NIH – HIV Drug Resistance: Genotype-Phenotype-Outcome Correlations (R01 Clinical Trial Not Allowed)

July 31, 2018 by School of Medicine Webmaster

HIV drug resistance (HIVDR) may compromise 90-90-90 treatment goals established by UNAIDS.  As antiretroviral drug coverage increases, rates of acquired drug resistance and transmitted resistance have increased in both resource rich and resource limited environments.  At current levels, HIVDR is expected to lead to increased rates of HIV-related deaths, new HIV infections, and increases in HIV related health costs over the next several years.  Routine HIV viral load testing, as well as HIVDR testing of viral failures, may help to formulate effective second line and later antiretroviral (ARV) regimens.  However, while genotypic HIVDR testing is generally accurate, some recent work has demonstrated that genotypic results do not always predict virologic response and clinical outcomes.

Traditional HIV drug resistance genotyping using Sanger sequencing can only detect mutations that occur at >20% frequency in the virus population of an individual. Failure of this sequencing method to detect mutations in quasispecies at lower frequencies (minority variants) may contribute to an underestimation of the rates of transmitted drug resistance.  Better methods to detect mutations and use this genotypic information for clinical care are needed. This information is particularly important when the definition of virologic failure, and the ability to detect antiretroviral drug resistance, requires a viral load of at least 1000 c/ml.

HIVDR in diverse clades and to newer agents is incompletely understood.  Some mutations that reflect HIV genotypic resistance in subtype B viruses occur at differing frequencies in non-B subtypes exposed to the same drugs. In some non-B subtypes, genotypic resistance does not appear to reflect phenotypic resistance ( vitro drug susceptibility) and may not accurately predict virologic success or failure, and potentially can result in the inaccurate selection of already limited treatment options.  More research is needed to understand the effects of resistance mutations and naturally occurring polymorphisms on sensitivity to antiretroviral agents in individuals with non-B subtypes, especially the effects of combinations of HIVDR mutations.

Results from recent large clinical trials indicate that some antiretroviral drugs retain activity even when the genotypic resistance profile suggests otherwise.  The construction of effective therapeutic regimens that include recycling drugs with residual clinical activity could expand therapeutic options and might lead to cost savings. However, it will be critical to know which patients can safely recycle some drugs and which patients will need to be safely transitioned to completely new regimens.

In contrast, some drugs fail when the resistance profile suggests that clinical success should be likely.  Although adherence may play an important role, mutations or polymorphisms in genes other than the RT or protease gene may be important in non-B subtypes. For example, mutations/polymorphisms in the gag region vary in frequency across HIV-1 subtypes and may confer resistance to protease inhibitors in the absence of mutations in the protease gene. Similarly, emerging data suggest that mutations in the polypurine tract (PPT) of the HIV genome can confer resistance to dolutegravir and other integrase inhibitors in the absence of integrase mutations.

This solicitation addresses research gaps related to HIVDR, which directly relate to the overall goal of optimizing treatment responses and improving outcomes.

Purpose and Research Objectives

The purpose of this Funding Opportunity Announcement (FOA) is to support research projects addressing knowledge gaps about the correlations between HIV drug resistance genotypes, the in vitro phenotypes of the virus (i.e., drug susceptibility), and virologic outcomes (i.e., virologic success or failure), and how to practically apply this knowledge.  Investigators are encouraged to test well-characterized clinical specimens (with regard to virologic outcome), especially viruses with combinations of mutations relevant to current ARV regimens.  Testing for in vitro susceptibility should be performed in the presence of single and relevant combinations of antiretroviral drugs.

Applications are sought in the following specific areas:

  • Studies of the contribution(s) of minor genetic variants to drug susceptibility and virologic outcomes, and the point at which minor variants become clinically relevant.  Studies of all HIV subtypes and all relevant mutations are acceptable.  Investigators are encouraged to use well-characterized clinical specimens to compare virologic outcomes in specimens from patients with and without minor genetic variants present at different levels in the viral quasispecies.
  • Correlation studies involving HIV resistance genotype, the in vitro resistance phenotype, and clinical outcome(s) that compare different clades/subtypes and tests against various ARVs and combinations of ARVs.  Studies focused only on subtype B viruses will be considered non-responsive.
  • Studies focused on determining the biological basis for virologic success in settings where resistance is predicted by genotypic drug resistance results.  Well-characterized clinical specimens are required to make appropriate correlations with virologic outcome.  Studies of all HIV subtypes are appropriate.
  • Studies focused on determining the biological basis for treatment failure in settings where resistance is not predicted by standard genotypic tests and adherence is thought to be optimal. Clinical specimens must be characterized in terms of virologic outcomes and adherence history.  Studies of all HIV subtypes are appropriate.

For the last 3 types of studies listed above, investigators are encouraged to include in vitro studies using genotypic and phenotypic analyses of well-characterized clinical samples (and/or molecular clones derived from such samples) in order to correlate the results with virologic outcomes, and to test susceptibility in the presence of single antiretroviral drugs and relevant combinations of such drugs.

Applications proposing the following types of studies will be deemed non-responsive and will not be reviewed:

  • Clinical trials, although the use of samples from prior clinical trials is encouraged.
  • Development of new cohorts, although the use of samples from established cohorts is permitted.
  • Surveys of resistance, although existing samples from surveys may be used.
  • Studies of genotype-phenotype-clinical correlations solely performed with subtype B HIV-1 infections (subtype B specimens can be included in studies examining other subtypes).
  • Studies primarily focused on adherence to HIV treatment regimens.
  • Studies of HIV resistance to neutralizing antibodies or other biologicals.
  • Cost effectiveness studies.

Deadline:  November 5, 2018 (letters of intent); December 5, 2018 (full proposals)


Filed Under: Funding Opportunities