Managing Drug Interactions in the Treatment
of HIV-Related Tuberculosis
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
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
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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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
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
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
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
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.