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Managing Drug Interactions in the
Treatment of HIV-Related
Tuberculosis
Rifampin and Antiretroviral
Therapy
The most important drug-drug interactions in the treatment
of HIV-related tuberculosis are those between rifampin and the NNRTIs, efavirenz
and nevirapine. Rifampin is the only rifamycin available in most of the world,
and initial antiretroviral regimens in areas with high rates of tuberculosis
consist of efavirenz or nevirapine (in combination with nucleoside analogues).
Furthermore, because of its potency and durability on randomized clinical trials,
efavirenz-based therapy is a preferred option for initial antiretroviral therapy
in developed countries.
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Rifampin and Efavirenz
Rifampin causes a measurable, though modest, decrease
in efavirenz concentrations 11, 12 (Table 2). Increasing the dose
of efavirenz from 600 mg daily to 800 mg daily compensates for the effect of
rifampin 11, 12, but it does not appear that this dose increase is
necessary to achieve excellent virological outcomes of therapy 12.
Trough concentrations of efavirenz, the best predictor of its virological activity,
remain well above the concentration necessary to suppress HIV in vitro
among patients on concomitant rifampin 13. A testament to the potency
of efavirenz against HIV is that the standard dose of efavirenz results in very
high rates of complete viral suppression despite 10-fold interpatient differences
in trough concentrations. Therefore, it is unlikely that the 20% decrease in
serum concentrations resulting from rifampin will have a clinically-significant
effect on antiretroviral activity. In several cohort studies, antiretroviral
therapy of standard-dose efavirenz + 2 nucleosides was well-tolerated and highly
efficacious in achieving complete viral suppression among patients receiving
concomitant rifampin-based tuberculosis treatment 14, 15. Furthermore,
there was no apparent benefit from a higher dose of efavirenz (800 mg daily)
in one randomized trial 12, and a small observational study documented
high serum concentrations and neurotoxicity among 7 of 9 patients receiving
the 800 mg dose with rifampin 16. Therefore, this combination –
efavirenz-based antiretroviral therapy and rifampin-based tuberculosis treatment,
at their standard doses – is the preferred treatment for HIV-related tuberculosis
(Table 1). Some experts recommend the 800 mg dose of efavirenz for patients
weighing > 60 kg.
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Alternatives to Efavirenz-Based
Antiretroviral
Therapy
Alternatives to efavirenz-based antiretroviral therapy
are needed for patients with HIV-related tuberculosis: efavirenz cannot be used
during pregnancy (at least during the first trimester), some patients are intolerant
to efavirenz, and some are infected with NNRTI-resistant strains of HIV.
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Rifampin and Nevirapine
Rifampin decreases serum concentrations of nevirapine
by 20-55% 17, 18 (Table 1). The common toxicities of nevirapine
– skin rash and hepatitis – overlap common toxicities of some first-line antituberculosis
drugs. Furthermore, nevirapine-based regimens are not recommended for patients
with higher CD4 cell counts (> 350 cells/mm3 for men, > 250
cells/mm3 for women) because of increased risk of severe hypersensitivity
reactions. Therefore, there are concerns about the efficacy and safety of using
nevirapine-based antiretroviral therapy during rifampin-based tuberculosis treatment.
At present, there have been no studies comparing efavirenz vs. nevirapine-based
antiretroviral therapy among patients being treated for tuberculosis. Trough
serum concentrations of nevirapine among patients on concomitant rifampin often
exceed the concentration necessary to suppress HIV in vitro 17, 19. Several cohort studies have shown high rates of viral suppression
among patients receiving nevirapine-based antiretroviral therapy 17, 20.
The risk of hepatitis among such patients was also comparable to patients receiving
first-line tuberculosis treatment without antiretroviral therapy 20.
Despite the interaction with rifampin, nevirapine-based antiretroviral therapy
appears to be reasonably effective and well-tolerated among patients being treated
for tuberculosis.
These studies are neither adequately powered nor reported
in sufficient detail to fully answer the concerns about the efficacy and safety
of nevirapine-based antiretroviral therapy during tuberculosis treatment. However,
the collected experience is sufficient to make nevirapine an alternative for
patients unable to take efavirenz and who do not have access to rifabutin.
Some investigators have suggested using an increased dose of nevirapine among
patients on rifampin 18. However, a recent randomized trial comparing
standard dose nevirapine (200 mg twice-daily) to a higher dose (300 mg twice
daily) among patients on rifampin demonstrated an increased risk of nevirapine
hypersensitivity among patients randomized to the higher dose of nevirapine
21. Therefore, the standard dose of nevirapine should be used among
patients on rifampin (200 mg daily for 2 weeks, followed by 200 mg twice-daily).
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Other Antiretroviral
Regimens for Use
With Rifampin
For patients who are infected with NNRTI-resistant
HIV, neither efavirenz nor nevirapine will be effective. Unfortunately, there
is little clinical experience with alternatives to NNRTI-based therapy among
patients being treated with rifampin. Standard doses of protease inhibitors
cannot be given with rifampin (Table 1); the > 90% decreases in trough concentrations
of the protease inhibitors would surely make them ineffective 22-24.
Most protease inhibitors are given with low-dose ritonavir (100-200 mg per dose
of the other protease inhibitor). However, low-dose ritonavir does not overcome
the effects of rifampin; serum concentrations of indinavir, lopinavir, and atazanavir
were decreased by > 90% when given with the standard ritonavir boosting dose
(100 mg) in the presence of rifampin 23-25, and a once-daily regimen
of ritonavir-boosted saquinavir (saquinavir 1600 mg + ritonavir 200 mg) resulted
in inadequate concentrations of saquinavir 26, 27. Therefore, standard
protease inhibitor regimens, whether boosted or not, cannot be given with rifampin.
The dramatic effects of rifampin on serum concentrations
of other protease-inhibitors can be overcome with high-doses of ritonavir (400
mg twice-daily, “super-boosted protease inhibitors”) or by doubling the dose
of the co-formulated form of lopinavir/ritonavir 23. However, high
rates of hepatoxicity occurred among healthy volunteers treated with rifampin
and ritonavir-boosted saquinavir (saquinavir 1000 mg + ritonavir 100 mg twice-daily
28) and those treated with rifampin and lopinavir/ritonavir (either
as lopinavir 400 mg + 400 mg ritonavir twice-daily or as lopinavir 800 mg +
ritonavir 200 mg twice-daily) 23, 29.
Whether patients with HIV-related tuberculosis will
have the same high rates of hepatotoxicity when treated with super-boosted protease
inhibitors or double-dose lopinavir/ritonavir has not been adequately studied.
Among patients receiving rifampin-based tuberculosis treatment, the combination
of ritonavir-boosted saquinavir (400 mg of each, twice daily) was not well-tolerated
30. The initial positive experience with super-boosted lopinavir
among young children (see below) suggests that these regimens may be tolerable
and effective among at least some patients with HIV-related tuberculosis. However,
these regimens should only be used with close clinical and laboratory monitoring
for possible hepatoxicity, when there is a pressing need to start antiretroviral
therapy.
Regimens composed entirely of nucleoside analogues
are less active than combinations of two classes of antiretroviral drugs (e.g.,
NNRTI + nucleosides) 31. A regimen of zidovudine, lamivudine, and
the nucleotide agent, tenofovir, has been reported to be active among patients
on rifampin-based tuberculosis treatment 32. However, this regimen
has not been compared to standard initial antiretroviral therapy (e.g., efavirenz
+ 2 nucleosides). Finally, a quadruple regimen of zidovudine, lamivudine, abacavir,
and tenofovir has been reported to be as active as an efavirenz-based regimen
in an initial small trial 33. While these regimens of nucleosides
and nucleotides cannot be recommended as preferred therapy among patients receiving
rifampin, their lack of predicted clinically-significant interactions with rifampin
make them an acceptable alternative, for patients unable to take NNRTIs or those
with NNRTI-resistant HIV 32, 34.
Rifampin has substantial interactions with the recently-approved
CCR5-receptor antagonist, maraviroc 35. An increased dose of maraviroc
has been recommended to allow concomitant use of rifampin and maraviroc, but
there is no reported clinical experience with this combination. Rifampin decreases
the trough concentrations of raltegravir, the recently-approved integrase inhibitor,
by ~ 60% 36. Because the antiviral activity of raltegravir 200
mg twice daily was very similar to the activity of the licensed dose (400 mg
twice-daily), the current recommendation is to use the standard dose of raltegravir
in a patient receiving concomitant rifampin. However, this combination should
be used with caution – there is very little clinical experience with using concomitant
raltegravir and rifampin. Finally, rifampin is predicted to substantially decrease
the concentrations of etravirine (a second-generation NNRTI 37 currently
available through an expanded access program). Additional drug-interaction studies
will be needed to further evaluate whether these new agents can be used among
patients receiving rifampin-based tuberculosis treatment.
Last Reviewed: 05/18/2008 Content Source: Division of Tuberculosis Elimination
National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention
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