No abstract

Treatment with a once-daily, single-tablet regimen of ledipasvir and sofosbuvir resulted in high rates of sustained virologic response among patients with HCV genotype 1 infection who had not had a sustained virologic response to prior interferon-based treatment. (Funded by Gilead Sciences; ION-2 ClinicalTrials.gov number, NCT01768286.).

BACKGROUND Effective treatment for hepatitis C virus (HCV) in patients coinfected with human immunodeficiency virus type 1 (HIV-1) remains an unmet medical need. METHODS We conducted a multicenter, single-group, open-label study involving patients coinfected with HIV-1 and genotype 1 or 4 HCV receiving an antiretroviral regimen of tenofovir and emtricitabine with efavirenz, rilpivirine, or raltegravir. All patients received ledipasvir, an NS5A inhibitor, and sofosbuvir, a nucleotide polymerase inhibitor, as a single fixed-dose combination for 12 weeks. The primary end point was a sustained virologic response at 12 weeks after the end of therapy. RESULTS Of the 335 patients enrolled, 34% were black, 55% had been previously treated for HCV, and 20% had cirrhosis. Overall, 322 patients (96%) had a sustained virologic response at 12 weeks after the end of therapy (95% confidence interval [CI], 93 to 98), including rates of 96% (95% CI, 93 to 98) in patients with HCV genotype 1a, 96% (95% CI, 89 to 99) in those with HCV genotype 1b, and 100% (95% CI, 63 to 100) in those with HCV genotype 4. Rates of sustained virologic response were similar regardless of previous treatment or the presence of cirrhosis. Of the 13 patients who did not have a sustained virologic response, 10 had a relapse after the end of treatment. No patient had confirmed HIV-1 viro-logic rebound. The most common adverse events were headache (25%), fatigue (21%), and diarrhea (11%). No patient discontinued treatment because of adverse events. CONCLUSIONS Ledipasvir and sofosbuvir for 12 weeks provided high rates of sustained virologic response in patients coinfected with HIV-1 and HCV genotype 1 or 4. (Funded by Gilead Sciences; ION-4 ClinicalTrials.gov number, NCT02073656.)

Colistin is a polymyxin antibiotic that was discovered in the late 1940s for the treatment of gram-negative infections. After several years of clinical use, its popularity diminished because of reports of significant nephrotoxicity and neurotoxicity. Recently, the antibiotic has resurfaced as a last-line treatment option for multidrug-resistant organisms such as Pseudomonas aeruginosa, Acinetobacter baumannii, and Klebsiella pneumoniae. The need for antibiotics with coverage of these gram-negative pathogens is critical because of their high morbidity and mortality, making colistin a very important treatment option. Unfortunately, however, resistance to colistin has been documented among all three of these organisms in case reports. Although the exact mechanism causing colistin resistance has not been defined, it is hypothesized that the PmrA-PmrB and PhoP-PhoQ genetic regulatory systems may play a role. Colistin dosages must be optimized, as colistin is a last-line treatment option; in addition, suboptimal doses have been linked to the development of resistance. The lack of pharmacokinetic and pharmacodynamic studies and no universal harmonization of dose units, however, have made it difficult to derive optimal dosing regimens and specific dosing guidelines for colistin. In critically ill patients who may have multiorgan failure, renal insufficiency may alter colistin pharmacokinetics. Therefore, dosage alterations in this patient population are imperative to achieve maximal efficacy and minimal toxicity. With regard to colistin toxicity, most studies show that nephrotoxicity is reversible and less frequent than once thought, and neurotoxicity is rare. Further research is needed to fully understand the impact that the two regulatory systems have on resistance, as well as the dosages of colistin needed to inhibit and overcome these developing patterns.

Patients with hepatitis C virus (HCV) infection and cirrhosis are underrepresented in clinical trials of interferon-free regimens of direct-acting antiviral agents, making it difficult to optimize therapy. We performed a post-hoc analysis of data from seven clinical trials to evaluate the efficacy and safety of the fixed-dose combination of ledipasvir (LDV) and sofosbuvir (SOF), with and without ribavirin (RBV), in 513 treatment-na€ ıve and previously treated patients with genotype 1 HCV and compensated cirrhosis. All patients received LDV-SOF for 12 or 24 weeks with or without RBV. We determined the rates of sustained virological response (SVR) 12 weeks after treatment (SVR12) overall and for subgroups. Of the 513 patients analyzed, 69% were previously treated and 47% had failed previous treatment with a protease-inhibitor regimen. Overall, 493 patients (96%; 95% confidence interval [CI]: 94%-98%) achieved SVR12, 98% of treatment-na€ ıve and 95% of previously treated patients. SVR12 rates did not vary greatly by treatment duration (95% of patients receiving 12 weeks and 98% of patients receiving 24 weeks of treatment), nor by addition of RBV (95% of patients receiving LDV-SOF alone and 97% of those who received LDV-SOF plus RBV), although previously treated patients receiving 12 weeks of LDV-SOF without RBV had an SVR12 rate of 90%. One patient discontinued LDV-SOF because of an adverse event (AE). The most common AEs were headache (23%), fatigue (16%-19%), and asthenia (14%-16%). One patient (<1%) of those receiving LDV-SOF alone, and 4 (2%) of those receiving LDV-SOF plus RBV had treatment-related serious AEs. Conclusions: This analysis suggests that 12 weeks of LDV-SOF is safe and effective for treatment-na€ ıve patients with HCV genotype 1 and compensated cirrhosis. The relatively lower SVR in treatment-experienced patients treated with 12 weeks of LDV-SOF raises the question of whether these patients would benefit from adding RBV or extending treatment duration to 24 weeks. (HEPATOLOGY 2015;62:79-86)