Low Frequency of Drug-Resistant Variants Selected by Long-Acting Rilpivirine in Macaques Infected with Simian Immunodeficiency Virus Containing HIV-1 Reverse Transcriptase

Melody, Kevin; McBeth, Sarah; Kline, Christopher E.; Kashuba, Angela D. M.; Mellors, John W.; Ambrose, Zandrea

doi:10.1128/aac.01937-15

Cited by 17 publications

(22 citation statements)

References 69 publications

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“…In the animal in which K103N arose (A99165), plasma viremia initially declined but rebounded around week 15, coinciding with the spread of resistance. We suspect that the expected resistance mutation did not fix in A99165 and A01198 because selection pressure was weak due to the rapid metabolism of NNRTIs in macaques (S2B Fig ), which we have observed previously [41, 42]. Because EFV was not present at consistently high concentrations, we did not estimate a selection coefficient s for K103N.…”

Section: Resultsmentioning

confidence: 94%

A spatio-temporal assessment of simian/human immunodeficiency virus (SHIV) evolution reveals a highly dynamic process within the host

et al. 2017

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The process by which drug-resistant HIV-1 arises and spreads spatially within an infected individual is poorly understood. Studies have found variable results relating how HIV-1 in the blood differs from virus sampled in tissues, offering conflicting findings about whether HIV-1 throughout the body is homogeneously distributed. However, most of these studies sample only two compartments and few have data from multiple time points. To directly measure how drug resistance spreads within a host and to assess how spatial structure impacts its emergence, we examined serial sequences from four macaques infected with RT-SHIVmne027, a simian immunodeficiency virus encoding HIV-1 reverse transcriptase (RT), and treated with RT inhibitors. Both viral DNA and RNA (vDNA and vRNA) were isolated from the blood (including plasma and peripheral blood mononuclear cells), lymph nodes, gut, and vagina at a median of four time points and RT was characterized via single-genome sequencing. The resulting sequences reveal a dynamic system in which vRNA rapidly acquires drug resistance concomitantly across compartments through multiple independent mutations. Fast migration results in the same viral genotypes present across compartments, but not so fast as to equilibrate their frequencies immediately. The blood and lymph nodes were found to be compartmentalized rarely, while both the blood and lymph node were more frequently different from mucosal tissues. This study suggests that even oft-sampled blood does not fully capture the viral dynamics in other parts of the body, especially the gut where vRNA turnover was faster than the plasma and vDNA retained fewer wild-type viruses than other sampled compartments. Our findings of transient compartmentalization across multiple tissues may help explain the varied results of previous compartmentalization studies in HIV-1.

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Section: Resultsmentioning

confidence: 94%

A spatio-temporal assessment of simian/human immunodeficiency virus (SHIV) evolution reveals a highly dynamic process within the host

et al. 2017

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“…Nevertheless, this murine model was ideal to study the efficacy of the NNRTI RPV to prevent WT and drug-resistant HIV-1 infection via vaginal exposure. In addition, RPV does not inhibit simian immunodeficiency virus (SIV) and is rapidly metabolized in macaques even at a high dose (68), precluding the use of that animal model. Administration of a single dose of RPV LA to female humanized mice led to similar plasma and genital tract RPV concentrations detected in human women, although they declined rapidly.…”

Section: Discussionmentioning

confidence: 99%

Long-Acting Rilpivirine (RPV) Preexposure Prophylaxis Does Not Inhibit Vaginal Transmission of RPV-Resistant HIV-1 or Select for High-Frequency Drug Resistance in Humanized Mice

Melody

Roy

Kline

et al. 2020

J Virol

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As a long-acting formulation of the nonnucleoside reverse transcriptase inhibitor rilpivirine (RPV LA) has been proposed for use as preexposure prophylaxis (PrEP) and the prevalence of transmitted RPV-resistant viruses can be relatively high, we evaluated the efficacy of RPV LA to inhibit vaginal transmission of RPV-resistant HIV-1 in humanized mice. Vaginal challenges of wild-type (WT), Y181C, and Y181V HIV-1 were performed in mice left untreated or after RPV PrEP. Plasma viremia was measured for 7 to 10 weeks, and single-genome sequencing was performed on plasma HIV-1 RNA in mice infected during PrEP. RPV LA significantly prevented vaginal transmission of WT HIV-1 and Y181C HIV-1, which is 3-fold resistant to RPV. However, it did not prevent transmission of Y181V HIV-1, which has 30-fold RPV resistance in the viruses used for this study. RPV LA did delay WT HIV-1 dissemination in infected animals until genital and plasma RPV concentrations waned. Animals that became infected despite RPV LA PrEP did not acquire new RPV-resistant mutations above frequencies in untreated mice or untreated people living with HIV-1, and the mutations detected conferred low-level resistance. These data suggest that high, sustained concentrations of RPV were required to inhibit vaginal transmission of HIV-1 with little or no resistance to RPV but could not inhibit virus with high resistance. HIV-1 did not develop high-level or high-frequency RPV resistance in the majority of mice infected after RPV LA treatment. However, the impact of low-frequency RPV resistance on virologic outcome during subsequent antiretroviral therapy still is unclear. IMPORTANCE The antiretroviral drug rilpivirine was developed into a long-acting formulation (RPV LA) to improve adherence for preexposure prophylaxis (PrEP) to prevent HIV-1 transmission. A concern is that RPV LA will not inhibit transmission of drug-resistant HIV-1 and may select for drug-resistant virus. In female humanized mice, we found that RPV LA inhibited vaginal transmission of WT or 3-fold RPV-resistant HIV-1 but not virus with 30-fold RPV resistance. In animals that became infected despite RPV LA PrEP, WT HIV-1 dissemination was delayed until genital and plasma RPV concentrations waned. RPV resistance was detected at similar low frequencies in untreated and PrEP-treated mice that became infected. These results indicate the importance of maintaining RPV at a sustained threshold after virus exposure to prevent dissemination of HIV-1 after vaginal infection and low-frequency resistance mutations conferred low-level resistance, suggesting that RPV resistance is difficult to develop after HIV-1 infection during RPV LA PrEP.

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“…A normalized input of 100 relative light units was used to infect untreated or DPV-treated TZM-bl cells in a luciferase-based single-round infection drug susceptibility assay (Britelite Plus; Perkin-Elmer) as previously described (24). DPV was kindly provided by International Partnership for Microbicides (Silver Spring, MD).…”

Section: Methodsmentioning

confidence: 99%

Frequent Cross-Resistance to Dapivirine in HIV-1 Subtype C-Infected Individuals after First-Line Antiretroviral Therapy Failure in South Africa

Penrose

Wallis

Brumme

et al. 2017

Antimicrob Agents Chemother

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A vaginal ring containing dapivirine (DPV) has shown moderate protective efficacy against HIV-1 acquisition, but the activity of DPV against efavirenz (EFV)-and nevirapine (NVP)-resistant viruses that could be transmitted is not well defined. We investigated DPV cross-resistance of subtype C HIV-1 from individuals on failing NVP-or EFV-containing antiretroviral therapy (ART) in South Africa. Plasma samples were obtained from individuals with Ͼ10,000 copies of HIV RNA/ml and with HIV-1 containing at least one non-nucleoside reverse transcriptase (NNRTI) mutation. Susceptibility to NVP, EFV, and DPV in TZM-bl cells was determined for recombinant HIV-1 LAI containing bulk-amplified, plasma-derived, full-length reverse transcriptase sequences. Fold change (FC) values were calculated compared with a composite 50% inhibitory concentration (IC 50 ) from 12 recombinant subtype C HIV-1 LAI plasmaderived viruses from treatment-naive individuals in South Africa. A total of 25/100 (25%) samples showed Ͼ500-FCs to DPV compared to treatment-naive samples with IC 50 s exceeding the maximum DPV concentration tested (132 ng/ml). A total of 66/ 100 (66%) samples displayed 3-to 306-FCs, with a median IC 50 of 17.6 ng/ml. Only 9/100 (9%) samples were susceptible to DPV (FC Ͻ 3). Mutations L100I and K103N were significantly more frequent in samples with Ͼ500-fold resistance to DPV compared to samples with a Յ500-fold resistance. A total of 91% of samples with NNRTI-resistant HIV-1 from individuals on failing first-line ART in South Africa exhibited Ն3-fold cross-resistance to DPV. This level of resistance exceeds expected plasma concentrations, but very high genital tract DPV concentrations from DPV ring use could block viral replication. It is critically important to assess the frequency of transmitted and selected DPV resistance in individuals using the DPV ring.KEYWORDS dapivirine, NNRTI, HIV-1, antiretroviral therapy, cross-resistance, drug resistance, human immunodeficiency virus, non-nucleoside reverse transcriptase inhibitor S ustained-release formulations of antiretrovirals could substantially decrease the incidence of HIV-1 infection in sub-Saharan Africa by improving product adherence compared to daily preexposure prophylaxis (PrEP) (1). Dapivirine (DPV) is a potent di-aryl-pyrimidine (DAPY) derivative in the non-nucleoside reverse transcriptase inhibitor (NNRTI) class of antiretrovirals. The development of DPV for antiretroviral therapy was halted due to suboptimal oral pharmacokinetics (2). Instead, it was formulated as a 25-mg slow-release vaginal ring for HIV-1 prevention because of its favorable safety profile and physical and chemical attributes. Recent phase III DPV ring studies in over 4,500 HIV-1-negative female participants in ASPIRE (MTN-020) (3) and the Ring Study

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Low Frequency of Drug-Resistant Variants Selected by Long-Acting Rilpivirine in Macaques Infected with Simian Immunodeficiency Virus Containing HIV-1 Reverse Transcriptase

Cited by 17 publications

References 69 publications

A spatio-temporal assessment of simian/human immunodeficiency virus (SHIV) evolution reveals a highly dynamic process within the host

A spatio-temporal assessment of simian/human immunodeficiency virus (SHIV) evolution reveals a highly dynamic process within the host

Long-Acting Rilpivirine (RPV) Preexposure Prophylaxis Does Not Inhibit Vaginal Transmission of RPV-Resistant HIV-1 or Select for High-Frequency Drug Resistance in Humanized Mice

Frequent Cross-Resistance to Dapivirine in HIV-1 Subtype C-Infected Individuals after First-Line Antiretroviral Therapy Failure in South Africa

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