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Centre of Excellence for Health, Immunity and Infections (CHIP)
Rigshospitalet, University of Copenhagen
Department of Respiratory Medicine
Bispebjerg Hospital, University of Copenhagen
Daria Podlekareva, MD, PhD, has no relevant conflicts of interest to report.
Tuberculosis (TB) remains the leading cause of mortality in people with HIV (PWH) worldwide. Simultaneous treatment of HIV and TB is complex, and drug–drug interactions between anti-TB drugs and antiretrovirals (ARVs), adverse events, pill burden, adherence issues, and risk of immune reconstitution inflammatory syndrome all must be taken into consideration.
In antiretroviral therapy (ART)–naive PWH presenting with TB, treatment of TB should be prioritized, following by initiation of ART. Current guidelines recommend initiation of ART within 2-8 weeks of start of TB treatment, depending on CD4+ cell count and clinical presentation of TB. The challenge is which ART regimen to choose to avoid drug–drug interactions with rifampicin, the main and most potent anti-TB drug for treatment of drug-susceptible TB. Therefore, it is crucial to understand the metabolic pathways for both rifampicin and ARVs.
Rifampicin is a potent inducer of cytochrome P450 enzymes, the uridine diphosphate glucuronosyltransferases, and drug transporters such as P-glycoprotein. It increases metabolism and reduces concentrations of drugs, metabolizing through the same pathways, which is true for many ARVs. In the end, it is these interactions with rifampin that govern choice of ART and leave us with few choices.
In people who already are receiving ART, the challenge may be managing their regimen. TB treatment with rifampicin and other drugs is for a minimum of 6 months. If the person is receiving a regimen with significant drug–drug interactions with rifampicin (eg, a boosted protease inhibitor [PI]–based regimen), the ART regimen must be changed.
Which ARVs to Choose?
Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
Efavirenz (EFV) plus 2 nucleos(t)ide reverse-transcriptase inhibitors (NRTIs) is the ART regimen best supported by data for use in PWH with TB. Until recently, this regimen was the preferred first-line regimen in international guidelines, particularly in its 1-pill, once-daily coformulation, EFV/tenofovir disoproxil fumarate/emtricitabine. Its choice also was supported by its compatibility with rifampicin. EFV metabolism is not significantly affected by rifampicin coadministration, and no dose adjustment is needed for patients receiving 600 mg daily. EFV-based ART is associated with excellent TB and HIV treatment outcomes and has relatively low rates of toxicities, and adherence to this regimen―particularly the 1-pill coformulation―is good.
However, EFV is no longer recommended as first-line ART in most guidelines. There have been concerns about the increasing prevalence of transmitted primary NNRTI resistance in low- and middle-income countries. Its use always has been hampered by neuropsychiatric adverse events that may occur in some patients in the first month(s) of use. This may be a particular problem in people who use injection drugs, as they often are at higher risk for TB.
Other NNRTIs (nevirapine, rilpivirine, etravirine, doravirine) should not be used with rifampicin.
What About Integrase Strand Transfer Inhibitors (INSTIs)?
Raltegravir (RAL), the first-generation INSTI, is another drug whose use with rifampicin is well studied. Rifampicin is known to reduce RAL concentrations by 40%. The open-label phase II REFLATE TB study showed that both RAL 400 mg twice daily and RAL 800 mg twice daily, each with lamivudine/tenofovir disoproxil fumarate, were noninferior to EFV 600 mg once daily at Weeks 24 and 48 in people with TB who received rifampicin. However, the larger phase III REFLATE TB2 study showed that RAL 400 mg twice daily was not noninferior to EFV 600 mg once daily in PWH who also were receiving rifampicin for their TB coinfection. Therefore, the suggested dose of RAL is now 800 mg twice daily when the person also is receiving rifampicin. The downside of using this regimen is that it is 2 pills of RAL twice daily plus the NRTIs, which is ≥5 pills total per day in addition to the TB regimen. The upside for RAL and for dolutegravir (DTG) is that they are very tolerable with few adverse events, which makes these regimens desirable when the person also is dealing with the adverse events of the TB medications.
DTG is now a recommended first-line ART choice (with 2 NRTIs) by most guidelines and is under global rollout in many low- and middle-income (ie, TB-endemic) countries. When prescribing DTG-based ART to people coinfected with HIV and TB who also are receiving rifampicin, it is important to remember that rifampicin increases DTG metabolism and reduces DTG concentration by more than one half. Therefore, the DTG dose should be increased to 50 mg twice daily. This recommendation is based on results from the INSPIRING study. TB treatment success rates were high in both double-dose, DTG-based ART and EFV-based ART groups in patients with HIV-associated TB who received rifampicin (88% vs 91%, respectively), as was the percentage of patients who achieved HIV-1 RNA suppression (75% vs 82%). Some evidence, however, supports once-daily DTG dosing during rifampicin cotreatment, and the RADIANT trial is designed to further address this question.
Other INSTIs bictegravir and elvitegravir/cobicistat are not part of the recommended first-line (or second-line) drug regimens in low- and middle-income countries, partly because of limited availability in these settings. However, both drugs are contraindicated for use with rifampicin, either because reduced concentration of the INSTI has been documented (bictegravir) or is expected (elvitegravir/cobicistat).
A very important issue to address when using INSTIs (DTG or RAL) with rifampicin for the treatment of PWH and TB is adherence, which may be compromised by the higher pill burden from the increased INSTI dosage and the requirement to take medication multiple times per day. For both TB and HIV treatment success, good adherence is the cornerstone. It must be supported in every patient and implemented on programmatic levels.
What About PIs?
The PIs are not recommended with rifampicin. Although rifabutin, another rifamycin, can be considered with protease inhibitors, it is not widely used globally due to limited availability and complexity with dose adjustments.
The HIV ASSIST tool can aid in the selection of ART for patients with tuberculosis, taking into consideration the specific drug-drug interactions with their tuberculosis treatment regimen.
In your practice, which ART are you choosing for your patients who are coinfected with HIV and TB? Are you more comfortable with EFV, or are you choosing INSTIs? Do you provide any adherence support? Join the discussion by posting a comment sharing your experiences.