Dosing, Safety and Pharmacokinetic Profile of Rifabutin in Children Receiving Concomitant Treatment With Kaletra

BACKGROUND AND RATIONALE The HIV and TB epidemics disproportionately affect sub-Saharan Africa, and have had a catastrophic impact in the region. The synergy between these pathogens has resulted in dramatic increases in TB incidence, with 58% of cases of adult TB in 2005 in South Africa being HIV-associated [1]. The impact of HIV co-infection on TB in children has not yet been well defined due to inadequate surveillance and diagnostic challenges of pediatric TB and HIV in resource poor settings. Studies have demonstrated that between 10 and 60% of children with TB in sub-Saharan Africa are co-infected with HIV [2-5]. The risk of diagnosing TB among HIV-infected children has been shown to be 8 times higher among HIV-infected children than among HIV-uninfected children [6]. The risk of TB among HIV-infected children is associated with the degree of immunodeficiency, with a 3-year risk of developing TB among immunocompromised children (CD4<15%) of 12,400/100,000, compared to 3,300/100,000 in less immunocompromised HIV-infected children [7]. TB in HIV infected children is not only a cause of morbidity, but is also a frequent cause of death among HIV-infected children [8].

Even though the treatment of HIV-associated TB is complicated by overlapping toxicities, high pill burden and the occurrence of immune reconstitution inflammatory syndrome (IRIS), experiences of concomitant TB and HIV treatment in children are positive, with HIV-infected children with active TB who start ART having similar outcomes to children who started on ART for a non-TB diagnosis [9].

Co-administration of TB and HIV medications is associated with clinically significant and highly complex drug-drug interactions. Protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs) are substrates for cytochrome P450 isozymes and P-glycoprotein. Rifampin (RIF), a key component of TB treatment regimens, is a potent inducer of hepatic and intestinal cytochrome P450 isozymes and P-glycoprotein [10]. Multiple studies have demonstrated decreased concentrations of PIs and NNRTIs when coadministered with rifampin [11]. The concentrations of Efavirenz (EFV), nevirapine (NVP) and LPV/RTV are decreased by as much as 22, 68 and 75%, respectively, when coadministered with RIF [12, 13]. While the interaction with EFV may not be clinically important or could be overcome by dose increase [12], investigations with LPV/RTV have not been able to provide full confidence that higher doses of LPV/RTV overcome induction of enzymes by RIF [14].

In resource-poor countries, most adults with HIV/TB co-infection receive a combination of EFV-based ART and RIF-based TB treatment. In children under 3 years of age, EFV is not recommended for antiretroviral treatment. The choice of ART regimen in TB/HIV co-infected children is further complicated by the limited options for pediatric drug formulations and/or dosing information. According to the World Health Organization guidelines, the first-line treatment recommendation for children with TB and HIV co-infection is a triple NRTI regimen consisting of d4T or AZT plus 3TC and ABC [15]. Alternatively, the standard first-line regimen of two NRTIs plus NVP can be used. Both of these regimens are suboptimal. The triple NRTI regimen has been shown to have suboptimal virologic potency [16], and the NVP-based regimen is problematic in children exposed to single dose NVP for prevention of PMTCT as many of these will have developed resistance [17].

In South Africa, the recommended regimen for children age < 3 years of age who receive concomitant treatment for TB is the combination of LPV/RTV with an NRTIs. A recent study demonstrated that this regimen also results in suboptimal doses of LPV/TRV when given concomitantly with RIF, and that even a double dose of LPV/RTV given concomitantly with RIF does not provide adequate LPV exposures [18] . Another study assessed super-boosted LPV as an alternative approach, using LPV/RTV with extra RTV to equal the dose of LPV but this study was stopped due to safety concerns [19].