First case of Dolutegravir and Darunavir/r multi drug-resistant HIV-1 in Cameroon following exposure to Raltegravir: lessons and implications in the era of transition to Dolutegravir-based regimens

Joseph Fokam,Mireille Mpoudi Ngole Etame,Vittorio Colizzi,Béatrice Dambaya ,Samuel Martin Sosso,Georges Této ,Desiré Takou ,Leonella Mossiang,Fatim Cham,Serge Clotaire Billong,Ezéchiel Ngoufack Jagni Semengue ,Grâce Beloumou ,Emmanuel Eben Moussi,Nelly Kamgaing,Anne-Cécile Zoung-Kanyi Bissek ,Carlo Federico Perno ,Joelle Nounouce Ngako Pamen,Maria Mercedes Santoro ,Sylvie Moudourou,Aubin Nanfack ,Edith Temgoua ,Rachel Kamgaing,Jean-Bosco Nfetam Elat ,Alexis Ndjolo

doi:10.1186/s13756-020-00799-2

Abstract

BackgroundSub-Saharan African countries are transitioning to dolutegravir-based regimens, even for patients with extensive previous drug exposure, including first-generation integrase strand-transfer inhibitors (INSTI) such as raltegravir. Such exposure might have implications on cross-resistance to dolutegravir-based antiretroviral therapies (ART).Case presentationWe report a 65 years old Cameroonian, previously exposed to raltegravir, and failing on third-line treatment with multi-drug resistance to darunavir/r and dolutegravir. Genotypic resistance testing (GRT) and viral tropism were performed during monitoring time points. The patient initiated ART in August 2007. At the time point of the first (29.04.2010), second (01.12.2017) and third (08.08.2019) GRT, prior ART exposure included 3TC, d4T, NVP and EFV; additionally TDF, DRV/r and RAL; and additionally ABC and DTG respectively. First GRT revealed mutations associated with resistance only to first-generation Non-nucleoside reverse transcriptase inhibitors (NNRTI). Second GRT revealed mutations associated with high-level resistance to all NRTIs, first generation NNRTIs, all ritonavir boosted protease inhibitors (PI/r), and all INSTI, while viral tropism (using geno2pheno) revealed a CCR5-tropic virus with a false positive rate (FPR) of 60.9% suggesting effectiveness of maraviroc (MRV). The third GRT showed high-level resistance to NRTI, NNRTI, all PI and all INSTI, with additional mutations (H221HY for NNRTI and S147G for INSTI), and a CCR5-tropic virus with a slightly reduced FPR (57.0%). Without any locally available active therapeutic option, the patient has been on a maintenance therapy with “DRV/r (600mg x 2/day)+TDF+3TC” and patient/family-centered adherence has been reinforced. Since the first viral load (VL) measurement in 2010, the patient has had 12 VL tests with the VL ranging from 4.97 Log to 6.44 Log copies/mL and the CD4 count never exceeded 200 cells/μL.ConclusionsAs African countries transition to dolutegravir-based regimens, prior raltegravir-exposure may prompt selection (and potential transmission) of dolutegravir-resistance, supporting case surveillance.

Highlights

Sub-Saharan African countries are transitioning to dolutegravir-based regimens, even for patients with extensive previous drug exposure, including first-generation integrase strand-transfer inhibitors (INSTI) such as raltegravir
He received a regimen consisting of superboosted ritonavir with darunavir (DRV/r) + raltegravir (RAL) + tenofovir (TDF) +3TC till November 2017, a period during which adherence was suboptimal
Detected Resistance-associated mutations (RAMs) were M41L, K70Q, V75I, Q151M, M184V and T215F for Nucleoside reverse-transcriptase inhibitor (NRTI); K103N and V108I for nucleoside reverse transcriptase inhibitors (NNRTI); and L10F, K20I, M36I, M46I, I47V, I54L, L63H, L76V, V82S and L89I for protease inhibitors (PI/r). These mutations revealed high-level resistance to all NRTIs, first generation NNRTIs (EFV and NVP) and to all PI/r, including DRV/r

Summary

Conclusions

As African countries transition to dolutegravir-based regimens, prior raltegravir-exposure may prompt selection (and potential transmission) of dolutegravir-resistance, supporting case surveillance. After completing anti-tuberculosis treatment in 2012, he was lost to follow-up (duration unclear) and later returned for clinical consultation Following clinical assessment, he received a regimen consisting of superboosted ritonavir with darunavir (DRV/r) + raltegravir (RAL) + tenofovir (TDF) +3TC (unclear start date) till November 2017, a period during which adherence was suboptimal (assessed by self-reporting). While completing anti-tuberculosis treatment the patient discontinued HIVtreatment Following clinical assessment, he was reinitiated with a regimen consisting of ritonavir boosted darunavir (DRV/r) + raltegravir (RAL) + tenofovir (TDF). These mutations revealed high-level resistance to all NRTIs, first generation NNRTIs (EFV and NVP) and to all PI/r, including DRV/r Another GRT, covering HIV-1 integrase (IN) region, performed on the sample plasma aliquot, revealed major RAMs, L74I, E138KQ, G140A, Q148R, and E157Q, to integrase strand transfer inhibitors (INSTI) including raltegravir, dolutegravir, bictegravir and elvitegravir. Following intensified/close adherence strategy implemented, the patient is compliant to treatment but the latest plasma viral load remains high, with a slight increment (5.86 Log copies/mL on January 27, 2020), which confirms the need of innovative drugs and close case surveillance, including MRV that is not locally available [3]

Findings

Discussion

Conclusion