As of 2011, approximately 2600 children aged <13 years were living in the United States with a diagnosis of HIV infection, and more than 360 had been diagnosed with AIDS.1 The estimated number of new HIV diagnoses in 2013 was 187 in children aged <13 years, and 1908 in children aged 13 to 19 years.1,2
For children, the primary route of HIV infection is through mother-to-child transmission. This can occur in a variety of ways, including in-utero transmission, infection during childbirth, and through the transmission of the virus in breast milk, although breastfeeding is not recommended in the United States. In 2013, 107 children were infected through mother-to-child transmission in the United States.3 Based on 2013 data, among adolescents and adults aged 13 to 24 years in the United States, male-to-male sexual contact is the most common cause of new HIV infections, accounting for approximately 92%, whereas infection through heterosexual contact accounts for approximately 3.5% of new infections in that age-group.2
Prevention of Transmission
For children born to mothers with HIV who did not receive any form of intervention to prevent mother-to-child transmission, the risk for transmission is approximately 15% to 45%.4 Guidelines have been developed to prevent mother-to-child HIV transmission, including strategies such as the initiation of a 3-drug regimen in the mother when HIV is diagnosed, prophylactic antiretroviral therapy for the mother during labor, a cesarean section for pregnant women with detectable viral loads, treatment of the infant with a 6-week course of oral zidovudine (Table 1), and avoidance of breastfeeding.5 For mothers who received no antepartum prophylaxis or whose viral load is unknown or is >1000 copies/mL, intravenous zidovudine should be used as intrapartum prophylaxis.5 If these preventive measures are properly used, the risk for infection is reduced to <2%.4 If the infant is born to a mother with HIV infection who received no antepartum prophylaxis, the child should also receive 3 doses of nevirapine in addition to the zidovudine treatment.5
Antibody tests, including rapid tests, in the HIV-exposed neonatal population are unreliable because of the transfer of maternal HIV antibodies from mother to child, and therefore virologic testing is a requirement for diagnosis of infection. All infants born to HIV-positive mothers should have virologic testing performed at age 14 to 21 days, 1 to 2 months, and again at 4 to 6 months.5 Testing should also be considered at birth in infants who are at high risk for HIV infection.
For nonbreastfed infants, HIV infection can be presumptively excluded on the basis of ≥2 negative virologic test results. Presumptive exclusion includes a negative test at age ≥14 days, in addition to another negative test result at age ≥1 months. Definitive exclusion of HIV infection diagnosis includes a negative test at age ≥1 months, in addition to another negative test result at age ≥4 months.5 If the result of any virologic test is positive, it should be confirmed by a repeated virologic test as soon as possible because of the risk for false positives.
Many sites use the ribonucleic acid (RNA) viral load as the confirmatory diagnostic test of choice, because it provides a specific and reliable result and is often less expensive than the DNA polymerase chain reaction method. For children aged ≥18 months with or without perinatal exposure to HIV infection, antibody assays can be used alone, because the effect of maternal antibodies is negligible by this age. Confirmatory testing should be used in the event of a positive antibody test. In rare situations, additional viral load testing may be warranted if antibody tests are negative and HIV infection is still suspected.6
Pharmacologic TherapyTherapy Initiation
The decision of when to start antiretroviral therapy in a child with HIV infection is controversial. Aggressive early therapy preserves immune system function, prevents disease progression and prevents transmission to others, and may prevent evolution of a more pathogenic virus with increased potential for drug resistance mutations. However, delaying therapy until symptoms appear may improve adherence to the regimen, will delay adverse effects of combination antiretroviral therapy (ART), and may decrease the evolution of a drug-resistant virus. Because children with HIV infection will receive lifelong combination ART, medication adherence, drug toxicity, and prevention of drug resistance are of particular concern, as well as the impact of antiretroviral choices on future treatment options should resistance develop. The regimen selection should aim to preserve as many antiretroviral options as possible for use later in life.6Drug Therapy Options and Dosing
The use of combination ART for HIV infection involves a regimen of at least 3 medications from at least 2 different drug classes. This strategy prevents the development of viral resistance to a specific antiretroviral medication or class of medications. Currently, 6 classes of antiretroviral medications are available for the treatment of HIV infection, including nucleoside reverse transcriptase inhibitors (NRTIs), nonnucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), fusion inhibitors, entry inhibitors, and integrase inhibitors.7 All these classes include medications that have US Food and Drug Administration (FDA) approval for use in pediatric patients; however, not all medications with a pediatric indication are appropriate for children of all ages.
Drug interactions are common with antiretroviral medications, among the different antiretrovirals themselves and with other drugs that may be administered concomitantly. Some antiretrovirals should not be administered together, and some combinations require dosage adjustments for one or both medications. In addition to contacting an expert in pediatric HIV infection, many resources are available for antiretroviral drug interaction information, such as the tables in the “Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents”7 and the database of antiretroviral drug interactions.8
Selection of the best patient-specific antiretroviral combination is complex and should be based on antiretroviral drug resistance testing through consultation with an expert in pediatric HIV. Selection of a child’s initial regimen should be individualized based not only on the results of this testing, but also on other characteristics of the proposed regimen and the child, such as comorbidities, concurrent medications, and availability of medication in appropriate formulations for the patient. In addition, factors affecting the child’s or caregiver’s ability to be adherent to the regimen selected must be considered. Adherence can be affected by the regimen’s daily pill burden, palatability of medications, side effects, and frequency of dosing required.6 Table 2 lists the current preferred regimens for initial therapy of treatment-naïve children; the “Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection” contain the most up-to-date information.6
NRTIs act by targeting the reverse transcriptase enzyme, which converts HIV RNA to HIV DNA. NRTIs act as a dummy DNA building block. When a reverse transcriptase incorporates these dummy pieces into the HIV DNA, the DNA chain cannot be completed and, therefore, the virus cannot be replicated.9
Side effects common to the NRTI class include mitochondrial toxicity and lactic acidosis with hepatic steatosis. Renal dosage adjustments are required for all medications in this class, with the exception of abacavir, which requires dose adjustments for hepatic dysfunction. The potential for drug interactions with NRTIs is minimal; however, because of overlapping toxicities, antagonistic effects, or similar resistance profiles, some NRTIs should not be combined. Only didanosine has food restrictions, because of its decreased absorption in the presence of food (Table 3).6 See the guidelines for the most up-to-date information.6
NNRTIs also act by targeting reverse transcriptase, but do so by directly binding to the enzyme, preventing its ability to convert HIV RNA to HIV DNA.9 A single resistance mutation to an NNRTI can cause high-level viral resistance, and cross-resistance between medications in this class is common.6 In addition, an infant who was exposed to a single dose of nevirapine as a component of a prophylactic regimen is at risk for virologic failure from a nevirapine-containing regimen. For this reason, NNRTIs are often not used as initial regimens for infants who are newly infected. However, the NNRTIs are more palatable than PIs, and generally offer a lower pill burden and have a lower risk for dyslipidemia and fat maldistribution, so they are often used as initial therapy in older children and adolescents.6
The common side effects of NNRTIs are hepatotoxicity and rash. Rash generally occurs within the first 6 weeks of therapy and can range from mild to severe, rarely including Stevens-Johnson syndrome. None of the NNRTIs requires dose adjustments for renal dysfunction; however, all but rilpivirine require dose adjustments for hepatic dysfunction. NNRTIs have extensive potential for drug interactions caused by effects on liver enzymes. Food restrictions vary by drug (Table 4).6 See the guidelines for the most up-to-date information.6
The PIs block the protease enzyme at a critical step in the conversion of immature noninfectious virus particles to infectious particles.7 PIs are used as initial regimens more often than NNRTIs in the treatment of infants and young children who are newly infected with HIV, because of the PI’s well-documented efficacy, and because resistance to PIs requires multiple viral mutations. However, these agents do confer a higher pill burden than NNRTIs, have a higher risk for metabolic complications, and the liquid formulations are often poorly tolerated by children, because of their taste.6
PIs are known to cause gastroenterology intolerance, hepatotoxicity, lipodystrophy, dyslipidemia (not so common with atazanavir), insulin resistance or hyperglycemia, and increased bleeding disorders in hemophiliacs.
Although no PIs require dose adjustment for renal dysfunction, all PIs undergo hepatic metabolism, mostly by cytochrome (CY)P4503A4, requiring hepatic dose adjustment and causing extensive potential for drug interactions. The PIs may increase the serum concentration of many other drugs and result in serious toxicities. Therefore, many drugs are contraindicated for use with PIs, and many agents need dosage adjustments. All PIs interact with hormonal contraceptives, and with fluticasone, which is often used in children with concomitant asthma or nasal allergies.
All PIs must be given with food, with the exception of the lopinavir plus ritonavir tablets, and unboosted fosamprenavir, which can be given with or without food.6,10 Ritonavir and lopinavir plus ritonavir solutions have very poor palatability, and taste-masking techniques (eg, mixing with chocolate syrup or numbing the tongue with popsicles or ice) may be required for children to tolerate these drugs (Table 5).6 See the guidelines for the most up-to-date information.6
aSome experts recommend atazanavir 300 mg + ritonavir 100 mg at ≥35 kg.
Source: Panel on Antiretroviral Therapy and Medical Management of HIV-Infected Children. Guidelines for the use of antiretroviral agents in pediatric HIV infection. Updated March 5, 2015.
Fusion inhibitors prevent HIV from fusing with the cellular membrane, thereby blocking entry into the host cell.9 Enfuvirtide is currently the only FDA-approved fusion inhibitor. It is an injectable antiretroviral medication approved for the treatment of patients aged 6 to 16 years at a dose of 2 mg/kg, given subcutaneously twice daily, and in patients aged >16 years, up to a maximum dose of 90 mg twice daily.6 Patients must be instructed on reconstitution and administration techniques before use. Local injection-site reactions, such as redness or swelling, are very common, and immune-mediated reactions have been reported. No significant drug interactions have been reported with enfuvirtide.9Entry Inhibitors
Entry inhibitors prevent HIV infection of the host cell by interfering with the ability of the virus to bind to cell surface receptors.9 Maraviroc is currently the only FDA-approved entry inhibitor; it is approved for the treatment of adolescents aged ≥18 years. A viral co-receptor tropism assay must be conducted to determine whether a patient is a candidate for therapy with maraviroc, and dosing is dependent on concurrent medications. Potential side effects include respiratory and musculoskeletal symptoms, and hepatotoxicity. Renal and hepatic dose adjustments are needed, and multiple drug interactions are possible.6Integrase Inhibitors
Integrase inhibitors act by preventing integration of viral DNA into the host cell’s DNA by blocking the integrase enzyme.9 The side effects common to this class of drugs include diarrhea, headache, hypersensitivity reactions, and insomnia. No dosage adjustments are required for mild-to-moderate renal or hepatic dysfunction. The potential for drug interactions is moderate, with requirements for dose separation from antacids, laxatives, oral iron, oral calcium, or other buffered medications being the most common drug interactions encountered. Only elvitegravir, which is not approved for pediatric patients, must be given with food (Table 6).6 Elvitegravir should only be used with a pharmacokinetic enhancer, such as ritonavir or cobicistat. See the guidelines for the most up-to-date information.6
Pharmacokinetic enhancers, such as ritonavir and cobicistat, take advantage of drug interactions, specifically potent inhibition of CYP3A4 and CYP2D6, to increase the plasma concentrations of other medications in the combination ART regimen. Small doses of the pharmacokinetic enhancer are used as “boosters” to decrease the metabolism of PIs (and the integrase inhibitor elvitegravir). This increases the plasma concentration of the boosted PI or the integrase inhibitor, allowing for lower and/or less frequent dosing.
The only pharmacokinetic enhancer approved for use in children is ritonavir. Ritonavir is a PI that is no longer used as a monotherapy. The dosing of ritonavir varies depending on which PI it is boosting. Ritonavir is available as a 100-mg tablet, 100-mg capsule, and 80-mg/mL oral solution. It must be administered 2 hours apart from didanosine, and the capsules must be refrigerated if they are not going to be used within 30 days, or if they cannot be stored at a temperature below 77°F.
For adolescents and adults with HIV infection, fixed-dose combination drugs are available.6,9 These combinations include multiple medications, often from more than 1 drug class, to reduce the number of drugs required for the patient’s combined ART regimen. In some cases, these combinations may allow a patient to take a 3-drug, multiclass, combination antiretroviral regimen in 1 pill, once daily. When clinically appropriate, these medications can greatly ease the daily pill burden on the patient and increase medication adherence.Efficacy and Safety Monitoring Parameters
Effective viral suppression is demonstrated with a normal CD4 cell count, and an HIV RNA level below the lower limit of the assay used. These laboratory values independently predict the risk for disease progression, and should be used together to accurately predict the patient’s prognosis. They also guide decisions regarding when to initiate therapy and when a change in therapy is needed.6
Before beginning ART, baseline laboratory tests, including CD4 T-cell count, HIV RNA level (ie, viral load), and genotyping for viral resistance, should be obtained. Within 1 to 2 weeks of starting a new antiretroviral regimen, or after any changes in therapy, patients should be assessed for toxicities (specific to the individual antiretroviral regimen) and for adherence. Within 2 to 8 weeks, patients should also be screened for virologic responses. Thereafter, most patients can be assessed every 3 to 4 months for adherence, toxicity, and efficacy. Infants aged <6 to 12 months, and all children with suspected deterioration, nonadherence, or abnormal laboratory values, should be monitored more frequently. Patients who are adherent and have sustained virologic suppression may be assessed less frequently. Therapeutic drug monitoring, or measuring plasma drug concentrations to optimize drug dosing, is not routinely recommended in ART.6
Using virologic, immunologic, and clinical criteria, a suboptimal response or lack of sustained response to therapy is deemed treatment failure. Careful assessment is required to determine the cause and appropriate management. Poor adherence, inadequate dosing, or drug interactions may be addressed without a change in the combination antiretroviral regimen; however, a change in the regimen may be required in other cases, such as in the face of drug resistance. For patients whose disease fails to respond to treatment, drug resistance testing (genotype and/or phenotype) is recommended before making changes to the antiretroviral regimen.6
Despite low levels of detectable virus, a relatively small number of patients with HIV infection can go an entire lifetime without ART while still maintaining a high CD4 cell count. These patients are known as long-term nonprogressors, and make up approximately 5% to 15% of the HIV-infected population.11 Another group of individuals, known as elite controllers, have the ability to maintain HIV plasma viral loads below the limit of detection in the absence of ART. This group accounts for <1% of the HIV-infected population.11
HIV infection treatment does not provide a cure and cannot eliminate the virus from the body. Rather, the goal of pediatric ART is to suppress viral replication (ideally to undetectable levels), reduce the negative impact of viral activity on the immune system, maintain normal patient growth and development, increase quality of life, and reduce the likelihood of transmission of the virus to other people. Adherence is essential and ART must be taken continuously to be effective; however, ART provides children with HIV infection the potential to lead long and healthy lives.9
For children with HIV infection, 90% to 95% adherence to the ART (ie, missing approximately 1 dose monthly) results in optimal viral suppression and immune system function.12 Because patients infected perinatally require longer and sometimes more complex regimens, these children often face more barriers to medication adherence than adolescents who acquire HIV infection behaviorally, based on our clinical experience. Many factors can influence medication adherence, including factors related to the patient, caregiver, drug therapy regimen, or healthcare system.
Some factors related to the patient and caregiver include disclosure of HIV infection status, depression or anxiety, level of education of the caregiver, and the child’s knowledge of his or her HIV infection status. In relation to the medication, factors such as taste or volume of the medication, storage requirements, pill burden, and regimen complexity can have an impact on adherence. Factors related to the healthcare system that may affect medication adherence include cost of clinic visits (including transportation), the relationship between the healthcare provider and the caregiver or child, availability of counseling services, and the accessibility of treatment and team-centered care.
Many strategies are available to promote medication adherence in the HIV-infected population. Among the most important is proper education regarding the medication regimen, which should be provided to all caregivers. Education should also be provided to the children when they reach an appropriate age and disclosure of HIV infection status is achieved. Other methods for improving adherence include medication reminders on cellular phones or alarms, the use of pillboxes or medication diaries, the use of blister packaging to prepack medications, and technological approaches (eg, pill bottles equipped with counting devices).
When feasible, a once-daily regimen should be used. If a once-daily regimen is not possible, the regimen should be simplified as much as possible to reduce the pill burden for the patient. As soon as it is developmentally appropriate, pill swallowing education can be initiated to avoid adherence issues related to poorly palatable liquid medications or liquid dose volumes that increase as the patient ages.
Role of the Pharmacist
Pharmacists can play an important role in the care of pediatric patients with HIV infection. The contribution of medication knowledge and support to the patient’s parents and caregivers, with selection of appropriate regimens and proper counseling, provides an invaluable service to the HIV infection care team. Pharmacists in pediatric HIV clinics can help develop adherence programs and teach children how to take their medications, as well as the importance of adherence and the complications when children are not adherent, to ensure proper medication administration. Pharmacists can also follow up regarding changes in therapy. Teach-back methods can be used with children when they are able to understand the information about their medications, to help children get involved in their therapy early. This will ensure that children remain adherent throughout their lives, improve patient outcomes, and decrease the spread of the disease from additional infections.
Pharmacists are also crucial in ensuring that medication doses for younger children are appropriately adjusted for increasing height and weight. Pharmacists play an important role in teaching children how to swallow pills, as well as teaching parents taste-masking techniques for liquids with poor palatability. As patients age, pharmacists can assist in simplifying patients’ regimens and reducing their pill burden based on the recommendation of different age- and weight-appropriate dosage forms and fixed-dose combination products. Providing clarification of medication-related questions, as well as medication interaction information, are also valuable roles of the pharmacist in this setting.
- Centers for Disease Control and Prevention. HIV Surveillance Reports. Updated February 22, 2017. www.cdc.gov/hiv/library/reports/surveillance/. Accessed April 26, 2017.
- Centers for Disease Control and Prevention. HIV surveillance in adolescents and young adults. Updated August 12, 2015. www.cdc.gov/hiv/pdf/library/slidesets/cdc-hiv-surveillance-adolescents-young-adults-2015.pdf. Accessed November 20, 2015.
- Centers for Disease Control and Prevention. Diagnoses of HIV infection in the United States and dependent areas, 2013. Updated September 11, 2015. www.cdc.gov/hiv/pdf/library/reports/surveillance/cdc-hiv-surveillance-report-2013-vol-25.pdf. Accessed April 13, 2017.
- World Health Organization. Mother-to-child transmission of HIV. 2017. www.who.int/hiv/topics/mtct/about. Accessed April 26, 2017.
- Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission. Recommendations for use of antiretroviral drugs in pregnant HIV-1-infected women for maternal health and interventions to reduce perinatal HIV transmission in the United States. Updated August 6, 2015. https://aidsinfo.nih.gov/contentfiles/lvguidelines/PerinatalGL.pdf. Accessed November 20, 2015.
- Panel on Antiretroviral Therapy and Medical Management of HIV-Infected Children. Guidelines for the use of antiretroviral agents in pediatric HIV infection. Updated March 5, 2015. https://aidsinfo.nih.gov/contentfiles/lvguidelines/PediatricGuidelines.pdf. Accessed November 20, 2015.
- Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Updated July 14, 2016. https://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf. Accessed April 24, 2017.
- University of California, San Francisco Center for HIV Information. Database of antiretroviral drug interactions. 2017. http://arv.ucsf.edu/insite?page=ar-00-02. Accessed April 24, 2017.
- National Institute of Allergy and Infectious Diseases. HIV/AIDS. Updated November 8, 2015. www.niaid.nih.gov/diseases-conditions/hivaids. Accessed November 20, 2015.
- Lexiva (fosamprenavir calcium) tablets [prescribing information]. Research Triangle Park, NC: ViiV Healthcare; 2013.
- Okulicz JF, Marconi VC, Landrum ML, et al; for the Infectious Disease Clinical Research Program (IDCRP) HIV Working Group. Clinical outcomes of elite controllers, viremic controllers, and long-term nonprogressors in the US Department of Defense HIV natural history study. J Infect Dis. 2009;200:1714-1723.
- Pontali E. Facilitating adherence to highly active antiretroviral therapy in children with HIV infection: what are the issues and what can be done? Paediatr Drugs. 2005;7:137-149.