Low Frequency Drug Resistance in HIV-infected Ugandans on Antiretroviral Treatment is Associated with Regimen Failure
BACKGROUND:
Most
patients failing antiretroviral treatment in Uganda will continue to fail their
treatment regimen even if a dominant drug resistant HIV-1 genotype is not detected.
In a recent retrospective study we observed that approximately 30% of
HIV-infected individuals in the Joint Clinical Research Centre (Kampala,
Uganda) experienced virologic failure with a susceptible HIV-1 genotype based
on standard Sanger sequencing. Selection of minority drug resistant HIV-1
variants (not detectable by Sanger sequencing) under antiretroviral therapy
pressure can lead to a shift in the viral quasispecies distribution, becoming
dominant members of the virus population and eventually causing treatment
failure.
METHODS AND FINDINGS:
Here
we used a novel HIV-1 genotyping assay based on deep sequencing (DEEPGEN) to
quantify low-level drug-resistant HIV-1 variants in thirty-three patients
failing a first-line antiretroviral treatment regimen in the absence of drug
resistant mutations, as screened by standard population-based Sanger
sequencing. Using this sensitive assay we observed that 64% (21/33) of these
individuals had low-frequency (or minority) drug resistant variants in the
intrapatient HIV-1 population, which correlated with treatment failure.
Moreover, the presence of these minority HIV-1 variants was associated with
higher intrapatient HIV-1 diversity, suggesting a dynamic selection or fading
of drug resistance HIV-1 variants from the viral quasispecies in the presence
or absence of drug pressure, respectively.
CONCLUSIONS:
This
study has identified low-frequency HIV drug resistance mutations by deep
sequencing in Uganda patients failing antiretroviral treatment but lacking
dominant drug resistance mutations as determined by Sanger sequencing methods.
We showed that these low-abundance drug resistant viruses could have
significant consequences on clinical outcomes, especially if treatment is not
modified based on a susceptible HIV-1 genotype based on Sanger sequencing.
Therefore, we propose to base clinical decisions using more sensitive methods
to detect minority HIV-1 variants.
By: Kyeyune F1, Gibson RM2, Nankya I3, Venner C2, Metha S4, Akao J4, Ndashimye E5, Kityo CM4, Salata RA6, Mugyenyi P4, Arts EJ7, Quiñones-Mateu ME8.
- 1Center for AIDS Research Uganda Laboratories, Joint Clinical Research Centre, Kampala, Uganda Department of Molecular Biology and Microbiology.
- 2Department of Microbiology and Immunology, University of Western Ontario, London, Ontario, Canada.
- 3Center for AIDS Research Uganda Laboratories, Joint Clinical Research Centre, Kampala, Uganda Department of Medicine, and Department of Pathology, Case Western Reserve University, Cleveland, Ohio, USA.
- 4Center for AIDS Research Uganda Laboratories, Joint Clinical Research Centre, Kampala, Uganda TREAT, Joint Clinical Research Centre, Kampala, Uganda.
- 5Center for AIDS Research Uganda Laboratories, Joint Clinical Research Centre, Kampala, Uganda.
- 6Department of Medicine, and Department of Pathology, Case Western Reserve University, Cleveland, Ohio, USA.
- 7Center for AIDS Research Uganda Laboratories, Joint Clinical Research Centre, Kampala, Uganda Department of Microbiology and Immunology, University of Western Ontario, London, Ontario, Canada Department of Medicine, and Department of Pathology, Case Western Reserve University, Cleveland, Ohio, USA earts@uwo.ca.
- 8Center for AIDS Research Uganda Laboratories, Joint Clinical Research Centre, Kampala, Uganda Department of Medicine, and Department of Pathology, Case Western Reserve University, Cleveland, Ohio, USA Department of Medicine, and Department of Pathology, Case Western Reserve University, Cleveland, Ohio, USA University Hospital Translational Laboratory, University Hospitals Case Medical Center, Cleveland, Ohio, USA meq@case.edu.
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