iconstar paper   HIV Articles  
Back grey arrow rt.gif
Cytokine-Mediated Systemic Adverse Drug Reactions in a Drug-Drug Interaction Study of Dolutegravir with Once-Weekly Isoniazid and Rifapentine
  Download the PDF here
Clin Inf Dis Feb 3 2018 - Kristina M. Brooks, PharmD1,a, Jomy M. George, PharmD1, Alice K. Pau, PharmD2, Adam Rupert, MT (ASCP)3, Carolina Mehaffy, PhD4, Prithwiraj De, PhD4, Karen M. Dobos, PhD4, Anela Kellogg, MSN5, Mary McLaughlin, BSN6, Maryellen McManus, MPH7, Raul M. Alfaro, MS1, Colleen Hadigan, MD6, Joseph A. Kovacs, MD7, Parag Kumar, PharmD1 1Clinical Pharmacokinetics Research Unit, Pharmacy Department, Clinical Center, National Institutes of Health (NIH), Bethesda, MD, USA aCurrent affiliation: Department of Pharmaceutical Sciences, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO, USA 2Division of Clinical Research, National Institute of Allergy and Infectious Diseases (NIAID), Bethesda, MD, USA 3AIDS Monitoring Laboratory, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, MD, USA 4Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO, USA 5Clinical Monitoring Research Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, MD, USA 6Clinical Research Section, NIAID, Bethesda, MD, USA 7Critical Care Medicine Department, Clinical Center, NIH, Bethesda, MD, USA

Once-weekly isoniazid and rifapentine for 3 months is a treatment option in persons with human immunodeficiency virus and latent tuberculosis infection. This study aimed to examine pharmacokinetic drug-drug interactions between this regimen and dolutegravir, a first-line antiretroviral medication.
This was a single-center, open-label, fixed-sequence, drug-drug interaction study in healthy volunteers. Subjects received oral dolutegravir 50 mg once-daily alone (Days 1-4) and concomitantly with once-weekly isoniazid 900 mg, rifapentine 900 mg, and pyridoxine 50 mg (Days 5-19). Dolutegravir concentrations were measured on days 4, 14, and 19, and rifapentine, 25-desacetyl-rifapentine, and isoniazid concentrations were measured on Day 19. Cytokines and anti-drug antibodies to isoniazid and rifapentine were examined at select time points during and after study drug completion.
The study was terminated following the development of serious toxicities in two of four subjects after the third isoniazid-rifapentine dose. Flu-like syndrome and elevated transaminase levels occurred. Markedly elevated levels of interferon-γ, CXCL10, CRP and other cytokines were temporally associated with symptoms. Anti-drug antibodies were infrequently detected. Dolutegravir area under the curve (AUC) was decreased by 46% (90% CI [0.27, 1.10], p=0.13) on Day 14, ~48-72 hours following the second isoniazid-rifapentine dose. Rifapentine and 25-desacetyl rifapentine levels were comparable to reference data, whereas isoniazid AUCs were ~67-92% higher in the subjects who developed toxicities.
The combined use of dolutegravir with once-weekly isoniazid-rifapentine resulted in unexpected and serious toxicities that were mediated by endogenous cytokine release. Additional investigations are necessary to examine the safety and efficacy of co-administering these medications.
Tuberculosis (TB) is the most common opportunistic infection in individuals with human immunodeficiency virus (HIV) worldwide [1], and treatment of latent TB infection (LTBI) is essential in preventing progression to active disease. Once-weekly isoniazid-rifapentine for three months (3HP) is an attractive LTBI treatment option for persons with HIV as it has similar efficacy to nine months of daily isoniazid, a shorter treatment duration, and higher rates of adherence and treatment completion [2-7]. Despite these benefits, 3HP is not widely used in adults with HIV receiving antiretroviral therapy due to limited data on drug-drug interactions with this regimen.
Rifamycins, including rifapentine, are potent inducers of drug-metabolizing enzymes [8], and can decrease systemic exposure to certain antiretroviral medications. Drug-drug interaction studies currently support the use of 3HP only in patients receiving efavirenz- or raltegravir-based regimens [9, 10]. The International Antiviral Society-USA guidelines [11] also support the use of twice-daily dolutegravir with 3HP based on extrapolation from a drug-drug interaction study with rifampin [12]. The use of dolutegravir with 3HP is of high interest as this agent is one of the first-line treatment options for persons with HIV [11, 13], and recently became available in generic form in several countries with a high prevalence of LTBI.
However, whether once-weekly rifapentine will lead to induction of drug-metabolizing enzymes and significant decreases in dolutegravir exposure is unclear.
The current study was undertaken to examine the drug-drug interaction between once-daily dolutegravir and once-weekly isoniazid-rifapentine in HIV-negative healthy volunteers. The study was terminated early due to the development of flu-like syndrome and serum transaminase elevations in two out of four participants. Here, we describe these adverse reactions and the results of cytokine, anti-drug antibody, and pharmacokinetic evaluations throughout the study and acute reaction periods.
Our study found a higher than expected frequency of flu-like symptoms in healthy volunteers after receiving three once-weekly doses of isoniazid-rifapentine concomitantly with once-daily dolutegravir, and demonstrated a temporal relationship between symptoms and plasma levels of cytokines, most prominently IFN-γ. While the number of participants studied is small, these preliminary findings suggest co-administration of dolutegravir and 3HP should be done cautiously, ideally in a clinical research setting, to further evaluate this combination.
Flu-like syndrome has typically been associated with the intermittent use of rifampin [18], although case reports also describe its occurrence with isoniazid [19, 20]. Flu-like syndrome and hepatotoxicity were previously reported in 3.8% and 0.4%, respectively, of nearly 4,000 subjects in large-scale efficacy studies of 3HP, and severe AEs were reported in 0.3% of subjects [21]. The infrequent occurrence of these AEs in large-scale clinical trials raises a concern that dolutegravir is contributing to these toxicities in some unknown manner. With 3HP alone, flu-like syndrome developed after a median of three doses, with symptom onset around four hours post-dose and resolution ~24 hours later [21], similar to what was observed in our subjects. Demographic risk factors for developing flu-like syndrome included white/non-Hispanic race/ethnicity, female sex, age over 35 years, and low BMI [21]. Re-challenge with either or both agents in these subjects found that rifapentine was better tolerated than isoniazid [21].
The cytokine data from our participants strongly support a role for acute release of endogenous IFN-γ alone or in combination with other cytokines in the development of these AEs. Increases in IFN-γ were detected after the second isoniazid-rifapentine dose, with marked elevations on Day 19 beginning ~4-6 hours post-dose, and peak levels ~24 hours after the third isoniazid-rifapentine dose. The timing of these elevations aligned with clinical symptoms as well as the neutrophilia and lymphocytopenia during the acute reaction period, and preceded the transaminase elevations. Flu-like symptoms are nearly universally seen in patients treated with IFN-γ, and transaminase elevations are also common [22]. Elevations in IFN-γ (and CXCL10) have been reported with a number of conditions, including idiosyncratic drug-induced liver injury (DILI) [23], bacterial sepsis [24], and cytokine storm/response syndrome to immunotherapy [25], with IFN-γ levels up to 5000 pg/mL measured in the latter two conditions, though lower than what was measured in this study. The extremely high IFN-γ and CXCL10 levels observed in this study suggest a primary role for T cells, especially CD4+ helper (TH1) and CD8+ cytotoxic or natural killer cells, in mediating these AEs. IFN-γ is predominantly secreted by these cells, and CXCL10 is secreted by a variety of cells in response to IFN-γ. Rifampin- and isoniazid-specific T-cells have previously been identified in patients whom developed drug reactions with eosinophilia and systemic symptoms syndrome [26]. Another recent study demonstrated isoniazid-specific cytokine release of IFN-γ, IL-10, IL-12, and IL-17A following isoniazid incubation with primary hepatocytes and dendritic cells [27]. Further investigations are needed to identify specific cell types and drugs involved with eliciting these immune responses.
Idiosyncratic drug reactions have previously been reported with rifamycins and isoniazid. Several theories regarding the mechanisms of these reactions exist, including hapten formation with the parent drug or reactive metabolites, anti-drug antibody development [18, 28], inhibition of bile salt excretion [29], and other patient-specific factors. One or more of these mechanisms may have factored into the toxicities observed in this study. Hypersensitivity reactions to dolutegravir alone have also been reported in <1% of patients [30]. Anti-rifapentine antibodies were detected in subjects 1 and 4 on single occasions, but are unlikely causative given the inconsistent pattern in antibody development. Furthermore, antibodies to isoniazid and 25-desacetyl rifapentine were detected in subjects 2 and 3, respectively, who did not develop reactions. However, sensitivity and selectivity issues in the current experimental assay may not have detected antibodies at other time points.
Previous drug-drug interaction studies between rifamycins and antiretroviral agents, particularly ritonavir-boosted protease inhibitors, have been associated with unexpected, high-grade toxicities including elevated transaminases and hypersensitivity reactions [31-33]. These were partially attributed to either the use of higher than FDA-approved doses of the antiretroviral agents [33], or increased levels of rifamycins and their metabolites [31, 32] due to cytochrome P450 3A4 (CYP3A4) inhibition by ritonavir. These studies were also conducted in healthy volunteers, and when the same combinations were studied in HIV/TB-coinfected patients, the safety findings were not replicated [34, 35]. Thus, unidentified mechanisms for differences in immune response or tolerability of these agents may also exist between these populations. Our study was performed in healthy volunteers, but exposure to rifapentine and its active metabolite were within previously reported ranges, and FDA-approved doses of all study medications were given. However, isoniazid AUCs were markedly higher in subjects 1 and 4, the mechanism behind which is unclear. Rifapentine does not alter the pharmacokinetics of isoniazid [17]. Subjects 1 and 4 were both slow acetylators, which may partially explain the higher isoniazid AUCs. However, 20-80% of the population share this phenotype depending on their ethnicity, and flu-like syndrome reactions are infrequently reported. Isoniazid is metabolized into several reactive metabolites that are capable of forming protein adducts with hepatocytes and activating macrophages [36]. The contribution of isoniazid metabolites to the AEs in this study is unclear as their levels were not examined. The limited PK data obtained from this study suggests that induction of UDP glucuronosyltransferase family 1 member A1 and CYP3A4, the enzymes involved in dolutegravir metabolism, will occur with once-weekly administration of rifapentine, resulting in decreased dolutegravir exposure. The extent of induction appears time-dependent, with maximal induction ~48-72 hours after rifapentine administration as evidenced by a 46% decrease in dolutegravir AUC, and 74% decrease in trough concentrations at this time point. Despite the decreased AUC that was observed, the geometric mean trough concentration for dolutegravir at this time point was still 5.3x the protein-adjusted in vitro concentration for 90% inhibition of 0.064 μg/mL reported for dolutegravir. However, one subject did have multiple trough concentrations below 0.3 ug/mL, a threshold below which higher rates of treatment failure with dolutegravir are observed [37]. Whether transient decreases in exposure may compromise the virologic efficacy of dolutegravir is unknown. Dolutegravir AUC on Day 19 was nearly restored to levels when administered alone, which may be due the waning of enzymatic induction, and mixed enzyme inhibition by rifapentine and isoniazid with simultaneous coadministration [38].
Though not the original intent, this study provides important insights into potential mechanisms resulting in the AEs seen in subjects receiving once-weekly isoniazid-rifapentine with dolutegravir. Further studies are needed to carefully evaluate the safety and efficacy of dolutegravir-based regimens when coadministered with isoniazid-rifapentine, especially given the recent availability of generic dolutegravir in countries with high TB burden, and the desire to use this once-weekly regimen in patients living with HIV.

  iconpaperstack View Older Articles   Back to Top   www.natap.org