Effects of long-term indiscriminate use of macrocyclic lactones in cattle: Parasite resistance, clinical helminthosis, and production losses.

Our aims were to describe a case of clinical helminthosis caused by parasite resistance to macrocyclic lactones (MLs) after the long-term frequent use of these drugs in a cattle herd, and to evaluate the production losses prevented by the use of an effective anthelmintic treatment to control these resistant gastrointestinal nematodes (GINs). A case of clinical helminthosis culminating in the death of steers was investigated, the history of the antiparasitic treatments used during an 11-year period in the herd was assessed, and an efficacy test involving seven different drugs was performed. Thereafter, two groups of heifers naturally infected by ML-resistant GINs were formed and strategically treated with either a highly effective (levamisole) or less effective drug (doramectin) over a 9-month period. The heifers were evaluated monthly based on eggs per gram of feces (EPG) counts and liveweights. An evaluation of the history of parasite control in the farm revealed that MLs were used in 96.5% of the treatments aimed at controlling GINs, ticks, and myiasis in the herd. The efficacy test showed the presence of GINs resistance to all the MLs tested. However, levamisole and albendazole sulphoxide were highly effective against these parasites. Heifers treated with levamisole gained 12.1 kg more liveweight on average, compared to those treated with doramectin. Thus, we conclude that indiscriminate and long-term use of MLs in the studied herd led to the failure of GINs control, a critical situation resulting in significant production losses, and a surge of clinical helminthosis in young cattle. In addition, we showed increase in liveweight gain due to using a highly effective drug, in comparison to an ML, during a 9-month period, in heifers naturally infected by ML-resistant GINs.

Benefit-risk assessment for sofosbuvir/velpatasvir/voxilaprevir based on patient population and hepatitis C virus genotype: U. S. Food and Drug Administration's evaluation.

On July 18, 2017, the U.S. Food and Drug Administration (FDA) approved sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX) (Vosevi) fixed-dose combination (FDC), an interferon-free, complete regimen for adult patients with chronic hepatitis C virus (HCV) infection without cirrhosis or with compensated cirrhosis (Child-Pugh A) who have: • genotype 1, 2, 3, 4, 5, or 6 infection and have previously been treated with an HCV regimen containing a nonstructural protein 5A (NS5A) inhibitor; and • genotype 1a or 3 infection and have previously been treated with an HCV regimen containing sofosbuvir without an NS5A inhibitor. Approval was based on an acceptable safety profile and high sustained virological response rates 12 weeks after the end of treatment (SVR12) in two phase 3 clinical trials in subjects previously treated with a direct-acting antiviral (DAA) regimen. In POLARIS-1, 96% of SOF/VEL/VOX-treated subjects achieved SVR12. In POLARIS-4, 98% of SOF/VEL/VOX-treated subjects achieved SVR12. A key and challenging question in evaluating the data was determining the contribution of VOX to SOF/VEL and how this differed depending on the genotype and patient population. In this article, we provide our perspective on the issues considered in making these determinations, especially regarding the POLARIS-4 data in subjects who have previously been treated with a chronic HCV regimen containing sofosbuvir without an NS5A inhibitor. Conclusion: We seek to provide context as to why a broad indication was given for NS5A inhibitor-experienced patients (HCV genotypes 1-6) while the indication for NS5A inhibitor- naïve patients was limited to HCV genotypes 1a and 3 only. (Hepatology 2018;67:482-491).