Globally, tuberculosis (TB) causes 25% of all deaths among individuals with HIV infection, and patients with HIV who have latent TB infection are 21 to 34 times more likely to develop TB disease than those without HIV.1 Increasingly, the 2 diseases will be treated concurrently in coinfected individuals, as recent studies evaluating the optimal timing for initiation of antiretroviral therapy (ART) among patients requiring treatment for active TB demonstrate a survival benefit for treating HIV soon after TB treatment initiation.2–5
Currently, rifamycins serve as the cornerstone of TB therapy because of their unique sterilizing activity. Rifampin (RIF), the most commonly used rifamycin, is a potent inducer of cytochrome P450 enzyme activity and also induces phase II drug metabolizing enzymes, including UDP-glucurosyltransferases (UGT).6 Because most protease inhibitors (PIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs) used to treat HIV are metabolized by CYP3A, induction of CYP3A by RIF can lead to reduced serum concentrations of antiretrovirals (ARVs) with risk for HIV treatment failure or emergence of resistance to ARVs. Among patients who must be treated with RIF-containing TB therapy that require concurrent ART, efavirenz-based ART can be used safely and effectively, but for those with contraindications or resistance to NNRTIs, there are few treatment options. Substitution of rifabutin (RBT) for RIF is a reasonable option for HIV/TB coinfected patients taking ART, as RBT is a less potent inducer of drug metabolizing enzymes.7 However, because CYP3A is involved in RBT clearance, RBT requires bidirectional dose adjustment when given with PIs. The optimal RBT dosing frequency is unknown.8 Furthermore, TB treatment is usually given in fixed-dose combinations, so substituting RBT for RIF is difficult in many settings. An ARV that could be taken with an NRTI backbone and be used safely and effectively with RIF for the treatment of HIV/TB coinfection without need for adjustment of the TB regimen would give physicians and patients an important treatment option.
Dolutegravir (DTG) is a promising investigational HIV integrase inhibitor that does not require ritonavir boosting and has a well-characterized pharmacokinetic/pharmacodynamic relationship.9 In a dose-ranging study among treatment-naive patients receiving DTG at a dose of 50 mg once daily together with an NRTI backbone of tenofovir plus emtricitabine or abacavir plus lamivudine, 88% of subjects had a viral load <50 copies/mL after 96 weeks of treatment (compared with 72% taking standard-dose efavirenz with 2 NRTIs and 78% taking DTG at a dose of 10 or 25 mg once daily).10,11 DTG may also be effective for treatment of HIV-1 among treatment-experienced patients, including those with baseline resistance to integrase inhibitors, and a dose of 50 mg twice daily in that population is under investigation.12,13
DTG is primarily metabolized by UGT1A1 with CYP3A as a minor route,14 and both enzymes are induced by RIF. As a large effect of RIF was anticipated, we compared the pharmacokinetics of DTG given alone at 50 mg once daily to the pharmacokinetics of DTG given at a dose of 50 mg twice daily together with standard dose RIF. We also evaluated the effects of RBT on DTG pharmacokinetics using the standard 50 mg once daily dose of DTG, as RBT is considered a weaker inducer of drug metabolizing enzymes. The short-term safety and tolerability of DTG with RIF or RBT were also assessed.
Healthy adults 18–65 years of age were recruited at a single site in Baltimore, MD. Eligible subjects had negative HIV and hepatitis C antibody tests and liver function enzymes less than 1.5 times the upper limit of normal. Subjects were excluded for creatinine >1.5 mg/dL, hemoglobin ≤12.0 g/dL (men), or ≤11.0 g/dL (women), absolute neutrophil count <1250 cells/mm3, platelets <125,000 cells/mm3, electrocardiogram with QTc > 450, or evidence of active TB. Other exclusion criteria included positive drug or alcohol screen, history of Gilbert disease, chronic illness, or current use of prescription medications. The study was approved by the institutional review board of Johns Hopkins University School of Medicine, and all subjects provided written informed consent. The trial was registered at clinicaltrials.gov (NCT01231542).
This was a phase I, open label, 2-arm, fixed-sequence crossover study (Fig. 1). Subjects in arm 1 received 50 mg of DTG once daily for 7 days (period 1), then 50 mg of DTG twice daily for 7 days (period 2), then 50 mg of DTG twice daily with 600 mg of RIF once daily for 14 days (period 3). In arm 2, subjects received 50 mg of DTG once daily for 7 days (period 1) then 50 mg DTG once daily with 300 mg of RBT once daily for 14 days (period 2). Plasma samples for DTG were collected predose then 1, 2, 3, 4, 5, 6, 8, and 12 hours postdose at the end of each period (during once daily dosing, a 24-hour sample was also collected). Doses preceding PK sampling were taken on an empty stomach.
Subjects underwent safety evaluations once or twice weekly during the study. Signs and symptoms and laboratory events were graded according to the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events Version 1.0 (December 2004, August 2009 clarification).15
Drug Concentration Analysis
Plasma Assay for DTG
DTG was quantified using a liquid chromatographic method with tandem mass spectrometric detection (LC-MS/MS), as previously described.16 In brief, plasma samples were extracted by protein precipitation with acetonitrile containing (15N2H7) DTG, as the internal standard, and analyzed for DTG using a validated LC-MS/MS method. The eluate was detected by using a Sciex API-4000 (AB Sciex; Framingham, MA) equipped with a TurboIonSpray ionization source using positive ion mode and multiple reaction monitoring. Data acquisition and processing were performed with Analyst 1.4 software (AB SCIEX, Framingham, MA). The calibration range for DTG was 20 ng/mL–20,000 ng/mL. Quality control samples were prepared at 4 different analyte concentrations and stored with study samples. Based on the analysis of these QC samples, the bias [% RE or relative error] ranged from 1.3% to 6.1%, and the coefficient of variance (% CV or standard deviation/mean) ranged from 6.1% to 7.9%.
Pharmacokinetic and Statistical Analyses
Based on a within-subject variability (CV%) of 33% (this was the highest CV% for area under the time–concentration curve (AUC), maximum concentration (Cmax), or concentration at the end of the dosing interval (Cτ) estimates from previous pharmacokinetic studies involving DTG), an expected withdrawal rate of 20%, and an assumption that only a difference of at least 25% in exposures would be clinically relevant, it was estimated that a sample size of 12 subjects to achieve 10 evaluable subjects in each arm would achieve a precision for half the width of the 90% confidence interval (CI) on the log scale for the treatment difference that would be within 26% of the point estimate for AUC, Cmax, and Cτ.
Pharmacokinetic and Statistical Evaluation
Noncompartmental analyses using WinNonlin software, version 6.1 (Pharsight, Cary, NC) were performed to estimate DTG pharmacokinetic parameters, including AUC, Cmax, CT, half-life (t1/2), and oral clearance (CL/F). For twice daily dosing, AUC0–24 were calculated by doubling the AUC0–12 estimates. Comparisons of pharmacokinetic parameters were performed using analysis of variance (ANOVA) in SAS (Version 9.1). Calculated geometric least squares mean ratios (GMRs) and 90% CIs were used to compare pharmacokinetic parameter estimates of DTG alone versus DTG together with RIF or RBT. Pharmacokinetic parameters were log-transformed, and point estimates and their associated 90% CI were constructed for the intrasubject differences between test and reference treatments. These estimates were back-transformed to provide the GMR and associated 90% CI.
In arm 1, 12 subjects were enrolled and 11 completed all PK sampling periods. Of the 12 enrolled subjects, the median age was 48 years (range, 31–59 years), and median weight was 79 kg (range, 63–99 kg). Eight (67%) participants were African American and 2 (17%) were women. In arm 2, 15 subjects were enrolled and 9 completed both PK sampling periods. Of the 14 enrolled participants who took at least one dose of study drug, median age was 43 years (range, 26–56 years), and median weight was 83 kg (range 66–97 kg). Five (36%) were women, and 10 (71%) were African American. In arm 1, one subject dropped out for personal reasons related to housing 1 day before completion of study drug dosing, so 11 were eligible for analysis of pharmacokinetic endpoints. In arm 2, one subject was discontinued before starting study drug because of abnormal baseline laboratory values. Another was discontinued for inadvertently taking extra doses of DTG. Two subjects dropped out for personal reasons (marital conflict leading to criminal arrest; scheduling issue related to change in employment hours), and there were 2 discontinuations for adverse events. Thus, in arm 2, nine participants were eligible for analysis of PK endpoints.
Effect of RIF on DTG Pharmacokinetics
Figure 2 shows the mean (SE) plasma concentration–time curves for 50 mg of DTG once daily alone (period 1), 50 mg of DTG twice daily alone (period 2), and 50 mg of DTG twice daily taken with steady-state 600 mg of RIF once daily (period 3). As expected, DTG concentrations in period 3 were reduced when compared with period 2 (Table 1). However, twice daily DTG plus RIF achieved mean pharmacokinetic parameters that were 20%–33% higher than once daily dosing alone (Table 1). Comparing period 3 (DTG twice daily plus RIF) to period 1 (DTG once daily), the GMR for the 24-hour AUC0–24 was 1.33 (90% CI: 1.15 to 1.53), and the GMR for the trough at the end of the dosing interval (Cτ) was 1.22 (90% CI: 1.01 to 1.48).
Effect of RBT on DTG Pharmacokinetics
Figure 3 shows the mean (SE) plasma concentration–time curves for 50 mg of DTG once daily alone (period 1) versus 50 mg of DTG once daily together with 300 mg of RBT once daily (period 2). Comparing period 2 to period 1, the GMR for the AUC0–24 was 0.95 (90% CI: 0.82 to 1.10) and the GMR for the Cmax was 1.15 (90% CI: 0.97 to 1.36)(Table 2). The Cτ in period 2 was less than that of period 1, with a GMR of 0.70 (90% CI: 0.57 to 0.87).
Safety and Tolerability of DTG Together With RIF or RBT
In arm 1, there were no discontinuations for adverse events and no grade 3 or higher adverse events. One subject experienced grade 2 lymphopenia at the end of period 3 and self-limited rash after completing study drugs. Another subject developed grade 2 headache while taking DTG together with RIF, and 2 participants had asymptomatic grade 2 lipase elevations while taking DTG alone.
One subject in arm 2 suffered a severe adverse event requiring discontinuation of study medications. The participant, a 36-year-old white woman, was admitted to the clinical trial unit for her scheduled inpatient PK visit at the end of period 1. At that time, after 7 daily doses of DTG, she felt well, reported no symptoms, and had a normal physical examination and normal safety laboratories. Before discharge, she received her eighth daily dose of DTG together with her first dose of RBT. That evening, she developed confusion, vertigo, and back and hip pain and was brought to the emergency department. On initial evaluation, she was found to be tachycardic and hypertensive. She subsequently developed fever to 39.9°C and hypotension requiring fluid resuscitation. Laboratory analysis revealed lymphopenia (790 cells/mm3, compared with 1970 cells/mm3 the previous day) but no liver function test abnormalities. She had no rash. She was admitted to the hospital for monitoring and discharged the following day in stable condition. On further questioning, she reported that she had never received RBT or other rifamycin antibiotics in the past. In arm 2, 4 volunteers developed asymptomatic grade 2 elevated lipase while taking DTG alone and 1 developed grade 2 elevated fasting glucose. One subject developed grade 2 lymphopenia, and another subject developed grade 3 lymphopenia, both while taking DTG together with RBT.
There is a mortality benefit of cotreatment of HIV and TB,2 and current guidelines recommend treating the 2 infections concurrently rather than waiting to complete TB treatment to initiate therapy for HIV.17,18 Antiretroviral options for those patients taking RIF-containing TB treatment, though, are limited, largely because of drug interactions related to rifamycin use. DTG, an investigational second-generation integrase inhibitor, is a substrate of UGT1A1 and CYP3A, both enzymes that are induced by RIF. In this study, giving DTG twice a day with RIF resulted in DTG concentrations that were similar to or higher than those achieved with DTG given once daily alone. The combination of multiple-dose RIF and DTG was also well tolerated. These results are encouraging and provide the pharmacokinetic and safety data to support evaluation of DTG-based ART and RIF-containing TB treatment among patients coinfected with HIV and TB.
RIF plays an essential role in the treatment of drug-sensitive TB because of its unique sterilizing activity. Among patients who cannot receive RIF as part of multidrug therapy, for example, those with multidrug resistant TB, treatment must be prolonged significantly—from 6 months to 18–24 months.19 To date, no drug has demonstrated sterilizing activity equal to that of rifamycins, so for treatment of drug-sensitive TB, drug interactions related to rifamycin use must be managed rather than avoided. RIF, though, is a promiscuous inducer of drug metabolizing enzymes and transporters, reducing concentrations of many companion drugs that are metabolized by cytochrome P450 or phase 2 enzymes, including many ARVs. For comanagement of TB and HIV, RIF-containing TB treatment can be given with efavirenz-based ART but the appropriate dose of efavirenz to give those patients who weigh more than 50 kg is unclear and may depend on CYP2B6 drug metabolizer genotype.20–22 The Food and Drug Administration recently recommended an increase in efavirenz dose from 600 to 800 mg for those patients taking RIF who weigh more than 50 kg, but prospective data comparing the 2 doses in this population are lacking, and the data supporting the need for dose adjustment are inconsistent. For those patients with HIV and TB who cannot take an NNRTI because of resistance or tolerability issues, options are few. RIF reduces HIV PI concentrations significantly and can compromise virologic suppression, but increasing the ritonavir or PI dose can lead to hepatotoxicity.23–25 Strategies to safely increase the PI dose without adversely affecting patient safety are being evaluated.26,27 In settings where RBT is available, it can be used in place of RIF, reducing the risk for rifamycin-related drug interactions with ARVs. In our study, overall plasma concentrations of DTG were similar when DTG was given with or without RBT, and no DTG dose adjustment was required. Trough plasma concentrations remained significantly higher than the protein-adjusted IC50 of 0.016 mcg/mL against HIV-1.28 Based on virologic responses observed across DTG doses ranging from 10 to 50 mg daily in SPRING-1, the 30% reduction in trough concentrations of DTG coadministered with RBT is unlikely to have a negative impact on DTG clinical efficacy.10,11
Giving raltegravir, another integrase inhibitor, at double the standard dose when it is coadministered with RIF results in similar overall raltegravir exposures but lower trough concentrations than when raltegravir is given at the standard dose without RIF.29 The clinical significance of low trough concentrations when the drug is given twice daily is unknown but is being explored in a phase 2 study among patients with HIV and TB.29,30 Clearly, more ART options that will allow for safe and effective treatment for both HIV and TB are needed.
Rifamycin use can be associated with rifamycin hypersensitivity syndrome (RHS), an immune-mediated syndrome characterized by flu-like symptoms. RHS symptoms have been well described and may include fever, rigors, headache, arthralgias, rhinorrhea, nausea, or hepatitis, but the immunopathogenesis has been incompletely characterized. Rarely, more serious adverse reactions, including thrombocytopenia, hemolytic anemia, acute renal failure, and hypotension can occur.31,32 With RIF, RHS incidence increases with increasing dose, generally occurs after several weeks of treatment, and is seen nearly exclusively with intermittent dosing.33–35
RBT has a different side effect profile than the other rifamycins. It alone causes uveitis, and incidence of drug-related cytopenias seems to be higher. In studies involving doses of RBT more than 300 mg daily or RBT at standard doses given together with an agent known to inhibit CYP3A metabolizing enzymes, such as ritonavir or clarithromycin, moderate to severe neutropenia occurs commonly.36–39 Among healthy volunteers in particular, moderate to severe neutropenia can occur even at standard doses of 300 mg daily, and in some cases, incidence may be unacceptably high, though the neutropenia is usually asymptomatic and not associated with clinical sequelae.40–43 In our study, dose-limiting neutropenia was not seen in arm 2 participants, but one subject developed a severe drug reaction with features suggestive of RHS. This individual had been taking twice daily DTG for 7 days with normal safety evaluations and no reported symptoms and subsequently developed fever, hypotension, and confusion after the first dose of RBT (taken together with DTG). Although consistent with RHS, the occurrence of symptoms after just a single dose of RBT was atypical. Although it is possible that DTG could have potentiated the development of RBT-related RHS, the mechanism by which it would do so is unclear. RBT is metabolized to a desacetyl derivative, and this metabolite is further metabolized by CYP3A enzymes.44 DTG does not inhibit CYP3A, so would be unlikely to increase RBT or 25-desacetylrifabutin concentrations.16
There are several limitations of this study. First, it was performed at a single site among a small number of healthy subjects and coadministration of DTG and RIF or RBT was limited to 2 weeks. Safety and tolerability data may, thus, not reflect the full tolerability profile of the 2 drugs coadministered for a longer period of time to patients taking multidrug treatment for HIV and TB. Also, in this trial, we gave DTG alone followed by RIF plus DTG, whereas in clinical practice, usually TB treatment is started first, and ART is initiated at least 2 weeks later. Although the hepatotoxicity associated with combined use of PIs and RIF seems to be more severe when RIF is started before the PI,23,45–47 recent studies suggest that RIF-containing TB treatment followed by integrase inhibitor-based ART is well tolerated.48 In addition, it is possible that reductions in DTG concentrations with RIF may differ by geographical setting. However, even reductions in DTG concentrations as high as 50% are unlikely to be clinically significant in integrase inhibitor-naive patients given that doses of DTG of 10 and 25 mg once daily (together with a NRTI backbone) produced high rates of virologic suppression over 96 weeks among antiretroviral-naive patients with HIV-1 infection, similar to that seen with an efavirenz-based regimen.11,49 We did not measure rifamycin concentrations in this study because preclinical and clinical studies have found that DTG is not a significant inhibitor or inducer of drug metabolizing enzymes or transporters and is therefore unlikely to have an effect on rifamycin concentrations.16 Also, we did not evaluate DTG concentrations in the posttreatment period after RIF was discontinued, so the duration for which DTG would need to be given twice daily to ensure adequate concentrations while the inducing effects of RIF on metabolizing enzymes wear off is unknown. Finally, in this study we only evaluated dosing strategies for DTG with RIF that would achieve DTG concentrations similar to those seen with a dose of 50 mg once daily. For patients with treatment failure on an integrase inhibitor containing regimen or patients with genotypic resistance to raltegravir or elvitegravir who may require higher exposures to DTG, further experiments will be necessary to determine the appropriate dose to use with RIF.
In conclusion, DTG at 50 mg twice daily given together with standard-dose RIF was well tolerated and resulted in DTG concentrations similar to those of 50 mg of DTG given once daily alone. Fifty milligrams of DTG with standard-dose RBT once daily resulted in overall plasma DTG concentrations similar to 50 mg of DTG once daily alone. Trough concentrations, though, were reduced by about 30% in this study population, a decrease unlikely to be clinically significant given the known pharmacokinetic–pharmacodynamic relationships for DTG from phase 2 dose-ranging studies. One subject receiving RBT and DTG had an adverse event consistent with RHS after the first dose of RBT; the contribution of DTG to this reaction is unknown. With proper monitoring, DTG plus RBT may be a reasonable option for the concomitant treatment of HIV and TB. However, RIF is the preferred rifamycin for TB treatment because of its lower cost, availability, and coformulation with other TB drugs, and target concentrations of DTG seem to be achievable when DTG is given with RIF when DTG dosing is increased to twice daily. Further experiments to determine the DTG dose required to treat patients with HIV-1 with baseline resistance to integrase inhibitors who require concurrent RIF-containing TB treatment will be necessary. HIV regimens including DTG twice daily may represent a new option for patients who require concomitant treatment of HIV and TB and should be evaluated among patients with HIV and TB coinfection.
The study team thanks the individuals who volunteered for and participated in this study. The authors would like to acknowledge Eric Zimmerman for providing quality control for this trial, James Johnson for processing and shipping study specimens, and the nursing staff of the Clinical Trials Unit on Osler 5 for provision of inpatient care to study subjects.
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