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

ABSTRACT 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 >10,000 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-1LAI containing bulk-amplified, plasma-derived, full-length reverse transcriptase sequences. Fold change (FC) values were calculated compared with a composite 50% inhibitory concentration (IC50) from 12 recombinant subtype C HIV-1LAI plasma-derived viruses from treatment-naive individuals in South Africa. A total of 25/100 (25%) samples showed >500-FCs to DPV compared to treatment-naive samples with IC50s exceeding the maximum DPV concentration tested (132 ng/ml). A total of 66/100 (66%) samples displayed 3- to 306-FCs, with a median IC50 of 17.6 ng/ml. Only 9/100 (9%) samples were susceptible to DPV (FC < 3). Mutations L100I and K103N were significantly more frequent in samples with >500-fold resistance to DPV compared to samples with a ≤500-fold resistance. A total of 91% of samples with NNRTI-resistant HIV-1 from individuals on failing first-line ART in South Africa exhibited ≥3-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.

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Frequent cross-resistance to rilpivirine among subtype C HIV-1 from first-line antiretroviral therapy failures in South Africa

Antiviral Chemistry and Chemotherapy ◽

10.1177/2040206618762985 ◽

2018 ◽

Vol 26 ◽

pp. 204020661876298 ◽

Cited By ~ 5

Author(s):

Kerri J Penrose ◽

Chanson J Brumme ◽

Maritsa Scoulos-Hanson ◽

Kristen Hamanishi ◽

Kelley Gordon ◽

...

Keyword(s):

South Africa ◽

Antiretroviral Therapy ◽

Reverse Transcriptase ◽

Nucleoside Reverse Transcriptase Inhibitor ◽

Transcriptase Inhibitor ◽

Cross Resistance ◽

Subtype C ◽

First Line ◽

Reverse Transcriptase Inhibitor ◽

Hiv 1

Background Rilpivirine (TMC278LA) is a promising drug for pre-exposure prophylaxis of HIV-1 because of its sub-nanomolar potency and long-acting formulation; however, increasing transmission of non-nucleoside reverse transcriptase inhibitor-resistant HIV-1 with potential cross-resistance to rilpivirine could reduce its preventive efficacy. This study investigated rilpivirine cross-resistance among recombinant subtype C HIV-1 derived from 100 individuals failing on first-line non-nucleoside reverse transcriptase inhibitor-containing antiretroviral therapy in South Africa whose samples were sent for routine HIV-1 drug resistance testing to Lancet Laboratories (Johannesburg, South Africa). Methods Plasma samples were selected from individuals with HIV-1 RNA > 10,000 copies/ml and ≥1 non-nucleoside reverse transcriptase inhibitor-resistance mutation in reverse transcriptase. Recombinant HIV-1LAI-containing bulk-cloned full-length reverse transcriptase sequences from plasma were assayed for susceptibility to nevirapine (NVP), efavirenz (EFV) and rilpivirine in TZM-bl cells. Fold-change (FC) decreases in drug susceptibility were calculated against a mean IC50 from 12 subtype C HIV-1 samples from treatment-naïve individuals in South Africa. Cross-resistance was evaluated based on biological cutoffs established for rilpivirine (2.5-FC) and the effect of mutation combinations on rilpivirine phenotype. Results Of the 100 samples from individuals on failing antiretroviral therapy, 69 had 2.5- to 75-fold decreased susceptibility to rilpivirine and 11 had >75-fold resistance. Rilpivirine resistance was strongly associated with K103N especially in combination with other rilpivirine-associated mutations. Conclusion The frequently observed cross-resistance of HIV-1 suggests that the preventive efficacy of TMC278LA pre-exposure prophylaxis could be compromised by transmission of HIV-1 from individuals with failure of first-line non-nucleoside reverse transcriptase inhibitor-containing antiretroviral therapy.

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High Prevalence of Cross-resistance to Rilpivirine in Subtype C HIV-1 Isolates from First-line ART Failures in South Africa

AIDS Research and Human Retroviruses ◽

10.1089/aid.2014.5346.abstract ◽

2014 ◽

Vol 30 (S1) ◽

pp. A166-A166 ◽

Cited By ~ 2

Author(s):

Kerri J. Penrose ◽

Carole L. Wallis ◽

Maritsa Scoulos-Hanson ◽

Raquel Viana ◽

John W. Mellors ◽

...

Keyword(s):

South Africa ◽

Cross Resistance ◽

Subtype C ◽

First Line ◽

High Prevalence ◽

Hiv 1

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Impact of transmitted HIV-1 drug resistance on the efficacy of first-line antiretroviral therapy with two nucleos(t)ide reverse transcriptase inhibitors plus an integrase inhibitor or a protease inhibitor

Journal of Antimicrobial Chemotherapy ◽

10.1093/jac/dky211 ◽

2018 ◽

Vol 73 (9) ◽

pp. 2480-2484 ◽

Cited By ~ 9

Author(s):

C Spertilli Raffaelli ◽

B Rossetti ◽

L Paglicci ◽

M Colafigli ◽

G Punzi ◽

...

Keyword(s):

Drug Resistance ◽

Antiretroviral Therapy ◽

Protease Inhibitor ◽

Reverse Transcriptase ◽

Integrase Inhibitor ◽

Reverse Transcriptase Inhibitors ◽

First Line ◽

Hiv 1

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HIV-1 drug resistance mutations in children after failure of first-line nonnucleoside reverse transcriptase inhibitor-based antiretroviral therapy

HIV Medicine ◽

10.1111/j.1468-1293.2010.00828.x ◽

2010 ◽

Vol 11 (9) ◽

pp. 565-572 ◽

Cited By ~ 19

Author(s):

T Puthanakit ◽

G Jourdain ◽

S Hongsiriwon ◽

P Suntarattiwong ◽

K Chokephaibulkit ◽

...

Keyword(s):

Drug Resistance ◽

Antiretroviral Therapy ◽

Reverse Transcriptase ◽

Transcriptase Inhibitor ◽

Resistance Mutations ◽

First Line ◽

Drug Resistance Mutations ◽

Nonnucleoside Reverse Transcriptase Inhibitor ◽

Reverse Transcriptase Inhibitor ◽

Hiv 1

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A Novel Nonnucleoside Analogue That Inhibits Human Immunodeficiency Virus Type 1 Isolates Resistant to Current Nonnucleoside Reverse Transcriptase Inhibitors

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01032-06 ◽

2006 ◽

Vol 51 (2) ◽

pp. 429-437 ◽

Cited By ~ 39

Author(s):

Zhijun Zhang ◽

Wen Xu ◽

Yung-Hyo Koh ◽

Jae Hoon Shim ◽

Jean-Luc Girardet ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Reverse Transcriptase ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Plasma Concentrations ◽

Cross Resistance ◽

Double Mutation ◽

Immunodeficiency Virus ◽

Hiv 1

ABSTRACT Nonnucleoside reverse transcriptase (RT) inhibitors (NNRTIs) are important components of current combination therapies for human immunodeficiency virus type 1 (HIV-1) infection. However, their low genetic barriers against resistance development, cross-resistance, and serious side effects can compromise the benefits of the two current drugs in this class (efavirenz and nevirapine). In this study, we report a novel and potent NNRTI, VRX-480773, that inhibits viruses from efavirenz-resistant molecular clones and most NNRTI-resistant clinical HIV-1 isolates tested. In vitro mutation selection experiments revealed that longer times were required for viruses to develop resistance to VRX-480773 than to efavirenz. RT mutations selected by VRX-480773 after 3 months of cell culture in the presence of 1 nM VRX-480773 carried the Y181C mutation, resulting in a less-than-twofold increase in resistance to the compound. A virus containing the double mutation V106I-Y181C emerged after 4 months, causing a sixfold increase in resistance. Viruses containing additional mutations of D123G, F227L, and T369I emerged when the cultures were incubated with increasing concentrations of VRX-480773. Most of the resistant viruses selected by VRX-480773 are susceptible to efavirenz. Oral administration of VRX-480773 to dogs resulted in plasma concentrations that were significantly higher than those required for the inhibition of wild-type and mutant viruses. These results warrant further clinical development of VRX-480773 for the treatment of HIV infection in both NNRTI-naive and -experienced patients.

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