Research Article: Nevirapine-Based Antiretroviral Therapy Impacts Artesunate and Dihydroartemisinin Disposition in HIV-Infected Nigerian Adults

Date Published: March 5, 2012

Publisher: Hindawi Publishing Corporation

Author(s): Fatai A. Fehintola, Kimberly K. Scarsi, Qing Ma, Sunil Parikh, Gene D. Morse, Babafemi Taiwo, Ibrahim Tope Akinola, Isaac F. Adewole, Niklas Lindegardh, Aphiradee Phakderaj, Oladosu Ojengbede, Robert L. Murphy, Olusegun O. Akinyinka, Francesca T. Aweeka.


Background. Nevirapine- (NVP-) based antiretroviral therapy (ART) and artesunate-amodiaquine are frequently coprescribed in areas of HIV and malaria endemicity. We explored the impact of this practice on artesunate and dihydroartemisinin pharmacokinetics. Methods. We conducted a parallel-group pharmacokinetic comparison between HIV-infected patients receiving NVP-based ART (n = 10) and ART-naive controls (n = 11). Artesunate-amodiaquine 200/600 mg was given daily for three days. Measurement of drug concentrations occurred between 0 and 96 hours after the final dose. Pharmacokinetic parameters were determined using noncompartmental analysis. Results. Comparing the NVP group to controls, clearance of artesunate was reduced 50% (1950 versus 2995 L/h; P = 0.03), resulting in a 45% increase in the AUC0-96 (105 versus 69 ug∗hr/L; P = 0.02). The half-life of dihydroartemisinin was shorter in the NVP group (1.6 versuss 3.2 h; P = 0.004), but other dihydroartemisinin pharmacokinetic parameters were unchanged. A lower conversion of artesunate to dihydroartemisinin was observed in the NVP group (dihydroartemisinin: artesunate AUC0-96 = 5.6 versuss 8.5 in NVP and control groups, respectively, P = 0.008). Conclusion. Although NVP-containing ART impacted some pharmacokinetic parameters of artesunate and dihydroartemisinin, overall exposure was similar or better in the NVP group.

Partial Text

Malaria remains a disease of public health importance with an estimated 169–294 million cases in 2009, resulting in approximately 781,000 deaths [1]. Sub-Saharan Africa not only carries a high burden of the morbidity and mortality associated with malaria but also a disproportionate burden of HIV disease. An estimated 33.3 million people are living with HIV throughout the world, with more than 65% living in sub-Saharan Africa, contributing 72% of the global HIV/AIDS-related mortality in 2009 [2]. HIV and malaria comorbidity is common given the overlapping geographic areas affected by both diseases [3, 4]. The safe and effective treatment of these common coinfections is a public health priority.

Patient recruitment, care, and follow up took place at the University College Hospital, Ibadan, Nigeria. The University of Ibadan/University College Hospital Institutional Review Board approved this study, and all patients provided written, informed consent. Eligible subjects had confirmed HIV-1 infection, were over 18 years of age, and had adequate renal and hepatic function, defined as serum creatinine <1.5 mg/dL and alanine transaminase and aspartate transaminase <1.5 times the upper limit of normal, respectively. Subjects were recruited into two groups: (1) NVP group and (2) control group. Subjects in the NVP group were on the same ART, consisting of lamivudine (3TC) 150 mg, zidovudine (AZT) 300 mg, and NVP 200 mg taken twice a day for a minimum period of 8 weeks prior to study enrolment, while all patients in the control group were not yet receiving antiretroviral therapy. Pregnant women, patients with known intolerance to study drugs, and patients who used artemisinin derivatives or other drugs known to induce or inhibit the CYP enzyme system in the preceding four weeks were excluded from the study. All the participants were in a good state of health, with leukocyte, haemoglobin, and hematocrit values within normal limits, no gastrointestinal symptoms or other physical complaints as judged by their primary physician. Patients remained on their current ART (NVP group) or were ART-free (control group) for the duration of the study. To our knowledge, this study represents the first investigation of the disposition kinetics of artesunate and DHA in HIV-infected adults with and without NVP containing ART. Overall, despite a shorter T1/2 for both artesunate and DHA, we found an increase in overall exposure (AUC0–96) of artesunate in patients receiving NVP compared to those not on ART (105 versus 69 ug ∗ L/hr; respectively; P = 0.02) and no difference in the overall exposure to DHA. While the clinical relevance of these results remains unclear, it is noteworthy that the half-life of DHA was significantly shorter when given with NVP, and the conversion of artesunate to DHA was lower in the NVP group. It is possible that a negative impact of NVP on the disposition kinetics of artesunate and DHA may be detected in larger studies. This demands an observant approach to malaria therapy in individuals on NVP containing ART until further investigation into the impact of this interaction can be performed. In summary, in HIV-infected patients receiving NVP-containing ART, standard multidose therapy with artesunate-amodiaquine resulted in higher overall exposure to artesunate and similar overall exposure to DHA, compared to HIV-infected patients not yet receiving ART. However, the conversion of artesunate to DHA was impaired in patients receiving NVP, and the T1/2 of DHA was shorter, both raising potential concern for the overall impact of NVP on the efficacy of artesunate. The impact of NVP on the amodiaquine component of the antimalarial therapy will provide additional insight into the safety and efficacy of combining artesunate-amodiaquine and NVP.   Source: