Early Bactericidal Activity of Delpazolid (LCB01-0371) in Patients with Pulmonary Tuberculosis.

Delpazolid, an oxazolidinone, has been studied in non-clinical studies of efficacy and toxicity and Phase 1 clinical studies. Delpazolid has in vitro activity against Gram-positive bacteria, including Mycobacterium tuberculosis. This study evaluated the bactericidal activity, safety, and pharmacokinetics of delpazolid in patients with pulmonary tuberculosis (TB). Seventy-nine subjects, aged 19 to 75 years with newly diagnosed smear-positive TB with no prior treatment for the current episode and no confirmed resistance to rifampin or isoniazid, were randomized to receive delpazolid 800 mg once a day (QD), 400 mg twice a day (BID), 800 mg BID or 1,200 mg QD or an active control of isoniazid, rifampin, pyrazinamide, and ethambutol (HRZE) or linezolid 600 mg BID. The primary endpoint was the average daily reduction in log transformed bacterial load, assessed on 7H11 solid-media culture, from days 0 to 14. The average daily decline in log-CFU was 0.044 ± 0.016, 0.053 ± 0.017, 0.043 ± 0.016, and 0.019 ± 0.017, for the delpazolid 800 mg QD, 400 mg BID, 800 mg BID, and the 1,200 mg QD groups, respectively. The average daily decline in log-CFU was 0.192 ± 0.028 for the HRZE group and 0.154 ± 0.023 for the linezolid 600 mg BID group. Three serious adverse events (SAE) were reported, one each in the delpazolid 400 mg BID group (death due to worsening of TB at day 2), the HRZE group (hospitalization due to pleural effusion) and the linezolid group (hyperkalemia); none of the SAEs were assessed as related to study drugs. This study has been registered at ClinicalTrials.gov with registration number NCT02836483.

Ledipasvir/sofosbuvir for treatment of hepatitis C virus in sofosbuvir-experienced, NS5A treatment-naïve patients: Findings from two randomized trials.

BACKGROUND & AIMS: We report data from two similarly designed studies that evaluated the efficacy, safety, and optimal duration of ledipasvir/sofosbuvir (LDV/SOF) ± ribavirin (RBV) for retreatment of chronic hepatitis C virus (HCV) in individuals who failed to achieve sustained virological response (SVR) with prior SOF-based, non-NS5A inhibitor-containing regimens. METHODS: The RESCUE study enrolled HCV mono-infected adults with genotype (GT) 1 or 4. Non-cirrhotic participants were randomized to 12 weeks of LDV/SOF or LDV/SOF + RBV. Compensated cirrhotic participants were randomized to LDV/SOF + RBV (12 weeks) or LDV/SOF (24 weeks). The AIDS Clinical Trials Group A5348 study randomized genotype 1 adults with HCV/HIV co-infection to LDV/SOF + RBV (12 weeks) or LDV/SOF (24 weeks). Both studies used SVR at 12 weeks post-treatment (SVR12) as the primary endpoint. RESULTS: In the RESCUE study, 82 participants were randomized and treated, and all completed treatment. Overall, SVR12 was 88% (72/82); 81-100% in non-cirrhotic participants treated with LDV/SOF or LDV/SOF + RBV for 12 weeks and 80-92% in cirrhotic participants treated with LDV/SOF + RBV for 12 weeks or LDV/SOF for 24 weeks. Adverse events (AEs), mostly mild-to-moderate in severity, were experienced by 78% of participants, with headache and fatigue most frequently reported. One serious AE, not related to treatment, was observed. No premature discontinuations of study drug, or deaths occurred. In the A5348 study, seven participants were randomized (cirrhotic n = 1; GT1a n = 5) and all attained SVR12, with no serious AEs or premature discontinuations. CONCLUSIONS: In this SOF-experienced, NS5A inhibitor-naïve population, which included participants with cirrhosis or HCV/HIV co-infection, high SVR12 rates were achieved.

Relationship of pregnancy to human papillomavirus among human immunodeficiency virus-infected women.

OBJECTIVE: Because parity is a reported risk factor for cervical cancer, we sought to estimate the effects of pregnancy on the prevalence, incident detection, and copy number of human papillomavirus (HPV) among human immunodeficiency virus (HIV)-infected women, patients at high risk for cervical cancer. METHODS: Human immunodeficiency virus-infected women who had a pregnancy in the Women's Interagency HIV Study (n = 178) and the Women and Infants Transmission Study (n = 450) underwent serial type-specific HPV DNA testing using MY09/MY11 polymerase chain reaction. During pregnancy and during the prepregnancy and postpregnancy periods, we assessed HPV prevalence, incident detection, and HPV copy number (estimated using hybridization signal strength) of both oncogenic and nononcogenic HPV. All binary-regression analyses incorporated generalized estimating equations to address the repeated observations of the same women over time, and were further adjusted for parity, gestational age, smoking, antiretroviral use, number of lifetime sexual partners, and oral contraceptive use. RESULTS: The prevalence and copy number of oncogenic and nononcogenic HPV did not significantly differ between pregnancy and either the prepregnancy or postpregnancy periods. Incident HPV detection was significantly lower for both oncogenic and nononcogenic HPV during pregnancy compared with the postpregnancy period (relative risk 0.534, 95% confidence interval 0.390-0.732, P < .001 and relative risk 0.577, 95% confidence interval 0.428-0.779, P < .001, respectively), but not compared with the prepregnancy period CONCLUSION: Among HIV-infected women, the incident detection of HPV is lower during pregnancy compared with postpregnancy, while prevalence and copy number do no differ between pregnancy and either prepregnancy or postpregnancy. LEVEL OF EVIDENCE: II-3.

Predictors of repeat pregnancy among HIV-1-infected women.

BACKGROUND: In the Women and Infants Transmission Study (WITS), a prospective cohort study of HIV-infected pregnant women at six US mainland and Puerto Rican sites, changes in the HIV-1 epidemic have included higher income, better education, and better-controlled HIV disease among more recently enrolled women. Because these changes may alter the reproductive patterns of these women an awareness of these women's current reproductive behaviors is essential. We examined predictors of repeat pregnancy among HIV-1-infected women enrolled in the Women and Infants Transmission Study (WITS). METHODS: Women enrolled in WITS without a history of sterilization were included. Using bivariate and multivariate analyses, predictors of a repeat pregnancy were modeled. Changes in risk factors for repeat pregnancy over time were examined and important predictors of repeat pregnancy were determined. RESULTS: Of 2246 eligible women, 22% had more than one WITS-enrolled pregnancy. In bivariate analyses, risk of repeat pregnancy was associated with younger age, lower educational status, higher CD4%, and lower viral loads. There was little change in risk factors for repeat pregnancy over time. CONCLUSIONS: HIV-1-infected women who are younger and healthier are more likely to have more than one pregnancy. Factors associated with repeat pregnancy among HIV-1-infected women have remained stable over time. Awareness of these factors will better equip healthcare providers to address the reproductive needs of HIV-1-infected women.