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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.

ABSTRACT: BACKGROUND: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. Such exposure might have implications on cross-resistance to dolutegravir-based antiretroviral therapies (ART). CASE PRESENTATION:We 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/?L. CONCLUSIONS:As African countries transition to dolutegravir-based regimens, prior raltegravir-exposure may prompt selection (and potential transmission) of dolutegravir-resistance, supporting case surveillance.

SUBMITTER: Fokam J

PROVIDER: S-EPMC7449072 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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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.

Fokam Joseph J Takou Desire D Semengue Ezechiel Ngoufack Jagni ENJ Teto Georges G Beloumou Grace G Dambaya Beatrice B Santoro Maria-Mercedes MM Mossiang Leonella L Billong Serge Clotaire SC Cham Fatim F Sosso Samuel Martin SM Temgoua Edith Saounde ES Nanfack Aubin Joseph AJ Moudourou Sylvie S Kamgaing Nelly N Kamgaing Rachel R Ngako Pamen Joelle Nounouce JN Etame Mireille Mpoudi Ngole MMN Bissek Anne-Cecile Z-K AZ Elat Jean-Bosco N JN Moussi Emmanuel Eben EE Colizzi Vittorio V Perno Carlo-Federico CF Ndjolo Alexis A

Antimicrobial resistance and infection control 20200826 1

<h4>Background</h4>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. Such exposure might have implications on cross-resistance to dolutegravir-based antiretroviral therapies (ART).<h4>Case presentation</h4>We report a 65 years old Cameroonian, previously exposed to raltegravir, and failing on third-line treatment with ...[more]

PMID: 32843050

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Project description:Background and objectivesLong-term use of antiretroviral therapy (ART) to treat HIV infection has been associated with dyslipidemia and metabolic and cardiovascular complications. Available options for patients at risk of cardiovascular disease include antiretroviral drugs with improved lipid profiles. Dolutegravir is one of a new generation of HIV integrase inhibitors recently incorporated into the US Department of Health and Human Services, German, Spanish, and Italian HIV treatment guidelines as a preferred first-line third agent in combination with dual nucleoside reverse transcriptase inhibitor (NRTI) backbone therapies. To understand the lipid profile of dolutegravir in the context of combination ART, we analyzed the lipid outcomes at 48 weeks in ART-naive participants in four phase IIb-IIIb clinical trials.MethodsVariables included in this analysis were total cholesterol (TC), low-density lipoprotein (LDL) cholesterol (LDL-C), high-density lipoprotein (HDL) cholesterol (HDL-C), TC/HDL ratio, and triglycerides at baseline and week 48.ResultsIn a comparative analysis, dolutegravir demonstrated a broadly neutral effect on lipids versus efavirenz or ritonavir-boosted darunavir; in both comparisons, patients taking dolutegravir exhibited smaller increases in TC, LDL-C, and triglyceride levels. In comparison with raltegravir, dolutegravir exhibited a similar lipid profile, including small increases in TC, LDL-C, and triglyceride levels for both agents. In the pooled dolutegravir analysis, minimal increases in LDL-C and triglycerides were observed but mean values at 48 weeks remained below National Cholesterol Education Program target levels. HDL-C levels increased at 48 weeks, and the mean TC/HDL-C ratio was 0.6 at 48 weeks; these values are associated with a lower risk of cardiovascular disease.ConclusionsTogether, these data show that dolutegravir has a safer lipid profile in combination ART and provides an important treatment option for older patients who may have other risk factors for metabolic syndrome or cardiovascular disease.

Project description:To ensure the long-term efficacy of dolutegravir (DTG), we evaluated the genotypic profile in viral reservoirs among patients on third-line (3L) antiretroviral therapy (ART) in Cameroon, according to prior exposure to raltegravir (RAL). A facility-based study was conducted from May through December 2021 among patients on 3L ART from HIV treatment centers in Yaoundé and Douala. Viral load was measured, and genotyping was performed on plasma RNA and proviral DNA. HIV-1 drug resistance mutations were interpreted using HIVdb.v9.1 and phylogeny analysis was performed using MEGA.v7, with P < 0.05 considered significant. Of the 12,093 patients on ART, 53 fully met our inclusion criteria. The median (IQR) age was 51 years (40 to 55 years), and the male/female ratio was 4/5. The median duration on integrase strand-transfer inhibitors (INSTI)-containing regimens was 18 months (12 to 32 months), and 15.09% (8/53) were exposed to RAL. The most administered 3L ART was TDF+3TC+DTG+DRV/r (33.96%, 18/53). Only 5.66% (3/53) had unsuppressed viremia (>1000 copies/mL). Resistance testing in proviral DNA was successful for 18/22 participants and revealed 1/18 patients (5.56%, in the RAL-arm) with archived mutations at major resistance positions (G140R and G163R). Five subtypes were identified, CRF02_AG (12/18), CRF22_01AE (3/18), A1 (1/18), G (1/18), and F2 (1/18). In Cameroon, 3L-experienced patients had a good virological response with a low level of archived mutations in the integrase. This finding underscored the use of DTG-containing ART for heavily treated patients in similar programmatic settings. However, patients with prior exposure to RAL should be closely monitored following a stratified or personalized approach to mitigate risks of INSTI-resistance, alongside pharmacovigilance. IMPORTANCE We described the analysis of the genotypes of the population within third-line antiviral therapy in Cameroon, with a focus on defining the effects of prior raltegravir (RAL) treatment and resistance mutations for current dolutegravir (DTG) treatment. While supporting the current transition to DTG-containing ART in resource-limited settings toward the achievement of the UNAIDS' goal of HIV elimination by 2030, our findings suggested that RAL-exposed patients may need a specific monitoring approach either in a stratified or personalized model of third-line ART to ensure the long-term success of DTG-containing regimens.

Project description:IntroductionThe COVID-19 pandemic has dramatically affected the Female and Functional Urology (FFU) practice, leading to massive waiting lists, while patients' quality of life remains severely impaired. The aim of the present study is to develop consensual recommendations to guide clinicians on the management of FFU patients. The present paper focuses on female LUTS.MethodsThe authors used the Delphi methodology to develop a robust survey questionnaire, covering the principal topics in FFU, based on literature review and expert opinions. Regarding female LUTS, a 98-question survey was distributed among FFU specialists to obtain optimized recommendations, under the auspicious of the International Continence Society (TURNOVER, ICS project). A quantitative analysis of the data was performed, categorizing the mean value from 0-10. Consensus achievement was defined as attaining ≥ 70% agreement.Results98 ICS members completed the F-LUTS survey. Recommendations for the diagnosis and management of female LUTS are summarized. Video-consultation should be used for initial assessment, sending questionnaires and bladder diaries in advance to the patient to be filled out before the consultation. However, face-to-face visits are mandatory if POP or continuous incontinence are suspected, and prior to any surgical procedure, regardless of the health alert. Moreover, prescribing medications such as anticholinergics or β 3 agonists in a telemedicine setting is not considered a safe practice. Follow-up teleconsultations can be used to assess the efficacy and treatment-related adverse events.Urodynamic testing should be only performed if consequences on F-LUTS treatment are expected. The study should be postponed until the pandemic local behaviour flattens.Invasive procedures should be postponed during a high alert. In case surgery is scheduled, outpatient clinics and local anaesthesia should be prioritized. Every patient should be screened for SARS-CoV-2 infection before invasive tests or procedures, following local authorities' guidance.ConclusionsDuring a pandemic, telemedicine offers a novel way of communication, maintaining medical care while preventing viral transmission. Non-urgent procedures should be postponed until the pandemic curve flattens. Ambulatory procedures under regional or local anaesthesia should be prioritized, aiming to reduce bed occupancy and risk of transmission.

Dataset Information

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.

Publications

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.

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