Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection

The information in the brief version is excerpted directly from the full-text guidelines. The brief version is a compilation of the tables and boxed recommendations.

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Management of Children Receiving Antiretroviral Therapy

Recognizing and Managing Antiretroviral Treatment Failure

Last Updated: April 14, 2020; Last Reviewed: April 14, 2020

Panel's Recommendations for Recognizing and Managing Antiretroviral Treatment Failure
Panel's Recommendations
  • The causes of antiretroviral (ARV) 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 ARV drug-resistance testing when virologic failure occurs, while the patient is still taking the failing regimen (AI*) (see Drug-Resistance Testing in the Adult and Adolescent Antiretroviral Guidelines for more information).
  • 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; the assessment of anticipated ARV activity should be based on treatment history and past resistance test results (AII*).
  • The goal of therapy following treatment failure is to achieve and maintain virologic suppression, which is defined as a plasma viral load that is below the limits of detection as measured by highly sensitive assays with lower limits of quantification of 20 copies/mL to 75 copies/mL (AI*).
  • 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 the development of additional drug resistance that could further limit future ARV drug 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

Categories of Treatment Failure

Treatment failure can be categorized as virologic failure, immunologic failure, clinical failure, or some combination of the three. Immunologic failure refers to a suboptimal immunologic response to therapy or an immunologic decline while on therapy, but there is no standardized definition. Clinical failure is defined as the occurrence of new opportunistic infections (OIs) (excluding immune reconstitution inflammatory syndrome [IRIS]) and/or other clinical evidence of HIV disease progression during therapy. Almost all antiretroviral (ARV) management decisions for treatment failure are based on addressing virologic failure.

Virologic Failure

Virologic failure refers to either an incomplete initial response to therapy or a viral rebound after virologic suppression is achieved. Virologic suppression is defined as having plasma viral load below the lower level of detection, as measured by highly sensitive assays with lower limits of quantitation of 20 to 75 copies/mL. Virologic failure is defined as repeated instances of a plasma viral load ≥200 copies/mL after 6 months of therapy. Laboratory results must be confirmed with repeat testing before a final assessment of virologic failure is made.

Infants with high plasma viral loads at initiation of ART occasionally take longer than 6 months to achieve virologic suppression. Because of this, some experts continue the treatment regimen for infants if viral load is declining but is still ≥200 copies/mL at 6 months. These infants should be monitored closely until they achieve virologic suppression.1 However, ongoing nonsuppression—especially with non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens—increases the risk of drug resistance.2,3

There is controversy regarding the clinical implications of HIV RNA levels that are between the lower level of detection and <200 copies/mL in patients on antiretroviral therapy (ART). Adults with HIV who have detectable viral loads and a quantified result <200 copies/mL after 6 months of ART generally achieve virologic suppression without changing regimens.4-6 However, some studies in adults have found that multiple viral load measurements of 50 copies/mL to <200 copies/mL may be associated with an increased risk of later virologic failure.7-10 “Blips”—defined as isolated episodes of a detectable but low level of plasma viral load (i.e., <500 copies/mL) that are followed by a return to viral suppression—are common and not generally reflective of short-term virologic failure, though they may indicate an increased risk of virologic failure after 12 months to 24 months.11-13 However, repeated or persistent plasma viral loads that are ≥200 copies/mL (especially viral loads that are >500 copies/mL) in patients who have achieved virologic suppression usually indicates virologic failure.6,13-15

Poor Immunologic Response Despite Virologic Suppression

Poor immunologic response despite virologic suppression is uncommon in children.16 Patients with baseline severe immunosuppression (i.e., a CD4 T lymphocyte [CD4] cell count >500 cells/mm3) often take more than 1 year to achieve immune recovery, even if virologic suppression occurs more promptly. During this early treatment period of persistent immunosuppression, additional clinical disease progression can occur.

In cases of poor immunologic response despite virologic suppression, clinicians should first exclude laboratory error in CD4 values or viral load measurements and ensure that CD4 values have been interpreted correctly in relation to the natural decline in CD4 count that occurs during 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 (e.g., HIV-1 non-M groups, HIV-2), resulting in falsely low or negative viral load results (see Diagnosis of HIV Infection in Infants and Children and Clinical and Laboratory Monitoring of Pediatric HIV Infection). Once laboratory results are confirmed, clinicians should evaluate patients for adverse events, medical conditions, and other factors that can cause CD4 values to decrease (see Table 17).

Patients who have very low baseline CD4 values before initiating ART are at higher risk of an impaired CD4 response to ART and, based on data from adult studies, may be at higher risk of death and AIDS-defining illnesses despite virologic suppression.17-19 In a study of 933 children aged ≥5 years who received ART that resulted in virologic suppression, 348 children (37%) had CD4 counts <500 cells/mm3 at ART initiation, including 92 (9.9%) who had CD4 counts <200 cells/mm3. After 1 year of virologic suppression, only seven children (1% of the cohort) failed to reach a CD4 count ≥200 cells/mm3, and 86% of children had CD4 counts >500 cells/mm3. AIDS-defining events were uncommon overall (occurring in 1% of participants), but they occurred both in children who did achieve improved CD4 counts and those who did not.16

Several drugs (e.g., corticosteroids, chemotherapeutic agents) and other conditions (e.g., hepatitis C virus, tuberculosis [TB], malnutrition, Sjogren’s syndrome, sarcoidosis, syphilis, cirrhosis, acute viral infections) are independently associated with low CD4 values.20

In summary, poor immunologic response to treatment can occur. Management consists of confirming that CD4 values and viral load measurements are accurate, avoiding the use of drugs that are associated with low CD4 values, and treating other conditions that could impair CD4 recovery. The Panel on Antiretroviral Therapy and Medical Management of Children Living with HIV does not recommend modifying an ART regimen based on lack of immunologic response if virologic suppression is confirmed.

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 ART; not all of these cases represent ART failure. At times, after initiation of ART, patients will suffer a clinical deterioration due to paradoxical worsening of a known OI, or unmasking of a previously undiagnosed OI, due to a profound immune response (IRIS) related to successful viral suppression. This does not represent ART treatment failure, and does not generally require discontinuation of, or a change in ART. IRIS does not mean that ART has failed, and it does not generally require discontinuation of ART.21,22 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.23 Such cases do not represent ART failure, and these children would not benefit from a change in ARV regimen. Before a definitive conclusion of ART clinical failure is reached, a child should also be evaluated to rule out (and, when indicated, treat) other causes or conditions that can occur with or without HIV-related immunosuppression, such as pulmonary TB, malnutrition, and malignancy.

Occasionally, however, children will develop new HIV-related OIs (e.g., Pneumocystis jirovecii pneumonia or esophageal candidiasis that occurs more than 6 months after achieving markedly improved CD4 values and virologic suppression) that are not related to IRIS, pre-existing organ damage, or another cause.16 Although such cases are rare, they may represent ART clinical failure, and improvement in CD4 values may not necessarily normalize 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 regarding the effectiveness of this strategy are inconclusive.24,25

Table 17. 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 value or viral load measurement)
  • Misinterpretation of normal, age-related CD4 count decline (i.e., the immunologic response is not actually poor)
  • Low pretreatment CD4 count or percentage
  • AEs that are associated with the use of certain drugs (e.g., ZDV, TMP-SMX, systemic corticosteroids)
  • Use of systemic corticosteroids or chemotherapeutic agents
  • Conditions that can cause low CD4 values (e.g., HCV, acute viral infections, TB, malnutrition, Sjogren’s syndrome, sarcoidosis, syphilis)
Poor Immunologic and Clinical Responses Despite Virologic Suppression:
  • Lab error
  • Falsely low viral load result for an HIV strain/type that is not detected by viral load assay (i.e., HIV-1 non-M groups, HIV-1 non-B subtypes, HIV-2)
  • Persistent immunodeficiency that occurs soon after initiating ART but before ART-related reconstitution
  • Primary protein-calorie malnutrition
  • Untreated TB
  • Malignancy
Differential Diagnosis of Poor Clinical Response Despite Adequate Virologic and Immunologic Responses
  • IRIS
  • A previously unrecognized, pre-existing infection or condition (e.g., TB, malignancy)
  • Malnutrition
  • Clinical manifestations of previous organ damage: brain (e.g., strokes, vasculopathy, worsening neurodevelopmental delay), lungs (e.g., bronchiectasis), cardiac (i.e., cardiomyopathy), renal (i.e., HIV-related kidney disease)
  • A new clinical event due to a non-HIV illness or condition
  • A new, otherwise unexplained HIV-related clinical event (e.g., treatment failure)
Key: AE = adverse effects; ART = antiretroviral therapy; CD4 = CD4 T lymphocyte; HCV = hepatitis C virus; IRIS = immune reconstitution inflammatory syndrome; TB = tuberculosis; TMP-SMX = trimethoprim-sulfamethoxazole; ZDV = zidovudine

Management of Virologic Failure

The approach to managing and subsequently treating virologic failure will differ depending on the etiology of the problem. When assessing a child with suspected virologic failure, clinicians should evaluate therapy adherence and medication intolerance, confirm that the prescribed dosing is correct (and understood by the child and/or caregiver) for all medications in the regimen, consider possible pharmacokinetic (PK) interactions that might lead to low drug levels, and test for possible drug resistance (see Drug-Resistance Testing in the Adult and Adolescent Antiretroviral Guidelines). While many factors can contribute to virologic failure, the main barrier to sustained virologic suppression in adults and children is incomplete adherence to medication regimens, with subsequent emergence of viral mutations that confer partial or complete resistance to one or more components of the ARV regimen. Please see Adherence to Antiretroviral Therapy in Children and Adolescents Living with HIV for guidance on assessing adherence and strategies for improving adherence.

Virologic Failure with No Antiretroviral Drug Resistance Identified

Persistent viremia in the absence of detectable viral resistance to current medications is usually a result of nonadherence, 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 discontinuing therapy, plasma viral strains may quickly revert to wild type and reemerge as the predominant viral population, in which case resistance testing would fail to reveal drug-resistant virus (see Drug-Resistance Testing in the Adult and Adolescent Antiretroviral Guidelines). In this situation, resistance can be identified by restarting the prior medications while emphasizing adherence and repeating resistance testing in 4 weeks if plasma virus remains detectable. If the HIV plasma viral load becomes undetectable, then nonadherence was likely the original cause of virologic failure.

Virologic failure of boosted protease inhibitor (PI)-based regimens is frequently associated with no detected major PI resistance mutations. Virologic suppression may be achieved by continuing the PI-based regimen, implementing adherence-improvement measures, and addressing any PI-related side effects.26,27

In some cases, if a new, more convenient regimen could address the main barrier to adherence, it may be reasonable for a clinician to switch a patient to this new regimen (e.g., a single fixed-dose combination [FDC] tablet taken once daily) while closely monitoring adherence and viral load. However, in cases where clinicians determine that patients have poor adherence to the current regimen and that adherence is unlikely to improve with a new regimen, clinicians should focus on improving adherence before initiating a new regimen (see Adherence to Antiretroviral Therapy in Children and Adolescents Living with HIV).

Virologic Treatment Failure with Antiretroviral Drug Resistance Identified

After deciding that a change in therapy is necessary, a clinician should attempt to identify at least two, but preferably three, fully active ARV agents from at least two different drug classes to use in a patient’s new regimen. The clinician should consider all of the patient’s past and recent drug-resistance test results, the patient’s prior exposure to ARV drugs, whether the patient is likely to adhere to the regimen, and whether the patient finds a particular regimen acceptable.28-32 This process often requires using agents from one or more drug classes that are new to the patient. However, clinicians should be aware that drug-resistance mutations can confer cross-resistance within a drug class, so a drug that is new to the patient may still have diminished antiviral potency. Substituting or adding a single drug to a failing regimen is not recommended, because this is unlikely to lead to durable virologic suppression and will likely result in additional drug resistance.

The process of switching a patient to a new regimen must include an extensive discussion of treatment adherence and potential toxicity with the patient and the patient’s caregivers. This discussion should be appropriate for the patient’s age and stage of development. Clinicians should be aware that some medications have conflicting food requirements of and concomitant medication restrictions that may complicate the administration of a regimen. Timing of medication administration is particularly important, as this helps ensure adequate ARV drug exposures throughout the day. Palatability, pill size, number of pills, and dosing frequency all need to be considered when choosing a new regimen.33

Therapeutic Options to Achieve Complete Virologic Suppression After Virologic Failure

A pediatric HIV specialist should be consulted when determining which new regimen will have the best chance of achieving complete virologic suppression in children who have already experienced treatment failure.

ARV regimens should be chosen based on a patient’s treatment history and drug-resistance test results to optimize ARV drug potency in the new regimen. A general strategy for regimen changes is shown in Table 18; however, as additional agents are licensed and studied for use in children, newer regimens that are better tailored to the needs of each patient may be constructed.

Data from adult and pediatric studies support the efficacy of regimen that contains a boosted PI plus two nucleoside reverse transcriptase inhibitors (NRTIs) for those who experience treatment failure on an initial NNRTI-based regimen.34 Studies of adults have found that a regimen that contains both a boosted PI and raltegravir (RAL) produces similar outcomes to a regimen that contains a boosted PI and two NRTIs.34,35

A clinical trial in adults who had experienced treatment failure on an initial NNRTI-based regimen reported that dolutegravir (DTG) had better efficacy and a better safety profile than lopinavir/ritonavir (LPV/r) when these drugs were used in second-line regimens that included at least one active NRTI.36 Pediatric and adolescent data support the use of two NRTIs plus an integrase strand transfer inhibitor (INSTI) following the failure of an NNRTI-based regimen.37,38

However, caution should be exercised when considering the use of regimens that include first-generation INSTIs with a lower barrier to resistance (e.g., RAL), because children who experience treatment failure on NNRTI-based regimens often have substantial NRTI resistance.39

Resistance to the NNRTI nevirapine (NVP) results in cross-resistance to the NNRTI efavirenz (EFV), and vice versa. The NNRTIs etravirine (ETR) and rilpivirine (RPV) can retain activity against NVP-resistant virus or EFV-resistant virus in the absence of certain key NNRTI mutations (see below), but ETR has generally been tested only in regimens that also contain a boosted PI.28,40

If a child experiences virologic failure on an initial PI-based regimen, there are often limited resistance mutations detected, indicating that poor adherence/tolerance of the regimen may be the cause of poor viral control.39,41 In these cases, an alternative PI that might be better tolerated and potent can be used. For example, LPV/r-based regimens have been shown to have durable ARV activity in some PI-experienced children.42-44 Darunavir/ritonavir-based therapy has also been used.45,46 Based on more limited data, switching to an INSTI-based regimen can be effective.37,47 When making the switch from a failing PI-based regimen to an INSTI-based regimen, preference might be given to the second-generation INSTIs DTG or bictegravir (BIC), as these drugs have a higher barrier to resistance than the first-generation INSTIs RAL and elvitegravir.48

The availability of newer drugs within existing drug classes and the introduction of new classes of drugs increase the likelihood of finding three active drugs, even for children with extensive drug resistance (see Table 18). As previously discussed, INSTI-based regimens are increasingly used for children who have experienced treatment failure on NNRTI-based regimens or PI-based regimens.37,49 RAL is the INSTI that has been studied and used most often in children, but both DTG and BIC are appealing for their once-daily administration, small pill size, and higher barrier to development of drug resistance; they also retain ARV activity in patients who have experienced treatment failure on RAL-based therapy (see the Dolutegravir and Bictegravir sections for the latest age/weight indications). However, use of DTG around the time of conception has been associated with a small, but significant, increase in the risk of infant neural tube defects (see the Dolutegravir section). Additional information and specific recommendations about the use of DTG in women and adolescents of childbearing potential and in those who are pregnant or who are trying to conceive are available in the Adult and Adolescent Antiretroviral Guidelines (see Adolescents and Young Adults with HIV and Management of the Treatment-Experienced Patient) and in the Perinatal Guidelines (see Teratogenicity, Recommendations for Use of Antiretroviral Drugs During Pregnancy, and Appendix D. Dolutegravir Counseling Guide for Health Care Providers).

Maraviroc, a CCR5 antagonist, provides a new drug class, but many ART-experienced children already harbor CXCR4-tropic virus, which precludes its use.50 Regimens that include an INSTI and a potent, boosted PI with or without ETR have been effective during small studies of extensively ART-experienced patients with multiclass drug resistance.51-54 It is important to review individual drug profiles for information about drug interactions and dose adjustments when devising a regimen for children with multiclass drug resistance. Appendix A: Pediatric Antiretroviral Drug Information provides detailed information on drug formulations, pediatric and adult doses, and toxicity, as well as discussions of the available data on the use of ARV drugs in children.

Previously prescribed drugs that were discontinued because of poor tolerance or poor adherence may sometimes be reintroduced if drug resistance did not develop and if prior difficulties with tolerance and adherence can be overcome (e.g., by switching to a new formulation, such as an FDC tablet).

Some studies in adults have suggested that lamuvidine (3TC) can still contribute to suppression of HIV replication in patients with 3TC resistance mutations. Continuation of 3TC can also maintain a 3TC mutation (184V) that can partially reverse the effects of other mutations that confer resistance to zidovudine and tenofovir disoproxil fumarate.55-57

The use of new drugs that have been evaluated in adults but have not been fully evaluated in children may be justified; ideally, this would be done in the framework of a clinical trial. Expanded access programs or clinical trials may be available (see New drugs should be used in combination with at least one, and ideally two, additional active agents.

Enfuvirtide (T-20) is approved by the Food and Drug Administration (FDA) for use in ART-experienced children aged ≥6 years, but it must be administered by subcutaneous injection twice daily.58,59 PK studies of regimens that included two boosted PIs (LPV/r with saquinavir) suggest that PK targets for both PIs can be achieved or exceeded when these drugs are used in combination in children.60-62 Regimens that contain more than three drugs (up to three PIs and/or two NNRTIs) have shown efficacy in a pediatric case series, but they are complex, often poorly tolerated, and subject to unfavorable drug-drug interactions.63 The availability of the PI darunavir for children aged ≥3 years, the newer NNRTIs ETR and RPV, and more recent classes of ARV drugs (e.g., INSTIs, CCR5 inhibitors) have lessened the need for T-20, dual-PI regimens, and regimens of four or more drugs. The FDA has recently granted approval for a humanized monoclonal antibody, ibalizumab, that must be infused every 2 weeks in adolescents (those aged >18 years) and adults with multidrug resistance.64

Studies have compared the use of NRTI-sparing and NRTI-containing regimens in adults with multidrug resistance who experienced virologic failure on a previous regimen. These studies have demonstrated no clear benefit of including NRTIs in the new regimen.65,66 One of these studies reported higher mortality in adults who were randomized to receive a regimen that included NRTIs than in adults who were randomized to receive an NRTI-sparing regimen.66 There are no studies of NRTI-sparing regimens in children with virologic failure and multidrug resistance, but an NRTI-sparing regimen 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 of new therapeutic agents that are not currently being studied in children or that may be approved for use in children in the future. Information about clinical trials can be found using the AIDSinfo Clinical Trial Search and by consulting 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.67 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.68

Off-label use of ARV agents may be necessary for children with HIV who have limited ARV drug options. In this circumstance, consulting 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 ART.

The decision to continue a nonsuppressive regimen must be made on an individual basis after weighing potential benefits and risks. Specifically, providers must balance the inherent tension between the benefits of virologic suppression and the risks of continued viral replication with potential evolution of viral drug resistance in the setting of inadequate ARV drug exposure (e.g., nonadherence or a nonsuppressive, suboptimal regimen). Nonsuppressive 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.69 However, persistent viremia in the context of ARV drug 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 who continue to use nonsuppressive regimens should be followed more closely than those with stable virologic status, and the potential to successfully initiate a fully suppressive ART regimen should be reassessed at every opportunity.

The use of NRTI-only holding regimens or a complete interruption of therapy are not recommended. One trial (IMPAACT P1094) randomized children with the M184V resistance mutation and documented nonadherence to continue their nonsuppressive, non-NNRTI-based regimen or to switch to a 3TC (or emtricitabine [FTC]) monotherapy holding regimen. Children who switched to monotherapy were significantly more likely to experience a 30% decline in absolute CD4 count (the primary outcome) over a 28-week period. Only patients in the 3TC/FTC arm experienced the primary outcome.70

Complete treatment interruption has also been associated with immunologic declines and poor clinical outcomes, and it is not recommended (see Considerations About Interruptions in Antiretroviral Therapy).71,72

Table 18. Options for Regimens with at Least Two Fully Active Agents to Achieve Virologic Suppression in Patients with Virologic Failure and Evidence of Viral Resistance

Clinicians should evaluate a patient’s treatment history and drug-resistance test results when choosing an ART regimen in order to optimize ARV drug effectiveness. This is particularly important when selecting the 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 and potent virologic suppression. If the M184V/I mutation associated with FTC and 3TC is present, these medications should be continued if the new regimen contains TDF, TAF, or ZDV. The presence of this mutation may increase susceptibility to these NRTIs.

Please see individual drug profiles for information about age limitations (e.g., do not use DRV in children aged <3 years), drug interactions, and dose adjustments when devising a regimen for children with multiclass drug resistance. Collaboration with a pediatric HIV specialist is especially important when choosing regimens for children with multiclass drug resistance. Regimens in this table are provided as examples, but the list is not exhaustive.

Table 18. Options for Regimens with at Least Two Fully Active Agents to Achieve Virologic Suppression in Patients with Virologic Failure and Evidence of Viral Resistance
Prior Regimen New Regimen Optionsa
Two NRTIs plus an NNRTI Two NRTIs plus a boosted PI

Two NRTIs plus an INSTIb
Two NRTIs plus a PI Two NRTIs plus an INSTI

Two NRTIs plus a different boosted PI

INSTI plus a different boosted PI with or without an NNRTI and with or without NRTI(s)
Two NRTIs plus an INSTI Two NRTIs plus a boosted PI

DTGa,b or BICb (if not used in the prior regimen) with a boosted PI with or without one or two NRTIs. DTG must be given twice daily if a patient has certain documented INSTI mutations, or if there is concern about certain mutations (see the Dolutegravir section).
Failed Regimen(s) That Included NRTI(s), NNRTI(s), and PI(s) If NRTIs Are Fully Active:
  • INSTI plus two NRTIs
If NRTIs Are Not Fully Active:
  • INSTI plus two NRTIs with or without an RTV-boosted PI
If There is Minimal NRTI Activity:
  • INSTI with or without an RTV-boosted PI with or without ETR or RPV with or without NRTI(s)
  • Consider adding T-20 and/or MVC if additional active drug(s) are needed.
a Exposure to DTG around the time of conception has been associated with a small but significant increase in the risk of infant NTDs. Additional information and specific recommendations about the use of DTG in women and adolescents of childbearing potential and in those who are pregnant or who are trying to conceive are available in the Adult and Adolescent Antiretroviral Guidelines (see Adolescents and Young Adults with HIV and Management of the Treatment-Experienced Patient) and in the Perinatal Guidelines (see Teratogenicity, Recommendations for Use of Antiretroviral Drugs During Pregnancy, and Appendix D. Dolutegravir Counseling Guide for Health Care Providers).

b RAL has a low barrier to resistance and requires twice-daily dosing in children and adolescents; BIC and DTG have a higher barrier to resistance and only require once-daily dosing.

Key: 3TC = lamivudine; ART = antiretroviral therapy; ARV = antiretroviral; BIC = bictegravir; DRV = darunavir; DTG = dolutegravir; ETR = etravirine; FTC = emtricitabine; INSTI = integrase strand transfer inhibitor; MVC = maraviroc; NNRTI = non-nucleoside reverse transcriptase inhibitor; NRTI = nucleoside reverse transcriptase inhibitor; NTD = neural tube defect; PI = protease inhibitor; RAL = raltegravir; RPV = rilpivirine; RTV = ritonavir; T-20 = enfuvirtide; TAF = tenofovir alafenamide; TDF = tenofovir disoproxil fumarate; ZDV = zidovudine


  1. 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:
  2. Babiker A, Castro nee Green H, Compagnucci A, et al. First-line antiretroviral therapy with a protease inhibitor versus non-nucleoside reverse transcriptase inhibitor and switch at higher versus low viral load in HIV-infected children: an open-label, randomised Phase 2/3 trial. Lancet Infect Dis. 2011;11(4):273-283. Available at:
  3. 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:
  4. 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. Abstract #580. Presented at: Conference on Retroviruses and Opportunistic Infections. 2009.
  5. Antiretroviral Therapy Cohort Collaboration, Vandenhende MA, Ingle S, et al. Impact of low-level viremia on clinical and virological outcomes in treated HIV-1-infected patients. AIDS. 2015;29(3):373-383. Available at:
  6. 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. Available at:
  7. Laprise C, de Pokomandy A, Baril JG, Dufresne S, Trottier H. Virologic failure following persistent low-level viremia in a cohort of HIV-positive patients: results from 12 years of observation. Clin Infect Dis. 2013;57(10):1489-1496. Available at:
  8. Vandenhende MA, Perrier A, Bonnet F, et al. Risk of virological failure in HIV-1-infected patients experiencing low-level viraemia under active antiretroviral therapy (ANRS C03 cohort study). Antivir Ther. 2015. Available at:
  9. Pernas B, Grandal M, Pertega S, et al. Any impact of blips and low-level viraemia episodes among HIV-infected patients with sustained virological suppression on ART? J Antimicrob Chemother. 2016;71(4):1051-1055. Available at:
  10. Fleming J, Mathews WC, Rutstein RM, et al. Low-level viremia and virologic failure in persons with HIV infection treated with antiretroviral therapy. AIDS. 2019;33(13):2005-2012. Available at:
  11. 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:
  12. 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:
  13. 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:
  14. 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:
  15. 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:
  16. Krogstad P, Patel K, Karalius B, et al. Incomplete immune reconstitution despite virologic suppression in HIV-1 infected children and adolescents. AIDS. 2015;29(6):683-693. Available at:
  17. 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:
  18. 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:
  19. 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:
  20. Claassen CW, Diener-West M, Mehta SH, Thomas DL, Kirk GD. Discordance between CD4+ T-lymphocyte counts and percentages in HIV-infected persons with liver fibrosis. Clin Infect Dis. 2012;54(12):1806-1813. Available at:
  21. 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:
  22. Meintjes G, Lynen L. Prevention and treatment of the immune reconstitution inflammatory syndrome. Curr Opin HIV AIDS. 2008;3(4):468-476. Available at:
  23. 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:
  24. 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:
  25. 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:
  26. 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:
  27. 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:
  28. 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:
  29. 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:
  30. 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:
  31. 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:
  32. 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:
  33. 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:
  34. Paton NI, Kityo C, Hoppe A, et al. Assessment of second-line antiretroviral regimens for HIV therapy in Africa. N Engl J Med. 2014;371(3):234-247. Available at:
  35. Kanters S, Socias ME, Paton NI, et al. Comparative efficacy and safety of second-line antiretroviral therapy for treatment of HIV/AIDS: a systematic review and network meta-analysis. Lancet HIV. 2017;4(10):e433-e441. Available at:
  36. Aboud M, Kaplan R, Lombaard J, et al. Dolutegravir versus ritonavir-boosted lopinavir both with dual nucleoside reverse transcriptase inhibitor therapy in adults with HIV-1 infection in whom first-line therapy has failed (DAWNING): an open-label, non-inferiority, Phase 3b trial. Lancet Infect Dis. 2019;19(3):253-264. Available at:
  37. Briand C, Dollfus C, Faye A, et al. Efficacy and tolerance of dolutegravir-based combined ART in perinatally HIV-1-infected adolescents: a French multicentre retrospective study. J Antimicrob Chemother. 2017;72(3):837-843. Available at:
  38. Nachman S, Alvero C, Teppler H, et al. Safety and efficacy at 240 weeks of different raltegravir formulations in children with HIV-1: a Phase 1/2 open label, non-randomised, multicentre trial. Lancet HIV. 2018;5(12):e715-e722. Available at:
  39. Harrison L, Melvin A, Fiscus S, et al. HIV-1 drug resistance and second-line treatment in children randomized to switch at low versus higher RNA thresholds. J Acquir Immune Defic Syndr. 2015;70(1):42-53. Available at:
  40. MacBrayne CE, Rutstein R, Yogev R, et al. Etravirine pharmacokinetics in treatment-experienced children ages 1- <6 years. Abstract 465. Presented at: Conference on Retroviruses and Opportunistic Infections. 2018. Boston, Massachusetts. Available at:
  41. Meyers T, Sawry S, Wong JY, et al. Virologic failure among children taking lopinavir/ritonavir-containing first-line antiretroviral therapy in South Africa. Pediatr Infect Dis J. 2015;34(2):175-179. Available at:
  42. 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:
  43. 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:
  44. Resino S, Bellon JM, Munoz-Fernandez MA, Spanish Group of HIV Infection. 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:
  45. Violari A, Bologna R, Kumarasamy N, et al. Safety and efficacy of darunavir/ritonavir in treatment-experienced pediatric patients: week 48 results of the ARIEL trial. Pediatr Infect Dis J. 2015;34(5):e132-137. Available at:
  46. 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:
  47. Viani RM, Alvero C, Fenton T, et al. Safety, Pharmacokinetics and efficacy of dolutegravir in treatment-experienced HIV-1 infected adolescents: 48-week results from IMPAACT P1093. Pediatr Infect Dis J. 2015. Available at:
  48. Tsiang M, Jones GS, Goldsmith J, et al. Antiviral activity of bictegravir (GS-9883), a novel potent HIV-1 integrase strand transfer inhibitor with an improved resistance profile. Antimicrob Agents Chemother. 2016;60(12):7086-7097. Available at:
  49. Viani RM, Ruel T, Alvero C, et al. Long-Term Safety and efficacy of dolutegravir in treatment-experienced adolescents with human immunodeficiency virus infection: results of the IMPAACT P1093 Study. J Pediatric Infect Dis Soc. 2019. Available at:
  50. Agwu AL, Yao TJ, Eshleman SH, et al. Phenotypic co-receptor tropism in perinatally HIV-infected youth failing antiretroviral therapy. Pediatr Infect Dis J. 2016. Available at:
  51. Huerta-Garcia G, Vazquez-Rosales JG, Mata-Marin JA, Peregrino-Bejarano L, Flores-Ruiz E, Solorzano-Santos F. Genotype-guided antiretroviral regimens in children with multidrug-resistant HIV-1 infection. Pediatr Res. 2016;80(1):54-59. Available at:
  52. Kirk BL, Gomila A, Matshaba M, et al. Early Outcomes of darunavir- and/or raltegravir-based antiretroviral therapy in children with multidrug-resistant HIV at a pediatric center in Botswana. J Int Assoc Provid AIDS Care. 2013;12(2):90-94. Available at:
  53. Thuret I, Chaix ML, Tamalet C, et al. Raltegravir, etravirine and r-darunavir combination in adolescents with multidrug-resistant virus. AIDS. 2009;23(17):2364-2366. Available at:
  54. Capetti AF, Sterrantino G, Cossu MV, et al. Salvage therapy or simplification of salvage regimens with dolutegravir plus ritonavir-boosted darunavir dual therapy in highly cART-experienced subjects: an Italian cohort. Antivir Ther. 2016. Available at:
  55. 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:
  56. 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:
  57. 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:
  58. 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:
  59. 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:
  60. 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:
  61. 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:
  62. 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:
  63. 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:
  64. Emu B, Fessel J, Schrader S, et al. Phase 3 Study of ibalizumab for multidrug-resistant HIV-1. N Engl J Med. 2018;379(7):645-654. Available at:
  65. 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:
  66. Tashima KT, Smeaton LM, Fichtenbaum CJ, et al. HIV salvage therapy does not require nucleoside reverse transcriptase inhibitors: a randomized, controlled trial. Ann Intern Med. 2015;163(12):908-917. Available at:
  67. 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:
  68. 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:
  69. 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:
  70. Agwu AL, Warshaw MG, McFarland EJ, et al. Decline in CD4 T lymphocytes with monotherapy bridging strategy for non-adherent adolescents living with HIV infection: Results of the IMPAACT P1094 randomized trial. PLoS One. 2017;12(6):e0178075. Available at:
  71. 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:
  72. Fairlie L, Karalius B, Patel K, et al. CD4+ and viral load outcomes of antiretroviral therapy switch strategies after virologic failure of combination antiretroviral therapy in perinatally HIV-infected youth in the United States. AIDS. 2015. Available at:

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