The US Department of Health and Human Services paediatric guidelines are reviewed on a monthly basis. The summary below is based on the guidelines published in September 2003.

Anti-HIV therapy can only be offered to new-born children if it is known that they have been exposed to HIV i.e. that their mother is HIV-positive. The guidelines point out that "universal HIV counseling and voluntary HIV testing with consent is recommended as standard of care for all pregnant women in the United States".

Testing during pregnancy allows an HIV-infected women to receive the appropriate treatment for her own health, as well as treatment to reduce the risk of mother-to-baby transmission. This is the subject of a separate set of guidelines.

The guidelines state that "If women are not tested during pregnancy, counseling and HIV testing should be recommended during the immediate postnatal period", to allow prompt initiation of postnatal anti-HIV therapy to reduce the risk of HIV infection. PCP prophylaxis is also universally recommended for all children born to HIV-infected women, starting at 4-6 weeks of age.

Diagnosing HIV infection

Tests for antibodies to HIV, including newer rapid tests, cannot determine HIV infection in infants due to the presence of maternal antibodies. The preferred test to establish whether a child is HIV-infected is a PCR test for HIV DNA, the form in which the virus' genetic material is found within infected cells.

HIV status can be determined in virtually all children born to HIV-positive mothers by the age of six months using the PCR DNA test. Thirty-eight percent of infected children test positive by this test during the first 48 hours of life, and 90% test positive at 14 days old. HIV culture tests are similarly effective but more expensive and take longer to provide results.

The guidelines note that standard viral load tests for HIV RNA, the form in which the virus's genetic materiel is found within virus particles, may have difficulty in detecting low levels of virus, and thus should be used with caution as a diagnostic tool in infants. However, some clinicians used the viral load test to confirm a positive DNA test, saving the cost of a second DNA test and helping to guide treatment decisions.

Initial testing is recommended within the first 48 hours of life. Children who test negative at this time-point should be re-tested at 14 days, and those that are still negative should be re-tested at 1 to 2 months, then at 4 to 6 months of age. If a child aged over 6 months has two or more negative antibody tests at least one month apart, and has no symptoms, HIV infection can reasonably be excluded. Antibody testing at 12 months is recommended to check that maternal HIV antibodies have disappeared. If a child retains HIV antibodies at that stage, further investigation is required.

Although the six-week course of AZT given to new infants born to HIV-positive mothers does not seem to affect detection of HIV, the current guidelines acknowledge that short-course combination therapy may reduce the ability of DNA testing to identify infected infants.

Currently available assays may not detect non-B subtypes of HIV and false negative HIV DNA PCR assays have been reported in infants infected with non-subtype B HIV. As a result, repeat testing with newer assays is recommended in infants suspected of infection with non-B subtypes.

Monitoring tests

Healthy children normally have higher CD4 counts than adults. The CDC has developed a staging system which, dividing children into different age categories, defines which CD4 count levels are associated with no immunosuppression, moderate immunosuppression or severe immunosuppression. Alternatively, CD4 percentages can be used without needing adjustment for age. For details, see the section Children: Centers for Disease Control and Prevention classification, 1994 in Introduction to HIV and AIDS: Definitions.

Among newly HIV-infected adults, HIV viral load initially rises to very high levels, falling to a much lower stable level (the 'set-point') after six to 12 months. Newly infected children tend to maintain high viral load levels for a longer period; in one study, the average viral load during the first year of life was 185,000. Then HIV RNA numbers slowly decline over the next few years of life.

The generally high level of viral load in infants makes predicting the risk of disease progression and death for an individual child from viral load very difficult. "Despite data indicating that high RNA levels are associated with disease progression, the predictive value of specific HIV RNA levels for disease progression and death for an individual child is moderate. HIV RNA levels may be difficult to interpret during the first year of life, because levels are high and there is marked overlap in levels between children who have and those who do not have rapid disease progression."

Some studies have suggested that viral loads over 100,000 or 300,000 copies/ml may be linked to disease progression but the guidelines state that consideration of CD4 percentage in combination with viral load is the best way to assess risk of progression in young children.

In a discussion of the differences between different commercial viral load tests, the guidelines point out that "Choice of HIV RNA assay, particularly for young children, may be influenced by the amount of blood required for the assay". The NASBA assay requires the least amount of blood (100 µl), while the Amplicor HIV-1 Monitor needs 200 µl and the Quantiplex uses 1 ml.

Starting treatment

Anti-HIV therapy is recommended for children who have either clinical symptoms related to HIV infection or evidence of immune suppression (CD4%<25%). Consideration of therapy is also recommended for HIV-infected infants under age 12 months who are asymptomatic and have normal immune parameters.

The guidelines state: " Because of the high risk for rapid progression of HIV disease, many experts would treat all HIV-infected infants < 12 months old, regardless of clinical, immunologic, or virologic parameters. Other experts would treat all infected infants < 6 months old, and use clinical and immunologic parameters and assessment of adherence issues for decisions regarding initiation of therapy in infants 6 to 12 months of age." The difficulty in assessing infants at risk of disease progression by viral load, the difficulty of pediatric dosing, and the risk of toxicity all inform consideration of treatment. Advanced disease in the mother may also predict progression in the infant, and may also inform the decision to treat.

For children aged over twelve months, treatment is recommended when a child has clinical symptoms of HIV or a CD4 percentage below 15%. Consideration of treatment is recommended for children with symptoms of mild-moderate immunosuppression or a CD4 percentage between 15 and 25% or a viral load over 100,000 copies/ml.

For asymptomatic children with normal CD4 percentages and viral load below 100,000 copies/ml, most experts recommend close monitoring in the absence of treatment.

The potential advantages of early treatment include a lower viral 'set point', fewer mutant viral strains, slower immune system destruction and prevention of clinical disease progression. On the other hand, delaying therapy until the appearance of clinical or immunologic symptoms of disease may result in reduced drug resistance, greater adherence to therapy, and reduced or delayed adverse effects of antiretroviral therapy.

Recommended regimens

Recommendations on the best initial therapy for children are regularly modified as new data, new therapies and new formulations become available.

Various factors influence these recommendations: antiviral potency; incidence and type of toxicities; availability of pediatric formulations, dosing information and palatability; dosing frequency; food and fluid requirements, and the potential for drug interactions.

US guidelines published in September 2003 make the following recommendations about initial therapy in HIV-positive children.

Strongly recommended initial regimen in children:

• Ritonavir-boosted lopinavir (Kaletra), nelfinavir or ritonavir plus two NRTIs.

• Efavirenz (for children over 3 years) plus two NRTIs.

• Nevirapine (children under 3 years or those who cannot swallow capsules) plus two NRTIs.

• Strongly recommended NRTIs: AZT plus 3TC, AZT plus ddI and d4T plus 3TC.

Alternatives:

• Nevirapine (for children over 3 years) + 2 NTRIs.

• Amprenavir (for children over 4 years) or indinavir + 2 NRTIs.

• Triple NRTI regimen: abacavir/AZT/3TC.

• Alternative NRTIs: AZT/abacavir, 3TC/abacavir and ddI/3TC.

Other recommendations:

• Special circumstance NRTI backbones: d4T plus ddI and AZT plus ddC.

• Not recommended: any monotherapy or the following combinations: d4T plus AZT, ddC plus ddI, ddC plus d4T, ddC plus 3TC and saquinavir plus two NRTIs

• Not yet recommended in children due to insufficient data: delavirdine plus two NRTIs; dual protease regimens except Kaletra; regimens containing FTC (emtricitabine, Emtriva), tenofovir (Viread), T-20 (enfuvirtide, Fuzeon) or atazanavir (Reyataz).

Finally, the guidelines note that "Data do not suggest that the antiretroviral regimen for infected infants should routinely be chosen on the basis of maternal antiretroviral use" although some infants do contract a viral type with mutations which confer resistance to antiviral drugs the mother was taking during pregnancy. As a result, the guidelines recommend "consideration of resistance testing prior to initiation of therapy in newly diagnosed infants under age 12 months, particularly if the mother has known or suspected infection with drug-resistant virus. There are no definitive data that demonstrate that resistance testing in this setting correlates with greater success of initial antiretroviral therapy, however."

Adherence

Children's adherence to medication presents particular difficulties. The guidelines survey these issues and then make the following directives: "A comprehensive assessment of adherence issues should be instituted for all children in whom antiretroviral treatment is considered; evaluations should include nursing, social, and behavioral assessments. Intensive follow-up is required particularly during the critical first few months after therapy is started; patients should be seen frequently to assess adherence, drug tolerance, and virologic response. Coordinated, comprehensive, family-centered systems of care often can address many of the daily problems facing families that may affect adherence to complex medical regimens."

Adherence to medication by adolescents also raises specific care issues. Treatment regimens for adolescents must balance the goal of prescribing a maximally potent antiretroviral regimen with realistic assessment of existing and potential supports to facilitate adherence.

Changing therapy

The main reasons for changing therapy are:

• Failure of the current regimen with evidence of disease progression based on virologic, immunologic or clinical parameters.

• Toxicity or intolerance to the current regimen.

• New data demonstrating that a drug or regimen is superior to the current regimen.

Assessment of adherence to medication is recommended before changing therapy, as a response may be the result of lapses in adherence.

The advice on using viral load changes to guide treatment modifications in children is slightly different from adults. Virologic indications for considering a change include:

• Less than a minimally acceptable fall in viral load after eight to twelve weeks of treatment (at least 1 log₁₀ for aggressive triple therapy).

• Failure to suppress viral load to below detection after four to six months of treatment. Suppression is not always achievable in children, and baseline viral load and available alternative regimens may influence a decision to change therapy. Treatment may not be changed if there had been a sustained 1.5 to 2.0 log₁₀ reduction in viral load.

• Detectable viral load in children who initially had undetectable levels in response to antiretroviral therapy. If viral load increase is limited (i.e. below 5000 copies/ml), a change in treatment may be delayed. If viral load is repeatedly detectable or increasing, drug resistance may be present.

• An increase in viral load among children who have had a substantial response to treatment (i.e. for children over 2 years, a greater than threefold or 0.5 log₁₀ increase or a greater than fivefold or 0.7 log₁₀ increase in children aged under 2 years.

Other indications for considering a change in therapy include immunological decline, such as a significant fall in CD4 cell count or percentage, and clinical progression such as neurodevelopmental deterioration, growth failure or progression to a more advanced clinical disease category.

Reasons for treatment failure should be fully investigated before changing therapy. Adherence, low drug exposure due to drug interactions or failure to comply with dosing instructions (e.g. dosing with food) and drug resistance should be considered. When high levels of adherence are established, testing for drug resistance should be conducted.

When choosing a new regimen, the doctor, family and child (where appropriate) should discuss issues such as adherence, dosing frequency and requirements, side-effects, palatability, pill size, and pill number associated with proposed new regimens. Many other issues to be considered when changing therapy are the same as in adults, as summarised earlier in this section.

Full text on the Internet

The full text of the United States guidelines is available at: http://www.aidsinfo.nih.gov/guidelines.