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U.S. Department of Health and Human Services

  

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.

 


Released October 2008
Centers for Disease Control and Prevention
National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention
Division of Tuberculosis Elimination - http://www.cdc.gov/tb

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