TDM in HIV-infected adolescents has similar indications to adults and is primarily used to monitor the adherence to ART, evaluate the cause of treatment failure and to manage drug-drug interactions. Depending on the availability of a TDM consultant and the acceptance of TDM in clinical practice, the use of ART TDM may extend to optimization of the ARV dose by targeting specific trough concentrations or ratios of trough concentration and viral susceptibility (i.e. inhibitory quotients). Several investigations have demonstrated the benefits of incorporating TDM into the clinical management of HIV infection.(2
) Very few studies, however, have evaluated the benefits of measuring ARV concentrations in HIV-infected adolescents and young adults.(17
) Our cases represent a summary of some of the diverse applications of TDM in the management of the pharmacotherapy of ART in adolescent patients. We have selected three patients, one of whom represented currently accepted clinical indications for the use of TDM, while two others would have not been considered for the application of TDM under current standard of care.
The First Scenario describes a challenging case of an adolescent patient with consistently reported 100% adherence despite the evidence of treatment failure. The high level of adherence was not only stated by the patient, but was also confirmed by the dedicated adult primary caregiver who also provided ART to twin siblings with HIV infection who are 3 years younger than patient A. Both of these siblings have consistently demonstrated high levels of medical adherence, which has been confirmed by TDM and clinical outcome. In addition, patient A had been fully aware of her HIV status since 12 years of age and had regularly participated in the treatment discussions. Despite the fact that some form of non-adherence had been long suspected by the clinical team, none of the involved home and medical providers foresaw her practice of withholding medications in the mouth and spitting them up until documented through TDM. The first and second PK studies confirmed the absence of the ARV drugs in plasma samples after an observed intake. The absence of the ARV saliva concentrations in the first study was likely related to prompt spitting up of the medications after intake. During the second PK study the patient was detained for about 10 minutes by the nurse despite her urge to use the bathroom right after taking the medications, which could be responsible for the detectable concentrations of ABC in saliva. We speculate that the patient either swallowed the medications and induced subsequent emesis, or retained the medications in her mouth without the staff noticing and discarded them after a 10 minute delay. It is plausible that capsule preparations of ATV and RTV were less likely to start dissolving in saliva than ABC tablets, and therefore the detectable concentrations of ABC in saliva were found after holding the medications in the mouth prior to spitting them up (TDF was not measured in saliva).
The results of the first two PK studies prompted more open, evidence-based discussion than previously possible with patient A and family members involved in her care. An assumption of the behaviorally motivated non-adherence without the evidence would have had the potential to disrupt the patient and caregiver liaison with the medical team. Even after psychological counseling, patient A clearly had selective acceptance of ARV drugs, as demonstrated by the repeat PK study with increased dose of ATV/RTV. The only 12- PK study which documented the presence of ATV demonstrated adequate concentrations of ATV with increased dose (ATV/RTV=600mg/200mg) and the absence of RTV in plasma samples. The PK parameters of ATV perfectly fit the PK of the unboosted ATV and together with absent RTV in plasma, provide strong evidence for continued oral withholding of RTV dose by the patient despite close observation by the medical staff at the GCRC. The therapy with an unboosted ATV regimen is not recommended in treatment-experienced pediatric patients with pre-existing PI mutations, as ATV resistance can develop through mutations associated with resistance to other PIs instead of through the ATV associated I50L mutation.(1
) Once placed on a fixed-dose co-formulated boosted PI (Kaletra®), patient A demonstrated normal absorption and PK parameters for RTV.
HIV-infected adolescents face multiple adherence challenges during their transition to adulthood. In addition to palatability issues, pill burden and interference of ART with lifestyle, adolescent patients with HIV experience growing independence, increased peer pressure and fear of stigmatization, increased risk-taking behavior (including substance abuse), denial and fear of HIV infection (particularly after witnessing the death from HIV as in case with our patient A who lost her mother to AIDS), long history of poor adherence and non-disclosure issues in perinatally infected patients, and psychiatric problems (depression, anorexia).(9
) In our recent study, we have shown that adolescents (13–18 yrs old) were significantly less likely to reach undetectable HIV RNA than younger children (<13 yrs old) (OR=0.38; 95% CI: 0.16, 0.89).(22
) For every year increase in age, the odds of reaching undetectable VL decreased by 10% after controlling for self-reported adherence and medications refill mechanism. While considered to be ready to assume the responsibility for adherence to an appropriate administration of their ARV medication, many adolescents lack social and financial autonomy, privacy, and mobility, and generally will decrease their adherence to ART.(23
) A comprehensive assessment of adherence through multiple indirect methods (self-report, caregiver report, pill count, pharmacy refills) should be incorporated into the management of every adolescent patient with HIV infection. While patient and caregiver reports are the main adherence measurement used in the majority of clinical setting,(20
) TDM is the only direct measure of verifying the patient compliance as all other methods do not prove the actual intake of ARV drugs.
Studies have shown that it is crucial to take the evolutionary nature of the caregiver’s and the child’s coping process into account when integrating adherence to ART into children’s daily lives.(25
) The care team should work continuously and concomitantly on three factors: knowledge, capacity, and motivation. In the case of patient A, TDM has allowed us to identify a cause of non-adherence in a form of a very complex behavioral pattern with selective acceptance of ARV medications. The TDM evidence created grounds for the motivation of the patient and the family and their cooperation with the implementation of DOT. While the adherence problems in this young woman are far from being solved, the success of the previous TDM based interventions allows us to continue our work with her and her family to explore further strategies to increase her ART adherence.
According to the current TDM guidelines the measurement of the ARV drugs concentrations would have not been indicated in the Second Scenario
with patients B and C due to the excellent virologic suppression and immunologic status with EFV based ART. Doses that result in excessive plasma drug concentrations are unlikely to be detected unless and until clinical toxicity develops, and without TDM, dose-dependent versus dose-independent toxicity cannot be distinguished. (5
) EFV is extensively metabolized by CYP2B6
with partial involvement of CYP3A4
) The CYP2B6 G to T
polymorphism at position 516 has been associated with elevated EFV plasma concentrations and an increase in neurotoxicity in adults and children.(30
) Most recently the CYP2B6 983T>C
genotypes have also been reported to affect EFV plasma concentrations.(34
) High EFV plasma concentrations and successful CYP2B6
genotype-based EFV dose reduction were demonstrated in adults with the haplotypes CYP2B6 *6/*6 (516G>T, 785A>G)
and *6/*26 (499C>G, 516G>T, 785A>G)
) Genotype CYP2B6
based dose reduction has also been proposed in several population PK models.(38
The identification of the high EFV exposure in our patients led to pharmacogenetic evaluation and confirmation of the “slow metabolizer” type of CYP2B6 polymorphism. Moreover, the lack of dose-proportionality in EFV AUC observed in patient C indicates that at the two higher doses, the PK behavior of EFV could best be described as Michaelis-Menten or zero order elimination. Michaelis-Menten PK occurs when clearance mechanisms become saturated, and a constant amount of drug, rather than a constant fraction, is eliminated per unit time. The implications of Michaelis-Menten PK are that clearance becomes dose-dependent () and small changes in dose can result in large changes in plasma concentration, as was observed when the dose was reduced by 50% from 400 mg to 200 mg daily, yet the AUC dropped by more than 90% (). Note that at all doses, the observed clearance was still well below the referenced adult values (). To our knowledge this is the first description of Michaelis Menten EFV PK associated with CYP2B6 “slow metabolizer” polymorphisms.
While the successful dose reduction of EFV has been described in adults and a single report in an adolescent patient, to our knowledge,(40
) this is the first report of successful reduction of the EFV dose in two African American adolescent pediatric patients based on the CYP2B6
genotype in combination with PK evaluations. The CYP 2B6 516 G>T
polymorphism is significantly higher in Sub-Saharan Africans (45.5%) and African Americans (46.7%) as compared to Hispanic (27.3%), European (21.4%) and Asian (17.4%) populations.(42
) In addition to the CYP2B6 516 G>T
polymorphisms, the DNA samples for both patients were analyzed for the presence of CYP 2B6 415>G, 785A>G, 983 T>C
and 1459 C>T
polymorphisms. Patient C had CYP2B6 785GG
polymorphism in addition to the CYP 516 TT
genotype, suggesting the presence of haplotype CYP2B6 *6/*6 (516G>T, 785A>G)
associated with “slow metabolizer” profile for EFV.(37
) Patient C had also the history of high NVP exposure in the past caused by his CYP2B6
) However, the plasma NVP concentrations were used only for the confirmation of adherence at that time. Interestingly, while both patients and their families recalled that children experienced transient sleep problems shortly after the initiation of EFV therapy, their high EFV exposure did not prompt treatment discontinuation. This is consistent with recently published data on the lack of association between CYP2B6
genotype and EFV plasma concentrations, and the risk of EFV discontinuations because of neurotoxicity.(46
) Equally, no other EFV associated toxicities were identified in both patients, particularly in patient B with more than 7 years of high EFV exposure. This patient was placed on the combination ART with EFV co-administered with APV prior to the wide acceptance of boosted fos-APV into pediatric practice. EFV has been reported to decrease the Cmax
, AUC and Cmin
of unboosted APV by approximately 40% in adults, however, this effect of EFV is compensated by the PK booster effect of RTV when APV is combined with RTV.(48
) While the treatment with EFV in combination with unboosted APV is not recommended, patient B continued his regimen due to the excellent virologic and immunologic outcome. In reality, his high EFV concentrations produced an APV exposure so negligible, that he can be considered to have been treated with dual (d4T and EFV) therapy for a prolonged period of time (>7 years). We would like to speculate that such a high degree of EFV exposure allowed him to avoid development of the K103N, Y181C and other multi-NNRTI resistance mutations on the ART regimen with a single efficient NRTI backbone.
In summary, our experience suggests that TDM evaluation (when available) should be considered in HIV-infected adolescent patients on ART independently of the degree of virologic suppression and immunologic outcome. We recognize that many of the currently identified barriers to the routine application of TDM in pediatric ART (prolonged time for laboratory processing, difficulties in coordinating sample collections at appropriate times, limited availability of certified laboratories for ARV drug concentrations, lack of third party reimbursement of costs) were not experienced at our site. The extended PK analyses were provided through grant funding. However, routine TDM measurements during clinic follow up are a well accepted standard of care in our program and we have not encountered difficulties in the reimbursement process. Clearly, through the availability of a dedicated pediatric GCRC and in house laboratory we were able to repeat the studies to eliminate significant limitations of ARV TDM such as high intrapatient variability from single drug concentration measurement.(2
) Finally, we hope that similar reports and randomized controlled studies will help to eliminate the most significant barrier to the successful TDM of ART such as inadequate information on safety and effectiveness of dose adjustment strategies in children and adolescents.