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Sexual transmission of an extensively drug-resistant HIV-1 strain
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August 01, 2020 The Lancet HIV
Emergence of drug-resistant HIV-1 has long been identified as a public health threat. However, there has so far been little transmission of multidrug-resistant strains, probably because of reduced replication fitness of highly mutated strains that makes them less adapted for establishing infection than wild-type strains among the viral quasispecies. In HIV-1 primary infections in France, less than 0·1% of transmitted viruses had triple-class resistance.
Here, we report a case of symptomatic primary HIV-1 infection diagnosed in September, 2019, in a 23-year-old French man who has sex with men. HIV-1 ELISA was negative in June, 2019, then became positive in September, with incomplete immunoblot (Fiebig stage IV), plasma HIV-1 RNA of 5·1 log10 copies per mL, and CD4 count of 821 cells per μL. He did not use pre-exposure prophylaxis.
A unique, extensively drug-resistant founder virus was identified by Sanger and next-generation sequencing with a homogeneous, fully mutated viral quasispecies that remained stable off-treatment (appendix p 1). This subtype-B strain had resistance mutations to all available nucleoside reverse-transcriptase inhibitors, non-nucleoside reverse-transcriptase inhibitors, and protease inhibitors, and near-complete resistance to integrase inhibitors, except low-level resistance to dolutegravir and bictegravir, according to the Stanford algorithm and the French National Agency for Research on AIDS algorithm (appendix p 2).
Entry coreceptor usage assessment by a recombinant virus assay revealed a pure R5 phenotype, in agreement with V3 env next generation sequencing (appendix p 3). The gp41 env gene sequence revealed only an Asn42Gly mutation.
We identified a second extensively drug-resistant HIV-1 strain with the same mutation pattern in the same region of France in a 54-year-old man who has sex with men. This patient had been HIV-positive since 1995, with a long history of virological failure. Plasma HIV-1 RNA was 5·5 log10 copies per mL, and CD4 count was 205 cells per μL (8%) in July, 2019, despite a regimen of tenofovir, emtricitabine, ritonavir-boosted darunavir, and dolutegravir. Quasispecies analyses of pol and env genes by next generation sequencing identified the same dominant extensively drug-resistant strain (appendix p 1), as well as major CCR5-using variants and minor CXCR4-using variants (appendix p 3). The strains in both patients were phylogenetically-related (appendix p 4), but a direct transmission history could not be established, suggesting unsampled intermediary links.
A five-drug regimen combining four drugs that target the virus entry step (ibalizumab, fostemsavir, maraviroc, enfuvirtide) with dolutegravir (50 mg twice a day) is planned for the patient with a pure R5 phenotype. The patient with mixed R5 and R4 phenotype will have the same regimen without maraviroc. Early access to the new GS-6207 capsid inhibitor might be an interesting additional therapeutic option.
The sexual transmission of such an extensively drug-resistant virus is an unprecedented event. Transmission of a multidrug-resistant HIV-1 strain was reported in New York (NY, USA) in 2004, but without resistance to tipranavir and integrase inhibitors at that time. Extensively drug-resistant HIV-1 strains might have a reduced viral fitness. However, the plasma viral load was more than 5 log10 copies per mL in the source patient at the time of transmission to the recipient patient, suggesting good adaptation of the viral strain to the host. However, the plasma viral load tended to decrease in the recipient patient after primary infection, which means that longer follow-up and additional studies on the viral fitness of this strain are needed. An epidemiological surveillance network of virologists, clinicians, and local actors of prevention should prevent the diffusion of this extensively drug-resistant HIV-1 strain. New antiretroviral drug classes are needed to open alternative therapeutic avenues for such strains.

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