Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection

Laboratory monitoring of children with HIV poses unique and challenging issues. In particular, the normal ranges of CD4 T lymphocyte (CD4) cell counts and plasma HIV RNA concentrations (viral loads) can vary significantly by age. The CD4 counts and viral load values that predict the risk of disease progression also change as a child ages. This section will address immunologic, virologic, general laboratory, and clinical monitoring of children with HIV, with information that is relevant to both those who have recently received an HIV diagnosis and those who are receiving antiretroviral therapy (ART). 

Clinical and Laboratory Monitoring of Children with HIV 

Initial Evaluation of Children Who Recently Received an HIV Diagnosis, or Are Entering or Transferring to a New Care Setting 

Children who have recently received an HIV diagnosis should have their CD4 counts and plasma viral loads measured. Children with HIV should have a complete, age-appropriate medical history and physical examination (see Table 6 below). Their growth and development should be evaluated for signs of HIV-associated abnormalities. Testing also should be performed to assess for HIV-associated conditions, including the following: 

• Anemia, leukopenia, thrombocytopenia
• Hypoalbuminemia 
• Nephropathy (urinalysis) 
• Renal insufficiency (creatinine) 
• Hyperglycemia 
• Hepatic transaminitis 

Baseline screening tests for coinfections and opportunistic infections (OIs), including tests for the following, should be performed:

• Tuberculosis, with tuberculin skin test if aged <2 years, or an interferon gamma release assay if aged ≥2 years 
• Hepatitis B virus (HBV), with HBV surface antibody, HBV surface antigen, and HBV core antibody tests 
• Hepatitis C virus (HCV), with HCV nucleic acid (HCV RNA) testing if aged <18 months or HCV antibody if aged >18 months 
• Cytomegalovirus (CMV), with CMV antibody tests if aged >12 months 

Monitoring for OIs should follow the guidelines that are appropriate for the child’s exposure history and clinical setting (see the Pediatric Opportunistic Infection Guidelines). Children with HIV who are relocating from outside the United States may benefit from additional evaluations—such as gastrointestinal parasites, lead level, and thyroid function. See Centers for Disease Control and Prevention International Adoption.¹ 

Laboratory confirmation of HIV infection should be obtained when available documentation is incomplete (see Diagnosis of HIV Infection in Infants and Children). Genotypic resistance testing should be performed, even if ART is not initiated immediately. In addition, a full antiretroviral (ARV) drug history should be obtained; this history should include any exposure to ARV drugs for the prevention of perinatal HIV transmission (see Drug-Resistance Testing in the Adult and Adolescent Antiretroviral Guidelines). HLA-B*5701 testing should be conducted on initial laboratory screening to allow for possible abacavir (ABC) initiation, and an alternative ARV drug should be used if the HLA-B*5701 test result is positive² (see the Abacavir section in Appendix A. Pediatric Antiretroviral Drug Information). 

Before initiating therapy or making changes to a patient’s ARV regimen, a clinician and multidisciplinary team members (where available) should assess potential barriers to adherence and discuss the importance of adherence with the patient and/or their caregiver (see Adherence to Antiretroviral Therapy in Children and Adolescents with HIV). 

If a child does not initiate ART after receiving an HIV diagnosis, the child’s CD4 count and plasma viral load should be monitored at least every 3 to 4 months.

Evaluation at Initiation of Antiretroviral Therapy 

At the time of ART initiation, a physical examination should be performed, including assessment of weight and height, sexual maturity rating, and baseline labs for CD4 count, and plasma viral load should be obtained to monitor ART response (see Table 6 below). To set the baseline for monitoring ART toxicity (see Management of Medication Toxicity or Intolerance), a complete blood count, urinalysis, and serum chemistry panel (including levels of electrolytes, creatinine, glucose, and hepatic transaminases) should be performed (see Table 6 below). The levels of serum lipids (cholesterol and triglycerides) also should be measured. For information about the adverse effects (AEs) associated with a specific ARV drug, see Appendix A. Pediatric Antiretroviral Drug Information for complete information on each drug. Tables 17a–17k in Management of Medication Toxicity or Intolerance provide information about specific toxicities associated with ARV drugs (e.g., osteopenia and osteoporosis, lipodystrophies and weight gain, nephrotoxic effects) and include guidance for prevention, monitoring, and management. 

Clinical and Laboratory Monitoring After Initiating or Changing an Antiretroviral Regimen 

Children who start ART or who change to a new regimen should be monitored to assess the effectiveness, tolerability, and AEs of the regimen and to evaluate medication adherence. Clinicians and multidisciplinary teams should schedule frequent clinical in-person and/or telemedicine visits to monitor patients closely during the first few months after initiating a new ARV regimen. The first few weeks of ART can be particularly difficult for children and their caregivers; they must adjust their schedules to allow consistent and routine administration of medication doses. Children also may experience the AEs of medications, and both children and their caregivers need assistance to determine whether the effects are temporary and tolerable or more serious or long term, requiring a clinical visit. It is critical that providers communicate with caregivers and children in a supportive, nonjudgmental manner and use plain language. This approach promotes interactive reporting and ensures that providers can have a productive dialogue with both children and their caregivers, particularly in situations where medication adherence is reported to be inconsistent. 

Telemedicine visits and telehealth communication platforms are particularly relevant to the care of adolescent patients based on their technology access and habits.^3,4 Additional check-ins via telephone and/or telehealth (emails, text messaging, app-based communications) may support adherence and early identification of medication side effects. The continuity of patient and caregiver interactions is an opportunity for clinicians and the multidisciplinary team to provide support and discuss adherence with patients and their caregivers. 

A systematic review of randomized controlled trials from the last 10 years that used a telemedicine approach as a study intervention or assessed telemedicine as a subspecialty of pediatric care found that telemedicine services for the general public and pediatric care are comparable to or better than in-person services.⁵ Use of telemedicine as remote, technology-based access to clinical services in HIV care is growing and has been shown to achieve similar outcomes as those associated with in-person care.⁶ People with HIV on ART achieve similar clinical responses to therapy, adherence to treatment, quality-of-life scores, and psychological and emotional status, whether treated through telemedicine or in person.^7-9 

When selecting the format for clinical follow-up, it is important to recognize differences and similarities between in-person and telemedicine visits (see Table 4 below). The benefits of telemedicine visits include patient and caregiver convenience, lack of travel, flexibility, and ability to visualize ART handling/swallowing and conduct directly observed therapy in the home setting. Telemedicine visits, however, require technological access and capacity and limit the provider’s ability to conduct physical examinations and obtain laboratory testing on site,^6-8 as well as to perform periodic measurements of body weight, which are important for dose modification in rapidly growing infants, and to monitor for excessive weight gain as a possible AE of some ARVs. Cooperative children can be weighed and have their height measured at home if a scale and measuring tape are available, with simple instructions for continuity, or directly observed during a synchronous visit or obtained from a recent pediatric or other specialty in-office visit.¹⁰ Additionally, providers need to arrange and coordinate access to the laboratory testing and be familiar with state and local requirements for carrying out, documenting, and billing telemedicine visits. Although both in-person and telemedicine visits involve considerations for stigma, privacy, and confidentiality, these considerations differ between health care and home/community-based settings. For example, the caregiver who has not disclosed the HIV and ART status of the child at home might prefer in-person visits at the clinic or specific hours and/or alternative locations for a telemedicine visit.

Within 2 Weeks of Initiating Antiretroviral Therapy

Within 2 weeks of initiating ART, children should be evaluated either in person, through telemedicine, or by telephone. During this evaluation, clinicians should identify clinical AEs and provide support for adherence. Many clinicians plan additional contacts (in person, through telemedicine, by telephone, or via email/texts/apps) with children and caregivers to support adherence during the first few weeks of therapy.

Two to 4 Weeks After Initiating Antiretroviral Therapy

Most experts recommend performing laboratory testing at 2 to 4 weeks (but no later than 8 weeks) after initiating ART to assess virologic response and laboratory toxicities, although this recommendation is based on limited data. The laboratory chemistry tests that a patient requires will depend on the ARV regimen that the patient is receiving (see Table 6 below). Plasma viral load monitoring is important as a marker of response to ART because a decline in viral load suggests that the patient is adherent to the regimen, that the appropriate doses are being administered, and that the virus is susceptible to the drugs in the regimen. Some experts favor measuring viral load at 2 weeks to ensure that viral load is declining. A significant decrease in viral load should be observed 4 to 8 weeks after initiation of ART.

Clinical and Laboratory Monitoring for Children Who Are Stable on Long-Term Antiretroviral Therapy

After the initial phase of ART initiation (1–3 months), clinicians should assess a patient’s adherence to the regimen and the regimen’s effectiveness (as measured by CD4 count and plasma viral load) every 3 to 4 months. Additionally, clinicians should review a patient’s history of drug toxicities and evaluate each patient for any new AEs using physical examinations and the relevant laboratory tests. Generally, if laboratory evidence of toxicity is identified, testing should be performed more frequently until the toxicity resolves, but specific management is guided by the degree of toxicity and ARV regimen. Tables 17a–17k in Management of Medication Toxicity or Intolerance provide information about specific toxicities associated with ARV drugs. 

Table 6 below provides one proposed general monitoring schedule, which should be adjusted based on the specific ARV regimen that a child is receiving. 

A patient’s baseline CD4 count affects how rapidly CD4 count improves after ART initiation; children with very low CD4 counts may take longer than 1 year to achieve their highest values after viral load suppression.¹¹ Studies that have critically evaluated the frequency of laboratory monitoring in both adults and children, particularly CD4 count and plasma viral load, support less frequent monitoring in stable patients who have been consistently virologically suppressed for ≥1 year.^12-18 The Adult and Adolescent Antiretroviral Guidelines—Laboratory Testing currently supports performing plasma viral load testing every 6 months for individuals who have both— 

• Consistent virologic suppression ≥2 years and 
• CD4 counts that are consistently >300 cells/mm³. 

The Panel on Antiretroviral Therapy and Medical Management of Children Living with HIV finds value in continuing to perform viral load testing every 3 to 4 months to provide enhanced monitoring of adherence or disease progression among children and adolescents. Some experts monitor CD4 count less frequently (e.g., every 6–12 months) in children and adolescents who are adherent to therapy, who have CD4 count values well above the threshold for OI risk, and who have had sustained virologic suppression and stable clinical status for more than 2 years.¹⁹ Furthermore, some experts monitor viral load more often (with each injection) in adolescents receiving injectable cabotegravir and rilpivirine.²⁰ 

Testing at the Time of Switching Antiretroviral Regimens 

When a patient switches regimens to simplify ART, clinicians should obtain the appropriate laboratory test results at baseline for the toxicity profile of the new regimen. Follow-up should include a measurement of plasma viral load at 4 weeks (and not >8 weeks) after the switch to ensure that the new regimen is effective. If the regimen is switched because the regimen is failing (see Recognizing and Managing Antiretroviral Treatment Failure), resistance testing should be performed while a patient is still receiving the failing regimen. This optimizes the chance of identifying resistance mutations, because resistant strains may revert to wild type within a few weeks of stopping ARV drugs (see Drug-Resistance Testing in the Adult and Adolescent Antiretroviral Guidelines). Clinicians should consider performing phenotypic resistance testing, including co-receptor tropism testing, in addition to genotypic viral resistance testing in children who have experienced prolonged or repeated periods of viral nonsuppression on multiple ARV regimens.²¹ 

Immunologic Monitoring in Children: General Considerations 

When interpreting CD4 counts and percentages in children, clinicians must consider age as a factor. CD4 count and percentage values in healthy infants without HIV are considerably higher than values observed in adults without HIV; these infant values slowly decline to adult values by age 5 years (see Table 5 below).²²

The current pediatric HIV disease classification is based on absolute CD4 count, which is the preferred assay for monitoring and estimating the risk for disease progression and OIs²³ (see Table A. HIV Infection Stage Based on Age-Specific CD4 Count or Percentage in Appendix C: CDC Pediatric HIV CD4 Cell Count/Percentage and HIV-Related Diseases Categorization). However, some clinicians find it useful to monitor CD4 percentages because they remain relatively consistent, whereas absolute CD4 counts vary with age and changes in total leukocyte counts. CD4 counts and percentages are best measured when patients are clinically stable, as several factors, including mild intercurrent illness and exercise, can transiently decrease levels.²⁴ Low CD4 values should be confirmed by a repeat test at least 1 week after the first test to inform clinical decisions.

CD4 count and percentage decline as HIV infection progresses; patients with lower CD4 counts or percentage values have a poorer prognosis than patients with higher values (see Tables A, Table B, and Table C in Appendix D: Supplemental Information). Children with higher baseline CD4 percentages, younger ages (<4 years), or early ART initiation²⁵ can potentially recover normal CD4 counts, whereas children with severe baseline immune suppression may not achieve normal CD4 levels with ART.^26-28 Although CD4 cells decline as a result of HIV infection, CD8 T lymphocyte (CD8) cells expand soon after infection. In adults with HIV, low CD4/CD8 ratios are a prognostic indicator for serious non-AIDS events.²⁹ In children with perinatal HIV, the CD4/CD8 ratio inversely correlates with immune activation, senescence, and exhaustion.²⁹ Some clinicians find CD4/CD8 ratios useful for gauging overall immune dysfunction. Guidelines recommend that all people with HIV receive ART, regardless of their CD4 count and clinical stage. However, CD4 counts are used to determine HIV stage, potential for immunologic recovery, and when to initiate or stop OI prophylaxis (see When to Initiate Antiretroviral Treatment in Children with HIV Infection).

HIV RNA Monitoring in Children: General Considerations

Quantitative HIV RNA assays measure the plasma concentration of HIV RNA as copies/mL. Without therapy, plasma viral load initially rises to peak level during the period of primary infection in adults and adolescents 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.^30,31 In adults with HIV, the virologic set point correlates with the subsequent risk of disease progression or death in the absence of therapy.³²

The pattern of change in plasma viral load in untreated infants with perinatal HIV differs from that in adults and adolescents with HIV. In the absence of treatment, plasma viral load peaks by age 2 months and remains high until 12 months, and then slowly declines until age 4 to 5 years.^33-34,35 This pattern probably reflects the lower efficiency of a developing immune system in containing viral replication and, possibly, the rapid expansion of HIV-susceptible cells that occurs with somatic growth.³⁶

Despite the established association between high plasma viral load and disease progression, a specific HIV RNA concentration has only moderate predictive value for disease progression and death in an individual child.³⁷ In both children and adults with HIV, CD4 count or percentage and plasma viral load are independent predictors of disease progression and mortality risk, and using the two markers together more accurately defines prognosis.^37-40

Methodological Considerations When Interpreting and Comparing HIV RNA Assays

Based on accumulated experience with currently available assays, the current definition of virologic suppression is a plasma viral load that is below the quantification limit of the assay used (generally <20 copies/mL to 75 copies/mL) (see Table 7 below). This definition of suppression has been much more thoroughly investigated in adults with HIV than in children with HIV (see the Adult and Adolescent Antiretroviral Guidelines). Temporary viral load elevations (“blips”) are often detected in adults on ART⁴¹ and generally defined as up to 200 copies/mL, but they may be as high as 500 copies/mL in children on ART⁴²; these temporary elevations do not represent virologic failure as long as the values have returned to below the level of detection when testing is repeated. For definitions and management of virologic treatment failure, see Recognizing and Managing Antiretroviral Treatment Failure. These definitions of virologic suppression and virologic failure are recommended for clinical use. Research protocols or surveillance programs may use different definitions.

Several different methods can be used for quantitating HIV RNA, each of which has a different level of sensitivity (see Table 7 below). Because different assays use different methods to measure HIV RNA, and because the tests have different levels of sensitivity, clinicians should consistently use a single HIV RNA assay method to monitor an individual patient when possible.^43-45 Moreover, because of biologic variability, only differences >0.7 log₁₀ copies/mL (a fivefold difference) in infants aged <2 years and differences >0.5 log₁₀ copies/mL (a threefold difference) in children aged ≥2 years should be considered as clinically significant plasma viral load changes.

The predominant HIV-1 subtype in the United States is subtype B, and early assays were designed to detect this subtype. Current kit configurations for all companies have been designed to detect and quantitate essentially all viral subtypes (see Diagnosis of HIV Infection in Infants and Children). This ability is important in many regions of the world where non-B subtypes are predominant, as well as in the United States for immigrant and adopted children who are born outside the United States or to non–U.S.-born parents.^43,46-50

Genetic Testing for Management of HIV

Modern disease intervention strategies often employ genetic testing to evaluate the genes of humans and pathogens. This approach to treatment is an important component in the rise of precision medicine. Clinicians who manage HIV have routinely probed HIV genetic sequences for mutations that are associated with HIV drug resistance. Some ARV drugs are metabolized differently based on specific human genotypes. For example, studies have shown that certain genotypes can affect efavirenz exposure in young children.^51-54 In addition, some human genetic polymorphisms are associated with drug toxicity or AEs (e.g., using HLA-B*5701 testing to predict ABC hypersensitivity)⁵⁵; for more information, see the Abacavir section in Appendix A. Pediatric Antiretroviral Drug Information. Future clinical practice will likely feature broader applications of multiple forms of genetic testing to guide management of health and disease.

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