Faculty Answers Questions on Next-Generation NNRTIs (coming soon)

Faculty:

Eric S. Daar, MD Joseph J. Eron, Jr., MD Anton L. Pozniak, MD, FRCP

Learning Objectives

Upon completion of this activity, participants should be able to:

• Cite the adverse events associated with the use of etravirine
• Discuss which patient populations have the most potential to benefit from etravirine-based antiretroviral therapy
• Explain the potential clinical applications of next-generation NNRTIs
• Describe next-generation NNRTIs in early clinical and preclinical development

Topics covered include:

• Table of Contents
• Introduction
• Dosing, Pharmacokinetics, and Safety
  What is the recommended dosing and total pill count for etravirine and rilpivirine?
• Dosing, Pharmacokinetics, and Safety
  What are the main adverse effects associated with the administration of etravirine?
• Dosing, Pharmacokinetics, and Safety
  Are any of the next-generation NNRTIs associated with CNS adverse effects, as there are with efavirenz?
• Dosing, Pharmacokinetics, and Safety
  At my center, if we need to interrupt treatment in a patient receiving a first-generation NNRTI-based regimen, we stop the NNRTI 1-2 weeks ahead of the other components of the regimen. Because of the long half-lives of the NNRTIs, there otherwise might be a period of unintended “monotherapy” due to persistent levels of the NNRTI. Do next-generation NNRTIs also have long half-lives, suggesting that a similar strategy may be appropriate in the event of treatment interruption?
• Specific Patient Populations
  Can etravirine be used in patients receiving treatment for tuberculosis?
• Specific Patient Populations
  Can etravirine be given to HIV-infected pregnant women or women with the potential to become pregnant?
• Specific Patient Populations
  Is it appropriate to use etravirine in treatment-naive patients with transmitted NNRTI resistance?
• Specific Patient Populations
  If a patient fails on a first-line NNRTI-based regimen, does it make sense to switch them to an etravirine-based regimen to defer the use of other classes such as PIs for as long as possible?
• Predictors of Response
  I read recent reports that allele-specific polymerase chain reaction has been able to detect minority populations of NNRTI-resistant virus in a substantial proportion of patients who were originally determined to harbor only wild-type virus by standard genotype testing and that such minority variants may be associated with an increased risk of virologic failure of an NNRTI-based regimen. Should I be concerned with minority variants when prescribing antiretroviral regimens in treatment-naive patients? In treatment-experienced patients?
• Predictors of Response
  Will the choice of NNRTI (efavirenz, nevirapine, delavirdine) in a patient’s initial NNRTI-based regimen differentially affect the efficacy of etravirine if needed in subsequent regimens?
• Predictors of Response
  Many of the identified etravirine resistance associated mutations were not reported on my patients’ past genotypic resistance tests. How then can I determine whether etravirine will be active in these NNRTI-experienced patients?
• Predictors of Response
  It is my understanding that it takes multiple PI resistance mutations for HIV to develop clinically significant resistance to a boosted PI, which provides the high genetic barrier to resistance observed with these agents. By contrast, HIV can develop resistance to the first generation of NNRTIs with only 1 resistance mutation; therefore, occasional lapses in adherence can provide the circumstances needed for the emergence of NNRTI-resistant HIV. How many mutations are required for HIV to develop resistance to next-generation NNRTIs?
• Predictors of Response
  A virtual phenotype estimation of etravirine activity is now available. Is this approach more or less useful than counting the number of etravirine resistance associated mutations?
• Predictors of Response
  Given that etravirine is a relatively new drug, how much confidence can we have that its efficacy in NNRTI-experienced patients will be sustained and durable?
• Clinical Strategies for the Use of Next-Generation NNRTIs
  Based on the available data, should etravirine always be combined with a boosted PI? If so, should the boosted PI simply be the one to which the patient’s virus is most susceptible by resistance testing?
• Clinical Strategies for the Use of Next-Generation NNRTIs
  I am planning a new regimen for a highly treatment-experienced patient who has full susceptibility to tipranavir, intermediate susceptibility to darunavir/ritonavir, and high-level resistance to all other PIs. The patient also has CCR5-tropic virus. In addition to using raltegravir and maraviroc, is it better to use darunavir/ritonavir plus etravirine in the new regimen, or to use tipranavir/ritonavir without etravirine?
• Clinical Strategies for the Use of Next-Generation NNRTIs
  Are there any straightforward rules of thumb that clinicians should remember when trying to decide which of the recently approved agents—maraviroc, raltegravir, and etravirine—to use in a specific treatment-experienced patient?
• Next-Generation NNRTIs in Clinical Development
  Can you clarify the clinical need for a next-generation NNRTI in initial therapy? If baseline resistance testing is performed before selecting the initial regimen, as is recommended by current guidelines, first-generation NNRTIs can be used effectively.
• Next-Generation NNRTIs in Clinical Development
  I read about another next-generation NNRTI, UK-453,061. What do you know about the development of this agent?
• Next-Generation NNRTIs in Clinical Development
  What is the anticipated timeline for the availability of additional next-generation NNRTIs through expanded access programs or regulatory approval?