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Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection
Management of Children Receiving Antiretroviral Therapy
Recognizing and Managing Antiretroviral Treatment Failure
(Last updated: March 5, 2015; last reviewed: March 5, 2015)
Panel's Recommendations for Recognizing and Managing Antiretroviral Treatment Failure
The causes of virologic treatment failure—which include poor adherence, drug resistance, poor absorption of medications, inadequate dosing, and drug-drug interactions—should be assessed and addressed (AII).
Perform antiretroviral (ARV) drug-resistance testing when virologic failure occurs, while the patient is still taking the failing regimen, and before changing to a new regimen (AI*).
The goal of therapy following treatment failure is to achieve and maintain virologic suppression, as measured by a plasma viral load below the limits of quantification using the most sensitive assay (AI*).
ARV regimens should be chosen based on treatment history and drug-resistance testing, including both past and current resistance test results (AI*).
The new regimen should include at least two, but preferably three, fully active ARV medications with assessment of anticipated ARV activity based on past treatment history and resistance test results (AII*).
When complete virologic suppression cannot be achieved, the goals of therapy are to preserve or restore immunologic function (as measured by CD4 T lymphocyte values), prevent clinical disease progression, and prevent development of additional drug resistance that could further limit future ARV options (AII).
Children who require evaluation and management of treatment failure should be managed by or in collaboration with a pediatric HIV specialist (AI*).
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
Definitions of Treatment Failure
Treatment failure can be categorized as virologic failure, immunologic failure, or clinical failure (or some combination of the three). Laboratory results must be confirmed with repeat testing before a final assessment of virologic or immunologic treatment failure is made. Almost all antiretroviral (ARV) management decisions for treatment failure are based on addressing virologic failure.
Virologic failure occurs as an incomplete initial response to therapy or as a viral rebound after virologic suppression is achieved. Virologic suppression is defined as having plasma viral load below the lower level of quantification (LLQ) using the most sensitive assay (LLQ 20–75 copies/mL). Older assays with LLQ of 400 copies/mL are not recommended. Virologic failure is defined for all children as a repeated plasma viral load >200 copies/mL after 6 months of therapy. Because infants with high plasma viral loads at initiation of therapy occasionally take longer than 6 months to achieve virologic suppression, some experts continue the treatment regimen for such infants if viral load is declining but is still >200 copies/mL at 6 months and monitor closely for continued decline to virologic suppression soon thereafter. Among many of those receiving lopinavir/ritonavir, suppression can be achieved without regimen change if efforts are made to improve adherence.1 However, ongoing non-suppression—especially with non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens—increases the risk of drug resistance.2 There is controversy regarding the clinical implications of HIV RNA levels between the LLQ and <200 copies/mL in patients on combination antiretroviral therapy (cART). HIV-infected adults with detectable viral loads and a quantified result <200 copies/mL after 6 months of cART often ultimately achieve virologic suppression without regimen change.3 “Blips,” defined as isolated episodes of plasma viral load detectable at low levels (<500 copies/mL) followed by return to viral suppression, are common and not generally reflective of virologic failure.4-6 Repeated or persistent plasma viral load detection above 200 copies/mL (especially if >500 copies/mL) after having achieved virologic suppression usually represents virologic failure.6-9
Immunologic failure is defined as a suboptimal immunologic response to therapy or an immunologic decline while on therapy. While there is no standardized definition, many experts would consider as suboptimal immunologic response to therapy the failure to maintain or achieve a CD4 T lymphocyte (CD4) cell count/percentage that is at least above the age-specific range for severe immunodeficiency. Evaluation of immune response in children is complicated by the normal age-related changes in CD4 cell count discussed previously (see Immunologic Monitoring in Children: General Considerations in Clinical and Laboratory Monitoring). Thus, the normal decline in CD4 values with age needs to be considered when evaluating declines in CD4 parameters. CD4 percentage tends to vary less with age. At about age 5 years, absolute CD4 cell count values in children approach those of adults; consequently, changes in absolute count can be used in children aged ≥5 years.
Clinical failure is defined as the occurrence of new opportunistic infections (OIs) and/or other clinical evidence of HIV disease progression during therapy. Clinical failure represents the most urgent and concerning type of treatment failure and should prompt an immediate evaluation. Clinical findings should be viewed in the context of virologic and immunologic response to therapy; in patients with stable virologic and immunologic parameters, development of clinical symptoms may not represent treatment failure. Clinical events occurring in the first several months after cART initiation often do not represent cART failure. For example, the development or worsening of an OI in a patient who recently initiated cART may reflect a degree of persistent immune dysfunction in the context of early recovery or, conversely, be a result of immune reconstitution inflammatory syndrome (IRIS). However, clinical failure may occur many months after CD4 cell counts have normalized.10 The occurrence of significant clinical disease progression should prompt strong consideration that the current treatment regimen is failing.
Discordance Between Virologic, Immunologic, and Clinical Responses
In general, cART that results in virologic suppression also leads to immune restoration or preservation as well as to prevention of HIV-related illnesses. The converse is also generally true: Ineffective cART that fails to suppress viremia is commonly accompanied by immunologic and clinical failure.11 However, patients may also present with discordant responses, with failure in one domain (e.g., immunologic failure) but with a good response in the other domains (e.g., virologic and clinical response). It is essential to consider potential alternative causes of discordant responses before concluding that cART failure has truly occurred.
Poor immunologic response despite virologic suppression is uncommon in children.10 For patients with baseline severe immunosuppression, virologic suppression may be achieved much sooner than immune recovery. During this early treatment period of persistent immunosuppression, additional clinical disease progression can occur.
The first considerations in cases of poor immunologic response despite virologic suppression are to exclude laboratory error in CD4 or viral load measurements and to ensure that CD4 values have been interpreted correctly in relation to the natural decline in CD4 cell count over the first 5 to 6 years of life. Another laboratory consideration is that some viral load assays may not amplify all HIV groups and subtypes (such as HIV-1 non-M groups or HIV-2), resulting in falsely low or negative viral load results (see Diagnosis of HIV Infection and Clinical and Laboratory Monitoring). Once laboratory results are confirmed, evaluation for adverse drug effects, medical conditions, and other factors that can result in lower CD4 values is necessary (see Table 15).
Patients who have very low baseline CD4 values before initiating cART are at higher risk of an impaired CD4 response to cART and, based on adult studies, may be at higher risk of death and AIDS-defining illnesses, despite virologic suppression.12-16 In a study of 933 children aged ≥5 years who received cART that resulted in virologic suppression, 92 (9.9%) had CD4 cell counts <200 cells/mm3 at cART initiation and 348 (37%) had CD4 cell counts <500 cells/mm3. After 1 year of virologic suppression, only 7 (1% of the cohort) failed to reach a CD4 cell count of at least 200 cells/mm3 and 86% had CD4 cell counts >500 cells/mm3. AIDS-defining events were uncommon overall (1%) but occurred in children who did and did not achieve improved CD4 cell counts.10
Certain ARV agents or combinations may be associated with a blunted CD4 response. For example, treatment with a regimen containing tenofovir disoproxil fumarate (tenofovir) and didanosine can blunt the CD4 response, especially if the didanosine dose is not reduced,17 and this combination is not recommended as part of initial therapy. Dosing of didanosine should be reduced when co-administered with tenofovir. In adults, ARV regimens containing zidovudine may also impair rise in CD4 cell count but not CD4 percentage, perhaps through the myelosuppressive effects of zidovudine.18 Fortunately, this ARV drug-related suboptimal CD4 cell count response to therapy does not seem to confer an increased risk of clinical events. It is not clear whether this scenario warrants substitution of zidovudine with another drug.
Several drugs (e.g., corticosteroids, chemotherapeutic agents) and other conditions (e.g., hepatitis C, tuberculosis, malnutrition, Sjogren’s syndrome, sarcoidosis, syphilis) are independently associated with low CD4 values.
Poor Clinical Response Despite Adequate Virologic and Immunologic Responses
Clinicians must carefully evaluate patients who experience clinical disease progression despite favorable immunologic and virologic responses to cART. Not all cases represent cART failure. One of the most important reasons for new or recurrent opportunistic conditions despite achieving virologic suppression and immunologic restoration/preservation within the first months of cART is IRIS, which does not represent cART failure and does not generally require discontinuation of cART.19,20 Children who have suffered irreversible damage to their lungs, brain, or other organs—especially during prolonged and profound pretreatment immunosuppression—may continue to have recurrent infections or symptoms in the damaged organs because the immunologic improvement may not reverse damage to the organs.21 Such cases do not represent cART failure and, in these instances, children would not benefit from a change in ARV regimen. Before a definitive conclusion of cART clinical failure is reached, a child should also be evaluated to rule out (and, if indicated, treat) other causes or conditions that can occur with or without HIV-related immunosuppression, such as pulmonary tuberculosis, malnutrition, and malignancy. Occasionally, however, children will develop new HIV-related opportunistic conditions (e.g., Pneumocystis jirovecii pneumonia or esophageal candidiasis occurring more than 6 months after achieving markedly improved CD4 values and virologic suppression) not explained by IRIS, pre-existing organ damage, or another reason.10 Although such cases are rare, they may represent cART clinical failure and suggest that improvement in CD4 values may not necessarily represent normalization of immunologic function. In children who have signs of new or progressive abnormal neurodevelopment, some experts change the ARV regimen, aiming to include agents that are known to achieve higher concentrations in the central nervous system; however, the data supporting the strategy are mixed.22-26
Table 15: Discordance Among Virologic, Immunologic, and Clinical Responses
Differential Diagnosis of Poor Immunologic Response Despite Virologic Suppression
Poor Immunologic Response Despite Virologic Suppression and Good Clinical Response:
Lab error (in CD4 or viral load result)
Normal age-related CD4 decline (i.e., immunologic response not actually poor)
Low pretreatment CD4 cell count or percentage
Adverse effects of use of zidovudine or the combination of tenofovir and didanosine
Use of systemic corticosteroids or chemotherapeutic agents
Conditions that can cause low CD4 values, such as hepatitis C
coinfection, tuberculosis, malnutrition, Sjogren’s syndrome,
sarcoidosis, and syphilis
Poor Immunologic and Clinical Responses Despite Virologic Suppression:
Lab error, including HIV strain/type not detected by viral load assay (HIV-1 non-M groups, non-B subtypes; HIV-2)
Persistent immunodeficiency soon after initiation of cART but before cART-related reconstitution
Primary protein-calorie malnutrition
Loss of immunologic (CD4) reserve
Differential Diagnosis of Poor Clinical Response Despite Adequate Virologic and Immunologic Responses
Previously unrecognized pre-existing infection or condition (e.g., tuberculosis, malignancy)
Clinical manifestations of previous organ damage: brain (strokes, vasculopathy), lungs (bronchiectasis)
New clinical event due to non-HIV illness or condition
Key to Acronyms: cART = combination antiretroviral therapy; CD4 = CD4 T
lymphocyte; IRIS = immune reconstitution inflammatory syndrome
Management of Virologic Treatment Failure
Since almost all ARV management decisions for treatment failure are based on addressing virologic failure, this section on managing treatment failure will address only virologic treatment failure (repeated plasma viral load >200 copies/mL after 6 months of therapy).
The approach to management and subsequent treatment of virologic treatment failure may differ depending on the etiology of the problem. Although the cause of virologic treatment failure may be multifactorial, it is generally the result of non-adherence. Assessment of a child with suspicion of virologic treatment failure should include evaluation of adherence to therapy, medication intolerance, pharmacokinetic (PK) explanations of low drug levels or elevated, potentially toxic levels, and evaluation of suspected drug resistance (see Antiretroviral Drug-Resistance Testing). The main barrier to long-term maintenance of sustained virologic suppression in adults and children is incomplete adherence to medication regimens, with subsequent emergence of viral mutations conferring partial or complete resistance to one or more of the components of the ARV regimen. Table 16 outlines a comprehensive approach to evaluating causes of virologic treatment failure in children, with particular attention to adherence.
Table 16. Assessment of Causes of Virologic Antiretroviral Treatment Failure
Cause of Virologic Treatment Failure
Interview child and caretaker.
Take 24-hour or 7-day recall.
Obtain description of:
WHO gives medications
WHEN medications are taken/given
WHAT medications are taken/given (names, doses)
WHERE medications are kept/administered
HOW medications make child feel
Have open-ended discussion of experiences taking/giving medications
Identify or re-engage family members to
Establish fixed daily times and routines for medication administration.
To avoid any patient/caregiver confusion with drug names, explain that
drug therapies have generic names and trade names, and many agents are
co-formulated under a third or fourth name.
Explore opportunities for facility or home-based DOT.
Review pharmacy records.
Assess timeliness of refills.
Observe medication administration.
Observe dosing/administration in clinic.
Conduct home-based observation by visiting health professional.
Admit to hospital for trial of therapy.
Monitor treatment response.
Simplify medication regimen, if feasible.
Substitute new agents if single ARV is poorly tolerated.
Use tools to simplify administration (e.g., pill boxes, reminders
[including alarms], integrated medication packaging for a.m. or p.m.
As a last resort, consider gastric tube placement to facilitate adherence.
Conduct psychosocial assessment.
Make a comprehensive family-focused assessment of factors likely to
impact adherence with particular attention to recent changes in:
Status of caregiver, housing, financial stability of household,
child/caretaker relationships, school, and child’s achievement level
Substance abuse (child, caretaker, family members)
Mental health and behavior
Child/youth and caretaker beliefs about cART
Disclosure status (to child and others)
Address competing needs through appropriate social services.
Address and treat concomitant mental illness and behavioral disorders.
Initiate disclosure discussions with family/child.
Consider need for child protective services and alternate care settings when necessary.
Pharmacokinetics and Dosing Issues
Recalculate doses for individual medications using weight or body surface area.
Identify concomitant medications including prescription,
over-the-counter, and recreational substances; assess for drug-drug
If no resistance to current drugs is detected, focus on improving adherence.
If resistance to current regimen is detected, optimize adherence
and evaluate potential for new regimen (see Management of Virologic
Key to Acronyms: ARV = antiretroviral; cART = combination antiretroviral therapy; DOT = directly observed therapy
Virologic Treatment Failure with No Viral Drug Resistance Identified
Persistent viremia in the absence of detectable viral resistance to current medications is usually a result of non-adherence, but it is important to exclude other factors such as poor drug absorption, incorrect dosing, and drug interactions. If adequate drug exposure can be ensured, then adherence to the current regimen should result in virologic suppression. Resistance testing should take place while a child is on therapy. After discontinuation of therapy, predominant plasma viral strains may quickly revert to wild-type and re-emerge as the predominant viral population, in which case resistance testing may fail to reveal drug-resistant virus (see Antiretroviral Drug-Resistance Testing). An approach to identifying resistance in this situation is to restart the prior medications while emphasizing adherence, and repeat resistance testing in 4 weeks if plasma virus remains detectable. If the HIV plasma viral load becomes undetectable, non-adherence was likely the original cause of virologic treatment failure.
Virologic failure of boosted protease inhibitor (PI)-based regimens (in the absence of prior treatment with full-dose ritonavir) is frequently associated with no detectable major PI resistance mutations, and virologic suppression may be achieved with continuation of the PI-based regimen accompanied by adherence improvement measures.27,28
In some cases, the availability of a new regimen for which the convenience (e.g., single fixed-dose tablet once daily) is anticipated to address the main barrier to adherence may make it reasonable to change to this new regimen with close adherence and viral load monitoring. In most cases, however, when there is evidence of poor adherence to the current regimen and an assessment that good adherence to a new regimen is unlikely, emphasis and effort should be placed on improving adherence before initiating a new regimen (see Adherence). When efforts to improve adherence will require several weeks or months, many clinicians may choose to continue the current non-suppressive regimen (see Management Options When Two Fully Active Agents Cannot Be Identified or Administered).29-31 Treatment with non-suppressive regimens in such situations should be regarded as an acceptable but not ideal interim strategy to prevent immunologic and clinical deterioration while working on adherence. Such patients should be followed more closely than those with stable virologic status, and the potential to successfully initiate a fully suppressive ARV drug regimen should be reassessed at every opportunity. Complete treatment interruption for a persistently non-adherent patient should prevent accumulation of additional drug resistance but has been associated with immunologic declines and poor clinical outcomes.32
Virologic Treatment Failure with Viral Drug Resistance Identified
After reaching a decision that a change in therapy is needed, a clinician should attempt to identify at least two, but preferably three, fully active ARV agents from at least two different classes on the basis of resistance test results, prior ARV exposure, acceptability to the patient, and likelihood of adherence.33-37 This often requires using agents from one or more drug classes that are new to the patient. Substitution or addition of a single drug to a failing regimen is not recommended because it is unlikely to lead to durable virologic suppression and will likely result in additional drug resistance. A drug may be new to the patient but have diminished antiviral potency because of the presence of drug-resistance mutations that confer cross-resistance within a drug class.
A change to a new regimen must include an extensive discussion of treatment adherence and potential toxicity with a patient in an age- and development-appropriate manner and with a patient’s caregivers. Clinicians must recognize that conflicting requirements of some medications with respect to food and concomitant medication restrictions may complicate administration of a regimen. Timing of medication administration is particularly important to ensure adequate ARV drug exposures throughout the day. Palatability, size and number of pills, and dosing frequency all need to be considered when choosing a new regimen.38
Therapeutic Options After Virologic Treatment Failure with Goal of Complete Virologic Suppression
Determination of a new regimen with the best chance for complete virologic suppression in children who have already experienced treatment failure should be made by or in collaboration with a pediatric HIV specialist. ARV regimens should be chosen based on treatment history and drug-resistance testing to optimize ARV drug potency in the new regimen. A general strategy for regimen change is shown in Table 17, although as additional agents are licensed and studied for use in children, newer strategies that are better tailored to the needs of each patient may be constructed.
If a child has received initial therapy with an NNRTI-based regimen, a change to a PI-based regimen or integrase strand transfer inhibitor (INSTI)-based regimen is generally effective. Resistance to the NNRTI nevirapine results in cross-resistance to the NNRTI efavirenz, and vice versa. However, the NNRTI etravirine can retain activity against nevirapine- or efavirenz-resistant virus in the absence of certain key NNRTI mutations (see below), but etravirine has generally been tested only in regimens that also contain a boosted PI. If a child received initial therapy with a PI-based regimen, a change to an NNRTI-based regimen or an INSTI-based regimen is generally effective. Lopinavir/ritonavir-based regimens have also been shown to have durable ARV activity in some PI-experienced children.39-41
The availability of new drugs in existing classes (e.g., the NNRTI etravirine) and other classes of drugs (e.g., INSTI) increases the likelihood of finding three active drugs, even for children with extensive drug resistance (see Table 17). Etravirine in combination with darunavir/ritonavir has been shown to be a safe and effective option for children for whom first-line cART fails.42,43 Etravirine is approved for use in children aged ≥6 years and darunavir in children aged ≥3 years. Raltegravir, an INSTI, is approved for children aged ≥4 weeks.44 Dolutegravir is approved for use in adolescents aged ≥12 years. Use of newer agents in novel combinations is becoming more common in aging perinatally infected youth in the United States.45 It is important to review individual drug profiles for information about drug interactions and dose adjustment when devising a regimen for children with multi-class drug resistance. Appendix A: Pediatric Antiretroviral Drug Information provides more detailed information on drug formulation, pediatric and adult dosing, and toxicity, as well as discussion of available pediatric data for the approved ARV drugs.
Previously prescribed drugs that were discontinued because of poor tolerance or poor adherence may sometimes be reintroduced if ARV resistance did not develop and if prior difficulties with tolerance and adherence can be overcome (e.g., by switching from a liquid to a pill formulation or to a new formulation [e.g., ritonavir tablet]). Limited data in adults suggest that continuation of lamivudine can contribute to suppression of HIV replication despite the presence of lamivudine resistance mutations and can maintain lamivudine mutations (184V) that can partially reverse the effect of other mutations conferring resistance to zidovudine, stavudine, and tenofovir.46-48 The use of new drugs that have been evaluated in adults but have not been fully evaluated in children may be justified, and ideally would be done in the framework of a clinical trial. Expanded access programs or clinical trials may be available (see www.clinicaltrials.gov). New drugs should be used in combination with at least one, and ideally two, additional active agents.
Enfuvirtide has been Food and Drug Administration-approved for treatment-experienced children aged ≥6 years but must be administered by subcutaneous injection twice daily.49,50 PK studies of certain dual-boosted PI regimens (lopinavir/ritonavir with saquinavir) suggest that PK targets for both PIs can be achieved or exceeded when used in combination in children.51-53 Multidrug regimens (up to 3 PIs and/or 2 NNRTIs) have shown efficacy in a pediatric case series, but they are complex, often poorly tolerated, and subject to unfavorable drug-drug interactions.54 Availability of newer PIs (e.g., darunavir) and new classes of ARV drugs (integrase and CCR5 inhibitors) have lessened the need for use of enfuvirtide, dual-PI regimens, and regimens of four or more drugs.
Studies of nucleoside reverse transcriptase inhibitor (NRTI)-sparing regimens in adults with virologic failure and multidrug resistance have demonstrated no clear benefit of including NRTIs in the new regimen,55,56 and one of these studies reported higher mortality in those adults randomized to a regimen with NRTIs compared to adults randomized to an NRTI-sparing regimen.56 There are no studies of NRTI-sparing regimens in children with virologic failure and multidrug resistance, but that may be a reasonable option for children with extensive NRTI resistance.
When searching for at least two fully active agents in cases of extensive drug resistance, clinicians should consider the potential availability and future use of newer therapeutic agents that may not be studied or approved in children or may be in clinical development. Information concerning potential clinical trials can be found at https://aidsinfo.nih.gov/clinical_trials and through collaboration with a pediatric HIV specialist. Children should be enrolled in clinical trials of new drugs whenever possible.
Pediatric dosing for off-label use of ARV drugs is problematic because absorption, hepatic metabolism, and excretion change with age.57 In clinical trials of several ARV agents, direct extrapolation of a pediatric dose from an adult dose, based on a child’s body weight or body surface area, was shown to result in an underestimation of the appropriate pediatric dose.58
Use of ARV agents that do not have a pediatric indication (i.e., off-label) may be necessary for HIV-infected children with limited ARV options. In this circumstance, consultation with a pediatric HIV specialist for advice about potential regimens, assistance with access to unpublished data from clinical trials or other limited off-label pediatric use, and referral to suitable clinical trials is recommended.
Management Options When Two Fully Active Agents Cannot Be Identified or Administered
It may be impossible to provide an effective and sustainable therapeutic regimen because no combination of currently available agents is active against extensively drug-resistant virus in a patient or because a patient is unable to adhere to or tolerate cART.
The decision to continue a non-suppressive regimen must be made on an individual basis, weighing potential benefits and costs. Specifically, HIV providers must balance the inherent tension between the benefits of virologic suppression and the risks of continued viral replication and potential evolution of viral drug resistance in the setting of inadequate ARV drug exposure (i.e., non-adherence, non-suppressive suboptimal regimen). Non-suppressive regimens could decrease viral fitness and thus slow clinical and immunologic deterioration while a patient is either working on adherence or awaiting access to new agents that are expected to achieve sustained virologic suppression.59 However, persistent viremia in the context of ARV pressure has the potential to generate additional resistance mutations that could further compromise agents in the same class that might otherwise have been active in subsequent regimens (e.g., continuing first-generation INSTIs or NNRTIs). Patients continuing non-suppressive regimens should be followed more closely than those with stable virologic status, and the potential to successfully initiate a fully suppressive cART regimen should be reassessed at every opportunity.
The use of NRTI-only holding regimens or complete interruption of therapy is not recommended. In a trial (IMPAACT P1094) randomizing children harboring the M184V resistance mutation with persistent non-adherence and virologic failure to continue their non-suppressive non-NNRTI-based cART regimen versus switching to a lamivudine (or emtricitabine) monotherapy holding regimen, children who switched to monotherapy experienced a 30% decline in absolute CD4 cell count (the primary outcome) over a 28-week period. The median age of the participants was 15 years and the median entry CD4 cell count was 472 cells/mm3, and the median number of interventions that had been used to address non-adherence was four. Only patients in the lamivudine/emtricitabine arm experienced the primary outcome.60 Although this was a small study (N = 33), it is the only study ever to randomize patients to continuing non-suppressive cART versus lamivudine/emtricitabine monotherapy, and it is unlikely that it will be repeated. Thus, NRTI-only holding regimens are not recommended as a treatment strategy for children failing non-suppressive cART.
Complete treatment interruption has also been associated with immunologic declines and poor clinical outcomes and is not recommended.32 See Treatment Interruption.
Table 17. Options for Regimens with at Least Two Fully Active Agents with Goal of Virologic Suppression in Patients with Failed Antiretroviral Therapy and Evidence of Viral Resistancea
2 NRTIs + NNRTI
2 NRTIs + PI
2 NRTIs + INSTI
2 NRTIs + PI
2 NRTIs + NNRTI
2 NRTIs + INSTI
2 NRTIs + different RTV-boosted PI
NRTI(s) + INSTI + (NNRTI or different RTV-boosted PI)
2 NRTIs + NNRTI
2 NRTIs + PI
2 NRTIs + INSTI
INSTI + 2 other active agents (chosen from NNRTI, PI, NRTI[s])
Failed Regimen(s) That Included NRTI(s), NNRTI(s), and PI(s)
2 NRTIs + INSTI (+ RTV-boosted PI if additional active drug needed)
NRTI(s) + RTV-boosted PI + INSTI (consider adding T20 and/or MVCb if additional active drug[s] needed)
NRTI(s) + RTV-boosted DRV, LPV, or SQV + ETR (consider adding one or
more of MVC,b T20, or INSTI if additional active drug[s] needed)
>1 NRTI + 2 RTV-boosted PIs (LPV/r + SQV, LPV/r + ATV) (consider
adding T20 or an INSTI if additional active drug[s] needed)
a ARV regimens should be chosen based on treatment history and drug-resistance testing to optimize ARV drug effectiveness. This is particularly important in selecting NRTI components of an NNRTI-based regimen where drug resistance to the NNRTI can occur rapidly if the virus is not sufficiently sensitive to the NRTIs. Regimens should contain at least two, but preferably three, fully active drugs for durable, potent virologic suppression. Please see individual drug profiles for information about drug interactions and dose adjustment when devising a regimen for children with multi-class drug resistance. Collaboration with a pediatric HIV specialist is especially important when choosing regimens for children with multi-class drug resistance. Regimens in this table are provided as examples, but the list is not exhaustive.
b No current Food and Drug Administration-approved pediatric indication for maraviroc
Chadwick EG, Capparelli EV, Yogev R, et al. Pharmacokinetics, safety and efficacy of lopinavir/ritonavir in infants less than 6 months of age: 24 week results. AIDS. 2008;22(2):249-255. Available at http://www.ncbi.nlm.nih.gov/pubmed/18097227.
Eshleman SH, Krogstad P, Jackson JB, et al. Analysis of human immunodeficiency virus type 1 drug resistance in children receiving nucleoside analogue reverse-transcriptase inhibitors plus nevirapine, nelfinavir, or ritonavir (Pediatric AIDS Clinical Trials Group 377). J Infect Dis. 2001;183(12):1732-1738. Available at http://www.ncbi.nlm.nih.gov/pubmed/11372025.
Ribaudo HJ, Lennox J, Currier J, et al. Virologic failure endpoint definition in clinical trials: is using HIV-1 RNA threshold <200 copies/mL better than <50 copies/mL? an analysis of ACTG Studies. CROI 2009 #580. Presented at: 16th Conference on Retroviruses and Opportunistic Infections. 2009. Montréal, Canada.
Lee KJ, Shingadia D, Pillay D, et al. Transient viral load increases in HIV-infected children in the U.K. and Ireland: what do they mean? Antivir Ther. 2007;12(6):949-956. Available at http://www.ncbi.nlm.nih.gov/pubmed/17926649.
Coovadia A, Abrams EJ, Stehlau R, et al. Reuse of nevirapine in exposed HIV-infected children after protease inhibitor-based viral suppression: a randomized controlled trial. JAMA. 2010;304(10):1082-1090. Available at http://www.ncbi.nlm.nih.gov/pubmed/20823434.
Grennan JT, Loutfy MR, Su D, et al. Magnitude of virologic blips is associated with a higher risk for virologic rebound in HIV-infected individuals: a recurrent events analysis. J Infect Dis. 2012;205(8):1230-1238. Available at http://www.ncbi.nlm.nih.gov/pubmed/22438396.
Karlsson AC, Younger SR, Martin JN, et al. Immunologic and virologic evolution during periods of intermittent and persistent low-level viremia. AIDS. 2004;18(7):981-989. Available at http://www.ncbi.nlm.nih.gov/pubmed/15096800.
Aleman S, Soderbarg K, Visco-Comandini U, Sitbon G, Sonnerborg A. Drug resistance at low viraemia in HIV-1-infected patients with antiretroviral combination therapy. AIDS. 2002;16(7):1039-1044. Available at http://www.ncbi.nlm.nih.gov/pubmed/11953470.
Boillat-Blanco N, Darling KE, Schoni-Affolter F, et al. Virological outcome and management of persistent low-level viraemia in HIV-1-infected patients: 11 years of the Swiss HIV Cohort Study. Antivir Ther. 2014. Advanced online publication. Available at http://www.ncbi.nlm.nih.gov/pubmed/24964403.
Krogstad P, Patel K, Karalius B, et al. Incomplete immune reconstitution despite virological suppression in HIV-infected children and adolescents. AIDS. 2015. Advanced online publication. Available at http://journals.lww.com/aidsonline/Abstract/publishahead/Incomplete_immune_reconstitution_despite_virologic.98148.aspx.
Oliveira R, Krauss M, Essama-Bibi S, et al. HIV viral load predicts World Health Organization (WHO) Stage 3 and 4 events among children in Latin America independent of CD4 level. Presented at: 1st International Workshop on HIV Pediatrics. 2009. Cape Town, South Africa.
Soh CH, Oleske JM, Brady MT, et al. Long-term effects of protease-inhibitor-based combination therapy on CD4 T-cell recovery in HIV-1-infected children and adolescents. Lancet. 2003;362(9401):2045-2051. Available at http://www.ncbi.nlm.nih.gov/pubmed/14697803.
Moore DM, Hogg RS, Chan K, Tyndall M, Yip B, Montaner JS. Disease progression in patients with virological suppression in response to HAART is associated with the degree of immunological response. AIDS. 2006;20(3):371-377. Available at http://www.ncbi.nlm.nih.gov/pubmed/16439870.
Resino S, Alvaro-Meca A, de Jose MI, et al. Low immunologic response to highly active antiretroviral therapy in naive vertically human immunodeficiency virus type 1-infected children with severe immunodeficiency. Pediatr Infect Dis J. 2006;25(4):365-368. Available at http://www.ncbi.nlm.nih.gov/pubmed/16567992.
Lewis J, Walker AS, Castro H, et al. Age and CD4 count at initiation of antiretroviral therapy in HIV-infected children: effects on long-term T-cell reconstitution. J Infect Dis. 2012;205(4):548-556. Available at http://www.ncbi.nlm.nih.gov/pubmed/22205102.
van Lelyveld SF, Gras L, Kesselring A, et al. Long-term complications in patients with poor immunological recovery despite virological successful HAART in Dutch ATHENA cohort. AIDS. 2012;26(4):465-474. Available at http://www.ncbi.nlm.nih.gov/pubmed/22112603.
Negredo E, Bonjoch A, Paredes R, Puig J, Clotet B. Compromised immunologic recovery in treatment-experienced patients with HIV infection receiving both tenofovir disoproxil fumarate and didanosine in the TORO studies. Clin Infect Dis. 2005;41(6):901-905. Available at http://www.ncbi.nlm.nih.gov/pubmed/16107993.
Huttner AC, Kaufmann GR, Battegay M, Weber R, Opravil M. Treatment initiation with zidovudine-containing potent antiretroviral therapy impairs CD4 cell count recovery but not clinical efficacy. AIDS. 2007;21(8):939-946. Available at http://www.ncbi.nlm.nih.gov/pubmed/17457087.
Smith K, Kuhn L, Coovadia A, et al. Immune reconstitution inflammatory syndrome among HIV-infected South African infants initiating antiretroviral therapy. AIDS. 2009;23(9):1097-1107. Available at http://www.ncbi.nlm.nih.gov/pubmed/19417581.
Meintjes G, Lynen L. Prevention and treatment of the immune reconstitution inflammatory syndrome. Curr Opin HIV AIDS. 2008;3(4):468-476. Available at http://www.ncbi.nlm.nih.gov/pubmed/19373007.
Graham SM. Non-tuberculosis opportunistic infections and other lung diseases in HIV-infected infants and children. Int J Tuberc Lung Dis. 2005;9(6):592-602. Available at http://www.ncbi.nlm.nih.gov/pubmed/15971385.
Antinori A, Giancola ML, Grisetti S, et al. Factors influencing virological response to antiretroviral drugs in cerebrospinal fluid of advanced HIV-1-infected patients. AIDS. 2002;16(14):1867-1876. Available at http://www.ncbi.nlm.nih.gov/pubmed/12351946.
Antinori A, Perno CF, Giancola ML, et al. Efficacy of cerebrospinal fluid (CSF)-penetrating antiretroviral drugs against HIV in the neurological compartment: different patterns of phenotypic resistance in CSF and plasma. Clin Infect Dis. 2005;41(12):1787-1793. Available at http://www.ncbi.nlm.nih.gov/pubmed/16288405.
Capparelli EV, Letendre SL, Ellis RJ, Patel P, Holland D, McCutchan JA. Population pharmacokinetics of abacavir in plasma and cerebrospinal fluid. Antimicrob Agents Chemother. 2005;49(6):2504-2506. Available at http://www.ncbi.nlm.nih.gov/pubmed/15917556.
Letendre S, Marquie-Beck J, Capparelli E, et al. Validation of the CNS Penetration-Effectiveness rank for quantifying antiretroviral penetration into the central nervous system. Arch Neurol. 2008;65(1):65-70. Available at http://www.ncbi.nlm.nih.gov/pubmed/18195140.
Patel K, Ming X, Williams PL, et al. Impact of HAART and CNS-penetrating antiretroviral regimens on HIV encephalopathy among perinatally infected children and adolescents. AIDS. 2009;23(14):1893-1901. Available at http://www.ncbi.nlm.nih.gov/pubmed/19644348.
van Zyl GU, van der Merwe L, Claassen M, et al. Protease inhibitor resistance in South African children with virologic failure. Pediatr Infect Dis J. 2009;28(12):1125-1127. Available at http://www.ncbi.nlm.nih.gov/pubmed/19779394.
Zheng Y, Hughes MD, Lockman S, et al. Antiretroviral therapy and efficacy after virologic failure on first-line boosted protease inhibitor regimens. Clin Infect Dis. 2014;59(6):888-896. Available at http://www.ncbi.nlm.nih.gov/pubmed/24842909.
Abadi J, Sprecher E, Rosenberg MG, et al. Partial treatment interruption of protease inhibitor-based highly active antiretroviral therapy regimens in HIV-infected children. J Acquir Immune Defic Syndr. 2006;41(3):298-303. Available at http://www.ncbi.nlm.nih.gov/pubmed/16540930.
Deeks SG, Hoh R, Neilands TB, et al. Interruption of treatment with individual therapeutic drug classes in adults with multidrug-resistant HIV-1 infection. J Infect Dis. 2005;192(9):1537-1544. Available at http://www.ncbi.nlm.nih.gov/pubmed/16206068.
Castagna A, Danise A, Menzo S, et al. Lamivudine monotherapy in HIV-1-infected patients harbouring a lamivudine-resistant virus: a randomized pilot study (E-184V study). AIDS. 2006;20(6):795-803. Available at http://www.ncbi.nlm.nih.gov/pubmed/16549962.
Saitoh A, Foca M, Viani RM, et al. Clinical outcomes after an unstructured treatment interruption in children and adolescents with perinatally acquired HIV infection. Pediatrics. 2008;121(3):e513-521. Available at http://www.ncbi.nlm.nih.gov/pubmed/18310171.
Katlama C, Haubrich R, Lalezari J, et al. Efficacy and safety of etravirine in treatment-experienced, HIV-1 patients: pooled 48 week analysis of two randomized, controlled trials. AIDS. 2009;23(17):2289-2300. Available at http://www.ncbi.nlm.nih.gov/pubmed/19710593.
Steigbigel RT, Cooper DA, Teppler H, et al. Long-term efficacy and safety of Raltegravir combined with optimized background therapy in treatment-experienced patients with drug-resistant HIV infection: week 96 results of the BENCHMRK 1 and 2 Phase III trials. Clin Infect Dis. 2010;50(4):605-612. Available at http://www.ncbi.nlm.nih.gov/pubmed/20085491.
De Luca A, Di Giambenedetto S, Cingolani A, Bacarelli A, Ammassari A, Cauda R. Three-year clinical outcomes of resistance genotyping and expert advice: extended follow-up of the Argenta trial. Antivir Ther. 2006;11(3):321-327. Available at http://www.ncbi.nlm.nih.gov/pubmed/16759048.
Baxter JD, Mayers DL, Wentworth DN, et al. A randomized study of antiretroviral management based on plasma genotypic antiretroviral resistance testing in patients failing therapy. CPCRA 046 Study Team for the Terry Beirn Community Programs for Clinical Research on AIDS. AIDS. 2000;14(9):F83-93. Available at http://www.ncbi.nlm.nih.gov/pubmed/10894268.
Tural C, Ruiz L, Holtzer C, et al. Clinical utility of HIV-1 genotyping and expert advice: the Havana trial. AIDS. 2002;16(2):209-218. Available at http://www.ncbi.nlm.nih.gov/pubmed/11807305.
Lin D, Seabrook JA, Matsui DM, King SM, Rieder MJ, Finkelstein Y. Palatability, adherence and prescribing patterns of antiretroviral drugs for children with human immunodeficiency virus infection in Canada. Pharmacoepidemiol Drug Saf. 2011;20(12):1246-1252. Available at http://www.ncbi.nlm.nih.gov/pubmed/21936016.
Galan I, Jimenez JL, Gonzalez-Rivera M, et al. Virological phenotype switches under salvage therapy with lopinavir-ritonavir in heavily pretreated HIV-1 vertically infected children. AIDS. 2004;18(2):247-255. Available at http://www.ncbi.nlm.nih.gov/pubmed/15075542.
Ramos JT, De Jose MI, Duenas J, et al. Safety and antiviral response at 12 months of lopinavir/ritonavir therapy in human immunodeficiency virus-1-infected children experienced with three classes of antiretrovirals. Pediatr Infect Dis J. 2005;24(10):867-873. Available at http://www.ncbi.nlm.nih.gov/pubmed/16220083.
Resino S, Bellon JM, Munoz-Fernandez MA, Spanish Group of HIVI. Antiretroviral activity and safety of lopinavir/ritonavir in protease inhibitor-experienced HIV-infected children with severe-moderate immunodeficiency. J Antimicrob Chemother. 2006;57(3):579-582. Available at http://www.ncbi.nlm.nih.gov/pubmed/16446377.
Briz V, Palladino C, Navarro M, et al. Etravirine-based highly active antiretroviral therapy in HIV-1-infected paediatric patients. HIV Med. 2011;12(7):442-446. Available at http://www.ncbi.nlm.nih.gov/pubmed/21395964.
Blanche S, Bologna R, Cahn P, et al. Pharmacokinetics, safety and efficacy of darunavir/ritonavir in treatment-experienced children and adolescents. AIDS. 2009;23(15):2005-2013. Available at http://www.ncbi.nlm.nih.gov/pubmed/19724191.
Nachman S, Acosta E, Zheng N, et al. Interim Results from IMPAACT P1066: RAL Oral Chewable Tablet Formulation for 2- to 5-Year-olds. Abstract 715. Presented at: 18th Conference on Retroviruses and Opportunistic Infections. 2011. Boston, MA.
Van Dyke RB, Patel K, Siberry GK, et al. Antiretroviral treatment of US children with perinatally acquired HIV infection: temporal changes in therapy between 1991 and 2009 and predictors of immunologic and virologic outcomes. J Acquir Immune Defic Syndr. 2011;57(2):165-173. Available at http://www.ncbi.nlm.nih.gov/pubmed/21407086.
Campbell TB, Shulman NS, Johnson SC, et al. Antiviral activity of lamivudine in salvage therapy for multidrug-resistant HIV-1 infection. Clin Infect Dis. 2005;41(2):236-242. Available at http://www.ncbi.nlm.nih.gov/pubmed/15983922.
Nijhuis M, Schuurman R, de Jong D, et al. Lamivudine-resistant human immunodeficiency virus type 1 variants (184V) require multiple amino acid changes to become co-resistant to zidovudine in vivo. J Infect Dis. 1997;176(2):398-405. Available at http://www.ncbi.nlm.nih.gov/pubmed/9237704.
Ross L, Parkin N, Chappey C, et al. Phenotypic impact of HIV reverse transcriptase M184I/V mutations in combination with single thymidine analog mutations on nucleoside reverse transcriptase inhibitor resistance. AIDS. 2004;18(12):1691-1696. Available at http://www.ncbi.nlm.nih.gov/pubmed/15280780.
Wiznia A, Church J, Emmanuel P, et al. Safety and efficacy of enfuvirtide for 48 weeks as part of an optimized antiretroviral regimen in pediatric human immunodeficiency virus 1-infected patients. Pediatr Infect Dis J. 2007;26(9):799-805. Available at http://www.ncbi.nlm.nih.gov/pubmed/17721374.
Zhang X, Lin T, Bertasso A, et al. Population pharmacokinetics of enfuvirtide in HIV-1-infected pediatric patients over 48 weeks of treatment. J Clin Pharmacol. 2007;47(4):510-517. Available at http://www.ncbi.nlm.nih.gov/pubmed/17389560.
Ananworanich J, Kosalaraksa P, Hill A, et al. Pharmacokinetics and 24-week efficacy/safety of dual boosted saquinavir/lopinavir/ritonavir in nucleoside-pretreated children. Pediatr Infect Dis J. 2005;24(10):874-879. Available at http://www.ncbi.nlm.nih.gov/pubmed/16220084.
Kosalaraksa P, Bunupuradah T, Engchanil C, et al. Double boosted protease inhibitors, saquinavir, and lopinavir/ritonavir, in nucleoside pretreated children at 48 weeks. Pediatr Infect Dis J. 2008;27(7):623-628. Available at http://www.ncbi.nlm.nih.gov/pubmed/18520443.
Robbins BL, Capparelli EV, Chadwick EG, et al. Pharmacokinetics of high-dose lopinavir-ritonavir with and without saquinavir or nonnucleoside reverse transcriptase inhibitors in human immunodeficiency virus-infected pediatric and adolescent patients previously treated with protease inhibitors. Antimicrob Agents Chemother. 2008;52(9):3276-3283. Available at http://www.ncbi.nlm.nih.gov/pubmed/18625762.
King JR, Acosta EP, Chadwick E, et al. Evaluation of multiple drug therapy in human immunodeficiency virus-infected pediatric patients. Pediatr Infect Dis J. 2003;22(3):239-244. Available at http://www.ncbi.nlm.nih.gov/pubmed/12634585.
Imaz A, Llibre JM, Mora M, et al. Efficacy and safety of nucleoside reverse transcriptase inhibitor-sparing salvage therapy for multidrug-resistant HIV-1 infection based on new-class and new-generation antiretrovirals. J Antimicrob Chemother. 2011;66(2):358-362. Available at http://www.ncbi.nlm.nih.gov/pubmed/21172789.
Tashima K, Smeaton LM, Klingman K, et al. Mortality among HIV+ participants randomized to omit NRTIs vs. add NRTIs in OPTIONS (ACTG A5241). Presented at: 21st Conference on Retroviruses and Opportunistic Infections. 2014. Boston, MA.
Kearns GL, Abdel-Rahman SM, Alander SW, Blowey DL, Leeder JS, Kauffman RE. Developmental pharmacology--drug disposition, action, and therapy in infants and children. N Engl J Med. 2003;349(12):1157-1167. Available at http://www.ncbi.nlm.nih.gov/pubmed/13679531.
Fletcher CV, Brundage RC, Fenton T, et al. Pharmacokinetics and pharmacodynamics of efavirenz and nelfinavir in HIV-infected children participating in an area-under-the-curve controlled trial. Clin Pharmacol Ther. 2008;83(2):300-306. Available at http://www.ncbi.nlm.nih.gov/pubmed/17609682.
Wong FL, Hsu AJ, Pham PA, Siberry GK, Hutton N, Agwu AL. Antiretroviral treatment strategies in highly treatment experienced perinatally HIV-infected youth. Pediatr Infect Dis J. 2012;31(12):1279-1283. Available at http://www.ncbi.nlm.nih.gov/pubmed/22926213.
Agwu A, Warshaw M, Siberry G, et al. for the Pediatric HIV/AIDS Cohort Study. Incomplete immune reconstitution in HIV infected children with virological suppression. Poster, Abstract #583. Presented at: 21st Conference on Retroviruses and Opportunistic Infections. 2014. Boston, MA.