Activity of Galidesivir in a Hamster Model of SARS-CoV-2.

Coronavirus disease 2019 (COVID-19) has claimed the lives of millions of people worldwide since it first emerged. The impact of the COVID-19 pandemic on public health and the global economy has highlighted the medical need for the development of broadly acting interventions against emerging viral threats. Galidesivir is a broad-spectrum antiviral compound with demonstrated in vitro and in vivo efficacy against several RNA viruses of public health concern, including those causing yellow fever, Ebola, Marburg, and Rift Valley fever. In vitro studies have shown that the antiviral activity of galidesivir also extends to coronaviruses. Herein, we describe the efficacy of galidesivir in the Syrian golden hamster model of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Treatment with galidesivir reduced lung pathology in infected animals compared with untreated controls when treatment was initiated 24 h prior to infection. These results add to the evidence of the applicability of galidesivir as a potential medical intervention for a range of acute viral illnesses, including coronaviruses.

Cost-efficacy comparison among three antiretroviral regimens in HIV-1 infected, treatment-experienced patients.

BACKGROUND AND OBJECTIVE: In the face of increasing antiretroviral (ARV) treatment options and costs, payers are progressively challenged with prioritising resources. The cost effectiveness of the ARV agent enfuvirtide has been shown to be comparable to that of other available HIV treatment strategies, based on Markov modeling. However, an evaluation of enfuvirtide treatment costs that considers the impact of virological and immunological responses to therapy may provide a more clinically meaningful perspective for primary HIV healthcare providers. The aim of this study was to assess the cost per unit change in efficacy (HIV RNA decreases and CD4 count increases) of three different ARV regimens for triple class-experienced HIV-1 infected patients using actual drug costs and data from randomised, controlled clinical trials. STUDY DESIGN: The analysis included three steps. First, re-analysis of 48-week clinical trial data (T-20 vs Optimized Regimen Only [TORO]) to allow for a more direct comparison of enfuvirtide versus other commonly used ARV agents. All patients included in the re-analysis received a common optimised background (COB) regimen of three drugs: two nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) and a ritonavir-boosted protease inhibitor (PI), lopinavir. HIV RNA levels and CD4 count changes were determined for three patient groups according to the treatment received - group 1: COB + enfuvirtide; group 2: COB + PI; group 3: COB + NRTI + PI. The second step of the analysis involved calculating the annualised regimen costs ($US wholesaler acquisition cost) for each patient group. In the third step, cost-efficacy ratios were calculated and compared between groups: (a) the annualised regimen cost ($US)/change in viral load from baseline, and (b) the annualised regimen cost ($US)/change in CD4+ cell count from baseline. RESULTS: One hundred and fifty-seven patients were included in this previously unplanned secondary analysis (group 1: 79 patients; group 2: 42 patients; group 3: 36 patients). HIV RNA and CD4 count changes from baseline to week 48 were -1.80, -0.89 and -0.61 log(10) copies/mL (p < 0.001 for enfuvirtide vs each non-enfuvirtide group) and +102, +57 and +52 cells/mm(3) (p < 0.05 for enfuvirtide versus each non-enfuvirtide subgroup) for groups 1, 2 and 3, respectively. The annualised costs of the combination therapies were $US 35,624, $US 27,549 and $US 30,624; and the costs per 0.50 log(10) copies/mL HIV RNA decrease were $US 9,872, $US 15,542 and $US 24,907 (p < 0.05 for enfuvirtide vs each non-enfuvirtide subgroup) for groups 1, 2 and 3, respectively. The costs per 25 cells/mm(3) CD4 count increase were $US 8,722, $US 12,127 and $US 14,636 for subgroups 1, 2 and 3, respectively. Similar patterns in regimen cost per unit change were achieved after adjusting for baseline prognostic variables. The incremental cost-efficacy ratios for group 1 versus the combination of groups 2 and 3 were $US 3,124 for HIV RNA reduction and $US 3,239 for CD4 count increase. CONCLUSION: Enfuvirtide-containing regimens are associated with higher cost as well as improved virological and immunological outcomes when compared with alternative four- and five-drug regimens. When costs and outcomes are considered jointly, an enfuvirtide-based regimen is more cost efficacious than alternative regimens in this patient population.

Association between specific enfuvirtide resistance mutations and CD4 cell response during enfuvirtide-based therapy.

Analysis of CD4 cell responses during 48 weeks of enfuvirtide therapy after virological failure (analysis of covariance) demonstrated significant associations between V38 mutations (n = 58 subjects) and continued CD4 cell increases and between Q40 mutations (n = 8) and loss of CD4 cell benefit (+34 versus -95 cells/mul, P < 0.001). Subjects with N43 (n = 20) or other mutations (n = 48) had intermediate CD4 cell responses. These data suggest that key enfuvirtide resistance mutations may be associated with reduced viral pathogenicity in vivo.

HIV-1 coreceptor use in triple-class treatment-experienced patients: baseline prevalence, correlates, and relationship to enfuvirtide response.

OBJECTIVE: We wished to assess, in heavily treatment-experienced patients, the prevalence of and baseline characteristics associated with HIV-1 coreceptor use and their relationship to responses to enfuvirtide treatment. METHODS: Samples were obtained from participants in phase 3 studies of enfuvirtide. Multiple logistic regression and analysis of covariance were performed on data for baseline coreceptor use, virological and immunological response, and changes in coreceptor use during treatment. RESULTS: Baseline envelopes were phenotyped for 724 patients; 50% harbored R5 strains, 48% harbored dual/mixed (D/M) strains, and 2% harbored X4 strains. D/M strains were associated with significantly lower CD4(+) cell counts but comparable viral loads, compared with R5 strains (P=.0005). Virological and immunological responses to enfuvirtide-based treatment showed no correlation with baseline coreceptor use. Changes in virus tropism from D/M to R5 strains during treatment were common, particularly in patients who received enfuvirtide (27%, vs. 14% who received no enfuvirtide; P<.05). CONCLUSION: At baseline, D/M strains were associated with lower CD4(+) cell counts but similar viral loads, compared with R5 strains, and were common across CD4(+) cell count strata. The comparable virological and immunological responses and bias toward shifts from D/M to R5 strains in patients who received enfuvirtide support its use in triple-class treatment-experienced patients and its study as a therapeutic partner for coreceptor-binding inhibitors.