Clinical pharmacology and pharmacokinetics of antiretrovirals in Asia

Pharmacokinetics can be used to establish dose response relationships in terms of efficacy and toxicity. Nevertheless the majority of the registered dose in the treatment of HIV are based on data from Caucasian men. It is questionable however if the recommended doses are optimal for all ethnicities and in all circiumstances. Several studies suggest that a more population-based approach may benefit different ethnicities. Here we review the pharmacokinetics of commonly used non-nucleoside analog reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs) in the Asian setting, for both adults and children. Studies of nevirapine, efavirenz, saquinavir, lopinavir, ritonavir, indinavir and atazanavir have been reported mostly among Thai patients. The data strongly indicated that Thai and most likely Asians have on average a significantly higher exposure to both the drugs classes (NNRTIs and PIs) compared to the Caucasian. In patients with active tuberculosis who are taking rifampicin, the standard dose of either efavirenz or nevirapine was found to be sufficient and efficacious for Asians with average body weight of 60 kg. Lower dose studies of saquinavir, indinavir, lopinavir and atazanaivr have shown promising efficacy results, however most are small scale studies. In pregnancy, nevirapine seems an adequate option whereas efavirenz has no PK data during the third trimester. In conclusion, more likely Asians are significantly higher exposed to both NNRTIs and PIs compared to the Caucasians. Further studies on pharmacokinetics, TDM and larger scale clinical trials among Asian populations are warranted to identify suitable low doses of ARVs for mclusion in the clinical practice guidelines of this region.

Antiretroviral therapy for HIV-associated tuberculosis

Tuberculosis (TB) remains an important problem in HIV-infected patients worldwide. HIV-related immunosuppression modifies the clinical presentation of TB, resulting in atypical signs and symptoms, and an increasing number of smear-negative pulmonary and extrapulmonary TB cases. HIV-associated TB patients also have increased morbidity and mortality due to TB and other HIV related diseases. The appropriate management of HIV-associated TB remains extremely challenging due to diagnostic difficulties, adherence concerns, the overlapping side effect profiles of anti-TB and antiretrovirals (ARV), the complexity of drug-drug interactions secondary to potent induction of cytochrome P450 enzymes by rifampin, and the occurrence of the immune reconstitution inflammatory syndrome (IRIS) after initiation of ARV. Highly active antiretroviral therapy (HAART) improves the clinical outcome of both HIV and TB. However, the optimal time to start HAART remains unknown. HAART should be started early in 2-8 weeks in the context of severe immune suppression. Efavirenz-based HAART is preferred. However, HIV-associated TB patients who are unable to use non-nucleoside reverse transcriptase inhibitors (NNRTI) such as NNRTI resistant virus or NNRTI intolerance are of particular concern. Replacing rifampin with rifabutin, which does not significantly affect ARV concentrations, is recommended.