Key points

• Rifampicin (RIF) is a potent inducer of certain drug-metabolising enzymes and drug transporters and reduces exposure to drugs in the InSTI, NNRTI and PI classes, necessitating dose adjustments of certain of these drugs.
• LPV/r is the only PI that can be used with RIF, but the LPV/r dose needs to be doubled.
• Rifabutin (RFB) can be used with all PIs, but a RFB dose adjustment is required.
• Several side-effects are shared between ARVs and TB drugs including gastrointestinal intolerance, hepatotoxicity, drug rashes, myelosuppression and neuropsychiatric side-effects.

Tuberculosis (TB) is the most frequent concomitant infection affecting people with HIV (PWH) in Southern Africa. Patients may be diagnosed with TB at entry or re-entry into HIV care, or diagnosed with active TB while on ART. Studies in South Africa have suggested that TB incidence remains higher in patients who are virally suppressed on long-term ART compared with HIVnegative people living in the same community, possibly because of persisting defects in anti-mycobacterial immunity. The co-treatment of HIV and TB is complex because of: (i) drug-drug interactions (discussed below); (ii) TB-IRIS (see module 26); and (iii) shared side-effects (discussed below). These issues, which have recently been reviewed, ¹⁰⁵ affect decisions regarding the timing of ART in ART-naïve patients with TB (see module 6).

Certain ART regimens need to be modified for compatibility with rifampicin (RIF). RIF is a critical component of the drug-sensitive TB regimen that substantially reduces the risk of relapse after completing TB treatment.

There are no significant interactions between NRTIs and RIF; however, InSTIs, NNRTIs, PIs and MVC all exhibit drug interactions with RIF. DTG can be used in patients receiving RIF, but a dose adjustment to 50mg twice daily is advised in most cases (Table 18). ⁸⁸ A recent phase 2 clinical trial in South Africa38 and observational data from Botswana ¹⁰⁶ showed that virologic outcomes were similar in patients who remained on standard dose DTG (50mg daily) compared with those in whom dose was adjusted to 50mg twice daily. Standard dosing of DTG with RIF is therefore an option, but we do not advise this in patients who have previously failed a regimen and may have NRTI resistance as this dosing strategy has not been evaluated in this patient group. EFV is the preferred NNRTI for use with RIF. NVP was previously recommended as an alternative in patients with contraindications to EFV (e.g. psychosis), but it carries a higher risk of virological failure when used with RIF and given the availability of the InSTI class, NVP is no longer recommended. RPV and ETR cannot be used with RIF.

The plasma concentrations of all PI/r are reduced to subtherapeutic ranges with RIF. Dose adjustment of LPV/r can overcome this induction (see Table 18), but there is a risk of hepatotoxicity; therefore, patients require counselling and ALT should be monitored frequently. ^{107, 108} Gastrointestinal side effects are frequent with LPV/r double dosing

TABLE 18: Antiretroviral drug interactions with rifampicin and recommendations for co-administration.
Drug class	ARV	Interaction	Dose of ART drug with RIF
NRTI	All in class	No significant pharmacokinetic interactions	No dose adjustment required
NNRTI	EFV	Mild reduction in EFV concentrations. INH increases EFV concentrations in genetically slow metabolisers (~20% of South Africans), who already have high EFV concentrations – this can result in toxicity.	No dose adjustment required (600 mg nocte)
	ETR and RPV	Marked reduction in concentrations	Do not prescribe concomitantly with RIF
PI/r	LPV/r	LPV plasma concentrations significantly decreased	Double the dose of LPV/r to 800 mg/200 mg 12-hourly. There is an increased risk of hepatotoxicity with this strategy. The dose adjustment can be made gradually over 1–2 weeks. Dose adjustment should be continued for 2 weeks after RIF is stopped.
	All other PI/r	Marked reduction in PI concentrations	Do not prescribe concomitantly
InSTI	RAL	Reduction in concentrations	Dose increase to 800 mg 12-hourly
	DTG	Significant reduction in concentrations	Dosing frequency increased to 50 mg 12-hourly
CCR5 blocker	MVC	Reduction in concentrations	Increase MVC dose to 600 mg twice daily when co-administered with RIF in the absence of a potent CYP3A4 inhibitor
ART, antiretroviral therapy; DTG, dolutegravir; EFV, efavirenz; ETR, etravirine; InSTI, integrase inhibitor (integrase strand transfer inhibitor); LPV, lopinavir; LPV/r, ritonavir-boosted lopinavir; MVC, maraviroc; NNRTI, non-nucleoside reverse transcriptase inhibitor; NRTI, nucleoside reverse transcriptase inhibitor; PI/r, ritonavir-boosted protease inhibitors; RAL, raltegravir; RIF, rifampicin; RPV, rilpivirine. † RIF reduces TAF concentration in the blood but the intracellular TFV-dp concentration remains adequate, and so no dose adjustment is needed.

An alternative approach is to replace RIF with rifabutin (RFB) in patients taking a PI/r. However, RFB is not coformulated with other TB drugs, and the evidence base for RFB in the treatment of TB is much less substantial than for RIF. ¹⁰⁹ There is also uncertainty regarding the optimal dose of RFB with PI/r; these guidelines recommend 150 mg daily (Table 19) for efficacy reasons, but careful monitoring for toxicity is required (ALT, neutrophil count and visual symptoms at least monthly). ¹¹⁰ RFB may be considered in patients who are not tolerating co-treatment with doubledose LPV/r and RIF-based TB treatment (i.e. patients unable to tolerate the increased LPV/r dose due to hepatotoxicity or gastrointestinal side-effects) or in ART-experienced patients on a regimen that is not compatible with RIF (e.g. third-line ART with DRV/r). In most patients on RIF-based TB treatment, however, a DTG regimen rather than a PI should be used, except in patients who are intolerant of DTG and those on third-line requiring both DTG and DRV/r.

Common pitfall:

• Co-administering RIF with LPV/r, but not adjusting the dose of LPV/r. This results in subtherapeutic LPV concentrations and development of PI resistance.
• Combining linezolid and AZT. These drugs should not be combined because both can cause bone marrow suppression (especially anaemia and neutropenia).