by HIV itself, so care should be taken to exclude other possible causes of illnesses before it is concluded that they are a result of ARVs.
The impact of side effects may vary from mild to severe and life-threatening. Some moderate or severe side effects may require drug substitution, or even the discontinuation of treatment. In general, mild side effects do not require such changes, and symptomatic treatment for them may be given. If side effects are regarded as life threatening, all ARVs should be stopped until the child has stabilised.³¹

Adherence

Children on HIV treatment need to take three or more types of ARVs every day for the rest of their lives. If drugs are not taken routinely, at around the same time every day, HIV may become resistant to the therapy, causing it to stop working.
A review of 17 studies regarding paediatric HIV treatment adherence found adherence ranging from 49% to 100%. Three-quarters of the studies showed adherence rates of 75%. Most of the studies in lower- and middle-income countries revealed adherence rates above 75%, whereas the opposite was true in higher-income countries.³²
There are a number of factors that commonly cause adherence problems: inadequate dosing; high pill burden; reluctance among young infants to take syrups and powders due to their unpleasant taste; dietary restrictions; and toxic side effects of drugs. Adherence issues can put an enormous strain on the daily lives of parents and caregivers, who are usually responsible for administering treatment. Some ARVs need to be taken with food, so carers may have to perform the often difficult task of providing a meal and administering drugs simultaneously. This is assuming that an adequate supply of food is actually available. If fixed-dose combinations appropriate for use in children became more widely available, it is likely that adherence would generally improve, since it is much easier to take a single dose every day rather than multiple doses.

Nutritional support whilst on HIV treatment

Malnutrition is common in children living with HIV in developing countries, and is a major cause of death. Ideally, children living with HIV who are asymptomatic need to consume 10% more calories than other children of their age and sex. Children who are symptomatic, or recovering from acute infections, need to consume 20-30% more calories than other children.³³

An HIV-positive child, South Africa

If a child is suffering from malnutrition, it is recommended that they receive treatment to stabilise their condition before HAART is started. In poorer areas, however, this is not always possible. Even where it is possible to treat malnutrition, recovery from this condition is likely to be slow and limited in HIV-positive children. If a child has not been cured of malnutrition after six to eight weeks of special feeding or appropriate treatment, it may be decided that HAART should be started despite their condition.
In the opposite situation, where a child experiences rapid weight gain as a result of ARVs, nutrition also needs to be monitored carefully. As a child’s weight changes, so does the recommended dosage of ARVs that they require, so drug doses need to be constantly reviewed.³⁴

Treating children for opportunistic infections

Opportunistic infections, which take advantage of weak immune systems, are a serious threat to children living with HIV. Tuberculosis and PCP (a form of pneumonia) in particular are major causes of illness and death among infected infants.
Children are at particular risk of tuberculosis (TB), particularly if they are suffering from a weak immune system due to HIV infection. Co-infection with HIV and tuberculosis in children is increasingly common in many areas.³⁵ While the basic principles of TB treatment are the same in HIV-positive children and uninfected children, the situation is complicated by drug interactions between ARVs and drugs that are used to treat TB. The drug rifampicin, which is commonly used to treat TB, can react negatively with NNRTIs such as nevirapine, as well as with protease inhibitors. Such interactions can lead to sub-therapeutic drug levels and an increased risk of toxic side effects. For HIV-positive children who are not yet receiving ARVs, it is recommended that treatment for TB should ideally be initiated some weeks before ARV treatment, allowing the child to stabilise on this therapy. For children who are diagnosed with TB while already receiving treatment, ARV regimens need to be carefully reviewed, and may need to be adjusted in accordance with official guidelines.³⁶ In order to avoid late diagnosis of HIV, it has been suggested that all TB-infected children should be considered for an HIV test.³⁷

Preventing opportunistic infections in children

Due to their weak immune systems, children living with HIV are very vulnerable to opportunistic infections, and need to be provided with drug prophylaxis to prevent such illnesses. For example, prophylaxis against PCP (one of the most common opportunistic infections in children living with HIV) is recommended for all children born to HIV-positive mothers, starting from about one month after birth.³⁸ For children who have no access to ARVs, treatment for opportunistic infections may delay the need for antiretroviral treatment.
Co-trimoxazole, an antibiotic that is included in PCP prophylaxis and can help to prevent other infections such as TB, was shown to reduce AIDS-related mortality by 43% and hospital admission rates by 28% among children with HIV in a major trial in Zambia.³⁹ Based on this trial and other evidence, experts agree that co-trimoxazole should be widely provided to all children living with HIV, especially where ARVs are not available. It is also recommended that all children born to HIV-positive mothers should be provided with co-trimoxazole until tests confirm that they are HIV-negative. Co-trimoxazole prophylaxis can be given to a child from 4 to 6 weeks of age.⁴⁰ As well as being effective, co-trimoxazole is cheap, costing as little as US$0.03 a day to provide. However, provision is extremely low with just 8% of infants born to pregnant women with HIV in 2008 initiating co-trimoxazole prophylaxis by two months of age.⁴¹
Another important intervention is vaccination or immunisation against common infections. There are some risks associated with providing routine vaccines to children living with HIV, but these risks are far outweighed by the benefits of immunisation. In general, routine vaccines are safe to administer in HIV-positive children, and are recommended.^{42 43} However, it should be noted that ‘live vaccines’ are often not considered safe for use in HIV-positive children.

Barriers to child testing and treatment

Unless barriers to HIV testing and treatment are addressed children will continue to die in their hundreds of thousands each year. The unavailability of paediatric HIV drugs means effective treatment for children is often elusive. Furthermore, stigma and discrimination directed towards people living with HIV are conducive to low levels of testing, and can contribute to poor adherence to ART where it is available.

Problems with testing

In 2008, less than 1-in-6 children born to women with living with HIV were tested within two months of birth.⁴⁴
A number of factors may prevent children from being tested. Health authorities’ lack of technical ability, poor systems for laboratory analysis, problems with transportation of specimens and results, and little confidence in caring for children are all significant factors.⁴⁵
Furthermore, parents may be unwilling to take their child for an HIV test for fear that the child will face prejudice once diagnosed. A lack of knowledge about testing and the fact HIV can be effectively treated could also lead to poor testing rates. Mothers who have not yet been tested may too be fearful of discovering their child is infected as this would likely mean they are infected also. Hospitals or clinics that provide testing may not be accessible and will lose contact with HIV-exposed children for follow-up tests. A mother may have to travel long distances to reach the nearest health service that can test her child, and this may be impractical and expensive.⁴⁶

Lack of appropriate treatment

Many of the drugs that are conventionally used to treat adults living with HIV are not available in an appropriate form, or licensed/approved for use in children. Those that are available are often unaffordable in the areas where they are most needed. The paediatric formulations that are available can be significantly more expensive than adult equivalents and therefore an expansion of the development of cheap, fixed-dose combinations for children is greatly needed.

Children performing a play about the benefits of antiretroviral medication

As more groups speak out about the unacceptably high cost of these formulations, some progress is being made. In December 2006, The Clinton HIV/AIDS Initiative (CHAI), founded by former US president Bill Clinton, announced that it had negotiated reductions in paediatric drug prices made by two Indian pharmaceutical companies. Under this agreement, 19 different ARVs that can be used in children were scheduled to be made available for an average 16 cents per day. This is 45% cheaper than previously available drugs.⁴⁷ This agreement has probably contributed considerably in increasing child access to ART in recent years. Since CHAI and UNITAID partnered in 2006, they claim to have reduced the cost of leading child treatments by 64 percent in low income countries.⁴⁸
Even though many governments have increased efforts to distribute co-trimoxazole, financial and logistical barriers still stand in the way of its provision. It is estimated that in 2007 just 4% of the four million children who could be benefiting from the drug had access to it.⁴⁹ Increasing the numbers of children receiving this relatively low-cost drug would save many lives.

Problems with adherence

As well as the unavailability of appropriate drugs, stigma surrounding HIV can also lead to adherence problems if parents and caregivers are unwilling to make it publicly known that the child in their care is HIV-positive. For instance, carers may be reluctant to fill out prescriptions in their local community, or may not make a child’s school aware of their condition, which can lead to them missing out on drug doses during the school day.⁵⁰ They may also hesitate to administer ARVs if other people are present when a child is due to receive them. For children who are old enough to administer their own ARVs, it can be hard to fit their treatment routine in with their increasingly active social lives:

“There are days when I can't be bothered [to take my medications] like when I am tired or if I am at someone else's house and have to hide it or whatever, then it's hard.”13 year old HIV-positive girl⁵¹

Improving testing and treatment for children

While stepping up efforts to prevent mother-to-child-transmission would decrease the need for paediatric treatment, it is likely that HIV will continue to infect many thousands of children for years to come. Given this situation, testing and treatment facilities for children need to be improved, and ARVs that can be used in children need to be made much more widely available.
The wider provision of cheaper, simplified drug formulations, fixed-dose combination tablets and low-cost generic versions of paediatric drugs would all have immense benefits. While there have been welcome increases in recent years in the number of children receiving ART, the vast majority go untreated. Governments, international organisations and donors need to focus on achieving much wider treatment coverage.
The degree to which HIV-related stigma can affect poor levels of testing and adherence to therapy indicates how negative attitudes towards those living with HIV need to be tackled. Efforts to maximise adherence should be strengthened and delivered before and alongside treatment.
General improvements in the health systems of developing countries would allow for greater resources to be allocated towards treating children. Many countries lack the resources and capacity needed to help children living with HIV, and suffer from a shortage of healthcare workers that are trained to test and treat children.
If such improvements are made, the problems of HIV and AIDS among children could potentially be minimised. At present, though, progress is not happening fast enough. Greater advocacy, funding and effort are required if the challenges surrounding HIV treatment for children are to be overcome.

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