Currently recommended regimens for MAC lung disease yield important pharmacologic interactions and low concentrations of key drugs including macrolides. Pharmacodynamic indices for rifampicin, clarithromycin, amikacin, and moxifloxacin are seldom met. This may partly explain the poor outcomes of currently recommended treatment regimens. Trials of new drugs and new dosing strategies are needed.

Since its approval by the United States Food and Drug Administration in 2002, voriconazole has become a key component in the successful treatment of many invasive fungal infections, including the most common, aspergillosis and candidiasis. Despite voriconazole’s widespread use, optimizing its treatment in an individual can be challenging due to significant interpatient variability in plasma concentrations of the drug. Variability is due to nonlinear pharmacokinetics and the influence of patient characteristics such as age, sex, weight, liver disease, and genetic polymorphisms in the cytochrome P450 2C19 gene (CYP2C19) encoding for the CYP2C19 enzyme, the primary enzyme responsible for metabolism of voriconazole. CYP2C19 polymorphisms account for the largest portion of variability in voriconazole exposure, posing significant difficulty to clinicians in targeting therapeutic concentrations. In this review, we discuss the role of CYP2C19 polymorphisms and their influence on voriconazole’s pharmacokinetics, adverse effects, and clinical efficacy. Given the association between CYP2C19 genotype and voriconazole concentrations, as well as the association between voriconazole concentrations and clinical outcomes, particularly efficacy, it seems reasonable to suggest a potential role for CYP2C19 genotype to guide initial voriconazole dose selection followed by therapeutic drug monitoring to increase the probability of achieving efficacy while avoiding toxicity.

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The era of the integrase strand transfer inhibitors (INSTIs) for the treatment of human immunodeficiency virus (HIV) infection began with raltegravir in 2007. Since that time, several other INSTIs have been introduced including elvitegravir, dolutegravir, and, most recently, bictegravir, that have shown great utility as part of antiretroviral regimens in both treatment-naive and treatment-experienced patients. At present, antiretroviral guidelines fully endorse the INSTI class as part of all first-line treatment regimens. After 10 years of experience with INSTIs, newer agents are on the horizon such as cabotegravir and MK-2048 for potential use as either HIV pre-exposure prophylaxis or maintenance therapy. This review provides a brief overview of the INSTI class including agents currently available and those still in development, reviews available data from both completed and ongoing clinical trials, and outlines simplification strategies using INSTIs. AUC = area under the curve; CYP = cytochrome P450; DHHS = U.S. Department of Health and Human Services; MATE1 = multidrug and toxin extrusion protein; OCT2 = organic cationic transporter 2; P-gp = P-glycoprotein; S cr = serum creatinine concentration; UGT = uridine diphosphate-glucuronosyltransferase. a Class drug-drug interactions: Integrase strand transfer inhibitor exposures are reduced when administered with polyvalent cation-containing supplements including acid-suppressive therapies and with potent CYP3A4/UGT1A1 inducers (e.g., carbamazepine, phenytoin, and rifamycins). b Stribild contains elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate; available only as a single-table formulation. c Genvoya contains elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide; available only as a single-table formulation. d Biktarvy contains bictegravir, emtricitabine, and tenofovir alafenamide; available only as a single-table formulation. EXPERIENCE WITH INTEGRASE INHIBITORS Brooks et al

Selection of an appropriate antiretroviral regimen for the patient infected with human immunodeficiency virus can be challenging, as various considerations must be taken into account including viral resistance mutations, patient comorbidities, drug interactions, and the potential for drug-related adverse effects and toxicities. Treatment is further complicated when a clinical scenario arises requiring an alteration in the dosage form. Factors ranging from dysphagia to administration through an enteral feeding tube can affect decisions regarding antiretroviral dosage forms. Limited pharmacokinetic data exist regarding the alteration of antiretroviral medications from their original form. Bioavailability may vary substantially between dosage forms, which can lead to unpredictable drug concentrations. Supratherapeutic or subtherapeutic antiretroviral drug concentrations can result in increased toxicity, virologic failure, or the emergence of drug resistance. We performed a systematic literature search to review the available antiretroviral literature on the modification of solid dosage forms as well as alternative routes of administration of oral antiretroviral agents and their application to clinical practice.

Tenofovir alafenamide (TAF) is indicated for adult patients with chronic hepatitis B virus (HBV) infection with compensated liver disease at an oral dose of 25 mg/day. TAF is a more stable prodrug in the plasma than tenofovir disoproxil fumarate (TDF), leading to decreased plasma exposure of tenofovir. Decreased exposure is thought to reduce the risk of long-term TDF toxicities, such as nephrotoxicity and decreased bone mineral density (BMD). TAF, a nucleotide reverse transcriptase inhibitor, has the same mechanism of action as TDF. The results of phase III primary trials and extensions showed that TAF is noninferior to TDF at suppressing the HBV viral load in treatment-naive and treatment-experienced HBeAg-negative and HBeAg-positive patients at 48 weeks, 96 weeks, and 144 weeks of therapy. The most commonly reported adverse events were headache, abdominal pain, fatigue, cough, nausea, and back pain. At all evaluated time points (out to 144 wks of treatment), patients who received TAF had less risk of nephrotoxicity and less of a decline in BMD than the patients who received TDF. TAF appears to be safe in patients with a creatinine clearance (Cl ) above 15 ml/min; however, TAF is not currently recommended in patients with an estimated Cl below this threshold. TAF is safe in patients with mild hepatic impairment but is not currently recommended in patients with moderate or severe hepatic impairment (Child-Pugh class B or C).

The increased raltegravir exposure observed with once-weekly rifapentine was safe and tolerable. Once-weekly rifapentine can be used with raltegravir to treat latent tuberculosis infection in patients who are infected with HIV.

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