Background: Virological failure to Dolutegravir (DTG) containing regimens is a rare event. So far only a few cases have been reported in treatment-experienced individuals, commonly associated with emergence of R263K in the integrase, a substitution that confers low-level resistance against DTG and disminishes HIV DNA integration and viral fitness. In first line therapy, DTG shows a higher barrier to resistance with no reported mutations at 96 or 148 weeks. Here we report a case of early virological failure in an antiretroviral naïve patient that started a DTG based first line therapy.
Methods: A 49 year old woman was diagnosed of HIV-1 infection while admission in June 19th 2017 for lumbar spine surgery. At diagnosis CD4+ count was 39 cells/µl and plasma HIV-1 RNA was 457.000 copies/ml. ART was started one week later with TDF/FTC and DTG 50 mg BID, as she was taking rifampicin,. On July 23th, VL was 3461 copies/ml and CD4+ increased to 113 cells/µl. On August 22nd, rifampicin was removed due to a cutaneous adverse reaction and DTG was given QD. On September 14th, CD4+ count was 42 cells/µl and VL had increased to 126.393 copies/ml. Adherence was confirmed both by hospital records and patient interview, and virological failure was confirmed in a second sample (VL 208.518 c/ml).
Results: Sanger sequencing in RT and Integrase genes was performed at all time points, showing the sequential emergence of M184I (replaced by M184V), R263K, E157Q and K70E. Treatment was changed to TDF, darunavir/cobicistat (DRV/cob) and rilpivirine (RPV), with a VL decrease to 25 copies/ml and a CD4+ increase to 302 cells/µl. A summary of resistance findings is shown in table 1. Deep sequencing of pol and env revealed infection by a recombinant CRF14_BG form.
Conclusions: To our knowledge, this is the first report of first-line treatment failure with DTG with the selection of mutations in the integrase. Using deep sequencing we were able to trace the development and replacement of mutations. Interestingly we have shown, for the first time in vivo, the restoration of viral fitness that E157Q exerts on R263K containing viruses.

Viral load (cop/ml)457.0213.461126.393208.5183.14859525
CD4 (cells/µl)3911342ND68177350
Sanger SequencingWTNDNDM184V R263KM184V R263KNDND
Deep Sequencing (relative prevalence%)WTM184I (39,57%)M184I (41,57%) M184V (57,32%) E157Q (3,83%) R263K (97,26%)M184I (14,24%) M184V (85,05%) E157Q (7,61%) R263K (98,02%)K70E (7,59%) M184I (5,8%) M184V (44,93%) E157Q (19,85%) R263K (98,38%)NDND

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