Impact of disease, drug and patient adherence on the effectiveness of antiviral therapy in pediatric HIV

ABSTRACT

Introduction: Maintaining effective antiretroviral treatment for life is a major problem in both resource-limited and resource-rich countries. Despite the progress observed in paediatric antiretroviral therapy, approximately 12% of children still experience treatment failure due to drug resistance, inadequate dosing and poor adherence. We explore the current status of antiretroviral therapy in children with focus on the interaction between disease, drug pharmacokinetics and patient behavior, all of which are strongly interconnected and determine treatment outcome.

Areas covered: An overview is provided of the viral characteristics and available drug combinations aimed at the prevention of resistance. In this context, the role of patient adherence is scrutinized. A detailed assessment of factors affecting adherence is presented together with the main strategies to enhance treatment response in children.

Expert opinion: Using modeling and simulation, a framework for characterizing the forgiveness of non-adherence for specific antiretroviral drugs in children is proposed in which information on pharmacokinetics, pharmacokinetic-pharmacodynamic relationships and viral dynamics is integrated. This approach represents an opportunity for the simplification of dosing regimens taking into account the interaction between these factors. Based on clinical trial simulation scenarios, we envisage the possibility of assessing the impact of variable adherence to antiretroviral drug combinations in HIV-infected children.

KEYWORDS:

• Pediatric HIV
• antiretroviral
• viral dynamics
• adherence
• dose rationale
• forgiveness
• PKPD modeling
• clinical trial simulations

Article highlights

• Pediatric HIV infection remains a worldwide public health problem as life-long treatment is required for these patients.

• According to WHO/UNAIDS data, approximately 86% of new infections in children occur in sub-Saharan Africa, where access to therapy and treatment choice is still limited.

• The relationship between adherence, exposure to antiretroviral drugs, and resistance is more complex than ‘non-adherence increases the risk of drug resistance’. Understanding this relationship is a critical step to reduce the risk of viral failure in highly active antiretroviral therapy (HAART).

• Forgiveness of non-adherence, defined as the ability of a drug or regimen to achieve and maintain viral suppression even in case of poor adherence, is ignored as a therapeutic criterion despite its implications for long term outcome in pediatric HIV.

• The development of a framework in which pharmacokinetic-pharmacodynamic modeling is integrated with viral dynamics may provide a powerful tool to predict the impact of variable patterns of adherence on treatment response. It also offers an opportunity to identify simplified dosing regimens for adults and children.

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Declaration of interest

O Della Pasqua is Senior Director Clinical Pharmacology at GlaxoSmithKline R&D. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

C Piana was partly funded by PENTA - LABNET an FP7 coordination action program funded by the European Union (Grant 201057). This review has contributed to her PhD research program.