Description of compensatory gyrA mutations restoring fluoroquinolone susceptibility in Mycobacterium tuberculosis.

OBJECTIVES: Resistance to fluoroquinolones (FQs) in Mycobacterium tuberculosis (Mtb) is mainly due to mutations in DNA gyrase (GyrA2B2), with the most common substitutions located at positions 90 and 94 in GyrA. Two clinical MDR Mtb (MDR-TB) strains harbouring an A90E or D94N substitution in GyrA were found to be surprisingly susceptible to FQs (ofloxacin MIC ≤2 mg/L). We studied the impact of the additional GyrA substitutions found in these strains (T80A and T80A + A90G, respectively) on FQ susceptibility. METHODS: Mutants of interest were generated by site-specific mutagenesis of GyrA alleles. WT and mutant TB DNA gyrase subunits were overexpressed in Escherichia coli and purified, and the in vitro susceptibility to FQs of their DNA supercoiling reaction was studied. RESULTS: IC50s of mutant gyrase complexes bearing GyrA D94N and A90E were 3- to 36-fold higher than WT IC50s, whereas IC50s of gyrase bearing T80A + A90G + D94N and T80A + A90E were close to the WT IC50s. CONCLUSIONS: We demonstrated that substitutions T80A and A90G restore FQ susceptibility when associated with a substitution implicated in high-level FQ resistance. Line probe assay misclassification of MDR-TB strains as pre-XDR or XDR can be corrected by sequence analysis of gyrA.

Time to Treatment Initiation and HIV Viral Suppression in People Diagnosed With HIV-1 During COVID-19 Pandemic in Ex-Aquitaine, France (ANRS CO3 AQUIVIH-NA Cohort-QuAliCOV Study).

OBJECTIVES: The COVID-19 pandemic's impact on initiation and effectiveness of antiretroviral therapy (ART) in people diagnosed with HIV remains unclear. We evaluated critical delays in HIV care in people diagnosed before and during the pandemic in ex-Aquitaine, France. METHODS: We considered adults diagnosed with HIV-1 in 2018-2021 and enrolled in the ANRS CO3 AQUIVIH-NA and followed them until October 10, 2022 for those diagnosed during the pandemic (April 01, 2020-December 31, 2021) and until March 31, 2020 for historical controls. We compared their characteristics at inclusion and the median time between diagnosis and ART initiation, ART initiation and viral suppression, and diagnosis and virologic, suppression (effective management). RESULTS: Eighty-three individuals were diagnosed during the pandemic versus 188 during the prepandemic period. Median follow-up was 549 (interquartile range: 329-713) days. Populations were similar in sex, age, HIV acquisition mode, hospital type, and clinical characteristics at diagnosis; however, fewer were foreign-born during the pandemic (15.7% versus 33.5%, P = 0.003). The probability of ART initiation, therapeutic success, and effective management was higher in people living with HIV (PLWH) diagnosed during the pandemic in adjusted analyses (hazard ratio [HR]: 2.0; 95% CI: 1.5 to 2.7; HR: 1.7; 95% CI: 1.2 to 2.3; HR: 1.8; 95% CI: 1.3 to 2.6, respectively). Those diagnosed during the pandemic were 2.3 (95% CI: 1.2 to 4.1) times more likely to be virologically suppressed within six months of diagnosis compared with historical controls. CONCLUSIONS: Pandemic-related reorganizations may have resulted in newly diagnosed PLWH being prioritized; however, the lower proportion of foreign-born PLWH diagnosed during the pandemic period, likely because of reduced migration and potential delays in diagnosis, may contribute to these preliminary findings.

Incidence of lung and human papilloma virus-associated malignancies in HIV-infected patients.

OBJECTIVE: Cancers represent one of the leading cause of mortality/morbidity in patients with HIV (PWH) in industrialized countries. The objective of our study was to compare incidence of lung and human papilloma virus (HPV)-related cancers among PWH with general population over the 2010-2017 period. DESIGN: Prospective and multicenter cohort study. METHODS: The study included patients with lung and HPV-related cancers from the ANRS CO3 Aquitaine cohort (PWH) and the general population-based cancer registry in Gironde area. We calculated incidence rates for 100 000 person-years and incidence rate ratios (IRR). RESULTS: Among the 3572 PWH, 70 cancers were diagnosed in 68 patients including 35 lung and 35 HPV-related cancers (18 oropharyngeal, 11 anal, 6 cervix). Incidence rates of lung and HPV-related-cancers were 311.1 in PWH and 209.8 in general population for 100 000 person-years, respectively. IRR were significantly increased in PWH for lung 1.8 [1.4-2.2] and HPV-related cancer 1.3 [1.0-1.6] and particularly high for patients between 40 and 49 years old [IRR 4.4 (2.3-8.4) for lung cancer and 3.7 (2.1-6.5) for HPV-related cancer]. CONCLUSION: We emphasized the persistent high risk of lung and HPV-related cancer despite advent of antiretroviral therapies, particularly in the age strata of 40-49 years. Screening procedures should take into account this finding.