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Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection

Immunologic Monitoring in Children 

Clinicians interpreting CD4 T lymphocyte (CD4 cell) counts in children must consider age as a factor. CD4 cell count and percentage values in healthy infants who are HIV-uninfected are considerably higher than values observed in uninfected adults and slowly decline to adult values by age 5 years.^1,2 In children younger than age 5 years, the absolute CD4 cell count tends to vary more with age than does CD4 percentage. Therefore, in HIV-infected children younger than age 5 years, CD4 percentage has generally been preferred for monitoring immune status, whereas absolute CD4 cell count has been the preferred option and is used for children ≥5 years and can be used in younger children if CD4 percentage is not available.^3-5 However, an analysis from the HIV Paediatric Prognostic Markers Collaborative Study (HPPMCS) found that CD4 percentage provided little or no additional prognostic value compared with absolute CD4 cell regarding short-term disease progression in children <5 years as well as in older children.⁶ Therefore, the pediatric guidelines include CD4 cell count thresholds as well as CD4 percentage thresholds for initiation of treatment in all children >12 months of age. In the case of discordance between CD4 percentage and absolute CD4 cell count, treatment decisions should be based on the lower value.⁶

In HIV-infected children, as in infected adults, the CD4 cell count and percentage decline as HIV infection progresses, and patients with lower CD4 values have a poorer prognosis than patients with higher values (Tables 3–5). Consequently, CD4 values should be obtained as soon as possible after a child has a positive test for HIV and every 3 to 4 months thereafter. Less frequent monitoring has been proposed for adults with high CD4 cell counts, but this has not been modeled for children in whom the risk of disease progression may differ substantially.⁷ More frequent evaluation may be needed for children with suspected clinical, immunologic, or virologic deterioration; to confirm an abnormal value; or when initiating or changing therapy. Because of the risk of rapid progression, initiation of antiretroviral therapy (ART) is now recommended for all HIV-infected infants younger than age 12 months^8,9 (see When to Initiate Therapy in Antiretroviral-Naive Children).

The prognostic value of CD4 percentage and HIV RNA copy number was assessed in a large individual patient meta-analysis (HPPMCS), which incorporated clinical and laboratory data from 17 pediatric studies and included 3,941 HIV-infected children receiving either no therapy or only zidovudine monotherapy.⁴ The analysis looked at the short-term (12-month) risk of developing AIDS or dying based on the child’s age and selected values of CD4 percentage and HIV RNA copy number at baseline. Figures 1 and 2 and Table 3 depict age-associated 1-year risk of developing AIDS or dying as a function of CD4 percentage. In a separate analysis of this data set, predictive value of absolute CD4 cell count for risk of death or AIDS/death in HIV-infected children age 5 years or older was similar to that observed in young adults, with an increase in the risk of mortality when CD4 cell count fell below 350 cells/mm³ (Table 4 and Figure 3).^3,10

The risk of disease progression associated with a specific CD4 percentage or count varies with the age of the child. Infants in the first year of life experience higher risks of progression or death than older children for any given CD4 stratum. For example, comparing a 1-year-old child with a CD4 percentage of 25% to a 5-year-old child with the same CD4 percentage, there is an approximately fourfold increase in the risk of AIDS and sixfold increase in the risk of death in the 1-year-old child (Figures 1 and 2). Children aged 5 years or older have a lower risk of progression than younger children, with the increase in risk of AIDS or death corresponding to absolute CD4 levels more similar to those in young adults (Figure 3). In the HPPMCS, there were no deaths among children 5 years of age or older with CD4 cell counts >350 cells/mm³, although in younger children there continued to be a significant risk of death even with CD4 cell counts >500 cells/mm³ (Table 4).

These risk profiles form the rationale for recommendations on when to initiate therapy in a treatment-naive HIV-infected child (see When to Initiate Therapy in Antiretroviral-Naive Children). A website using the meta-analysis from the HPPMCS is available to estimate the short-term risk of progression to AIDS or death in the absence of effective ART according to age and the most recent CD4 percentage/absolute CD4 cell count or HIV-1 RNA viral load measurement (http://hppmcs.org). ⁴

Measurement of CD4 values can be associated with considerable intrapatient variation.⁵ Even mild intercurrent illness or the receipt of vaccinations can produce a transient decrease in CD4 cell count and percentage, thus, CD4 values are best measured when patients are clinically stable. No decision about therapy should be made in response to a change in CD4 values until the change has been substantiated by at least a second determination, with a minimum of 1 week between measurements.

HIV RNA Monitoring in Children

Viral burden in peripheral blood can be determined by using quantitative HIV RNA assays. During the period of primary infection in adults, HIV RNA copy number initially rises to high peak levels and then declines by as much as 2 to 3 log₁₀ copies to reach a stable lower level (the virologic set point) approximately 6 to 12 months after acute infection.^11,12 In infected adults, the viral set point correlates with the subsequent risk of disease progression or death.¹³

The HIV RNA pattern in perinatally infected infants differs from that in infected adults and adolescents. High HIV RNA copy numbers persist in infected children for prolonged periods.^14,15 In one prospective study, HIV RNA levels generally were low at birth (i.e., <10,000 copies/mL), increased to high values by age 2 months (most infants had values >100,000 copies/mL, ranging from undetectable to nearly 10 million copies/mL), and then decreased slowly; the mean HIV RNA level during the first year of life was 185,000 copies/mL.¹⁶ In addition, in contrast to the adult pattern, after the first year of life, HIV RNA copy number slowly declines over the next few years.^16-19 This pattern probably reflects the lower efficiency of an immature but developing immune system in containing viral replication and possibly the rapid expansion of HIV-susceptible cells that occurs with somatic growth.²⁰

HIV RNA levels (i.e., >299,000 copies/mL) in infants younger than age 12 months have been correlated with disease progression and death, but RNA levels overlap considerably in young infants who have rapid disease progression and those who do not.^14,16 RNA levels (that is, >100,000 copies/mL) in older children also have been associated with high risk of disease progression and mortality, particularly if CD4 percentage is <15% (Table 5).^18,19 The most robust data set available to elucidate the predictive value of plasma RNA for disease progression in children was assembled in the HPPMCS (see Immunologic Monitoring in Children).⁴ As for CD4 percentage, analyses were performed for age-associated risk in the context of plasma RNA levels in a cohort of children receiving either no therapy or only zidovudine monotherapy. Similar to data from previous studies,18,19 the risk of clinical progression to AIDS or death dramatically increases when HIV RNA exceeds 100,000 copies (5.0 log₁₀ copies)/mL; at lower values, only older children show much variation in risk (Figures 4 and 5 and Table 3). At any given level of HIV RNA, infants younger than 1 year of age were at higher risk of progression than older children, although these differences were less striking than those observed for the CD4 percentage data.

Despite data indicating that high plasma HIV RNA concentrations are associated with disease progression, the predictive value of specific HIV RNA concentrations for disease progression and death for an individual child is moderate.¹⁸ HIV RNA concentration may be difficult to interpret during the first year of life because values are high and are less predictive of disease progression risk than in older children.¹⁵ In both HIV-infected children and adults, CD4 percentage or count and HIV RNA copy number are independent predictors of disease progression and mortality risk, and use of the two markers together more accurately defines prognosis.^18,19,21,22

HIV RNA copy number should be assessed as soon as possible after a child has a positive virologic test for HIV and every 3 to 4 months thereafter; more frequent evaluation may be necessary for children experiencing virologic, immunologic, or clinical deterioration or to confirm an abnormal value (see Management of Treatment-Experienced Infants, Children, and Adolescents).

Note that it is recommended that genotypic resistance testing be obtained before initiating ART and it is often performed in this monitoring period before a child qualifies for therapy (see Monitoring of Children on Antiretroviral Therapy).

Methodological Considerations in Interpretation and Comparability of HIV RNA Assays
The use of HIV RNA assays for clinical purposes requires specific considerations,²³ which are discussed more completely elsewhere.²⁴ Several different methods can be used for quantitating HIV RNA, each of which has a different level of sensitivity. Although the results of the assays are correlated, the absolute HIV RNA copy number obtained from a single specimen tested by two different assays can differ by twofold (0.3 log₁₀ copies/mL) or more.^25,26

 Six Food and Drug Administration (FDA)-approved viral load assays using one of four different methodologies currently exist:

• HIV-1 reverse transcriptase (RT) quantitative polymerase chain reaction (PCR) assays: the Amplicor HIV-1 Monitor Test, version 1.5 (Roche Diagnostics), for which the lower limit of quantification differs between the “ultrasensitive” assay (<50 copies/mL) and the “regular sensitivity” assay (<400 copies/mL); the AmpliPrep/TaqMan HIV-1 Test, including the COBAS automated format (Roche Diagnostics); and the Real Time HIV-1 Assay (Abbott Molecular Incorporated);
• HIV-1 nucleic acid sequence-based amplification test (NucliSens HIV-1 QT, bioMerieux);
• HIV-1 in vitro signal amplification, branched chain nucleic acid probe assay (VERSANT Quantiplex HIV-1 RNA 3.0 Assay, Bayer Corporation); and
• Aptima HIV-1 RNA Qualitative assay (Gen-Probe Inc., San Diego, CA), primarily used for HIV diagnosis, as well as detection of less than full viral suppression during therapy.

The lower limits of quantification of the assays differ (<40 copies/mL for the Abbott Real Time HIV-1 test, <48 copies/mL for the AmpliPrep/TaqMan HIV-1 Test, <50 copies/mL for the Amplicor HIV-1 Monitor Test, <80 copies/mL for the NucliSens HIV-1 QT assay, and <75 copies/mL for the VERSANT assay). Use of ultrasensitive viral load assays is recommended to confirm that ART is producing maximal suppression of viremia. Because of the variability among assays in techniques and quantitative HIV RNA measurements, if possible, a single HIV RNA assay method should be used consistently to monitor an individual patient.^27,28

The predominant virus subtype in the United States is subtype B—the subtype for which all initial assays were targeted. Current kit configurations for all companies have been designed to detect and quantitate essentially all viral subtypes, with the exception of the uncommon O subtypes.^29,30 This is important for many regions of the world where non-B subtypes are predominant as well as for the United States, where a small subset of individuals are infected with non-B viral subtypes.^27,31-35 It is particularly relevant for children who are born outside the United States or to foreign-born parents. Choice of HIV RNA assay, particularly for young children, may be influenced by the amount of blood required for the assay. The NucliSens assay requires the least blood (100 µL of plasma), followed by the RT-PCR assays such as the Amplicor HIV-1 Monitor (200 µL of plasma) and VERSANT assays (1 mL of plasma).

Biologic variation in HIV RNA levels within one person is well documented. In adults, repeated measurement of HIV RNA levels using the same assay can vary by as much as threefold (0.5 log₁₀ copies/mL) in either direction over the course of a day or on different days.^21,24,26 This biologic variation may be greater in infected infants and young children. In children with perinatally acquired HIV infection, RNA copy number slowly declines even without therapy during the first several years after birth, although it persists at higher levels than those observed in most infected adults.^16-18 This decline is most rapid during the first 12 to 24 months after birth, with an average decline of approximately 0.6 log₁₀ copies/mL per year; a slower decline continues until approximately 4 to 5 years of age (average decline of 0.3 log₁₀ copies/mL per year).

This inherent biologic variability must be considered when interpreting changes in RNA copy number in children. Thus, on repeated testing, only differences greater than fivefold (0.7 log₁₀ copies/mL) in infants younger than age 2 years and greater than threefold (0.5 log₁₀ copies/mL) in children aged 2 years and older should be considered reflective of changes that are biologically and clinically substantial.

No alteration in therapy should be made as a result of a change in HIV copy number unless the change is confirmed by a second measurement. Because of the complexities of HIV RNA testing and the age-related changes in HIV RNA in children, interpretation of HIV RNA levels for clinical decision making should be done by or in consultation with an expert in pediatric HIV infection.

Table 3. Likelihood of Developing AIDS or Death Within 12 Months, by Age and CD4 T-Cell Percentage or Log₁₀ HIV-1 RNA Copy Number in HIV-Infected Children Receiving No Therapy or Zidovudine Monotherapy
Click here to view this table as an image 

Table modified from: HIV Paediatric Prognostic Markers Collaborative Study Group. Lancet. 2003;362:1605-1611.

Table 4. Death and AIDS/Death Rate per 100 Person-Years by Current Absolute CD4 Cell Count and Age in HIV-Infected Children Receiving No Therapy or Zidovudine Monotherapy (HIV Paediatric Prognostic Markers Collaborative Study) and Adult Seroconverters (CASCADE Study)

References

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