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.

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.