Coronavirus disease (COVID-19) pandemic determined a 10 years-set back in tuberculosis (TB) control programs. Recent advances in available therapies may help recover the time lost. While Linezolid (LZD) and Bedaquiline (BDQ), previously Group D second line drugs (SLDs) for TB, have been relocated to Group A, other drugs are currently being studied in regimens for drug resistant TB (DR-TB). Among these, Pretomanid (PA), a recently introduced antimycobacterial drug derived from nitroimidazole with both solid bactericidal and bacteriostatic effect, and with an excellent effectiveness and tolerability profile, is in the spotlight. Following promising data obtained from recently published and ongoing randomized controlled trials (RCTs), the World Health Organization (WHO) determined to include PA in its guidelines for the treatment of rifampicin-resistant (RR), multi drug resistant (MDR) and pre-extensively drug resistant TB (pre-XDR-TB) with BDQ, LZD and Moxifloxacine (MFX) in a 6-month regimen. Although further studies on the subject are needed, PA may also represent a treatment option for drug-susceptible TB (DS-TB), latent TB infection (LTBI) and non tuberculous mycobacteria (NTM). This narrative review aims to examine current implementation options and future possibilities for PA in the never-ending fight against TB.

Lamivudine/dolutegravir (3TC/DTG) is effective and safe for most people with HIV infection (PWH) who are virologically suppressed, but specific individual’s characteristics, such as previous detection of archived resistance-associated mutations (RAMs) to 3TC and prior HBV infection, could represent a risk for virological failure (VF). We conducted a retrospective monocentric cohort study to assess rates and predictors of treatment discontinuation (TD) and VF in PWH switched to 3TC/DTG after reaching virological suppression (HIV-RNA<50 cp/mL). Overall, 188 PWH were included. Over 5145 patient-years follow-up (PYFU), 16 (8.5%) PWH experienced TD (2.87 per 1000 PYFU), whereas over 5082 PYFU, 8 (4.3%) experienced VF (1.45 per 1000 PYFU). Probabilities of TD and VF were 1.3%, 2.8%, 7.5%, 12.9%, 34.5% and 0.6%, 2.7%, 2.7%, 4.2%, 22.3% after 1, 2, 3, 4 and 5 years respectively. Independent predictors of VF were a detectable baseline HIV-RNA of 20-49 copies/ml (versus<20 copies/ml, aHR 9.11, 95 % CI 1.05-79.40; p= 0.046), and a higher GSS-score for 3TC (per 10 points more, aHR 1.57, 95 % CI 1.07-2.29; p= 0.023), with a borderline significance for anti-HBcAg positive serostatus (versus negative, aHR 8.88, 95 % CI 0.89-88.45; p= 0.062). After adjustment for age and gender, those with anti-HBcAg positivity who switched from a tenofovir-containing regimen had the highest risk of VF (versus negative anti-HBcAg and no prior tenofovir use, aHR 15.06, 95% CI 1.40-161.38; p-value= 0.025).

Lamivudine/dolutegravir (3TC/DTG) is an effective and well-tolerated antiretroviral regimen for most people with HIV (PWH) who are virologically suppressed; however, specific clinical characteristics, such as prior hepatitis B virus (HBV) exposure or archived resistance-associated mutations (RAMs), may influence the risk of virological failure (VF). We conducted a retrospective, monocentric cohort study to evaluate the incidence and predictors of VF among PWH who switched to 3TC/DTG after achieving virological suppression (HIV-RNA < 50 copies/mL). A total of 188 PWH were included. Over 5082 patient-years of follow-up (PYFU), 8 individuals (4.3%) experienced VF, corresponding to an incidence rate of 1.45 per 1000 PYFU. The cumulative probabilities of VF at 1, 2, 3, 4, and 5 years were 0.6%, 2.7%, 2.7%, 4.2%, and 22.3%, respectively. In exploratory multivariable analyses, anti-HBc positivity was associated with an increased risk of VF (adjusted hazard ratio [aHR] 4.80, 95% CI 1.03–22.43; p = 0.046). After adjustment for age and sex, individuals with anti-HBc positivity who had switched from a tenofovir-containing regimen showed the highest risk of VF compared with anti-HBc-negative individuals without prior tenofovir exposure (aHR 15.06, 95% CI 1.40–161.38; p = 0.025). Given the limited number of virological events, these findings should be interpreted with caution. Nevertheless, they suggest that prior HBV exposure, particularly in the context of tenofovir discontinuation, may represent a clinically relevant factor when considering simplification to 3TC/DTG.