The following clinical care issues are unique to HIV-infected children:

• Age-related differences in virologic, immunologic, and pharmacokinetic parameters
• Differences in tolerability and palatability of pediatric formulations of the medications
• Obstacles associated with adherence to complex regimens
• The dynamics of working with a family unit rather than a single individual

During the first 5 years of the pediatric HIV epidemic, prior to the advent of ARV therapy, clinicians could only deliver palliative care targeting HIV-related complications. As treatment advances were made, monotherapy gave way to combination ARV therapy, which initially consisted of two ARV drugs. In the past few years, these regimens have become more complex, highly active antiretroviral therapy (HAART), consisting of three to four agents, and in some situations, salvage therapy with as many as five to six agents. This historical perspective is important because many children have been treated with sequential courses of monotherapy and combination regimens consisting of two to three ARV drugs. This approach typically caused incomplete suppression of viral replication and selection of resistant virus, thereby complicating the choice and diminishing the likelihood of success of subsequent therapeutic regimens. In addition, our current knowledge of what is the best therapy for children is continually being modified as our understanding of surrogate and clinical markers for disease progression increases and new therapies are developed. The most appropriate therapy for an individual child will depend on multiple factors, including the potency, complexity, and toxicity of the regimen, the child’s ability to adhere to the regimen, the child’s home situation, and the treatment history. Clinicians should base decisions regarding the best available treatment for an HIV-infected child on data from pediatric clinical trials and, when relevant, data from adult trials.

In contrast to most infections in which eradication of the pathogen requires treatment for a finite period, HIV is a chronic infection requiring treatment for an indefinite period and possibly for the entire life of the patient. Recent advances in the understanding of the interplay between HIV and the infected host and the discovery of newer ARV agents have resulted in greater optimism and prolongation of wellness. These improved treatments, however, require greater clinician sophistication, greater diligence in medication adherence, and possibly the patient’s acceptance of side effects. Although strategic use of drug-drug interactions to affect pharmacokinetic parameters has enhanced treatment efficacy, new agents and their combinations also have resulted in potentially more drug interactions and both short- and long-term toxicities. Medication side effects and complicated regimen schedules continue to make the delivery of safe and effective therapy a challenge.

The most significant advance and success in the pediatric HIV epidemic has been the dramatic reduction in the rates of maternal-infant transmission. As a result, there are far fewer HIV-infected infants born in the United States, which limits the ability to perform clinical trials in ARV-naïve children. Therefore, management decisions for pediatric patients often have to be based, at least in part, on results from adult trials. Future clinical trials in children are likely to be small, targeted studies focusing on issues unique to children.

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II. Assessment of the HIV-Infected Infant or Child Before Initiating ARV Therapy

July 2004

Recommendations:

When a child is identified as HIV-infected, the clinician should begin an immediate assessment of the child’s clinical and immunologic status, viral burden, resistance profile, and ability to adhere to an ARV regimen. This assessment should be repeated at least every 3 to 4 months to monitor for changes that may necessitate initiating ARV therapy or may affect a child’s ability to receive or tolerate ARV therapy.

Before initiating therapy, clinicians should perform a comprehensive physical examination and should obtain a complete history and the following laboratory evaluations:

• Complete blood count (CBC)
• Assessment of kidney and hepatic function
• Amylase, lipase, glucose, and lipid profile (total cholesterol, HDL, LDL, and triglycerides)
• Viral load
• CD4 count and percentage
• Resistance profile

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A. Clinical Status

Clinical status should be assessed using the CDC classification system, which categorizes children as clinical class A (mild), B (moderate), C (severe), or N (no symptoms) based on the presence or absence of clinical signs and symptoms of HIV on physical examination, history, or basic laboratory parameters. See Appendix A.

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B. Immunological Status

Recommendation:

Clinicians should obtain an assessment of lymphocyte subsets (absolute count and percentage) for HIV-infected infants and children.

Immunologic status should be assessed using the CDC immunologic categories of 1 (no or mild immune suppression), 2 (moderate immune suppression), or 3 (severe immune suppression). These categorizations are based on the child’s CD4 count and percentage. See Appendix A.

CD4 counts vary with age. Infants in the first year of life normally have CD4 counts >2000 cells/mm³, and significant immune compromise would be defined as <1500 cells/mm³. Regardless of CD4 count, all children in the first year of life should receive PCP prophylaxis. Although the absolute CD4 numbers continue to decrease with age, they do not approach adult normal values until 5 to 6 years of age.

An important finding from multiple clinical trials has been that, despite having relatively high CD4 percentages and numbers, clinically stable children may not demonstrate normal immunologic function. For example, it was shown that only one third of HIV-infected, clinically stable children (mean age, 6 years) who had completed the recommended tetanus immunization schedule had protective levels of tetanus antibody.5 Similarly, specific immunologic responses against HIV and other recall antigens have been shown to be minimal in this population.

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C. Viral Load

Recommendations:

Clinicians should obtain a baseline measurement of plasma HIV-1 RNA copy number (viral load) for all HIV-infected infants and children.

Clinicians should use one assay consistently in a patient because there is significant interassay variability.

The availability of assays that are capable of reliably quantifying the amount of viral RNA in circulating blood has dramatically altered the way providers approach therapy (see Appendix B for a description of the available methodologies for measuring viral load). Specifically, these assays have resulted in the following:

• A better description of the natural history of HIV infection
• The utilization of HIV viral load for predicting disease progression
• The ability to rapidly assess the magnitude and durability of viral suppression resulting from therapy
• Establishment of the gold standard of therapy, which is an undetectable plasma load defined as <400 copies/mL or <40 to 50 copies/mL (with ultrasensitive assay)
• Development of technology that is capable of assessing the genotype and phenotype of the patient’s virus to facilitate selection of ARV agents

HIV-1 RNA viral load measurements in serum represent only 2% of the total viral burden; however, the assessment of viral load has proven useful as a prognostic marker in HIV-infected adults and children. During primary HIV-1 infection in adults, there is a burst of relatively uncontrolled viral replication with HIV-1 RNA concentrations of 106 to 107 copies/mL. Within 6 months, newly infected adults establish a lower set point, most often ranging between 104 and 106 copies/mL; the set point has prognostic significance. The lower the viral set point is, the better the patient’s prognosis. Over a 10-year study period, untreated adults with <3,000 copies/mL at diagnosis were unlikely to progress to AIDS or death, whereas those with set points >30,000 copies/mL had a median time to an AIDS diagnosis of 2.8 years and a median time to death of 4.4 years.⁶

Studies in HIV-infected infants and children have shown that, in the absence of ARV therapy, children generally have significantly higher viral loads, especially during infancy, than adults.⁷ In children not receiving treatment, viral set points vary according to age. During the first 2 months of life, infected infants have RNA levels ranging from 200,000 to >1 million copies/mL.⁷ In untreated children, viral load levels slowly decrease over the first 2 years of life (median values remain at >100,000 copies/mL at 18 months of age), although the levels are still higher than adult levels. Children with persistently high levels of plasma HIV-1 RNA, especially infants and younger children with RNA values >750,000 copies/mL, are at risk for rapid disease progression, opportunistic infections, or irreversible neurologic disease. During a 5-year study period, children >2 years of age with baseline levels of <100,000 HIV-1 copies/mL and CD4 cell percentage >15% were shown to be unlikely to progress to AIDS or death, even in the absence of combination ARV therapy.^8,9 Furthermore, many of these longitudinal studies were performed prior to the widespread use of Pneumocystis jirovecii pneumonia (PCP) prophylaxis. Such therapy has resulted in the dramatic decrease in the incidence of PCP, which further decreases the likelihood of disease progression and death.

Plasma viremia may be transiently affected by intercurrent illnesses, vaccinations, techniques and timing of specimen processing, and immunologic status (i.e., greater variability with lower CD4 counts). Given the large number of variables that may affect viral replication, single measurements should be repeated before making a major treatment decision.

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D. Genotypic/Phenotypic Resistance Testing

Recommendations:

Clinicians should obtain resistance testing before initiating treatment in ARV-naïve infants, children, and adolescents or changing a failing regimen for patients already receiving treatment.

Clinicians should consult with an expert for interpretation of resistance testing results.

Resistance testing to determine the susceptibility of a specific viral isolate to ARV agents is a relatively new tool for the identification of the best combination of medications for a patient. The results of resistance testing are most predictable for the agents that the patient is receiving at the time of testing; once a patient stops receiving a drug, the selective pressure that led to a mutation is removed, and overgrowth with wild-type virus may obscure the presence of the resistant virus.

Because an increasing number of newly infected individuals have resistant virus as their initial isolate, resistance assays should be used to help determine an initial regimen, although there are no pediatric-specific data as of yet. Data from studies in adults that affirm the benefit of resistance testing when changing a failing regimen are applicable to children, and use in such circumstances is warranted.¹⁰ However, when the need for medication is urgent or when infants are found to be infected, some experts prefer to initiate medication while the results of the resistance testing are pending.

Interpretation of results is difficult because the mutations that lead to resistance are not yet fully understood. In addition, each of the available test methods has significant limitations and is costly. The New York Medicaid and ADAP reimbursement programs provide reimbursement for three assays (either genotype or phenotype) per year (within 12 months following date of first use). The available test methods are described below.

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1. Genotypic Resistance Testing

Genotypic resistance testing requires sequencing selected portions of the viral genome to identify nucleic acid substitutions. This method, typically automated, can assay large numbers of samples and evaluate multiple mutations known to be associated with resistance. Some disadvantages of this methodology are that the automated systems require detectable levels of virus (generally >1000 copies/mL HIV-1 RNA), the mutated (resistant) virus must be at least 20% of the circulating virus population, and the mutations that confer resistance must have been previously described. Mutations that decrease susceptibility to one agent may actually improve susceptibility to another. For example, the RT mutation M184V dramatically decreases virus susceptibility to lamivudine but modestly increases susceptibility to zidovudine. Such mutational interactions can best be evaluated using a phenotypic resistance assay.

One method of genotypic testing establishes a patient’s genotype, and then predicts susceptibility by comparing a patient’s viral genotype to those in a large data set of viral isolates with correlated genotypic and phenotypic data.

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2. Phenotypic Resistance Testing

Phenotypic resistance testing is labor-intensive and requires separate assays for each agent. Turnaround time is considerably longer than that for genotypic assays. It is also considerably more expensive than genotypic testing.

Phenotypic resistance testing requires using recombinant virus in the presence of therapeutic levels of the ARV agent of interest. Segments of reverse transcriptase and protease that are important for resistance are inserted and amplified into a laboratory HIV isolate, which is then grown in vitro in the presence of the medications. Replicative capacity measurements may appear with phenotypic testing results, but there are no data regarding the clinical utility of this measurement.

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E. Potential Barriers to Treatment Adherence

Recommendations:

Clinicians should identify and address potential barriers to adherence with caregivers and patients before initiating a regimen.

The clinician should discuss the importance of consistent adherence to the ARV regimen with the child in an age-appropriate way.

If adherence barriers cannot be overcome, the clinician and family may choose to defer treatment.

Discussions about successful implementation of a treatment regimen are especially important because incomplete adherence may be more harmful than not starting the medication at all. In order to assess a caregivers and patient’s ability to adhere to an ARV regimen, the clinician needs to identify potential barriers for each individual patient. For example, if the caregiver is concerned that the ARV medications will harm the child, he/she may not adhere to the regimen. The clinical team should also be aware of medical, psychiatric, psychological, or cognitive limitations of the caregiver who is responsible for supervising (for an older child/adolescent) or administering (to a younger child) a complicated medical regimen.

Table 1 lists potential barriers that need to be addressed before beginning a treatment regimen. Multiple meetings with the caregiver may be necessary to explain these issues before starting or changing therapy. The family’s and patient’s understanding and perception of HIV infection are important factors in adherence to a therapeutic regimen.

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III. DECIDING WHEN TO INITIATE ARV THERAPY

July 2004

Recommendations:

The clinician should discuss the risks and benefits of a treatment regimen with HIV-infected children and their caregivers, allowing them to make an informed decision regarding initiating therapy. If the potential risks outweigh the benefits, the clinician and family may choose to defer treatment.

In most cases, clinicians should initiate treatment soon after HIV infection is identified in an infant, either immediately or as soon as the resistance profile is available.

Clinicians should initiate treatment in children older than 1 year of age with symptomatic disease or advancing immunosuppression (see Table 2).

Multiple factors influence the decision as to the optimal time to initiate ARV treatment in a treatment-naïve, HIV-infected child. This decision has become more complicated due to 1) the rapid development of new drugs, each with distinct safety and efficacy parameters, which may be altered when used in combinations, and 2) the recognition that strict adherence is essential for long-term efficacy. There are little available data regarding the optimal time to initiate ARV therapy in pediatric populations.

Initiating treatment early is supported by the finding that a durable suppression of virus is more likely in the presence of a more intact immune system and a lower viral load at baseline.¹¹ In addition, effective early treatment allows normal immune maturation or preservation of immune function and better growth and development.¹² It has also been speculated that durable suppression of virus would be more easily attained early in life because the child would be infected with a more homogeneous population of HIV-1. The subsequent challenge is to maintain viral suppression for extended periods of time with acceptable toxicity.

Infants

The Committee recommends treating almost all infants as soon as they are identified as HIV-infected, even in the absence of symptoms and with normal CD4 cell numbers. This approach is based on the observation that some HIV-infected infants may demonstrate early and rapid disease progression in the first year of life and that this progression is frequently not predictable using surrogate markers such as CD4 enumeration and/or viral loads. Early initiation of therapy can lead to prolonged virologic suppression, immune preservation, clinical stability, and normal growth velocity and cognitive development. Other experts have recommended deferring therapy in asymptomatic infants with low viral loads and good immune function; however, this Committee concluded that therapy for infants should rarely be deferred except in cases in which a family absolutely cannot or will not adhere to the HAART regimen. In rare cases, some clinicians would defer treatment in infants who have good clinical, immunologic, and virologic parameters based on the concern that adherence is particularly difficult for mothers who just discovered that their infant is HIV-infected.

Children >1 year of age

When children are identified as being HIV-infected after 1 year of age, laboratory and clinical markers provide useful prognostic information. Children beyond the neonatal period with HIV RNA <100,000 copies/mL and normal-for-age CD4 parameters are unlikely to experience clinical progression over a 5-year period.⁸ A history of normal growth and development further assures that the child will not experience rapid disease progression. The clinical history and clinical, immunologic, and virologic status at the time of diagnosis should be considered when evaluating the risks and benefits of initiating ARV therapy in children older than 1 year of age (see Table 2). The clinician needs to discuss the pros and cons of initiating therapy with the family. Because viral eradication is not attainable with current therapy, consideration should be given to the fact that treatment may be required for life.

Indications for initiation of ARV therapy in post-pubertal HIV-infected adolescents should follow the adult guidelines (see the NYSDOH AI guidelines² and the federal guidelines³).

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IV. INITIATING AND SELECTING AN ARV REGIMEN

July 2004

Recommendations:

ARV treatment should be initiated and/or changed by a pediatric HIV Specialist who is experienced with the issues that distinguish pediatric patients from adults (see Appendix I: HIV Specialist Policy).

Clinicians should obtain a maternal and infant (or child) ARV treatment history and should assess the resistance profile in the context of the ARV history before choosing a regimen.

The clinician should initiate an ARV regimen of at least three drugs, including two nucleoside reverse transcriptase inhibitors (NRTIs) in combination with a protease inhibitor (PI) or a non-nucleoside reverse transcriptase inhibitor (NNRTI) (see Table 4 for recommended regimens and Appendix C for formulations and dosages for each drug).

The available ARV therapies that have been approved by the Food and Drug Administration (FDA) are categorized in four classes:

• Nucleoside and nucleotide reverse transcriptase inhibitors (NRTI, NtRTI)
• Non-nucleoside reverse transcriptase inhibitors (NNRTI)
• Protease inhibitors (PI)
• Fusion inhibitors (FI)

Although each agent in a class has similar mechanisms of action and overlapping toxicities, each also has unique features that need to be considered, including pharmacokinetic parameters, drug-drug interactions, palatability, toxicities, and HIV mutations associated with drug resistance. Unique drug-drug interactions are frequently exploited to enhance the pharmacokinetic parameters of some therapies. For example, ritonavir increases drug exposure to other PI agents, allowing either increased intervals between doses or decreased amounts of administered drug, by increasing the trough levels and/or the drug exposure as measured by the area under the concentration versus time curve (AUC).

The goal of therapy needs to be individualized for each child. Clinicians should consider both the child’s and the family’s ability to adhere to the proposed regimen. When initiating ARV therapy, all resources to maximize adherence should be mobilized. Specific measures, such as clearly detailing the treatment schedule, electronic devices, pill boxes, telephone calls, and home visits, should be used as appropriate. Additional counseling sessions are advised when new medications are started or when current regimens are altered. When possible, treatment regimens should be tailored to ease administration (see Table 3). For more information on facilitating adherence, see Supportive Care; for adherence issues particular to HIV-infected adolescents, refer to Ambulatory Care of HIV-Infected Adolescents.

When a decision is made to initiate therapy in a child, initial regimens should include two NRTIs in combination with an NNRTI or a PI (see Table 4). Choosing a particular regimen will depend on a multitude of factors, especially those listed in Table 3. Treatment regimens used in children are often based on data from adult clinical trials. Ideally, clinical trials will occur in children as well, but as the population of newly infected young children diminishes in this country, some information may need to be gleaned from adult trials.

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V. FOLLOW-UP MONITORING FOR PATIENTS RECEIVING ARV THERAPY

July 2004

Recommendations:

Children receiving HAART should be followed by a pediatric HIV Specialist either as their primary care clinician or through consultation with their primary care clinician.

Clinicians should either contact patients/caregivers by phone or arrange to see them in person 1 to 2 weeks after initiating therapy to monitor adherence and assess for side effects.

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A. Monitoring for Efficacy

Recommendations:

Clinicians should obtain a repeat viral load within 4 to 6 weeks after initiating or changing ARV therapy. If there is no decrease in viral load, adherence should be reviewed.

Clinicians should routinely obtain lymphocyte subsets and viral load every 3 to 4 months. Children with significant ongoing viral replication may require more frequent monitoring.

Clinicians should repeat all tests that suggest a significant change (either positive or negative) in plasma RNA copy numbers.

CD4 percentages show less age variability and are typically used to measure changes in CD4 levels across different ages. During all periods of childhood, it is preferred to maintain a CD4 percentage >25%. Repeated enumeration of CD4 cell numbers may not be helpful in individuals with extremely low CD4 cell numbers and advanced disease.

Numerous studies show that children who are adherent to HAART can achieve suppression of viral replication to below detectable levels and can gain concurrent clinical and immunologic benefit.^11,12 However, the presence of an undetectable viral load in peripheral blood does not mean that the virus has been eradicated from the peripheral circulation or other reservoirs, such as lymphoid tissue, the gastrointestinal tract, and the central nervous system.

There is also evidence suggesting that patients who respond only partially to ARV therapy can still gain clinical and immunologic benefit even when complete viral suppression is not achieved.¹³ Prolonged viral suppression can prevent or delay the development of ARV-resistant mutations.

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B. Monitoring for Toxicities and Side Effects

Recommendations:

Clinicians should perform a history, physical examination, and laboratory monitoring for toxicity within 4 weeks after initiating ARV therapy, and should repeat these at least every 3 months in children receiving ARV therapy.

Laboratory assessments for toxicity should include CBC, assessment of renal and hepatic function, amylase, lipase, and glucose.

When nevirapine is initiated, the clinician should obtain serum liver enzymes every 2 weeks until 6 weeks after initiating therapy, and then monthly for 3 to 4 months.

Screening of serum cholesterol, triglycerides, low-density lipoprotein, and high-density lipoprotein should be performed in HIV-infected children initiating HAART, 3 to 6 months after initiation, and approximately every 6 months thereafter. Abnormal results warrant repeat studies performed in the fasting state.

Clinicians should assess lactic acid levels in patients receiving NRTIs who develop clinical manifestations (abdominal pain, anorexia, nausea/vomiting, hyperventilation, and/or myalgias) or laboratory markers suggestive of lactic acidosis.

All the available ARV agents have significant potential toxicities. Interactions between ARV agents and other drugs that may be used in HIV-infected children can lead to additional and potentially more severe reactions. Careful monitoring should occur and includes laboratory as well as clinical assessments. Although adverse events can occur at any time, even after years of treatment, problems are usually noted in the first few weeks or months after starting a new drug. For some of the well-described drug toxicities, the initial symptoms may mimic other diagnoses. This can lead to a delay in diagnosis in cases in which the relationship between the adverse event and the drug were not recognized promptly.

Short- and long-term toxicities include abnormal fat distribution, hyperlipidemia, mitochondrial toxicity, hypersensitivity reactions, peripheral neuropathy, liver toxicity, diabetes, renal toxicity, anemia, neutropenia, pancreatitis, and diarrhea.

Chronic compensated lactic acidemia can occur during treatment with NRTIs. Although symptomatic decompensated lactic acidemia with hepatomegaly and hepatic steatosis is rare (approximately 1 case in 1000 person-years), the condition may be fatal. The clinical features of lactic acidemia are nausea, vomiting, abdominal pain, and weight loss. Hepatic involvement is common and includes hepatomegaly, ascites, encephalopathy, elevation of liver enzymes, and hepatic steatosis. Hepatic necrosis has been reported in fulminant cases. The postulated pathogenesis of lactic acidemia is through mitochondrial toxicity. Although nearly all reports of NRTI-associated mitochondrial dysfunction with lactic acidosis are in adult patients, children are not free of risk for this disorder.¹⁴ Fatal lactic acidemia reported in two pregnant women receiving dual NRTI therapy with stavudine and didanosine may indicate that women, especially during pregnancy, have a greater risk.¹⁵ Assessment of lactic acid is warranted in individuals receiving NRTIs who develop clinical manifestations suggestive of lactic acidosis. It has been suggested that levels >2.5 mmol/L are abnormal and warrant repeating. In symptomatic individuals with levels >4 mmol/L, discontinuation of NRTIs may be required. Supportive measures and cessation of NRTIs have resulted in recovery.¹⁴ Currently, however, routine monitoring of lactic acid levels is not generally recommended because of the rarity of symptomatic lactic acidemia and the frequency of falsely elevated lactic acid levels due to the significant technical problems in obtaining specimens.

For a list of specific toxicities that have been observed with the use of particular ARV agents, the clinician should refer to the federal guidelines.¹

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C. Monitoring Adherence

Recommendations:

The clinician should regularly discuss the importance of consistent adherence to the ARV regimen with the caregiver and the child in an age-appropriate way.

At each visit, clinicians should assess adherence in children and adolescents receiving ARV therapy. In cases in which adherence becomes problematic and cannot be resolved, simplification or discontinuation of therapy should be included as a potential management strategy.

While a child is receiving therapy, clinicians should continue monitoring adherence because both anticipated (e.g., changes in developmental stages) and unforeseen circumstances (e.g., change in care provider, acting out behavior) frequently occur. For more information on adherence issues and strategies that are specific to pediatric patients, see Supportive Care.

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VI. CHANGING HAART REGIMENS

July 2004

Recommendations:

Decisions regarding changing therapy should be individualized and should be made in consultation with a pediatric HIV Specialist.

The clinician should decide whether to change therapy, or modify or continue the present regimen in any of the following circumstances:

• Clinical progression
• Sustained increase in viral load
• Progressive immunodeficiency
• Significant toxicity
• Significant unmodifiable adherence issues have developed with the current regimen

When new regimens are selected because of virologic failure, the clinician should perform resistance testing while the child is still on the failing regimen (see Section II. D. Genotypic/Phenotypic Resistance Testing).

When the regimen is changed because of virologic failure, clinicians should switch all drugs at the same time. Ideally, the new regimen should have three new active drugs that the child has not previously taken and that are not cross-resistant to medications the child has taken.

The clinician should discuss the risks and benefits of the specific medications under consideration with the family and child when changing treatment.

Considerations when deciding whether to change therapy:

• Previous ARV therapy and resistance profile
• Likelihood of adherence
• Clinical and immunologic status
• The child’s ability to take and tolerate the medications
• The likelihood of achieving complete viral suppression
• The possibility of toxicities or drug-drug interactions

Clinicians should consider changing therapy following a significant increase in virus replication (> 0.5 log), sustained plasma RNA values in excess of 50,000 to 100,000 copies/mL, a significant decrease in CD4 percentage, or significant toxicity.

When changing therapy, the clinician should choose a treatment regimen consisting of multiple drugs to which that child is naïve. Genotypic and phenotypic resistance testing are useful in these circumstances and should be obtained while the patient is still receiving therapy.¹⁰ A new regimen is occasionally selected for children with limited previous experience based on history alone. However, for children with extensive previous treatment history and limited switch options, it is general practice to use genotypic or phenotypic resistance testing information plus the patient’s ARV history to choose a new regimen. ARV therapy-experienced children are likely to carry quasi-species of HIV-1 containing genetic mutations associated with resistance to some or all of the previously used classes.

The decision to change therapy should take into account the findings that continued HIV replication in the presence of ARV therapy facilitates selection of resistant virus, which may demonstrate cross-resistance with multiple agents within the same class of therapies. Similarly, if medications are switched and the new combination does not completely suppress virus replication, new mutations in the virus will occur. At that point, subsequent control of viremia would become even more difficult. Alternatively, some clinicians would wait until new agents become available. Therefore, when the risks and benefits of switching therapy are considered, these issues, as well as adherence, toxicity, the child’s ability to take multiple therapies, and drug-drug interactions, should be taken into consideration.

Many children who have been on long-term ARV therapy experience treatment fatigue. This occurs as the thought of having to take medication for many years, and possibly the rest of their lives, becomes overwhelming, particularly to pre-adolescents and adolescents. Often these children experience a rebound in viral load, and clinicians later discover that this is a result of diminished adherence. In patients with good clinical and immunologic function, some clinicians accept a temporary discontinuation of ARV therapy with very close monitoring of viral load and CD4 cell counts. The rationale is that a complete discontinuation of ARV therapy will maintain viral sensitivity and prevent the development of resistance that would occur with partial or intermittent discontinuation. No data exist to support or discredit this theory.

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VII. SPECIAL CONSIDERATIONS FOR ARV-EXPERIENCED CHILDREN WHO ARE NÄIVE TO PIs AND NNRTIs

July 2004

Many pediatric HIV clinicians manage children who have been treated with non-HAART regimens (e.g., dual nucleosides) for extended periods of time and have continued to be clinically well with fairly low copy numbers and relatively intact CD4 cell counts. For these children, one acceptable approach may be to allow low levels of viremia while maintaining a stable immunologic profile and to wait for a more appropriate therapeutic option to develop. However, continued viral replication in the presence of ARV medications ultimately leads to selection of resistance mutations to those agents.

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VIII. PI- AND NNRTI-EXPERIENCED CHILDREN: SALVAGE THERAPIES

July 2004

Recommendation:

The choice of salvage therapy in PI- and NNRTI-experienced children should be made on a case-by-case basis and should be guided by the child’s ARV history, resistance profile, and ability to adhere to a regimen.

Despite having been treated with PIs, NNRTIs, and NRTIs, a growing number of HIV-infected children have not been able to sustain viral replication below the level of quantification. Although incomplete adherence may be a factor in some of these cases, other contributors include the previous use of these agents in the child (i.e., sequential mono or dual therapies or addition of new agents without changing the entire regimen), inadequate dosing due to poorly described pharmacokinetic parameters, and toxicity management. In these cases, the pros and cons of continuing an ARV treatment regimen instead of switching to an alternative treatment regimen need to be closely considered and discussed with the child and family.

There is no consensus regarding the best approach to treat these patients. Choice of the new regimen should be guided by the child’s ARV history and results from resistance assays. If the child has been exposed to PIs, NNRTIs, and NRTIs, it is unlikely that a simple three- or even a four-drug regimen will sustain suppression of virus to undetectable levels. In this setting, viremia alone, in the face of stable clinical and immunologic status, does not require a medication change in a heavily pre-treated child.

None of the following approaches have been validated in large-scale pediatric clinical trials; however, they constitute the most reasonable approaches to a difficult problem, which may be ameliorated in the future by the development of new ARV agents.

• Continuing a regimen that allows viral replication at a level that will not cause additional immunologic or clinical deterioration while waiting for newer therapeutic approaches and agents to be developed. This strategy may involve simplification of the regimen, such as stopping the PI or NNRTI component of the regimen.
• Choosing an aggressive regimen of four to six agents in an attempt to suppress viral replication to undetectable levels with an acceptable level of toxicity. This regimen may contain two NRTIs, an NNRTI, two to three PIs, and enfuvirtide (for patients older than 6 years of age).
• Withholding ARV therapy for a period of time in the expectation that while the child is not receiving therapy, the wild-type virus may outgrow resistant viruses and again predominate. After this interim period, an aggressive regimen can then be initiated. There are limited clinical data on this approach in adults and children, and it should be used with extreme caution, especially in children with significant immune suppression. It is expected that resistant virus is archived in the genome of the patient’s cells and will reappear in due time.

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REFERENCES

1. Working Group on Antiretroviral Therapy and Medical Management of HIV-Infected Children. Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection. National Resource Center at the François-Xavier Bagnoud Center, UMDNJ, The Health Resources and Services Administration (HRSA), and The National Institutes of Health (NIH); 2005. Available at: http://www.aidsinfo.nih.gov

2. New York State Department of Health AIDS Institute. Antiretroviral Therapy; 2005. Available at: http://www.hivguidelines.org/clinical-guidelines/adults/antiretroviral-therapy/

3. Panel on Clinical Practices for Treatment of HIV infection. Guidelines for the Use of Antiretroviral Agents in HIV-infected Adults and Adolescents. Department of Health and Human Services; 2003. Available at: http://www.aidsinfo.nih.gov

4. New York State Department of Health AIDS Institute. Prevention of Perinatal HIV Transmission; 2002. Available at: http://www.hivguidelines.org/

5. Wiznia A, Stanley K, Krogstad P, et al. Combination nucleoside analog reverse transcriptase inhibitor(s) plus nevirapine, nelfinavir, or ritonavir in stable antiretroviral therapy-experienced HIV-infected children: Week 24 results of a randomized controlled trial (PACTG 377). Pediatric AIDS Clinical Trials Group 377 Study Team. AIDS Res Hum Retroviruses 2000;16:1113-1121.

6. Mellors JW, Rinaldo CR Jr, Gupta P, et al. Prognosis in HIV-1 infection predicted by the quantity of virus in plasma. Science 1996;272:1167-1170.

7. Abrams EJ, Weedon J, Steketee RW, et al. Association of human immunodeficiency virus (HIV) load early in life with disease progression among HIV-infected infants. New York City Perinatal HIV transmission Collaborative Study Group. J Infect Dis 1998;178:101-108.

8. Mofenson LM, Korelitz J, Meyer WA III, et al. The relationship between serum human immunodeficiency virus type 1 (HIV-1) RNA level, CD4 lymphocyte percent, and long-term mortality risk in HIV-1-infected children. National Institute of Child Health and Human Development Intravenous Immunoglobulin Clinical Trial Study Group. J Infect Dis 1997;175:1029-1038.

9. Dunn D, HIV Paediatric Prognostic Markers Collaborative Study Group. Short-term risk of disease progression in HIV-1-infected children receiving no antiretroviral therapy or zidovudine monotherapy: A meta-analysis. Lancet 2003;362:1605-1611.

10. Hirsch MS, Brun-Vezinet F, D’Aquila RT, et al. Antiretroviral drug resistance testing in adult HIV-1 infection: Recommendation of an International AIDS Society — USA Panel. JAMA 2000;283:2417-2426.

11. Nachman SA, Stanley K, Yogev R, et al. Nucleoside analogs plus ritonavir in stable antiretroviral therapy-experienced HIV-infected children: A randomized controlled trial. Pediatric AIDS Clinical Trials Group 338 Study Team. JAMA 2000;283:492-498.

12. Luzuriaga K, McManus M, Catalina M, et al. Early therapy of vertical human immunodeficiency virus type 1 (HIV-1) infection: Control of viral replication and absence of persistent HIV-1 specific immune responses. J Virol 2000;74:6984-6991.

13. Deeks SG, Wrin T, Liegler T, et al. Virologic and immunologic consequences of discontinuing combination antiretroviral-drug therapy in HIV-infected patients with detectable viremia. N Engl J Med 2001;344:472-480.

14. Church JA, Mitchell WG, Gonzalez-Gomez I, et al. Mitochondrial DNA depletion, near-fatal metabolic acidosis, and liver failure in an HIV-infected child treated with combination antiretroviral therapy. J Pediatr 2001;138:748-751.

15. United States Food and Drug Administration. FDA/Bristol Myers Squibb issues caution for HIV combination therapy with Zerit and Videx in pregnant women. Available at: http://www.fda.gov/bbs/topics/answers/ans01063.html

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APPENDIX A

CDC CLINICAL AND IMMUNOLOGIC STATUS CLASSIFICATIONS

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APPENDIX B

AVAILABLE METHODOLOGIES FOR MEASUREMENT OF VIRAL LOAD AND INTERPRETATION OF RESULTS

Current methodologies that measure viral load include the polymerase chain reaction (PCR), branched chain DNA (bDNA) amplification, and nucleic acid sequence-based analysis (NASBA).

No single RNA quantitation assay has been shown to be superior. The PCR, bDNA, and NASBA assays quantify the amount of replicating virus present in the plasma at a given time with results reported as HIV copy numbers/mL of plasma. Each method has different blood volume and anticoagulant requirements and slightly different characteristics with regard to reproducibility. At the present time, non-B clade HIV subtypes are usually assessed by bDNA assays; however, new PCR assays are sensitive and specific for non-B clade HIV subtypes. If this technology is available, there would be no need to use the bDNA assay. Although many investigational studies used a cutoff of 400 copies/mL as “undetectable,” assays that can quantify virus at levels of 40 or 50 RNA copies/mL have become available and are commonly used in clinical practice.

When interpreting plasma RNA copy numbers, the intra-assay standard deviation is between 0.15 and 0.3 log₁₀. For an individual child, less than a 0.5 log10 (3-fold) change may represent assay variability and not true biologic difference. Table 1 uses a hypothetical patient with a starting viral copy number of 100,000 copies/mL to illustrate how viral load reductions can be expressed in different terms.

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APPENDIX C

AVAILABLE ANTIRETROVIRAL DRUGS

March 2010

Because dosing requirements vary greatly based on concurrent medications and age of patient, dosing for an individual patient should be checked with the federal Pediatric Antiretroviral Guidelines and a pediatric HIV Specialist.

Click here to view Table C-1: Nucleoside and Nucleotide Reverse Transcriptase Inhibitors: Preparations and Dosing

Click here to view Table C-2: Non-Nucleoside and Nucleotide Reverse Transcriptase Inhibitors: Preparations and Dosing

Click here to view Table C-3: Protease Inhibitors: Preparations and Dosing

Click here to view Table C-4: Fusion Inhibitors: Preparations and Dosing

Click here to view Table C-5: CCR5 Co-receptor Antagonists: Preparations and Dosing

Click here to view Table C-6: Integrase Inhibitors: Preparations and Dosing

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