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.
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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