For adults, 22 anti-HIV drugs are currently licensed in Europe. For children, fewer drugs are formally approved or available.

The nucleoside reverse transcriptase inhibitors which are available for infants or children are:

• AZT (zidovudine, Retrovir): approved for use in children. Syrup available. Injectable liquid also available.

• ddI (didanosine, Videx): a second generation liquid is available with an improved taste. The need to take ddI on an empty stomach can be a problem with children and infants.

• ddC (zalcitabine, Hivid): ddC syrup is no longer available. Children have to be given the tablets for adults, although they can be cut in half and ground up into powder. ddC may be useful for children who are intolerant of ddI, and it is easy to take because each dose is small and can be taken with food.

• 3TC (lamivudine, Epivir): approved for children. A 3TC liquid is available.

• d4T (stavudine, Zerit): approved for children. A solution is also available.

• Abacavir (Ziagen): a liquid formulation with strawberry and banana flavouring is available. The tablets can be crushed if necessary. Not approved for infants under three months of age.

• FTC (emtricitabine, Emtriva): a liquid formulation is available.

The nucleotide reverse transcriptase inhibitor tenofovir (Viread) can be used in children aged two or over, although a suspension will not be avaialble until early 2006.

The non-nucleoside reverse transcriptase inhibitor (NNRTI) drugs which are available for infants or children are:

• Nevirapine (Viramune): suspension is approved for children aged two months and over, and the tablets can be crushed if necessary.

• Efavirenz (Sustiva): approved for children three years or older or over 10kg. A syrup is available although the oily texture may be difficult for some children to tolerate. Capsules may be opened and the contents added to food or drink but the peppery taste may not be palatable.

• Delavirdine (Rescriptor) is rarely used, but tablets can be dispersed in water or cola.

The protease inhibitors which are available for infants and/or children are:

• Nelfinavir (Viracept): formally approved for use in neonates, infants and children. It is available in tablets and as a powder. Generally well-tolerated, although diarrhoea can be a problem (Hoffmann 2002). The powder can be mixed with food, milk or juice, but it appears to be less well tolerated than crushed tablets (Ramos 2003).

• Amprenavir (Agenerase): approved for use in children over four years. Liquid formulation is available but should definitely not be taken by children under four years of age due to toxicity. Fosamprenavir (Telzir) is not yet approved for use in children, although studies are underway.

• Ritonavir (Norvir): available in liquid form but it has an unpleasant taste which makes dosing difficult, especially in children. The drug is easiest to take with fatty and strong-tasting foods like peanut butter or chocolate. Liver enzyme abnormalities and nausea have been significant problems in children taking ritonavir as a single protease inhibitor. Ritonavir may be phased in over five days to reduce the risk of nausea and vomiting.

• Ritonavir-boosted lopinavir (Kaletra): approved for use in children six months and older. A solution is available. The liquid formulation is bitter.

• Indinavir (Crixivan) is approved for children aged four years and over, and is only available in capsules. Although it has been used to treat a few children aged around ten to twelve, side-effects related to kidney stones have been problematic. These have also been seen among adults and can often be avoided by drinking plenty of liquids, but it is harder to ensure that children drink enough. Indinavir liquid is being developed. Nevertheless, research is ongoing to establish appropriate pediatric dosage.

• Saquinavir (Invirase / Fortovase) is also unlicensed for children under 16 years, but a new granule formulation has been developed for use in trials and pediatric dosing studies are underway.

• Atazanavir (Reyataz) is not approved for use in children, but it has been used with ritonavir in children aged over four years. It should be taken with food.

• Tipranavir (Aptivus) is under study in children over two years, but is only approved for treatment-experienced adults.

The fusion inhibitor T-20 (enfuvirtide, Fuzeon) is not approved in children aged under six years. As this drug must be given by subcutaneous injection, it may be less attractive than oral HIV medication, if such options are available.

Recently, doctors from St Mary's HIV Clinic have been using gastrostomies (a tube into the stomach) to minimise dosing difficulties attributable to the unpleasant taste of antiretroviral liquids. The tubes may be particularly useful in infants and small children, since the medication can be given while the child is asleep, making it easier for mothers to maintain complex treatment regimens without daily support and without an unpleasant daily ritual of attempting to make children take medicine.

Once daily regimens are thought to be another way to improve adherence in children, particularly for HIV-infected adolescents.

First-line treatment for children

In the United Kingdom, paediatricians will usually recommend that infants should start treatment with a triple combination which includes either lopinavir/ritonavir or nevirapine. Children aged one year and over are recommended to start treatment with a triple combination of either Kaletra, nelfinavir, nevirapine or efavirenz, plus two nucleoside analogues. d4T should not be included in the NRTI backbone for first line treatment owing to its association with lipoatrophy.

The Penta 5 study found that an abacavir-containing nucleoside backbone was more potent than an AZT plus 3TC backbone, with or without nelfinavir, but abacavir/3TC was associated with a higher rate of resistance after viral rebound than AZT plus abacavir (PENTA 2002).

However, three-drug therapy has not shown particularly high rates of viral load suppression when compared to adult studies. Studies of PI-containing triple regimens have typically shown that less than 40% of infants achieve viral load below 400 copies after 24 weeks (Kline 1998; Krogstad 1998; Rutstein 1997), with even lower proportions achieving viral load below 50 copies (Faye 2001).

In treatment-experienced children four-drug HAART has proven superior to three-drug HAART. PACTG 377, a study of nevirapine and nelfinavir or ritonavir in combination with one or two nucleoside analogues, showed superiority at week 24 for the four-drug arm, as did PACTG 382 (efavirenz and nelfinavir with one or two nucleoside analogues) at week 48. An observational study in which 36 HIV-infected children were started on four- or five-drug combinations found that 89% achieved viral suppression to below 50 and 78% sustained suppression for over two years. The authors of this study reported that side effects were limited to mild neutropenia and mild liver toxicity (Melvin 2002).

Another study, in children below the age of 2 with no more than ten weeks prior treatment experience, found that four-drug therapy was superior to three-drug therapy. PACTG 356 assigned infants sequentially to one of three regimens: AZT, 3TC and nevirapine; AZT, 3TC, nevirapine and abacavir; or d4T, 3TC, nevirapine and nelfinavir. The drug doses used are not reported in the study. The children continued to receive therapy for up to 200 weeks, if viral load was less than 1000 copies/ml by 16 weeks.

After 16 weeks of treatment, HIV viral loads had fallen from a median of 200,000 copies/ml to below 1000 copies/ml in 32 (62%) of the children. This decrease was similar across all three treatment groups. After 48 weeks of treatment, 15 (83%) of the 18 children receiving d4T, 3TC, nevirapine and nelfinavir had viral loads of below 400 copies/ml. In contrast, four (24%) in the AZT/3TC/nevirapine group, and seven (41%) in the AZT/3TC/nevirapine/abacavir group had low viral loads. After 200 weeks of treatment, 13 (72%) of the children receiving d4T, 3TC, nevirapine and nelfinavir still had viral loads below 400 copies/ml, in contrast to five (29%) in each of the other two groups (Luzuriaga 2004).

The major drawback of most these regimens was the use of all three classes of drugs, which is especially problematic in a first line regimen for a patient group with a high risk of treatment failure.

Doctors at St Mary's Family HIV Clinic, London, currently use a four-drug, PI-sparing regimen as first-line treatment - nevirapine, abacavir, AZT, 3TC. This provides advantages such as twice daily dosing, no food restrictions, palatable liquids, good absorption and antiviral potency. The key drawback of this combination is the potential for toxicity and the difficulty in differentiating between side-effects caused by abacavir and nevirapine. Treatment may be commenced in hospital so the child can be closely monitored and given medications to reduce the likelihood of side-effects. A study found that 17/17 infants who received this regimen had viral load below 400 copies/ml at week 48, and subsequently experienced normalisation of CD4 count and weight for age (Tudor-Williams 2002).

Kaletra combined with d4T and 3TC appears more likely to control viremia than other three drug regimens in treatment-naive children. The M98-940 study (see Lopinavir - overview in Drugs used by people with HIV: Protease inhibitors) demonstrated that 84% of treatment naﶥ children had viral load below 400 copies after 48 weeks on treatment. In treatment-experienced children nevirapine was added to the regimen, and 54% of PI-experienced children achieved viral load below 50 copies at week 48.

Lopinavir/ritonavir is relatively effective in highly treatment-experienced children. Of 36 children who took lopinavir/ritonavir plus two to four other antiretrovirals, 42% had undetectable viral load at 12 months. A viral load reduction of at least 1 log occurred in 62% of the group. These impressive results were produced despite an average of five protease inhibitor resistance mutations at baseline (Ramos 2003).

In terms of the nucleoside 'backbone', children who have started treatment with AZT/ddI may find switching to d4T/3TC a good option, should they need to change therapy. Alternatively, treatment may be started with the combination of d4T plus either ddI or (less often) 3TC. ddC in combination with AZT seems to be less popular when starting treatment, especially after the results of adult combination therapy trials suggested that this combination was less effective than AZT/ddI.

Researchers in California used the combination of AZT, ddI and nevirapine to treat eight children very early in life, all of whom were born to HIV-positive women and were themselves definitely infected with HIV. Viral load fell below the limit of detection in two of the infants, and has remained suppressed. The hope of substantially changing the progression of HIV disease in infected children by starting three- or even four-drug combinations early in life will now be studied in both the USA and Europe.

Treatment simplification may also be possible in children. One study has shown that children taking a protease inhibitor along with two NRTIs may be able to discontinue the protease inhibitor even if they have a detectable viral load. In this study of 26 children, viral load did not change and there was no HIV disease progression, despite a fall in CD4 cell percentage after simplification to dual NRTI treatment^[1].

For more details and research summaries see individual drug overviews and drug research entries in Drugs used by people with HIV.

Treatment failure and subsequent options

The definition of virological failure in children is still controversial and is being addressed in the PENPACT 1 study, which is randomising children to switch to second line treatment at viral load thresholds of 1000 or 30,000 copies/ml. Children continue to derive immunological benefit from HAART despite detectable viral load

A second-line regimen is likely consist of a PI and two new NRTIS if a NNRTI-based regimen was used, or an NNRTI-based regimen if a PI was used in first-line treatment. A new ritonavir-boosted PI is also an option for PI-treated children, particularly those who experience failure of nelfinavir or lopinavir-based regimens with no or few PI-associated mutations.

Multi-drug salvage regimens and treatment interruption prior to salvage therapy are still untested in children.

Treatment of children in resource-poor settings

In resource-poor settings, few treatments are available for the majority of HIV-infected children. Generic manufacturers have been slow to produce, and even slower to export or secure licenses to sell, low-cost liquid formulations of ARV drugs. Where patients are expected to pay for their own treatments out of pocket, most children who need treatment will have parents who also need treatment and must prioritise their own. In spite of this, many households are impoverished through caring for sick children - through the loss of income by adult carers as well as their efforts to pay for treatment.

The tests needed to detect HIV infection in children below the age of 18 months are expensive and difficult to use outside well-equipped laboratories. Until the age of 18 months the standard antibody test used to diagnose HIV infection in adults may produce a misleading result in children because the mothers antibodies linger in the childs body. Instead doctors use a viral load test (also known as a PCR test) to directly test for HIVs genetic material.

However viral load tests are expensive, even after a recent price reduction negotiated with manufacturers Roche Diagnostics and Bayer. They also require specialised training and a sophisticated laboratory, so they are out of reach of many clinics in rural settings or the poorest countries.

Peer support and adherence support for children are also needed if treatment is to succeed, together with engagement with caregivers who are often family members other than the childs mother.

Nevertheless, several recent studies demonstrate that treatment of HIV-infected infants and children in resource-poor settings can be successful. For example, 77 infants with low CD4 percentages or signs of AIDS in Abidjan received combination therapy. Most of these infants survived to 18 months and improvements in diarrhoea, pneumonia, and immune function occurred (Msellati 2003).

One orphanage in Nairobi has tried treating children with intermittent (one week on, one week off) triple therapy. Significant reductions in viral load and increases in CD4 cell levels have been reported in the treated children, and only three AIDS-related deaths have been reported since this programme commenced in August 2000 (Chakraborty 2003). This strategy remains experimental, and treatment in line with clinical guidelines is recommended where possible.

In Uganda, the Mildmay Centre treats about 120 HIV-positive children with antiretrovirals. Only four of ten antiretrovirals with pediatric suspensions are available in Uganda, which reduces the treatment options. Due to shortages in pediatric formulations, many of the children at Mildmay are receiving AZT/3TC (Barigye 2003). Thirty-nine Ugandan children aged 2.5-4.5 years were treated with AZT/3TC/chloroquine as part of the PETRA Plus study. Viral load did reach undetectable levels in most of the children but then rebounded. Nevertheless, the researchers reported health benefits, improved quality of life, generally lower viral load and higher CD4 percentage. Three children died over 96 weeks of follow-up and five were advised to stop choroquine due to eye damage (Pakker 2003).

In Thailand, the Thai Government Pharmaceutical Organization manufactures a combined treatment of nevirapine (200mg), 3TC (150mg) and d4T (30mg). Thirty HIV-infected children with CD4 percentage below 15% were treated with this combination known as GPO-vir. Three of the children had to stop treatment due to side-effects but those who tolerated the drug had an average viral load reduction of 3 log at week 8 (Puthanakit 2003).

Prophylaxis

Preliminary data suggest that isoniazid prophylaxis may reduce mortality in children. A South African study randomised children to receive isoniazid (10mg/kg) or placebo and in an additional randomisation, to receive co-trimoxazole daily or three times a week. The study recruited HIV-positive children; asymptomatic infants below the age of 12 months and symptomatic infants aged 12 months and over. The median age of children enrolled to the study was 23.5 months.

The placebo arm was discontinued in May 2004. By this point there had been a total of 32 deaths: 20 in the placebo group and 12 in the INH group, a statistically significant difference (p = 0.026). Isoniazid treatment was associated with a 53% reduction in mortality.

Survival benefit appeared early during prophylactic treatment with isoniazid (within 50 days), and was apparent in all CDC categories of HIV disease severity and at both treatment centres. The risk of death was nine times higher in children below the age of eight months when compared to children of 21 months age and over but there was no interaction between age and isoniazid treatment, suggesting that children below the age of 21 months had a higher risk of dying irrespective of which treatment they received.

Isoniazid prophylaxis also helped to prevent cases of tuberculosis. Of the 14 incident cases of tuberculosis which occurred during the study period nine were in the placebo group and five in the isoniazid group. This difference did not, however, reach statistical significance (Zar 2004).

Co-trimoxazole prophylaxis for children under the age of 15 years has been shown to reduce the risk of death by almost half in a randomised study that recruited 534 children with symptomatic hIv infection in Zambia. Children were randomised to receive co-trimoxazole or placebo. Children younger than 5 years received 240 mg (5 ml suspension) co-trimoxazole daily, and those older than 5 years 480 mg (10 ml), or matching placebo.

After median follow-up of 19 months, 74 (28%) children in the co-trimoxazole group and 112 (42%) in the placebo group had died (hazard ratio [HR] 0.57, p=0.0002), amounting to a 43% reduction in the risk of death. This benefit applied in children followed up beyond 12 months (n=320, HR 0.48 [0.270.84]) and across all ages and baseline CD4 counts (Chintu 2004).

WHO, UNAIDS and UNICEF recommend that all HIV exposed children (children born to HIV infected mothers) from 4-6 weeks of age (whether or not part of a prevention of mother-to-child transmission [PMTCT] programme) should receive co-trimoxazole, and that any child identified as HIV-infected with any clinical signs or symptoms suggestive of HIV, regardless of age or CD4 count should receive the drug.

Cotrimoxazole is required to be taken as follows:

• in HIV exposed children until HIV infection has been definitively ruled out AND the mother is no longer breastfeeding

• HIV infected children - indefinitely where ARV treatment is not yet available.

• Where ARV treatment is being given - cotrimoxazole can be stopped only once clinical or immunological indicators confirm restoration of the immune system for 6 months or more (also see below). With current evidence it is not yet clear if cotrimoxazole continues to provide protection after immune restoration is achieved.

Dosing and therapeutic drug monitoring

In children, antiretroviral dosage is based on the size or weight of the child or infant. Drug levels in children tend to be lower and more prone to variation than those in adults, which means that therapeutic drug monitoring may have particular benefits in this group. Therapeutic drug monitoring is a blood test which checks that enough drug is present in the blood to suppress HIV.

Metabolism of drugs in children under the age of six years is faster than in adults. For instance, young children metabolise saquinavir, indinavir and nelfinavir faster than adults, meaning that even after adjusting for their lower body weight, they need to be given more drug to achieve the same levels in the blood. This means children may have to consume a lot of drug to ensure adequate drug levels are achieved, further adding to the difficulty of dosing.

For example in the PENTA 7 study of d4T/ddI and nelfinavir in treatment-naïve children, the initial nelfinavir dose of 120mg/kg was increased to 150mg/kg after it became clear that the original dose was producing sub-optimal trough levels.

A recent retrospective study conducted by doctors at St Marys Hospital in London and the North Manchester Hospital involving 74 children who were prescribed nevirapine between 1997 and 1999 found that the pediatric dosage recommended by the manufacturer (120-200 mg/m² twice daily may be a little low. This study reported optimum viral suppression when a daily dosage of 300 mg/m² or above was used (Verweel 2003). The average age of children in this study was five years; given that nevirapine clearance is highest before the age of two years and then falls significantly between 8-12 years, the utility of therapeutic drug monitoring in children taking nevirapine is clear.

Recent data also suggest that children are often given too low doses of antiretroviral drugs. A survey of prescribing in the United Kingdom and Ireland found that children received subtherapeutic doses of anti-HIV drugs between 6 and 62% of the time, depending on which drugs they were taking, but particularly affecting protease inhibitors and non-nucleoside reverse transcriptase inhibitors (NNRTIs). This may result in elevated rates of treatment failure.

The difficulties stem from revisions to dosing recommendations after licensing, drugs being given different dosing strategies for children of different ages and the use of weight bands to determine drugs doses: at the top ends of each weight band, children may be given too low a dose of a drug. Doctors may also fail to increase doses adequately as children grow^[2].

Metabolism begins to slow down as a child matures, in step with the development of an adult immune system, and drug levels become less variable in older children.

Detailed information on dosing for all approved antiretrovirals can be found in the PENTA treatment guidelines.

References

Barigye H et al. The challenges of paediatric ARV formulations in resource-poor countries - the Ugandan experience. Second International AIDS Society Conference on HIV Pathogenesis and Treatment, Paris, abstract 1080, 2003.

Chakraborty R et al. Management of severely immunocompromised human immunodeficiency virus type 1-infected African orphans with structured treatment interruption: another kind of salvage therapy. Clinical Infectious Diseases 36(11): 1483-1485, 2003.

Chintu C et al. Co-trimoxazole as prophylaxis against opportunistic infections in HIV-infected Zambian children (CHAP): a double-blind randomised placebo-controlled trial. The Lancet 364: 1865-71, 2004.

Dunn D et al. HIV Paediatric Prognostic Markers Collaborative Study Group. Short term risk of disease progression in HIV-1 infected children receiving no antiretroviral therapy or zidovudine monotherapy: a meta-analysis. The Lancet 362: 1605-1611, 2003.

Faye A et al. Evaluation of toxicity, tolerability and antiviral activity of early d4T and ddI and nelfinavir therapy in HIV-1 vertically infected infants: 24 week preliminary results from the Penta 7 study. Eighth Annual Conference on Retroviruses and Opportunistic Infections, Chicago, abstract 678, 2001.

Hoffmann F et al. Effect of antiretroviral triple combination including the protease inhibitor nelfinavir in heavily pretreated children with HIV-1 infection. European Journal of Medical Research 7(7): 330-334, 2002.

Kline MW et al. A pilot study of combination therapy with indinavir, d4T and ddI in children infected with HIV-1. Journal of Pediatrics 132: 543-546, 1998.

Krogstad P et al. Treatment of HIV-1 infected infants and children with the protease inhibitor nelfinavir. Clinical Infectious Diseases 28: 1109-1118, 1998.

Luzuriaga K et al. A trial of three antiretroviral regimens in HIV-1-infected children. N Engl J Med 350: 2471-2480, 2004.

Msellati P et al. Highly active antiretroviral therapies among HIV-1-infected children in Abidjan, Cote d'Ivoire (ANRS 1244). Second International AIDS Society Conference on HIV Pathogenesis and Treatment, Paris, abstract 31, 2003.

Paediatric European Network for Treatment of AIDS (PENTA). Comparison of dual nucleoside analogue reverse-transcriptase inhibitor regimens with and without nelfinavir in children with HIV-1 who have not previously been treated: the PENTA 5 randomised trial. The Lancet 359: 733-740, 2002.

Pakker N et al. Antiretroviral treatment for HIV-infected children in Uganda:96 weeks results of the PETRA Plus study. Second International AIDS Society Conference on HIV Pathogenesis and Treatment, Paris, abstract 1088, 2003.

Puthanakit T et al. Efficacy of nevirapine-based HAART among antiretroviral naive HIV-infected children in Thailand. Second International AIDS Society Conference on HIV Pathogenesis and Treatment, Paris, abstract 1081, 2003.

Ramos JT et al. Antiviral response at 12 months to lopinavir-ritonavir (Kaletra) in HIV-infected children experienced with three classes of antiretrovirals. Second International AIDS Society Conference on HIV Pathogenesis and Treatment, Paris, abstract 1096, 2003.

Rutstein RM et al. Protease inhibitor therapy in children with perinatally acquired HIV infection. AIDS 11: F107-111, 1997.

van Rossum AM et al. Therapeutic drug monitoring of indinavir and nelfinavir to assess adherence to therapy in human immunodeficiency virus-infected children. Pediatric Infectious Diseases Journal 21(8): 743-747, 2002.

Sharland M et al. PENTA guidelines for the use of antiretroviral therapy, 2004. HIV Medicine 5 (suppl 2): 61-86, 2004.

Tudor-Williams G et al. Baby cocktail! A protease-sparing 4 drug combination for symptomatic children. XIV International AIDS Conference, Barcelona, abstract MoOrB1129, 2002.

Verweel G et al. Nevirapine use in HIV-1-infected children. AIDS 17: 1639-1647, 2003.

Zar H et al. Early and unexpected benefit of isoniazid in reducing mortality in HIV-infected children in an area of high tuberculosis prevelance. Fifteenth International AIDS Conference, Bangkok, late breaker abstract LbOrB12, 2004.