Highly active antiretroviral therapy (HAART) for human immunodeficiency virus (HIV) has resulted in significant morbidity and mortality reductions. Lifelong antiretroviral therapy must be incorporated into each patient's medical regimen. Patients with HIV may also have simultaneous chronic medical conditions, resulting in the possibility of complex drug-drug interactions. We report a possible drug-drug interaction between HAART and warfarin in two patients, as assessed by the Naranjo adverse drug reaction probability scale and the Drug Interaction probability scale. Both patients' pharmacotherapy regimens included a nonnucleoside reverse transcriptase inhibitor (NNRTI), nevirapine, or a protease inhibitor, nelfinavir or lopinavir-ritonavir, and two nucleoside analogs. In both patients, high warfarin doses were required to maintain therapeutic international normalized ratios (INRs). Warfarin has two enantiomers, R-and S-warfarin, which are substrates primarily of cytochrome P450 (CYP) 3A4 (R-warfarin), CYP1A2 (R-warfarin), and CYP2C9 (S-warfarin). Protease inhibitors and NNRTIs have variable effects on CYP: induction, inhibition, or mixed. The increased warfarin doses required in these two patients may have been caused by induction of CYP3A4 by nevirapine, CYP2C9 by nelfinavir, or CYP2C9 by lopinavir-ritonavir. Thus, practitioners should prudently monitor INRs in patients receiving warfarin with concomitant HAART that includes either a protease inhibitor or an NNRTI.
HIV-related symptomatology represents both an indirect measure of immune functioning and a clinically significant indicator of disease progression. The most widely used classification system for HIV-related symptomatology is the Center for Disease Control (CDC) system. Although the CDC scale has widely recognized clinical utility, it provides only nominal-level measurement, which may be problematic for both clinicians and researchers. This article describes the revision and validation of the HIV Center Medical Staging Scale (rHCMSS), and ordinal-level physical illness scale that provides a means of independently measuring the progression of HIV-disease symptomatology and immunological decline. Concurrent use of the rHCMSS, the CDC classification system, and T-lymphocyte and viral load data will provide a more comprehensive indication of HIV-disease progression for clinical and research purposes.
P atients with human immunodeficiency virus (HIV) have a near-normal life expectancy and as a result are experiencing common age-related medical conditions (e.g., atrial fibrillation) and polypharmacy (1, 2). Significant drug-drug interactions (DDIs) with concurrent antiretroviral therapy (ART) and direct oral anticoagulants are common and result in an increased risk for major bleeding (3, 4). As an example, concurrent use of apixaban or rivaroxaban with ritonavir or cobicistat (COBI) is not recommended due to cytochrome P450 (CYP) inhibition, resulting in supratherapeutic concentrations and increased hemorrhagic risk (4-6). Dabigatran is not CYP metabolized, is primarily renally eliminated, and is a substrate of intestinal permeability glycoprotein (p-gp) and renal multidrug and toxin extrusion-1 (MATE-1) transporter (6-8). Both ritonavir and COBI inhibit p-gp and MATE-1 (6-8). In a recent study of 34 healthy volunteers, dabigatran was administered concurrently or separated by 2 h from either ritonavir or COBI (9-11). Increased dabigatran and thrombin time concentrations resulted with concurrent COBI but not with ritonavir (9-11). We report a case of concurrent dabigatran and ritonavir-boosted darunavir in a patient with multidrug resistant (MDR) HIV and summarize previously reported data.A 74-year-old African-American male (weight, 63 kg; glomerular filtration rate, 75 ml/min) with MDR HIV (viral load undetectable) who had undergone triple cardiac bypass surgery with a pacemaker was anticoagulated with warfarin for approximately 8 years. Dabigatran at 150 mg twice daily was substituted for warfarin by his cardiologist. At his infectious diseases appointment, an expected DDI between COBI and dabigatran led to ART substitution, including darunavir-COBI discontinuation, darunavir-ritonavir initiation, and continuation of rilpivirine, emtricitabine-tenofovir alafenamide, and raltegravir (9). Dabigatran peak (2 h after ingestion) and trough concentrations were monitored and remained therapeutic, 285 ng/ml and 59 ng/ml, respectively (12)(13)(14). An activated partial thromboplastin time of 60 s resulted, with no bleeding events. The patient remained on concurrent therapy for 11 months.In the recent study evaluating dabigatran with ART, p-gp inhibition appears to be the mechanism of the DDI, as renal elimination was not affected (9,11). In patients receiving p-gp inhibitors and dabigatran, more-frequent monitoring of bleeding is recommended (15). Dabigatran peak (64 to 443 ng/ml) and trough (recommended, Ͻ73 ng/ml) concentrations in atrial fibrillation patients are correlated with decreased hemorrhagic and thromboembolic risks (12)(13)(14). In our patient, dabigatran concentrations were therapeutic, with no documented adverse/thromboembolic events.In two previous case reports using dabigatran with concurrent atazanavir-ritonavir or lopinavir-ritonavir, dabigatran concentrations remained within the therapeutic range
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