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

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

doi:10.1186/s13756-020-00799-2

Cited by 14 publications

(18 citation statements)

References 17 publications

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“…Between 2017 and November 2020, only three complete and two fragmented IN sequences have been deposited to LANL. The latter two are from the same HIV-1 CRF18_cpx-infected individual who developed multi-drug InSTI resistance in 2017 based on G140A, Q148R, and E157Q DRMs, which further aggravated in 2019 additionally involving E138K/Q and S147G ( Fokam et al, 2020 ). Our structural simulations suggest that CRF02_AG IN has a comparable quaternary structure with clade B, including surface and drug-binding site charge distribution ( Supplementary Figures 13 , 14 ).…”

Section: Discussionmentioning

confidence: 99%

“…Emerging IN drug resistance is an imminent threat requiring broad and widespread monitoring efforts across Cameroon and beyond ( Inzaule et al, 2018 ; Lubke et al, 2019 ). Particular attention should be paid to patients that previously used Raltegravir-containing regimens as in the case of DTG and Darunavir/r multi-drug resistance in HIV-1 CRF18_cpx infection described recently in Cameroon ( Fokam et al, 2020 ). Furthermore, recent data suggest a reduced InSTI efficacy in patients with DRMs in RT ( Siedner et al, 2020 ), stressing the importance of studying full pol .…”

Section: Discussionmentioning

confidence: 99%

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Antiretroviral Imprints and Genomic Plasticity of HIV-1 pol in Non-clade B: Implications for Treatment

et al. 2022

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Combinational antiretroviral therapy (cART) is the most effective tool to prevent and control HIV-1 infection without an effective vaccine. However, HIV-1 drug resistance mutations (DRMs) and naturally occurring polymorphisms (NOPs) can abrogate cART efficacy. Here, we aimed to characterize the HIV-1 pol mutation landscape in Cameroon, where highly diverse HIV clades circulate, and identify novel treatment-associated mutations that can potentially affect cART efficacy. More than 8,000 functional Cameroonian HIV-1 pol sequences from 1987 to 2020 were studied for DRMs and NOPs. Site-specific amino acid frequencies and quaternary structural features were determined and compared between periods before (≤2003) and after (2004–2020) regional implementation of cART. cART usage in Cameroon induced deep mutation imprints in reverse transcriptase (RT) and to a lower extent in protease (PR) and integrase (IN), according to their relative usage. In the predominant circulating recombinant form (CRF) 02_AG (CRF02_AG), 27 canonical DRMs and 29 NOPs significantly increased or decreased in RT during cART scale-up, whereas in IN, no DRM and only seven NOPs significantly changed. The profound genomic imprints and higher prevalence of DRMs in RT compared to PR and IN mirror the dominant use of reverse transcriptase inhibitors (RTIs) in sub-Saharan Africa and the predominantly integrase strand transfer inhibitor (InSTI)-naïve study population. Our results support the potential of InSTIs for antiretroviral treatment in Cameroon; however, close surveillance of IN mutations will be required to identify emerging resistance patterns, as observed in RT and PR. Population-wide genomic analyses help reveal the presence of selective pressures and viral adaptation processes to guide strategies to bypass resistance and reinstate effective treatment.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Antiretroviral Imprints and Genomic Plasticity of HIV-1 pol in Non-clade B: Implications for Treatment

et al. 2022

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“…Recently, many studies have focused on DRV/r + INSTIs (Calza et al, 2020;Fokam et al, 2020). Stellbrink et al (Stellbrink et al, 2016) suggested that DRV/r + INSTIs was more effective than TT in increasing body fat and improving physical fitness.…”

Section: Discussionmentioning

confidence: 99%

Effectiveness and Safety Analysis of PIs/r Based Dual Therapy in Treatment-Naïve, HIV/AIDS Patients: A Network Meta Analysis of Randomized Controlled Trials

et al. 2022

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Background: Dual anti-retroviral therapy is the main proven valuable intervention type for treating naïve HIV/AIDS. Currently, no high-quality evidence is available regarding the best dual schemes.Objectives: The aim of this study is to evaluate the effectiveness and safety of PIs/r-based dual therapy in treatment-naïve HIV/AIDS patients by using network meta-analysis.Methods: Randomized controlled trials of PIs/r-based dual therapy in treatment-naïve HIV/AIDS were searched based on Embase, PubMed and Cochrane library database from January 2006 to June 2021. Taking viral suppression rate, CD4+T cell count changes from baseline as the primary indicator and adverse events rate as secondary indicator, the network meta-analysis was performed on Review Manager and STATA software. Heterogeneity was assessed by the Q statistic and I2. We registered our protocol in Prospero with ID CRD42021275466.Results: Among 15 randomized controlled trials (3,497 patients and 7 PIs/r-based dual therapy) were reviewed in this study. According to the forest map, DRV/r + INSTIs was more effective compared to triple therapy (TT) in viral suppression [OR 0.82, 95% CI (0.61–1.11)], in CD4+T cell count changes from baseline [MD 1.9, 95% CI (0.7, 3.1), I2 86%], in adverse events [OR 0.98, 95% CI (0.68–1.39)]. Furthermore, SUCRA ranking analysis indicated that DRV/r + INSTIs was superior to TT in viral suppression (DRV/r + INSTIs 75.5% > TT 41.2%) and in immune construction (DRV/r + INSTIs 67% > TT 42%). In addition, DRV/r + INSTIs was similar to TT in adverse events (DRV/r + INSTIs 54.9% ≈ TT 54.7%).Conclusion: DRV/r + INSTIs was obviously superior to TT in viral suppression and immune reconstruction, and was not higher than TT in adverse events.Systematic Review Registration:https://www.crd.york.ac.uk/prospero/, identifier CRD42021275466

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“…Globally, cases of INSTIs transmission resistance are still rare, [14][15][16] especially those with high levels of drug resistance at multiple sites. More importantly, we have seen that in Guangxi, China, resource constraints have affected the choice of treatment options for patients, resulting in patients failing to receive timely and effective ART.…”

Section: Discussionmentioning

confidence: 99%

The Emergence of Resistance Under Firstline INSTI Regimens

Xie¹,

Zhou²,

Liu³

et al. 2022

IDR

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We reported an HIV-naïve patient from a resource-limited area who was detected with multiple resistance sites associated with nucleoside reverse transcriptase inhibitors (NRTIs) and integrase strand transfer inhibitors (INSTIs) after the failure of the initial antiviral regimen dolutegravir/lamivudine (DTG/3TC) and subsequent Bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF). On May 8, 2021, a 53-year-old man was diagnosed with AIDS, Marneffei talaromycosis and fungal esophagitis, and was suspected of having tuberculosis (TB) in Guangxi, China. His baseline HIV RNA was 559,000 copies/mL and the CD4 count was 12 cells/µL, but resistance genotype testing was not performed. The patient remained immunosuppressed (CD4 count 3 cells/µL) after 12 weeks of initial antiviral treatment (ART) with DTG/3TC. After he was switched to BIC/FTC/TAF and started anti-TB treatment, the viral load (HIV RNA 163,200 copies/mL) was not effectively controlled, and there were multiple NRTIs drug-resistant mutations (D67N, K70R, M184V, T215V, K219Q) and INSTIs mutations (E138K, G140A, S147SG, Q148R). This suggested that in resource-limited areas, for HIV-naïve patients in advanced stages with active opportunistic infections, HIV RNA>500,000 copies/mL, and low CD4 count, baseline resistance testing and increased HIV RNA testing frequency should be recommended, DTG/3TC was not recommended as initiation, and opportunistic infections should be treated promptly. In addition, switching to other INSTIs was not recommended in the absence of resistance testing and ineffective use of DTG.

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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

Cited by 14 publications

References 17 publications

Antiretroviral Imprints and Genomic Plasticity of HIV-1 pol in Non-clade B: Implications for Treatment

Antiretroviral Imprints and Genomic Plasticity of HIV-1 pol in Non-clade B: Implications for Treatment

Effectiveness and Safety Analysis of PIs/r Based Dual Therapy in Treatment-Naïve, HIV/AIDS Patients: A Network Meta Analysis of Randomized Controlled Trials

The Emergence of Resistance Under Firstline INSTI Regimens

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