Strategies to increase primary care provider capacity for hepatitis C care: The California ECHO-PLUS study.

Expanding capacity to screen and treat those infected with the hepatitis C virus (HCV) is an essential element of the global elimination strategy. We evaluated the hub-and-spoke Project ECHO training versus telementoring models to educate, train and support HCV care by primary care providers in 13 targeted counties in northern California. A novel provider engagement strategy was used. Provider engagement and retention, time to readiness to treat HCV, and knowledge and confidence were the outcomes of interest. 94 participants from 60 unique clinics in the target counties participated in the ECHO-PLUS programme; 39.4% were physicians, 48.9% were advanced practice providers, and 11.7% were nurses. The median (range) participation time was 5 (1-49) hours. Confidence scores (minimum score = 13 and maximum score = 65) increased by a mean of 14.0 (SD:8.2) and 11.4 (SD:12.0) points for the hub-and-spoke and telementoring programmes, respectively (p = .53), with the largest changes in confidence seen in treating patients per guidelines, managing side effects and in serving as a consultant for HCV in their clinic. Among 24 participants with data on time to treatment, median time from beginner to experienced was 8 h (IQR:6-12) for hub-and-spoke and 2 h (IQR:1-2.4) for the telementoring programme (p = .01). A 'boots on the ground' approach to recruiting HCV champions was effective within rural communities. Both tele-ECHO hub-and-spoke and telementoring approaches to training primary care providers yielded increase in knowledge and confidence in HCV care and amplified the number of patients who were screened and treated. Telementoring accelerated the timeline of novice providers being 'ready to treat'.

Comparing Hepatitis C Virus Screening in Clinics Versus the Emergency Department.

INTRODUCTION: New evidence suggests that emergency department (ED)-based infectious diseases screening programs have utility. We aimed to compare clinic-based and ED-based hepatitis C virus (HCV) screening programs within a single health system, to identify key differences in HCV antibody (Ab) positivity and chronic HCV, as well as population demographics. METHODS: In the clinic-based program, adults in the birth cohort (born 1945-1965) were screened for HCV. In the ED-based program, non-targeted HCV screening of all adults was conducted. We included patients screened between June 2019-June 2020. Patients were screened for anti-HCV Ab, and positive results were followed by HCV viral load (VL) testing. Our primary outcomes were seroprevalence of HCV Ab and HCV VL. RESULTS: There were 1,296 and 12,778 patients screened for HCV in the clinics and the ED, respectively. In the clinic setting, 13 patients (1%) screened positive for HCV Ab and nine (69%) completed VL testing, which was positive in one patient (11%). In the ED, 1,053 patients (8%) screened positive for HCV Ab and 847 (80%) underwent reflex VL testing, which was positive in 381 patients (45%). In an ED birth cohort sub-analysis, Hepatitis C virus Ab seroprevalence was 15% (675/4521). CONCLUSION: In this study of patients in a single healthcare system, ED-based HCV screening was higher yield than clinic-based screening.

Pharmacist Intervention Lowers HgbA1c in Diabetic Patients Regardless of HIV Status.

AIM: Compare glycemic control in human immunodeficiency (HIV)-positive patients on antiretroviral therapy to HIV-negative patients following pharmacist interventions. METHODS/RESULTS: This retrospective observational cohort study conducted at a Federally Qualified Health Center included adults with type II diabetes mellitus who attended at least two clinical pharmacy appointments between January 1, 2018 and July 31, 2019. Exclusion criteria included missing pre- or post-hemoglobin A1c (HgbA1c) values, type 1 diabetes, pregnancy, breastfeeding, deceased, or untreated HIV. The primary endpoint was change in HgbA1c from baseline to month 3. Secondary endpoints were change in HgbA1c at 6, 9, and 12 months, and time to goal. Additional endpoints included changes in number of anti-diabetic agents, blood pressure, body mass index, hypoglycemic events, percent of patients on a sodium-glucose co-transporter-2 (SGLT-2) inhibitor or glucagon-like peptide (GLP-1) agonist. This study was exempt from the University of California, Davis Institutional Review Board as a continuous quality improvement study.Seventy-eight patients were included, 17 of whom were HIV-positive. At 3 months, HgbA1c was reduced by -1.7% and -1.2% (p =0.31) for HIV-positive and -negative patients, respectively. In the pooled cohort, HgbA1c was reduced from baseline at all time points, and 24% of patients achieved HgbA1c below 7.0%. The number of antidiabetic medications remained unchanged or was decreased in 60% of patients. CONCLUSION: The study demonstrated clinically important HgbA1c reductions without increasing the medication burden in most patients. There was no significant difference in glycemic management between HIV-positive and HIV-negative patients.

De novo hepatocellular carcinoma occurrence in hepatitis C cirrhotics treated with direct-acting antiviral agents.

AIM: Recent studies raise concerns for higher incidence of hepatocellular carcinoma (HCC) after direct-acting antiviral therapy for hepatitis C virus (HCV). METHODS: In this study, using analysis of liver imaging pre- and post-DAA treatment, we queried new occurrence or 'de novo' of HCC in patients with HCV-cirrhosis treated with DAAs. Of 150 patients who met study criteria, 7 (4.7%; 95% CI: 2.1-9.5%) patients developed de novo HCC which did not differ from historical rates of 3% (p = 0.22). RESULTS: Notably, patients with decompensated cirrhosis had significantly higher rate of de novo HCC (9.3%; 95% CI: 3.12-22.2%; p = 0.04). CONCLUSION: Our data support the need for continued surveillance for HCC in HCV cirrhotics even after successful therapy.

The combined anti-HIV-1 activities of emtricitabine and tenofovir plus the integrase inhibitor elvitegravir or raltegravir show high levels of synergy in vitro.

Highly active antiretroviral therapy (HAART) involves combination treatment with three or more antiretroviral agents. The antiviral effects of combinations of emtricitabine (FTC) plus tenofovir (TFV) plus antiretroviral agents of all the major drug classes were investigated. Combinations of FTC and TFV with a nonnucleoside reverse transcriptase inhibitor (NNRTI) (efavirenz or rilpivirine) or with a protease inhibitor (PI) (atazanavir, lopinavir, or darunavir) showed additive to synergistic anti-HIV-1 activity. FTC-TFV with an HIV-1 integrase strand transfer inhibitor (INSTI) (elvitegravir or raltegravir) showed the strongest synergy. Anti-HIV-1 synergy suggests enhancement of individual anti-HIV-1 activities within cells that may contribute to potent treatment efficacy and open new areas of research into interactions between reverse transcriptase (RT) and integrase inhibitors.

Impact of primary elvitegravir resistance-associated mutations in HIV-1 integrase on drug susceptibility and viral replication fitness.

Elvitegravir (EVG) is an effective HIV-1 integrase (IN) strand transfer inhibitor (INSTI) in advanced clinical development. Primary INSTI resistance-associated mutations (RAMs) at six IN positions have been identified in HIV-1-infected patients failing EVG-containing regimens in clinical studies: T66I/A/K, E92Q/G, T97A, S147G, Q148R/H/K, and N155H. In this study, the effect of these primary IN mutations, alone and in combination, on susceptibility to the INSTIs EVG, raltegravir (RAL), and dolutegravir (DTG); IN enzyme activities; and viral replication fitness was characterized. Recombinant viruses containing the six most common mutations exhibited a range of reduced EVG susceptibility: 92-fold for Q148R, 30-fold for N155H, 26-fold for E92Q, 10-fold for T66I, 4-fold for S147G, and 2-fold for T97A. Less commonly observed primary IN mutations also showed a range of reduced EVG susceptibilities: 40- to 94-fold for T66K and Q148K and 5- to 10-fold for T66A, E92G, and Q148H. Some primary IN mutations exhibited broad cross-resistance between EVG and RAL (T66K, E92Q, Q148R/H/K, and N155H), while others retained susceptibility to RAL (T66I/A, E92G, T97A, and S147G). Dual combinations of primary IN mutations further reduced INSTI susceptibility, replication capacity, and viral fitness relative to either mutation alone. Susceptibility to DTG was retained by single primary IN mutations but reduced by dual mutation combinations with Q148R. Primary EVG RAMs also diminished IN enzymatic activities, concordant with their structural proximity to the active site. Greater reductions in viral fitness of dual mutation combinations may explain why some primary INSTI RAMs do not readily coexist on the same HIV-1 genome but rather establish independent pathways of resistance to EVG.

In vitro resistance selections using elvitegravir, raltegravir, and two metabolites of elvitegravir M1 and M4.

Elvitegravir is a strand transfer inhibitor of HIV-1 integrase that is currently undergoing phase 3 clinical testing. The two predominant metabolites of elvitegravir, M1 and M4 (elvitegravir hydroxide and elvitegravir glucuronide), have been shown to inhibit HIV-1 integrase in vitro. While they are markedly less potent than elvitegravir and present only at low levels in plasma clinically, we investigated their potential to select for elvitegravir resistance in vitro. Resistance selection experiments using metabolites M1 and M4 led to the development of the previously reported elvitegravir integrase resistance mutations H51Y, T66A, E92G, and S147G, as well as a novel S153F substitution. Additional resistance selection experiments using elvitegravir led to the development of previously reported integrase inhibitor resistance mutations (T66I, F121Y, and S153Y) as well as a novel R263K integrase mutation. Phenotypic analyses of site-directed mutants with these mutations demonstrated broad cross-resistance between elvitegravir and its M1 and M4 metabolites with more limited cross-resistance to the integrase inhibitor raltegravir. Overall, our in vitro studies demonstrate that the resistance profile of the M1 and M4 metabolites of elvitegravir overlaps with that of the parent molecule elvitegravir; as such, their presence at low levels is not considered clinically relevant.

Triazole derivatives as non-nucleoside inhibitors of HIV-1 reverse transcriptase--structure-activity relationships and crystallographic analysis.

A series of 3,4,5-trisubstituted 1,2,4-4H triazole derivatives was synthesized and investigated for HIV-1 reverse transcriptase inhibition. An X-ray structure with HIV-1 RT secured the binding mode and allowed the key interactions with the enzyme to be identified.