Managing Drug Interactions in the Treatment of HIV-Related Tuberculosis
Limitations in antiretroviral agents that can be used during pregnancy
A number of issues complicate the treatment of the HIV-infected pregnant woman on antiretrovirals who has active tuberculosis. Most importantly, the choice of antiretroviral drugs among pregnant women is limited. Efavirenz is not generally recommended during the first trimester of pregnancy because of concerns about potential teratogenicity, although recent data do not suggest any elevation in this risk. 95, 96, 97 Furthermore, pregnant women have an increased risk of severe toxicity from didanosine and stavudine and, therefore, this dual NRTI combination is not recommended.98 Women with CD4 cell counts > 250 cells/mm3 at the time that antiretroviral therapy is initiated have an increased risk of nevirapine-related hepatotoxicity. Consequently, initiation of NVP among women with CD4 cell counts > 250 cells/mm3 is not recommended in the United States, while World Health Organization guidelines allow for its use in women with CD4 counts up to 350 cells/mm3.1,36,99
Because of concerns about potential fetal bone effects based on non-human primate data, tenofovir is considered an alternative rather than a preferred antiretroviral drug during pregnancy (unless chronic hepatitis B virus infection is also present).100 The pharmacokinetics and safety of etravirine and maraviroc among pregnant women have yet to be established. In a small study of HIV-infected pregnant women, raltegravir appeared to be safe, and drug concentrations during the third trimester among trial participants were similar to their postpartum concentrations.101
The Department of Health and Human Services Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission provides detailed recommendations regarding use of antiretroviral drugs in HIV-infected pregnant women (available at http://AIDSInfo.nih.gov).100 Antiretroviral drugs that are preferred in pregnancy include zidovudine, lamivudine, nevirapine, and ritonavir-boosted lopinavir. Alternative NRTIs include abacavir, didanosine, emtricitabine, stavudine, and tenofovir; alternative protease inhibitors include ritonavir-boosted atazanavir or saquinavir. Use of efavirenz after the first trimester can be considered in special circumstances, such as if an HIV-infected pregnant woman requires tuberculosis therapy with rifampin and nevirapine is not tolerated. If efavirenz is continued postpartum, adequate contraception must be assured.
The Effect of Pregnancy on the Pharmacokinetics of Antiretroviral Drugs
Pregnancy alters the pharmacokinetics of a number of drugs, including antiretrovirals.102 For nevirapine, the data are mixed, with some studies showing decreased concentrations in pregnant women and others showing similar pharmacokinetics in pregnant and nonpregnant women. 103, 104, 105, 106
Small sample sizes and highly variable intra-patient plasma concentrations complicate interpretation of these comparative pharmacokinetic studies. 107 Pharmacokinetic and efficacy data for efavirenz in pregnancy are limited, but a study of 25 women receiving efavirenz during the third trimester and postpartum found standard dosing to be adequate. 108 The concentrations of ritonavir-boosted lopinavir are decreased during the latter stages of pregnancy, and some recommend increasing the dose to 600 mg lopinavir/150 mg ritonavir twice daily during the third trimester of pregnancy, while others think standard-dose lopinavir/ritonavir with appropriate monitoring is sufficient. 109, 110, 111, 112, 113 Once-daily lopinavir-ritonavir is not recommended in pregnancy because there are no data to address adequacy of drug levels.
Treatment of HIV-related Tuberculosis Among Pregnant Women
There are no published data on the combined effects of pregnancy and rifampin on antiretroviral drug concentrations and HIV treatment efficacy. With limited 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. There is clearly an urgent need for research in this arena.
For women with a CD4 count less than 250 cells/mm3 receiving rifampin-based tuberculosis treatment, nevirapine-based HIV treatment could be used, but the optimal dose is not known. 114 Pregnant women already receiving nevirapine-based regimens can continue nevirapine regardless of CD4+ cell count, as toxicity appears limited to those first initiating nevirapine-based therapy. Efavirenz-based therapy may be an option after the first trimester of pregnancy. The quadruple nucleoside/nucleotide regimen (zidovudine, lamivudine, abacavir, and tenofovir) is an alternative, especially for women with high CD4+ lymphocyte counts who are receiving antiretroviral drugs for prevention of perinatal transmission rather than for maternal health indications, though additional experience during pregnancy is needed. Rifabutin is classified as pregnancy class B by the United States Food and Drug Administration, 115 and lopinavir/ritonavir with rifabutin is also a reasonable option. Pregnant women receiving both antiretroviral and anti-tuberculosis drugs should have HIV RNA levels monitored more frequently, and if virologic response is less than expected, therapeutic drug monitoring or a change in regimen should be considered.