Melody, Kevin
(2017)
HIV-1 resistance to rilpivirine in the context of pre-exposure prophylaxis.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
This is the latest version of this item.
Abstract
To prevent further incidences of human immunodeficiency virus type 1 (HIV-1), pre-exposure prophylaxis (PrEP) is effective at inhibiting infection in high-risk populations; however, PrEP efficacy is correlated with adherence. Currently, the only approved PrEP regimen requires taking daily pills. To improve adherence, rilpivirine (RPV), a non-nucleoside reverse transcriptase inhibitor approved for antiretroviral therapy, has been developed into an injectable long-acting nanoparticle formula (RPV LA). RPV LA provides a depot of drug for sustained release and monthly dosing instead of daily pills. A concern with using approved antiretroviral drugs for both therapy and PrEP is the selection of drug-resistant mutations that may confer cross-resistance to multiple drugs. This issue has public health relevance, as individuals with cross-resistant mutations will have limited therapy options and could transmit drug-resistant virus to others. To study HIV-1 resistance to RPV in the context of PrEP, we treated macaques and humanized mice with RPV LA and characterized selection of drug-resistant virus and the ability to prevent mucosal transmission of drug-resistant HIV-1, respectively. We found that RPV LA monotherapy in macaques selected for transient low-level RPV-resistant mutations. We also found that RPV LA prevented vaginal transmission of HIV-1 with low- but not high-level resistance in a concentration dependent manner. Similar to macaques, we found no evidence of consistent resistance selection in breakthrough infections in mice. Together, these animal models indicate the risk of resistance selection by RPV LA is low; however, the in vivo protective concentration of RPV LA should be better defined before Phase 3 clinical trials to measure efficacy. To counter HIV-1 drug resistance, new antiretroviral compounds must be developed. We studied three experimental RPV analogs and found that one compound selected for a novel combination of two mutations in reverse transcriptase. Together the mutations conferred cross-resistance to all approved NNRTIs; however, hypersusceptibility to several non-NNRTI drugs was observed. This indicates that the analog has a novel interaction with HIV-1 reverse transcriptase that could be exploited to design better antiretroviral compounds.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
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| ETD Committee: |
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| Date: |
29 June 2017 |
| Date Type: |
Publication |
| Defense Date: |
30 November 2016 |
| Approval Date: |
29 June 2017 |
| Submission Date: |
21 November 2016 |
| Access Restriction: |
1 year -- Restrict access to University of Pittsburgh for a period of 1 year. |
| Number of Pages: |
224 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Public Health > Infectious Diseases and Microbiology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
antiretroviral, BLT humanized mice, drug resistance, rilpivirine, HIV-1, macaque, NNRTI, pre-exposure prophylaxis, RT-SHIV |
| Date Deposited: |
29 Jun 2017 23:45 |
| Last Modified: |
01 May 2018 05:15 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/30646 |
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HIV-1 resistance to rilpivirine in the context of pre-exposure prophylaxis. (deposited 29 Jun 2017 23:45)
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