P028

1:Lyon University Hospital, Bacteriology Laboratory, Lyon, France; 2:International Center for Infectious Disease Research (CIRI), Lyon, France; 3:Lyon University Hospital, Infectious and Tropical Diseases Department, Lyon, France

We report a unique case of reversible rifampicin resistance in a patient with Mycobacterium tuberculosis (Mtb) infection. The patient, HIV-positive at the AIDS stage, received anti-tuberculosis (TB) treatment over three years with poor adherence. Treatment alternated between rifampicin, isoniazid, pyrazinamide, ethambutol, levofloxacin, and tedizolid. Clinical progression from lymphatic and pulmonary TB to a miliary form was observed. Serial phenotypic drug susceptibility testing (Bactec MGIT 960 System and minimum inhibitory concentration (MIC) determination), PCR (Xpert® MTB/RIF Ultra and Deeplex), and whole genome sequencing (WGS) were performed over time. Initially, Mtb was rifampicin-sensitive, with no resistance-associated mutations. Fifteen months later, PCR detected resistance mutation, and WGS revealed the rpoB H445N mutation, associated with low-level rifampicin resistance. MIC testing showed elevated but subcritical values for rifampicin, as well as for rifapentine and rifabutin. Two years after this episode, the patient was hospitalized for another relapse and phenotypic and genotypic sensitivity testing showed the absence of rifampicin resistance. WGS confirmed that the case represented a true relapse rather than a reinfection, while multiple closely related variants of the same Mtb strain were detected throughout the course of infection. This case is particularly striking as it represents the first documented instance in the literature of mutation reversion during the course of the patient’s infection. This raises several important issues: the factors driving the emergence of secondary resistance during discontinuous drug treatment, the role of the immune system in an HIV-co-infected patient in selecting for resistance, and the fitness cost associated with rifampicin-resistance.