The FDA has approved a new pediatric dosage form and label changes for atazanavir. Please see the FDA announcement for more information.
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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: February 12, 2014; last reviewed: February 12, 2014)
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 a 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 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 and adolescents but not studies limited to postpubertal 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.
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 HIV RNA below the level of quantification using the most sensitive assay (<20 to 75 copies/mL). Older assays with lower limits of 200 or 400 copies/mL are not recommended. Virologic failure is defined for all children as a plasma HIV RNA >200 copies/mL after 6 months of therapy or repeated plasma HIV RNA greater than the level of quantification using the most sensitive assay after 12 months of therapy. Occasionally, infants with high plasma HIV RNA levels at initiation of therapy have HIV RNA levels that are declining but remain >200 copies/mL after 6 months of therapy. Among many of those receiving ritonavir-boosted lopinavir, suppression can be achieved without regimen change if efforts are made to improve adherence.1 However, ongoing non-suppression—especially with non-nucleoside reverse transcription inhibitor (NNRTI)-based regimens—increases risk of drug resistance.2 HIV-infected adults with detectable HIV RNA and a quantified result <200 copies/mL after 6 months of combination antiretroviral therapy (cART) often ultimately achieve virologic suppression without regimen change.3 “Blips,” defined as isolated episodes of plasma HIV RNA <500 copies/mL followed by return to viral suppression, are common and not generally reflective of virologic failure.4-6 Repeated or persistent plasma HIV RNA detection above the level of quantification (especially if >500 copies/mL) after having achieved virologic suppression usually represents virologic failure.6-8
Immunologic failure is defined as an incomplete immunologic response to therapy or an immunologic decline while on therapy. While there is no standardized definition, many experts would consider as incomplete 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 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, 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.9 However, patients may also present with failure in one domain (e.g., immunologic failure) but with a good response in the other domains (e.g., virologic and clinical response). In fact, the discordance in responses to cART can occur in any of these three domains in relation to the other two. It is essential to consider potential alternative causes of discordant responses before concluding that cART failure has truly occurred.
Incomplete Virologic Response Despite Adequate Clinical and Immunologic Responses
Some patients who are maintained on cART may sustain immunologic and clinical benefit for up to 3 years despite persistent low-level viremia.10-19 This observation is the rationale for continuing non-suppressive cART for immunologic and clinical benefit in selected patients for whom a completely suppressive regimen is not available or practical. The proposed mechanisms for immunologic and clinical benefit without complete virologic suppression are maintenance of a lower viral load or selection for strains harboring drug-resistance mutations that impair viral replicative capacity or fitness. Another potential explanation for this discordance is that some of these children may have host genetic and/or virologic characteristics that would have allowed them to be either “slow-progressors” or “long-term non-progressors” without therapy.
Poor Immunologic Response Despite Virologic Suppression Regardless of Clinical Response
Poor immunologic response despite virologic suppression can occur in the context of adequate or poor clinical response. 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 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 non-B subtypes, HIV-2), resulting in falsely low or negative viral load results (see Diagnosis of HIV Infection and Clinical and Laboratory Monitoring). Once lab results are confirmed, evaluation for adverse drug effects, medical conditions, and other factors that can result in lower CD4 values is necessary (see Table 13).
In addition, it is common for patients with baseline severe immunosuppression to achieve virologic suppression weeks to months before achieving immunologic recovery, resulting in a transient early treatment period of persistent immunosuppression during which additional clinical disease progression can occur. 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.20-24
Certain antiretroviral (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,25 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.26 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 immunological and virological 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.27,28 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.29 Such cases do not represent cART failure and, in these instances, children would not benefit from a change in ARV regimen. Before reaching a definitive conclusion of cART clinical failure, 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. Although such cases are rare, they may represent cART clinical failure and suggest that improvement in CD4 values may not necessarily represent the return of complete immunologic function.
Key to Acronyms: cART = combination antiretroviral therapy; CD4 = CD4 T lymphocyte; IRIS = immune reconstitution inflammatory syndrome
Management of Virologic Treatment Failure
Each patient with incomplete virologic suppression on cART should be assessed to determine the cause of virologic treatment failure because the approach to management and subsequent treatment may differ depending on the etiology of the problem. Treatment failure is generally the result of non-adherence but is often multifactorial. Assessment of a child with suspicion of virologic treatment failure should include evaluation of adherence to therapy, medication intolerance, issues related to pharmacokinetics (PK) that could result in 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 14 outlines a comprehensive approach to evaluating causes of virologic treatment failure in children, with particular attention to adherence.
If minimal or no resistance detected to current drugs, focus on improving adherence
If resistance to current regimen detected, optimize adherence and evaluate potential for new regimen (see Management of Virologic Treatment Failure).
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 suggests that the virus is not being exposed to the ARV agents. This lack of ARV drug exposure 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 plasma virus is undetectable with the most sensitive assays, the virus is likely to be susceptible to the current therapy.
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, some clinicians may choose to continue the current non-suppressive regimen or use a simplified, nucleoside reverse transcriptase inhibitor (NRTI)-only, non-suppressive regimen that may provide some clinical and immunologic benefit while preserving future ARV drug choices (see Therapeutic Options When Two Fully Active Agents Cannot Be Identified or Administered).30-32 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.33
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.34-38 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 should not be done 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. In children who are changing therapy owing to the occurrence or progression of abnormal neurodevelopment, many experts strive to include in the new treatment regimen agents (e.g., zidovudine) that are known to achieve higher concentrations in the central nervous system.39-43
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.44
Choice of Therapy 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 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 15, 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 a NNRTI-based regimen, a change to a protease inhibitor (PI)-based regimen is recommended. 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). If a child received initial therapy with a PI-based regimen, a change to an NNRTI-based regimen is generally recommended. Ritonavir-boosted-lopinavir-based regimens have also been shown to have durable ARV activity in some PI-experienced children.45-47
The availability of new drugs in existing classes (e.g., the NNRTI etravirine) and newer classes of drugs (e.g., integrase inhibitors) increases the likelihood of finding three active drugs, even for children with extensive drug resistance (Table 15). Etravirine in combination with ritonavir-boosted darunavir, as part of a new cART regimen, has been shown to be a safe and effective option for children in whom first-line cART fails.48,49 Etravirine is approved for use in children aged ≥6 years and darunavir in children aged ≥3 years. Raltegravir, an integrase inhibitor, is approved for children aged 4 weeks or older by the Food and Drug Administration (FDA).50 Use of newer agents in novel combinations is becoming more common in aging perinatally infected youth in the United States.51 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.52-54 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.
Safety, dosing, and efficacy of enfuvirtide have been established in treatment-experienced children aged ≥6 years, and enfuvirtide has been FDA-approved for this population.55,56 Enfuvirtide must be administered by subcutaneous injection twice daily, a disadvantage that presents a greater challenge to adherence in adolescents than in younger children. Enfuvirtide can be considered an option when designing a new regimen for children in whom multiple classes of ARV medications have failed, but newer and better tolerated agents have largely supplanted use of enfuvirtide.
PK studies of certain dual-boosted PI regimens (ritonavir-boosted lopinavir with saquinavir and ritonavir-boosted lopinavir with atazanavir/ritonavir) suggest that PK targets for both PIs can be achieved or exceeded when used in combination in children.57-59 PK studies of other dual-boosted PI combinations, on the other hand, are limited but suggest inadequate drug levels of one or both PIs.60,61 The use of multidrug regimens, sometimes including up to 3 PIs and/or 2 NNRTIs, has shown efficacy in a pediatric case series;62 however, multidrug regimens should be used cautiously because of their complexity, poor tolerability, and unfavorable drug-drug interactions. Therapeutic drug monitoring may be helpful for confirming therapeutic PI levels when using PIs in combinations that result in complex drug interactions or when there is partially reduced PI activity because of the presence of drug-resistance mutations (see Role of Therapeutic Drug Monitoring in Management of Treatment Failure). Availability of newer potent PIs and new classes of ARV drugs (integrase and CCR5 inhibitors) may lessen the need for dual-PI regimens and for regimens of four or more drugs.
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 http://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.63 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.64
Use of ARV agents without a pediatric indication is an absolute necessity for treatment of some HIV-infected children, but such off-label use must be done with care. It is essential that a provider consult with a pediatric HIV specialist to identify any particular concerns with each agent, to access any available data from clinical trials or other limited off-label pediatric use, and to investigate the availability of suitable clinical trials.
Therapeutic 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.
In such cases, non-suppressive regimens (or holding regimens) are sometimes used pending availability of additional active, tolerable drugs or improvement in ability to adhere. This interim strategy allows for the overall objective of preventing clinical and immunological deterioration until new agents are available to design a regimen that can be expected to achieve sustained virologic suppression. This approach should be regarded as acceptable but not ideal. Such patients 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.
Even when NRTI drug-resistance mutations are present, patients can derive immunologic and clinical benefit despite persistent viremia from treatment with lamivudine monotherapy or with lamivudine or emtricitabine in combination with one or more other NRTIs.31,32
The newer NNRTI etravirine retains activity against many nevirapine- or efavirenz-resistant viruses with a limited number of NNRTI resistance-associated mutations. Ongoing use of efavirenz or nevirapine as part of a failing regimen should be avoided because it may lead to accumulation of additional NNRTI resistance mutations that will reduce etravirine activity and preclude its use in a future, suppressive regimen,65 and it may allow for accumulation of additional NRTI resistance.66
Continued use of a PI in the face of persistent viremia can lead to accumulation of additional mutations conferring resistance to that PI as well as other, newer PIs. Such acquisition of additional PI drug resistance occurs slowly, especially if the viral load is relatively low.2,67-69 However, continued PI use in the presence of resistance may limit viral replication and be beneficial to some patients.
When clinical or immunologic deterioration occurs while patients are receiving such holding regimens, it is important to reassess patient readiness and regimen availability. It may be appropriate to use investigational agents or agents approved for older age groups as second fully active drugs in the new regimen. In general, a single, new, fully active agent should not be added to non-suppressive holding regimens because resistance is likely to develop quickly.
Table 15. 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 Resistance
Recommended Change (In Order of Relative Preference)a
2 NRTIs + NNRTI
2 NRTIs + PI
2 NRTIs + integrase inhibitor
2 NRTIs + PI
2 NRTIs + NNRTI
2 NRTIs + different RTV-boosted PI
2 NRTIs + integrase inhibitor
NRTI(s) + integrase inhibitor + (NNRTI or different RTV-boosted PI)
2 NRTIs + (NNRTI or PI)
2 NRTIs + integrase inhibitor
Integrase inhibitor + 2 other active agents (chosen from NNRTI, PI, NRTI[s])
Failed Regimen(s) That Included NRTI(s), NNRTI(s), and PI(s)
1 NRTI + RTV-boosted PI
NRTI(s) + RTV-boosted PI + integrase inhibitor (consider adding T-20 and/or MVC,b if additional active drug[s] needed)
NRTI(s) + RTV-boosted DRV, LPV or SQV + ETR (consider adding one or more of MVC,b T-20, or integrase inhibitor, if additional active drug[s] needed)
> 1 NRTI + 2 RTV-boosted PIs (LPV/r + SQV, LPV/r + ATV) (consider adding T-20 or an integrase inhibitor 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 listed in relative order of preference and are provided as examples but the list is not exhaustive. b No current FDA-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. Jan 11 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. Jun 15 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. Paper presented at: Conference on Retroviruses and Opportunistic Infections (CROI); 2009.
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. Sep 8 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. Apr 15 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. Apr 30 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. May 3 2002;16(7):1039-1044. Available at http://www.ncbi.nlm.nih.gov/pubmed/11953470.
Siberry GK, Harris DR, Oliveira RH, et al. Evaluation of viral load thresholds for predicting new World Health Organization stage 3 and 4 events in HIV-infected children receiving highly active antiretroviral therapy. JAIDS 2012;60:214-8, Available at: http://www.ncbi.nlm.nih.gov/pubmed/22343177
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