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Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection
Clinical and Laboratory Monitoring of Pediatric HIV Infection
(Last updated: February 12, 2014; last reviewed: February 12, 2014)
CD4 T lymphocyte (CD4) percentage is generally preferred for monitoring immune status in children younger than age 5 years because of age-related changes in absolute CD4 cell count; however, absolute CD4 count may also be used (AII).
CD4 cell count/percentage and plasma HIV RNA (viral load) should be measured at the time of diagnosis of HIV infection and at least every 3 to 4 months thereafter for children not on combination antiretroviral therapy (cART) (AIII).
More frequent CD4 cell count/percentage and plasma viral load monitoring should be considered in children with suspected clinical, immunologic, or virologic deterioration or to confirm an abnormal value (AIII).
After initiation of cART (or after a change in cART regimen), children should be evaluated for clinical side effects and to support treatment adherence within 1 to 2 weeks, with laboratory testing for toxicity and viral load response recommended at 2-4 weeks after treatment initiation (AIII).
Children on cART should have evaluation of therapy adherence, effectiveness (by CD4 cell count/percentage and plasma viral load), and toxicities (by history, physical, and selected laboratory tests) routinely be assessed every 3 to 4 months. (AII*).
CD4 cell count/percentage can be monitored less frequently (every 6–12 months) in children and youth who are adherent to therapy and have CD4 cell value well above the threshold for opportunistic infection risk, sustained viral suppression, and stable clinical status for more than 2 to 3 years (BII).
Rating of Recommendations: A = Strong; B = Moderate; C = Optional Rating of Evidence: I = One or more randomized trials in children† with clinical outcomes and/or validated endpoints; I* = One or more randomized trials in adults with clinical outcomes and/or validated laboratory endpoints with accompanying data in children† from one or more well-designed, nonrandomized trials or observational cohort studies with long-term clinical outcomes; II = One or more well-designed, nonrandomized trials or observational cohort studies in children† with long-term outcomes; II* = One or more well-designed, nonrandomized trials or observational studies in adults with long-term clinical outcomes with accompanying data in children† from one or more similar nonrandomized trials or cohort studies with clinical outcome data; III = expert opinion † Studies that include children or children/adolescents, but not studies limited to post-pubertal adolescents
Laboratory monitoring of HIV-infected children poses unique and challenging issues. In particular, normal ranges and the value of CD4 T lymphocyte (CD4) cell count and plasma HIV-1 RNA concentration (viral load) for prediction of risk of disease progression varies significantly by age. This section will address immunologic, virologic, and general laboratory monitoring of HIV-infected children, relevant to both those who are and are not receiving combination antiretroviral therapy (cART).
Immunologic Monitoring in Children: General Considerations
Clinicians interpreting CD4 cell count and percentage 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 for children aged ≥5 years, although CD4 cell count can be used in younger children if CD4 percentage is not available.3-5 An analysis from the HIV Paediatric Prognostic Markers Collaborative Study (HPPMCS) found that CD4 percentage provided little or no additional prognostic value compared with CD4 cell count regarding short-term disease progression in children aged <5 years as well as in older children,6 and either or both can be used in decisions on when to initiate cART (see When to Initiate).
In HIV-infected children, as in infected adults, the CD4 cell count and percentage decline as HIV infection progresses and patients with lower CD4 cell count/percentage values have a poorer prognosis than patients with higher values (see Tables A-C in Appendix C: Supplemental Information).
The prognostic value of CD4 cell count and percentage, and plasma viral load 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 a child’s age and selected values of CD4 cell count or percentage and plasma viral load at baseline (see Figures A and B and Table A in Appendix C: Supplemental Information). In a separate analysis of this dataset, predictive value of CD4 cell count for risk of death or AIDS/death in HIV-infected children aged 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 (see Figure C and Table B in Appendix C: Supplemental Information).3,7
The risk of disease progression associated with a specific CD4 cell count or percentage 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 six fold increase in the risk of death in the 1-year-old child (see Figures A and B in Appendix C: Supplemental Information). 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 CD4 cell count more similar to those in young adults (see Figure C and Table B in Appendix C: Supplemental Information). In the HPPMCS, there were no deaths among children aged 5 years or older with CD4 cell count >350 cells/mm3, although in younger children there continued to be a significant risk of death even with CD4 cell count >500 cells/mm3 (see Table B in Appendix C: Supplemental Information).
These risk profiles contribute to the rationale for recommendations on when to initiate therapy in a treatment-naive HIV-infected child (see When to Initiate). 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 cART 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 cell count and percentage can be associated with considerable intrapatient variation.5 Mild intercurrent illness or the receipt of vaccinations can produce a transient decrease in CD4 cell count and percentage, thus, CD4 cell count/percentage are best measured when patients are clinically stable. No decision about therapy should be made in response to a change in CD4 cell count/percentage 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: General Considerations
Quantitative HIV-1 RNA assays measure the plasma concentration of HIV RNA as copies/mL, commonly referred to as the plasma viral load. During the period of primary infection in adults and adolescents, in the absence of therapy, plasma viral load 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.8,9 In infected adults, the stable lower level (or viral set point) correlates with the subsequent risk of disease progression or death in the absence of therapy.10
The pattern of change in plasma viral load in untreated perinatally infected infants differs from that in infected adults and adolescents. High plasma viral load persists in untreated infected children for prolonged periods.11,12 In one prospective study of infants with perinatal infection born prior to antiretroviral (ARV) availability in children, plasma viral loads 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, with a mean plasma viral load during the first year of life of 185,000 copies/mL.13 After the first year of life, plasma viral load slowly declined over the next few years.13-16 Viral load during the first 12 to 24 months after birth showed an average decline of approximately 0.6 log10 copies/mL per year, followed by an average decline of 0.3 log10 copies/mL per year until age 4 to 5 years. 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.17
High plasma viral load (i.e., >299,000 copies/mL) in infants younger than age 12 months has been correlated with disease progression and death, but the range of plasma viral loads overlap considerably in young infants who have rapid disease progression and those who do not.11,13 Plasma viral load >100,000 copies/mL in older children also has been associated with high risk of disease progression and mortality, particularly if CD4 percentage is <15% (see Table C in Appendix C: Supplemental Information).15,16 The most robust data set available to elucidate the predictive value of plasma viral load for disease progression in children was assembled in the HPPMCS4 (see Immunologic Monitoring in Children: General Considerations) in children on no therapy or only zidovudine monotherapy, which showed that the risk of clinical progression to AIDS or death dramatically increases when viral load exceeds 100,000 copies (5.0 log10 copies)/mL; at lower values, only younger children show much variation in risk (see Figures D and E and Table A in Appendix C: Supplemental Information). At any given viral load, infants younger than aged 1 year 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 viral load is associated with disease progression, the predictive value of specific HIV RNA concentrations for disease progression and death for an individual child is moderate.15 Plasma viral load 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.12 In both HIV-infected children and adults, CD4 cell count or percentage and plasma viral load are independent predictors of disease progression and mortality risk, and use of the two markers together more accurately defines prognosis.15,16,18,19
Methodological Considerations in Interpretation and Comparability of HIV RNA Assays
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.20,21
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 in vitro signal amplification, branched chain nucleic acid probe assay (VERSANT HIV-1 RNA 3.0 Assay [bDNA], Siemens); 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 (less than 40 copies/mL for the Abbott Real Time HIV-1 test, less than 20 copies/mL for the AmpliPrep/TaqMan HIV-1 Test/Version 2, less than 50 copies/mL for the Amplicor HIV-1 Monitor Test, less than 20 copies/mL for the NucliSENS EasyQ® HIV-1 v2.0, and less than 50 copies/mL for the VERSANT assay). Use of ultrasensitive viral load assays is recommended to confirm that cART 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.22-24
The predominant HIV-1 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.25,26 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.22,27-31 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 plasma viral load within one person is well documented. In adults, repeated measurement of plasma viral load 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.18,21 This biologic variation may be greater in infected infants and young children. This inherent biologic variability must be considered when interpreting changes in plasma viral load 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 plasma viral load changes that are biologically and clinically substantial.
No clinical decisions should be made as a result of a change in plasma viral load unless the change is confirmed by a second measurement. Interpretation of plasma viral load for clinical decision making should be done by or in consultation with an expert in pediatric HIV infection because of the complexities of HIV RNA testing and the age-related changes in plasma viral load in children.
Based on accumulated experience with currently available assays, viral suppression is currently defined as a plasma viral load below the detection limit of the assay used (generally <20 to 75 copies/mL). This definition of suppression has been much more thoroughly investigated in HIV-infected adults than in HIV-infected children (see the Adult and Adolescent Antiretroviral Guidelines).32 Temporary viral load elevations (“blips”) between the level of detection and 500 copies/mL often are detected in adults33 and children on cART and should not be considered to represent “virologic failure” as long as the values return to below the level of detection at the time of repeat testing. For definitions and management of virologic treatment failure, see Recognizing and Managing Antiretroviral Treatment Failure in Management of Children Receiving Antiretroviral Therapy. These definitions of viral suppression and virologic failure are recommended for clinical use. Research protocols or surveillance programs may use different definitions.
Clinical and Laboratory Monitoring of Children with HIV Infection
Table 3 provides one proposed general monitoring schedule, which should be adjusted based on the specific cART regimen a child is receiving.
Entry into Care—Baseline Evaluation
At entry into care, HIV-infected children should have a complete age-appropriate medical history, physical examination, and laboratory evaluation (see Table 3). This should include a general medical and social history (e.g., immunizations, nutrition, physical and social environment), evaluation for HIV-specific physical conditions (e.g., growth delay, microcephaly, motor or cognitive neurologic problems), evaluation for HIV-associated laboratory abnormalities (e.g., anemia, leukopenia, thrombocytopenia, elevated glucose, transaminases or creatinine, hypoalbuminemia), and assessment of presence or risk of opportunistic infections (see the Pediatric Opportunistic Infections Guidelines).
Laboratory confirmation of HIV infection should be obtained if available documentation is incomplete (see Diagnosis of HIV Infection). CD4 cell count and percentage, as well as plasma HIV RNA measurements (i.e., viral load), should be obtained at entry into care to help guide decisions about timing of cART initiation (see When to Initiate). Genotype resistance testing should be performed, even if cART is not initiated immediately. For patients previously treated with ARV drugs, resistance evaluation requires a complete ARV history (see Antiretroviral Drug-Resistance Testing).
Monitoring of Children Not Receiving Antiretroviral Therapy
Children not receiving cART should be evaluated every 3 to 4 months with measurement of CD4 cell count and percentage, and plasma viral load; evaluation of growth and development for signs of HIV-associated change; and laboratory evaluation for HIV-associated conditions including anemia, leukopenia, thrombocytopenia, elevated glucose, transaminases, or creatinine, and hypoalbuminemia. Urinalysis should be obtained every 6 to 12 months to monitor for HIV-associated nephropathy. Opportunistic infection monitoring should follow guidelines appropriate for the child’s exposure history and clinical setting (see the Pediatric Opportunistic Infection Guidelines).
More frequent evaluation may be necessary for children experiencing virologic, immunologic, or clinical deterioration or to confirm an abnormal value.
Initiation of Combination Antiretroviral Therapy—Overview
Children who start cART or who change to a new regimen should be followed to assess effectiveness, tolerability, and side effects of the regimen and to evaluate medication adherence. Frequent patient visits and intensive follow-up during the initial months after a new ARV regimen is started are necessary to support and educate the family. The first few weeks of cART can be particularly difficult for children and their caregivers; they must adjust their schedules to allow for consistent and routine administration of medication doses. Children may also experience side effects of medications, and both children and their caregivers need assistance to determine whether the effects are temporary and tolerable or are more serious or long-term and require a visit to the clinician. It is critical that providers speak to caregivers and children in a supportive, non-judgmental manner using layman’s terms. This promotes honest reporting and ensures dialogue between providers and both children and their caregiver(s), even when medication adherence is reported to be inconsistent.
Monitoring of Children Receiving Antiretroviral Therapy
Within 1 to 2 weeks of initiating therapy, children should be evaluated either in person or by phone to identify clinical side effects and to support adherence. Many clinicians plan additional contacts (in person or by telephone) with children and caregivers to support adherence during the first few weeks of therapy.
2 to 4 Weeks after Initiation of cART
While data are limited on which to base an exact recommendation about precise timing, most experts recommend laboratory testing at 2 to 4 weeks (and not more than 8 weeks) after initiation of cART to assess virologic response and laboratory toxicity. Laboratory chemistry tests to measure are regimen-specific (see above). Evaluation of hepatic transaminases is recommended at 2 weeks and 4 weeks for patients starting treatment that includes nevirapine (see Nevirapine in Appendix A: Pediatric Antiretroviral Drug Information). Plasma viral load monitoring is important as a marker of response to cART because a fall in viral load suggests medication adherence, administration of appropriate doses, and viral drug susceptibility. Some experts favor measuring viral load at 2 weeks to ensure that viral load is declining. Because of higher baseline viral load in infants and young children, the decline in viral load after cART initiation may be slower than in adults. A significant decrease in viral load in response to cART should be observed by 4 to 8 weeks of therapy.
Routine Testing for Patients Receiving Combination Antiretroviral Therapy
After the initial phase of cART initiation, regimen adherence, effectiveness (CD4 cell count and percentage and plasma viral load), and toxicities (history, physical, and laboratory testing as above) should be assessed every 3 to 4 months in children receiving cART. Children who develop symptoms of toxicity should have appropriate laboratory evaluations (such as evaluation of serum lactate in a child receiving NRTIs who develops symptoms suspicious for lactic acidosis). If laboratory evidence of toxicity is identified, testing should be performed more frequently until the toxicity resolves.
Testing for Patients Who are Stable on Long-Term cART
Some experts monitor CD4 cell count and percentage less frequently (e.g., every 6 to 12 months) in children and youth who are adherent to therapy and have CD4 cell value well above the threshold for opportunistic infection risk, sustained viral suppression, and stable clinical status for more than 2 to 3 years. Recent studies have critically evaluated the frequency of laboratory monitoring in both adults and children, particularly CD4 cell count and plasma viral load. These studies support less frequent monitoring in stable patients in whom viral suppression has been sustained for at least a year.34-39 Some clinicians find value in visits every 3 months even when lab testing is not performed in order to review adherence and update dosing for interim growth.
1 See text for details of appropriate tests to send. 2 Readiness for ARV adherence is assessed prior to starting cART. If abacavir is being considered as part of the regimen, send HLA-B*5701 testing prior to initiation of that ARV, and choose an alternative ARV if HLA-B*5701 is positive (see Abacavir in Appendix A: Pediatric Antiretroviral Drug Information). Genotype resistance testing is recommended if not already performed (see Antiretroviral Drug-Resistance Testing). Send tests appropriate to the toxicities expected from each patient’s cART regimen and history (see text). 3 If cART is initiated within 30 to 45 days of a pre-therapy lab result, repeat testing may not be necessary. 4 CD4 cell count and percentage can be monitored less frequently (every 6 to 12 months) in children and youth who are adherent to therapy and have CD4 cell value well above the threshold for opportunistic infection risk, sustained viral suppression, and stable clinical status for more than 2 to 3 years. 5 If lipids have been abnormal in the past, more frequent monitoring might be needed. For patients treated with tenofovir, more frequent urinalysis is considered.
Key to Acronyms: ARV = antiretroviral, cART = combination antiretroviral therapy, CBC = complete blood count
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