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Managing Drug Interactions in the
Treatment of HIV-Related
Tuberculosis
Special Populations
Pregnant Women
A number of issues complicate the treatment of the
HIV-infected woman who is pregnant and has active tuberculosis. Efavirenz is
contraindicated during at least the first 1-2 trimesters. Furthermore, pregnant
women have an increased risk of severe toxicity from didanosine and stavudine
43, and women with CD4 cell counts > 250 cells/mm3
have an increased risk of nevirapine-related hepatitis 44. Therefore,
the choice of antiretroviral agents is limited among pregnant women.
Pregnancy alters the distribution and metabolism of
a number of drugs, including antiretroviral drugs 45 (there is very
little information on whether the metabolism of anti-tuberculosis drugs is altered
during pregnancy). Notably, the serum concentrations of protease-inhibitors
are decreased during the latter stages of pregnancy 46, 47. There
are no published data on drug-drug interactions between anti-tuberculosis and
antiretroviral drugs among pregnant women. However, it is likely that the effects
of rifampin on protease inhibitors are exacerbated during pregnancy.
In the absence of pharmacokinetic data and published
clinical experience it is difficult to formulate guidelines for the management
of drug-drug interactions during the treatment of HIV-related tuberculosis among
pregnant women. Nevirapine-based therapy could be used among women on rifampin-based
tuberculosis treatment, with the caveat that there be a good monitoring system
for symptoms and laboratory tests for hepatotoxicity. Efavirenz-based therapy
may be an option during the later stages of pregnancy. The quadruple nucleoside/nucleotide
regimen (zidovudine, lamivudine, abacavir, and tenofovir) is an alternative,
though additional experience is required, particularly during pregnancy. Finally,
despite their sub-optimal activity, triple nucleoside or nucleoside/nucleotide
regimens are an alternative during pregnancy. Where rifabutin is available,
the preferred option is protease-inhibitor-based antiretroviral therapy.
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Children
HIV-infected children in high-burden countries have
very high rates of tuberculosis, often with severe, life-threatening manifestations
(e.g., disseminated disease, meningitis). Such children may also have advanced
and rapidly-progressive HIV disease, so there are pressing reasons to assure
potent treatment for both tuberculosis and AIDS. In addition to the complexities
raised by the drug interactions discussed above, children with HIV-related tuberculosis
raise other challenges. There are very limited data on the absorption, metabolism,
and elimination of anti-tuberculosis drugs among children, particularly among
very young children (< 2 years of age).
Some antiretroviral agents are not yet available in
suspension formulations, and there are limited pharmacokinetic data for all
antiretroviral drugs among young children. The use of single-dose nevirapine
selects for NNRTI-resistant strains among those infants who are infected despite
perinatal prophylaxis, and such children have inferior outcomes if subsequently
treated with nevirapine-based combination antiretroviral therapy 48.
Therefore, there is understandable reluctance to use NNRTI-based therapy among
perinatally-infected infants who were exposed to single-dose nevirapine. As
above, the inability to use NNRTI-based antiretroviral therapy limits options
for antiretroviral therapy among children receiving rifampin-based tuberculosis
treatment.
There are emerging, though unpublished, pharmacokinetic
data and clinical experience with using protease-inhibitor-based antiretroviral
therapy among young children (< 5 years of age) with HIV-related tuberculosis.
Children treated with super-boosted lopinavir (ritonavir in addition to doses
of co-formulated lopinavir/ritonavir) while on rifampin-based tuberculosis treatment
had serum concentrations of lopinavir comparable to those of children treated
with standard dose lopinavir/ritonavir in the absence of rifampin 49.
Furthermore, a cohort study found similar virological and immunological outcomes
of antiretroviral therapy among children treated with super-boosted lopinavir
and rifampin-based tuberculosis treatment compared with children treated with
standard dose lopinavir/ritonavir 50. Therefore, super-boosted lopinavir
plus appropriate nucleoside agents is the preferred antiretroviral regimen among
children on rifampin-based tuberculosis treatment.
The triple nucleoside regimen of zidovudine, lamivudine,
and abacavir has been suggested for young children who are taking rifampin-based
tuberculosis treatment 51. However, there is limited published clinical
experience with this regimen among young children, with or without concomitant
tuberculosis. Furthermore, young children often have very high HIV RNA levels,
suggesting the need for highly-potent antiretroviral regimens. While awaiting
additional studies, the triple-nucleoside regimen is an alternative for young
children receiving rifampin-based tuberculosis treatment.
In an initial pharmacokinetic study, efavirenz concentrations
were not significantly different among children on rifampin, compared to children
without tuberculosis 49. However, efavirenz concentrations were
sub-optimal in both groups, raising concerns about the adequacy of current efavirenz
dosing recommendations among children 52. However, efavirenz-based
antiretroviral therapy is highly-active among older children 53, 54,
and can be used with rifampin-based tuberculosis treatment.
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Patients with Multidrug-Resistant
Tuberculosis
Outbreaks of multidrug-resistant tuberculosis among
HIV-infected patients have been documented since the 1980s. Recently, an outbreak
of highly-lethal multidrug-resistant tuberculosis was discovered in South Africa,
primarily involving HIV-infected patients 55. Prompt initiation
of antiretroviral therapy may be one way to decrease the alarmingly high death
rate among HIV-infected patients with multidrug-resistant tuberculosis.
Most of the drugs used to treat multidrug-resistant
tuberculosis (the “second-line drugs”: fluoroquinolone antibiotics, ethionamide,
cycloserine, kanamycin, amikacin, capreomycin, para-amino salicylate) were developed
and approved nearly 40 years ago, prior to the development of modern laboratory
techniques to determine pathways of drug metabolism. Furthermore, there are
no published studies of possible drug-drug interactions between second-line
antituberculosis drugs and antiretroviral drugs. Based on the existing, albeit
incomplete, knowledge of the metabolism of the second-line drugs, only ethionamide
has a significant possibility of an interaction with antiretroviral drugs 22
(ethionamide is thought to be metabolized by the CYP450 system, though it is
not known which of the CYP isozymes are responsible). Whether doses of ethionamide
and/or certain antiretroviral drugs should be modified during the co-treatment
of multidrug-resistant tuberculosis and HIV disease is completely unknown.
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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