Human Immunodeficiency Virus Type 1 Resistance or Cross-Resistance to Nonnucleoside Reverse Transcriptase Inhibitors Currently under Development as Microbicides

Abstract

Microbicides based on nonnucleoside reverse transcriptase inhibitors (NNRTIs) are currently being developed to protect women from HIV acquisition through sexual contact. However, the large-scale introduction of these products raises two major concerns. First, when these microbicides are used by undiagnosed HIV-positive women, they could potentially select for viral resistance, which may compromise subsequent therapeutic options. Second, NNRTI-based microbicides that are inactive against NNRTI-resistant strains might promote the selective transmission of these viruses. In order to address these concerns, drug resistance was selected in vitro by the serial passage of three viral isolates from subtypes B and C and CRF02_AG (a circulating recombinant form) in activated peripheral blood mononuclear cells (PBMCs) under conditions of increasing concentrations of three NNRTIs (i.e., TMC120, UC781, and MIV-160) that are currently being developed as candidate microbicides. TMC120 and MIV-160 displayed a high genetic barrier to resistance development, whereas resistance to UC781 emerged rapidly, similarly to efavirenz and nevirapine. Phenotypically, the selected viruses appeared to be highly cross-resistant to current first-line therapeutic NNRTIs (i.e., delavirdine, nevirapine, and efavirenz), although they retained some susceptibility to the more recently developed NNRTIs lersivirine and etravirine. The ability of UC781, TMC120, and MIV-160 to inhibit the in vitro-selected NNRTI-resistant viruses was also limited, although residual activity could be observed for the candidate microbicide NNRTI MIV-170. Interestingly, only four p2/p7/p1/p6/PR/RT/INT recombinant NNRTI-resistant viruses (i.e., TMC120-resistant VI829, EFV-resistant VI829, MIV-160-resistant VI829, and EFV-resistant MP568) showed impairments in replicative fitness. Overall, these in vitro analyses demonstrate that due to potential cross-resistance, the large-scale introduction of single-NNRTI-based microbicides should be considered with caution.

In Vitro Cross-Resistance Profiles of Rilpivirine, Dapivirine, and MIV-150, Nonnucleoside Reverse Transcriptase Inhibitor Microbicides in Clinical Development for the Prevention of HIV-1 Infection

“…The K101E, E138K, K103N/S, F227C, Y181C, and K101E/G190A substitutions con- ferred low-level resistance to DPV, whereas the L100I/V, M230L, K101E/K103N, and Y181C/G190A substitutions and the Y188L, K101P, Y181I/V, K101E/Y181C, and K103N/ Y181C substitutions were found to confer intermediate and high-level resistance, respectively. The DPV cross-resistance profile reported in our study is consistent with prior in vitro studies of DPV resistance selection and cross-resistance profiling (15)(16)(17). Additionally, Penrose et al recently reported that there was frequent cross-resistance to DPV in subtype C-infected individuals after first-line therapy failure and reported that the L100I and K103N substitutions were significantly more frequent in samples with Ͼ500-fold resistance to DPV compared to samples with Յ500-fold resistance (18).…”

“…To our knowledge, this is the first study to define in detail the crossresistance profile for MIV-150, although one prior study identified different combinations of E138K, Y181I, Y181C, K103N, L100I, or K101E in simian immunodeficiency viruses expressing HIV reverse transcriptase (SHIV-RT viruses) exposed to MIV-150 in rhesus macaques, although no phenotypic data were provided (19). Additionally, prior studies have reported on the resistance profiles of the MIV-150 analogs, namely, MIV-160 and MIV-170 (16,17). Recently, we reported that an E138A substitution occurs more frequently in subtype C sequences (range, 5.9 to 7.5%) than subtype B sequences (range, 0 to 2.3%) from treatment-naive individuals (P Ͻ 0.01) (11).…”

Using Glycosaminoglycan/Chemokine Interactions for the Long-Term Delivery of 5P12-RANTES in HIV Prevention

“…Results from a recent clinical trial delivering tenofovir using a gel based on hydroxyethylcellulose (HEC) have yielded especially encouraging results, as HIV acquisition was reduced by an estimated 39% 9 . A major concern with the large scale use of reverse transcriptase inhibitors (RTIs) is that if these agents are simultaneous used in HIV therapy there is the potential for the development of resistant strains 6, 7, 12 . Use of these therapeutics in undiagnosed HIV-positive women, could potentially promote the selection for resistant viruses 5–7, 12 .…”

“…A major concern with the large scale use of reverse transcriptase inhibitors (RTIs) is that if these agents are simultaneous used in HIV therapy there is the potential for the development of resistant strains 6, 7, 12 . Use of these therapeutics in undiagnosed HIV-positive women, could potentially promote the selection for resistant viruses 5–7, 12 . Of additional significance is the increasing prevalence of viruses resistant to classes of antiretrovirals widely used in a community 13 .…”

Peptide and protein-based inhibitors of HIV-1 co-receptors

“…One concern of small molecule drugs though, is the propensity for the development of resistant HIV strains. 14–17 Macromolecular co-receptor inhibitors, by contrast, require HIV to undergo more difficult and arduous evolutionary paths to either utilize the original receptor in a new way or to switch tropism, particularly in going from R5 to X4 receptor usage. 18,19 The development of macromolecular inhibitors of these co-receptors, such as peptides and proteins, presents a potentially innovative means to develop new anti-HIV compounds.…”