Detailed guidelines for the treatment of infants and children in resource-limited settings have been issued this week by the World Health Organization ahead of the World AIDS Conference next week in Toronto.
The guidelines highlight the difficulties in determining drug doses for children, and urge pharmaceutical companies to work towards producing fixed dose combinations that can be used to treat children.
They also urge national governments to invest in better methods for diagnosing HIV infection in children below 18 months, where diagnosis with HIV antibody tests is complicated by the presence of maternal antibodies in the infant’s bloodstream.
WHO wants national governments to strengthen laboratory capacity so that they can use real-time PCR testing to detect genetic material from the virus itself (HIV RNA or DNA), rather than having to wait until a child is 18 months old.
But the guidelines point out that while HIV antibody testing can’t be used to diagnose HIV definitively before 18 months of age, it can be used to rule out HIV infection as early as 9-12 months of age if they are not breastfed or ceased breastfeeding more than six weeks before the antibody test, as most uninfected HIV-exposed infants have lost maternal antibody by the age of 12 months. A positive test at this point in an asymptomatic child should be confirmed at 18 months of age.
Virological testing to detect HIV should also wait for at least six weeks after breastfeeding ceases, the WHO expert panel concluded, except in children whose mothers are receiving antiretroviral therapy. In these infants, virological testing can be carried out while breastfeeding continues.
Where virological testing is not available clinical signs of HIV disease will continue to be the main means of diagnosis in children under the age of 18 months, but the WHO guidelines warn that clinical algorithms are rarely more than 70% sensitive and are least reliable in children below the age of 12 months, underscoring the need for diagnostic alternatives that can be used in children below the age of 18 months where laboratory facilities are limited or non-existent.
A presumptive diagnosis can be made in children below the age of 18 months if:
- the child is confirmed as HIV-positive
- and diagnosis of an AIDS indicator condition can be made or the infant is symptomatic with two or more of the following: oral thrush, severe pneumonia or severe sepsis.
All children below the age of 12 months with symptoms of advanced or severe HIV disease should receive antiretroviral treatment because the risk of death is so high; children with advanced symptomatic HIV disease (WHO stage 3) above the age of 12 months may not require treatment if their immunodeficiency is less advanced. The recommended threshold for starting treatment is a CD4 percentage below 20 in children aged 12-35 months,
In children, first-line treatment should consist of AZT (zidovudine) and 3TC (lamivudine) or d4T (stavudine) plus 3TC or abacavir plus 3TC together with either nevirapine or efavirenz. In children below the age of three years nevirapine should be used because appropriate weight-related dosing has not been determined for efavirenz. A triple nucleoside regimen of AZT/3TC/abacavir may also be used, particularly in children receiving treatment with rifampicin for TB.
The guidelines note that large volumes of AZT liquid formula are poorly tolerated, and that although d4T is better tolerated, it carries a long-term risk of lipoatrophy in children. Tenofovir, now recommended for first-line treatment in adults, is not available in a paediatric formulation and dosing studies of the tablet formulation have not been carried out in children.
Fixed dose triple combinations for children containing nevirapine are being developed by several Indian companies and are expected to be approved within the next year.
Detailed dosing tables for all drugs according to weight are available within the guidelines document.
The guidelines say that for children exposed to antiretrovirals around the time of birth as part of prevention of mother to child transmission, it is still too early to say whether drug resistance acquired during short-term exposure will compromise the paediatric response to antiretroviral therapy. Ongoing trials in South Africa and Botswana may provide an answer, WHO says. Continuing exposure to antiretrovirals in breast milk should not affect the choice of treatment for a breastfeeding infant that requires treatment.
For children experiencing failure of first-line treatment, second-line treatment should consist of ddI and abacavir unless abacavir was used in first-line treatment, plus either lopinavir/ritonavir (Kaletra), saquinavir/ritonavir (Invirase) or nelfinavir (Viracept).
Nutritional support recommended
WHO points out that children and infants who have symptomatic HIV disease or who are recovering from an acute infection need to consume 20-30% more calories than HIV-negative children if they are not suffer poor growth and poor recovery from illness.
Since severe wasting is a common clinical presentation in children with HIV infection, the guidelines advise that severe malnutrition needs to be stabilised before antiretroviral therapy is begun. Although this phase shouldn’t take longer than ten days in HIV-negative children, the guidelines warn that the response to malnutrition treatment may be limited and slow in HIV-positive children. If after six to eight weeks a child has not achieved a weight for height of 85% as a result of special feeding, antiretroviral therapy should probably be initiated.
Once a child begins to gain weight on antiretroviral treatment, drug doses need to be reviewed regularly to ensure that the child is still receiving an adequate dose, WHO warns. Conversely, there are no available data on the effectiveness, pharmacokinetics and safety of antiretrovirals in severely malnourished children, so it is not known what doses are necessary in children who are seriously underweight for their age (drug metabolism is governed by age as well as body size).
The guidelines also contain detailed discussion of monitoring protocols for children with HIV, as well as considerations for antiretroviral therapy in adolescents and methods for judging treatment failure in children where virological monitoring is not available.
The full guidelines document can be downloaded from the WHO website at http://www.who.int/hiv/pub/guidelines/art/en/index.html