Managing Drug Interactions in the Treatment of HIV-Related Tuberculosis

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Recommendations

Treating Children with HIV-associated Tuberculosis

Special Challenges Related to Treating Children with HIV and Tuberculosis

HIV-infected children in high-burden countries have very high rates of tuberculosis, often with severe, life-threatening manifestations (e.g., extensive pulmonary disease, 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 HIV. In addition to the complexities raised by the drug interactions discussed above, treatment of pediatric HIV-related tuberculosis has additional challenges. There are limited data on the absorption, metabolism, and elimination of anti-tuberculosis drugs in children, particularly in very young children (< 2 years of age). The World Health Organization has recently compiled pharmacokinetic and efficacy data for children and updated their treatment guidelines for pediatric tuberculosis. ¹¹⁶ The new guidelines suggest that higher doses of first-line tuberculosis drugs, including most notably isoniazid and rifampin, be used. Pediatric formulation and dosing guidelines for rifabutin are not available for children.

Some antiretroviral drugs are not available in liquid formulations (though increasingly, chewable and dissolvable tablets are becoming available for pediatric use), and there are limited pharmacokinetic data for many antiretroviral drugs among young children. NNRTI-based therapy is not recommended as preferred therapy for perinatally-infected infants under age 1 year, whether or not they were exposed to single-dose nevirapine as part of maternal-child HIV transmission prophylaxis, because of higher failure rates compared to those initiating ritonavir-boosted lopinavir-based therapy. ^{117, 118, 119, 120} This inability to use NNRTI-based antiretroviral therapy limits options for antiretroviral therapy among children less than 1 year of age receiving rifampin-based tuberculosis treatment. ^{(Tables 1band 2b)} More specifically, limited pharmacokinetic data in children younger than age 3 or who weigh less than 13 kg have shown that it is difficult to achieve target efavirenz trough concentrations in this age group, even with very high (>30 mg/kg) doses of an investigational liquid formulation. Thus, efavirenz is not recommended for use in children younger than age 3 years at this time.

Rifampin and protease inhibitors for children with HIV and tuberculosis

There are emerging pharmacokinetic data and clinical experiences with protease-inhibitor-based antiretroviral therapy among children with HIV-related tuberculosis. Ritonavir alone should not be used as the protease inhibitor component of antiretroviral therapy in children receiving tuberculosis therapy. ¹²¹ Ritonavir-boosted lopinavir, though, may be a reasonable option. Optimal dosing for ritonavir-boosted lopinavir in children with HIV-related tuberculosis is being explored. In one study, children treated with super-boosted lopinavir (ritonavir in addition to doses of co-formulated lopinavir/ritonavir to achieve mg to mg parity of ritonavir and lopinavir) while on rifampin-based tuberculosis treatment achieved serum concentrations of lopinavir comparable to those of children treated with standard dose lopinavir/ritonavir in the absence of rifampin. ¹²² In a separate study of 15 South African children, while oral clearance was higher among children on tuberculosis treatment receiving super-boosted lopinavir than among children receiving standard pediatric ritonavir-boosted lopinavir doses who were not taking tuberculosis treatment, trough concentrations were therapeutic in all children. ¹²³ Retrospective studies suggest that virologic response among children receiving super-boosted lopinavir and rifampin appears to be similar to that of children receiving standard-dose lopinavir/ritonavir without tuberculosis treatment. However, response to double-dose lopinavir plus rifampin appears to be inferior. ^{124 125} The preferred antiretroviral regimen among children on rifampin-based tuberculosis treatment is super-boosted lopinavir plus appropriate NRTI drugs.Additional prospective studies are needed to evaluate whether or not the higher doses of rifampin now recommended for children will affect the activity of super-boosted lopinavir. Additional research will also be needed to determine whether or not double-dose lopinavir/ritonavir will be as efficacious among children receiving rifampin-containing tuberculosis treatment as super-boosted lopinavir.

Rifampin and NNRTIs for Children with HIV and Tuberculosis

Efavirenz and rifampin for children
In a small pharmacokinetic study conducted among South African children with a median age of 6 years, efavirenz concentrations were commonly subtherapeutic with standard weight-based dosing of efavirenz, whether or not they were taking rifampin. ¹²⁶ However, among children age >3 years participating in a retrospective cohort study in South Africa, those receiving efavirenz-based antiretroviral therapy had high rates of viral suppression whether or not they were taking concomitant rifampin-containing tuberculosis therapy.¹²⁵

Although more data are needed, use of standard dose efavirenz-based antiretroviral therapy may be considered in children over age 3 years receiving concurrent rifampin-containing tuberculosis therapy when the recommended antiretroviral regimen with super-boosted lopinavir-ritonavir is not tolerated or contraindicated. ¹²⁷ Careful virologic monitoring to ensure that viral suppression is achieved is recommended. Therapeutic drug monitoring to evaluate efavirenz levels may be considered, if available. Additional studies are required to determine the appropriate dose of efavirenz in infants and young children. Furthermore, studies on efavirenz pharmacokinetics in older children receiving the higher dose of rifampin recommended by the World Health Organization are needed.

Nevirapine and rifampin for children
Data on the influence of concomitant rifampin on nevirapine levels in HIV-infected children are very limited. Substantial reductions in nevirapine concentrations were observed in a pharmacokinetic study in 21 Zambian HIV-infected children with tuberculosis treated with nevirapine, stavudine, and lamivudine antiretroviral therapy and receiving concurrent rifampin-based tuberculosis treatment.¹²⁸ No studies were found of increased nevirapine dosing in children receiving rifampin-containing tuberculosis therapy. Therefore, there are insufficient data to recommend use of nevirapine-based antiretroviral therapy in children receiving rifampin.

Rifampin and triple nucleos(t)ide regimens for children with HIV and tuberculosis

The triple nucleoside regimen of zidovudine, lamivudine, and abacavir has been suggested for young children who are taking rifampin-based tuberculosis treatment.¹²⁹ However, there is limited published clinical experience with this regimen among young children with HIV, with or without concomitant tuberculosis. Furthermore, young children often have very high HIV RNA levels, raising the concern for increased risk of treatment failure with triple NRTI regimens. Until additional studies become available, and given the limited number of treatment options available for young children with HIV and tuberculosis, the triple-nucleoside regimen is recommended as an alternative for children <3 years receiving rifampin-based tuberculosis treatment.