5.0 Drug/drug interactions (see Table 1 & 2)

Drug/drug interactions between HIV and TB therapy arise through shared routes of metabolism and are often due to enzyme induction or inhibition. 35,36

One important family of enzymes is the hepatic cytochrome P450 (CYP) system.  The isoform CYP3A4 is involved in the metabolism of many drugs including the protease inhibitors and non-nucleoside reverse transcriptase inhibitors (NNRTI), which makes up the core of most HAART regimens.

The non-nucleoside reverse transcriptaseinhibitors and protease inhibitors have clinically important drug interactions with therifamycins, as the latter are potent inducers of CYP3A4. 37,38

However, the inducing effect of rifampicin not only takes at least 2 weeks to become maximal but will also persist for at least 2 weeks after rifampicin has been stopped. If antiretrovirals have been started or changed at the end of TB treatment this persistent effect on enzyme induction should be taken into consideration. In addition, rifampicin increases the activity of the efflux multi-drug transporter P-glycoprotein (P-gp) that contributes to the elimination of PI. 39,40

Rifabutin is a less potent inducer of CYP3A4. Unlike rifampicin, it is also a substrate of the enzyme  41 Therefore any CYP3A4 inhibitors will increase the concentration of rifabutin but will have no effect on rifampicin metabolism.  Thus, when rifabutin is given with PI, which are inhibitors of CYP3A4, its plasma concentration and that of its metabolites may increase and cause toxicity..

Individual drug/drug interactions between rifamycins and antiretroviral agents are shown in table 1 and 2.  The complexity of drug/drug interactions requires expertise in use of both antiretroviral and anti-TB drugs. One particular drug interaction should be noted: the metabolism of corticosteroids is accelerated by rifampicin and therefore doses of such drugs e.g. prednisolone, which are commonly used in TB should be increased proportionately.

5.1 Rifamycins and nucleoside / nucleotide analogues

Most nucleosides have either unknown or little change in pharmacokinetics when given together with rifampicin based regimens.  Rifampicin reduces the AUC and increases the clearance of zidovudine via the mechanism of increased glucuronidation of zidovudine. This is not clinically significant and dose alteration is not required. In contrast, rifabutin does not appear to affect the clearance of zidovudine. 42,43

The previous formulation of didanosine contained a buffer, which affected the solubility and absorption of rifampicin and ingestion of the drugs had to be separated in time. This is no longer necessary as buffer-free enteric-coated didanosine is routinely used.

 

5.2       Rifamycins and protease inhibitors

 

5.2.1   Rifampicin

Rifampicin causes a 75 to 95% reduction inserum concentrations of PI other than ritonavir. Suchreductions lead to loss of antiretroviral activity of PI-containing regimens and consequently can result in the emergence of resistance to one or more of the other drugs in the HAART regimen.

Currently, most patients are given combinations of PI, which includes low dose ritonavir [usually 100mg per dose] in order to take advantage of its enzyme inhibiting properties. In effect ritonavir boosts the concentrations of the other PI allowing easier and more tolerable dosing.  Data from the drug/drug interaction of rifampicin with lopinavir/ritonavir suggest that ritonavir at this low dose may compensate for the induction effect of rifampicin on lopinavir metabolism. 44,45

Preliminary data suggested that ritonavir 100mg twice daily may be used with daily rifampicin. Once daily saquinavir/ritonavir has also been used. 46  However recent studies of subjects exposed to rifampicin twice daily together with ritonavir boosted saquinavir developed significant hepatocellular toxicity and this combination cannot be recommended. (alert letter Roche Pharmaceuticals Ltd, February 2005). Although there is CDC guidance on the use of PI with rifamycins, it is based on the limited available data, 47

We recommend that until more data are available low dose ritonavir/PI combinations should not be given with rifampicin-based regimens. In these cases rifampicin should be substituted for rifabutin, or the protease inhibitor and ritonavir switched to an alternative antiretroviral if alternatives exist  (see below).

 

5.2.2   Rifabutin

Rifabutincan be used with single (unboosted) PI except saquinavir. However, because of the balance between rifabutin induction and protease inhibition of CYP3A4, when this combination is used a modification in the dose of the PI may be required (see table 2) and the dose of rifabutin should be decreased by half to 150mg. If PI are used with 100mg ritonavir boosting then the dose of rifabutin should be reduced to 150mg and should only be given three times a week.

Complex interactions may occur whena rifamycin is given with salvage regimens such as two PI plus boosted ritonavir, or with a boosted or non-boosted PI and a NNRTI. These combinations are used in patients who have had virological failure or intolerance to simpler regimens.These multiple interactions have yet to be fully studied and there are no clear guidelines regarding dosing of rifabutin when given in this situation. Here TDM should be used

 

5.3       Rifamycins and NNRTI

The NNRTI nevirapine is both partially metabolized by CYP 3A4 and also induces this enzyme system.  The other commonly used NNRTI efavirenz behaves in a similar way.  Because of this inducing effect the clinical use of these drugs together with the rifamycins is complex.

 

5.3.1   Rifampicin

When Rifampicin is used with efavirenz-based regimens for patients >50kg an increase in the dose of efavirenz to 800mg/day is required.  Standard doses of efavirenz are used if the patient weighs <50Kg.48-50[AII]

Rifampicin reduces the AUC and Cmax of nevirapine in HIV-infected patients by 31% and 36% respectively; Although no major impact on clinical and virological responses have been reported data suggest that rifampicin (two times a week) may be given with nevirapine-based regimens. 51-54

These observations, have led some guideline committees to suggest that nevirapine may be co-administered with rifampicin in standard doses during the treatment of co-infection. However the numbers of patients studied are small and follow up is limited.

We recommend that daily rifampicin should not be used with nevirapine. [AIII]

 

5.3.2   Rifabutin

If rifabutin is used with efavirenz the rifabutin dose should be increased to 450mg/day because of the induction effect of efavirenz. Rifabutin and nevirapine have been given together with no adjustment in either of their dosages. More data are needed before this strategy can be recommended.

 

 

5.4 Isoniazid

Pharmacokinetic or clinical interactions between isoniazid and antiretroviral agents have not been extensively studied. In-vitro studies have shown that isoniazid, at clinically relevant concentrations, is a reversible inhibitor of CYP3A4 and CYP2C19, and that it mechanistically inactivates CYP1A2, CYP2A6, CYP2C19 AND CYP3A4 in human liver microsomes. Isoniazid, co-administered with drugs such as PI and NNRTI, which are metabolized by these isoforms, may result in significant drug-drug interactions.

These interactions might be significant when isoniazid is given alone to treat latent TB infection in an HIV co-infected patient who is receiving PI or NNRTI. The pharmacokinetic and clinical consequences of concurrent therapy with rifampicin (inducer) and isoniazid (inhibitor) together with PI and NNRTI on CYP3A4 have not been studied but may be clinically important. 55,56

 

5.5       Non-rifamycin regimens

HIV related tuberculosis may be treated with non-rifamycin containing regimens. These should be only contemplated inpatients with serious toxicity to rifamycins, where desensitization/reintroduction has failed, or in those with rifamycin-resistantisolates. 

Drug/druginteractions might be fewer but a non-rifamycinregimen is inferior to a rifampicin-based regimen for the treatmentof HIV-related tuberculosis. 

It should be noted that high TB relapserates, greater than 15%, have been seen when an initial 2 months rifampicin-containing regimen is then switched in the continuation phase to isoniazid and ethambutol

5.2 Rifamycins and protease inhibitors

5.2.1 Rifampicin

Rifampicin causes a 75 to 95% reduction inserum concentrations of PI other than ritonavir. Suchreductions lead to loss of antiretroviral activity of PI-containing regimens and consequently can result in the emergence of resistance to one or more of the other drugs in the HAART regimen.

Currently, most patients are given combinations of PI, which includes low dose ritonavir [usually 100mg per dose] in order to take advantage of its enzyme inhibiting properties. In effect ritonavir boosts the concentrations of the other PI allowing easier and more tolerable dosing.  Data from the drug/drug interaction of rifampicin with lopinavir/ritonavir suggest that ritonavir at this low dose may compensate for the induction effect of rifampicin on lopinavir metabolism. 44,45

Preliminary data suggested that ritonavir 100mg twice daily may be used with daily rifampicin. Once daily saquinavir/ritonavir has also been used. 46  However recent studies of subjects exposed to rifampicin twice daily together with ritonavir boosted saquinavir developed significant hepatocellular toxicity and this combination cannot be recommended. (alert letter Roche Pharmaceuticals Ltd, February 2005). Although there is CDC guidance on the use of PI with rifamycins, it is based on the limited available data, 47

We recommend that until more data are available low dose ritonavir/PI combinations should not be given with rifampicin-based regimens. In these cases rifampicin should be substituted for rifabutin, or the protease inhibitor and ritonavir switched to an alternative antiretroviral if alternatives exist  (see below).

5.2.2 Rifabutin

Rifabutincan be used with single (unboosted) PI except saquinavir. However, because of the balance between rifabutin induction and protease inhibition of CYP3A4, when this combination is used a modification in the dose of the PI may be required (see table 2) and the dose of rifabutin should be decreased by half to 150mg. If PI are used with 100mg ritonavir boosting then the dose of rifabutin should be reduced to 150mg and should only be given three times a week.

Complex interactions may occur whena rifamycin is given with salvage regimens such as two PI plus boosted ritonavir, or with a boosted or non-boosted PI and a NNRTI. These combinations are used in patients who have had virological failure or intolerance to simpler regimens.These multiple interactions have yet to be fully studied and there are no clear guidelines regarding dosing of rifabutin when given in this situation. Here TDM should be used

5.2.1 Rifampicin

Rifampicin causes a 75 to 95% reduction inserum concentrations of PI other than ritonavir. Suchreductions lead to loss of antiretroviral activity of PI-containing regimens and consequently can result in the emergence of resistance to one or more of the other drugs in the HAART regimen.

Currently, most patients are given combinations of PI, which includes low dose ritonavir [usually 100mg per dose] in order to take advantage of its enzyme inhibiting properties. In effect ritonavir boosts the concentrations of the other PI allowing easier and more tolerable dosing.  Data from the drug/drug interaction of rifampicin with lopinavir/ritonavir suggest that ritonavir at this low dose may compensate for the induction effect of rifampicin on lopinavir metabolism. 44,45

Preliminary data suggested that ritonavir 100mg twice daily may be used with daily rifampicin. Once daily saquinavir/ritonavir has also been used. 46  However recent studies of subjects exposed to rifampicin twice daily together with ritonavir boosted saquinavir developed significant hepatocellular toxicity and this combination cannot be recommended. (alert letter Roche Pharmaceuticals Ltd, February 2005). Although there is CDC guidance on the use of PI with rifamycins, it is based on the limited available data, 47

We recommend that until more data are available low dose ritonavir/PI combinations should not be given with rifampicin-based regimens. In these cases rifampicin should be substituted for rifabutin, or the protease inhibitor and ritonavir switched to an alternative antiretroviral if alternatives exist  (see below).

5.2.2 Rifabutin

Rifabutincan be used with single (unboosted) PI except saquinavir. However, because of the balance between rifabutin induction and protease inhibition of CYP3A4, when this combination is used a modification in the dose of the PI may be required (see table 2) and the dose of rifabutin should be decreased by half to 150mg. If PI are used with 100mg ritonavir boosting then the dose of rifabutin should be reduced to 150mg and should only be given three times a week.

Complex interactions may occur whena rifamycin is given with salvage regimens such as two PI plus boosted ritonavir, or with a boosted or non-boosted PI and a NNRTI. These combinations are used in patients who have had virological failure or intolerance to simpler regimens.These multiple interactions have yet to be fully studied and there are no clear guidelines regarding dosing of rifabutin when given in this situation. Here TDM should be used

5.3 Rifamycins and NNRTI

The NNRTI nevirapine is both partially metabolized by CYP 3A4 and also induces this enzyme system.  The other commonly used NNRTI efavirenz behaves in a similar way.  Because of this inducing effect the clinical use of these drugs together with the rifamycins is complex.

5.3.1 Rifampicin

When Rifampicin is used with efavirenz-based regimens for patients >50kg an increase in the dose of efavirenz to 800mg/day is required.  Standard doses of efavirenz are used if the patient weighs <50Kg.48-50[AII]

Rifampicin reduces the AUC and Cmax of nevirapine in HIV-infected patients by 31% and 36% respectively; Although no major impact on clinical and virological responses have been reported data suggest that rifampicin (two times a week) may be given with nevirapine-based regimens. 51-54

These observations, have led some guideline committees to suggest that nevirapine may be co-administered with rifampicin in standard doses during the treatment of co-infection. However the numbers of patients studied are small and follow up is limited.

We recommend that daily rifampicin should not be used with nevirapine. [AIII]

5.3.2 Rifabutin

If rifabutin is used with efavirenz the rifabutin dose should be increased to 450mg/day because of the induction effect of efavirenz. Rifabutin and nevirapine have been given together with no adjustment in either of their dosages. More data are needed before this strategy can be recommended.

5.3.1 Rifampicin

When Rifampicin is used with efavirenz-based regimens for patients >50kg an increase in the dose of efavirenz to 800mg/day is required.  Standard doses of efavirenz are used if the patient weighs <50Kg.48-50[AII]

Rifampicin reduces the AUC and Cmax of nevirapine in HIV-infected patients by 31% and 36% respectively; Although no major impact on clinical and virological responses have been reported data suggest that rifampicin (two times a week) may be given with nevirapine-based regimens. 51-54

These observations, have led some guideline committees to suggest that nevirapine may be co-administered with rifampicin in standard doses during the treatment of co-infection. However the numbers of patients studied are small and follow up is limited.

We recommend that daily rifampicin should not be used with nevirapine. [AIII]

5.3.2 Rifabutin

If rifabutin is used with efavirenz the rifabutin dose should be increased to 450mg/day because of the induction effect of efavirenz. Rifabutin and nevirapine have been given together with no adjustment in either of their dosages. More data are needed before this strategy can be recommended.

5.4 Isoniazid

Pharmacokinetic or clinical interactions between isoniazid and antiretroviral agents have not been extensively studied. In-vitro studies have shown that isoniazid, at clinically relevant concentrations, is a reversible inhibitor of CYP3A4 and CYP2C19, and that it mechanistically inactivates CYP1A2, CYP2A6, CYP2C19 AND CYP3A4 in human liver microsomes. Isoniazid, co-administered with drugs such as PI and NNRTI, which are metabolized by these isoforms, may result in significant drug-drug interactions.

These interactions might be significant when isoniazid is given alone to treat latent TB infection in an HIV co-infected patient who is receiving PI or NNRTI. The pharmacokinetic and clinical consequences of concurrent therapy with rifampicin (inducer) and isoniazid (inhibitor) together with PI and NNRTI on CYP3A4 have not been studied but may be clinically important. 55,56

5.5 Non-rifamycin regimens

HIV related tuberculosis may be treated with non-rifamycin containing regimens. These should be only contemplated inpatients with serious toxicity to rifamycins, where desensitization/reintroduction has failed, or in those with rifamycin-resistantisolates. 

Drug/druginteractions might be fewer but a non-rifamycinregimen is inferior to a rifampicin-based regimen for the treatmentof HIV-related tuberculosis. 

It should be noted that high TB relapserates, greater than 15%, have been seen when an initial 2 months rifampicin-containing regimen is then switched in the continuation phase to isoniazid and ethambutol