Drug‐Drug Interactions in Inmates Treated for Human Immunodeficiency Virus andMycobacterium tuberculosisInfection or Disease: An Institutional Tuberculosis Outbreak

Abstract

The use of rifamycins is limited by drug interactions in human immunodeficiency virus (HIV)-infected persons who are receiving highly active antiretroviral therapy (HAART). During a tuberculosis (TB) outbreak at a prison housing HIV-infected inmates, rifabutin was used to treat 238 men (13 case patients and 225 contacts). Steady-state peak plasma rifabutin concentrations were obtained after rifabutin dosages were adjusted for men receiving single-interacting HAART (with either 1 protease inhibitor [PI] or efavirenz), multi-interacting HAART (with either 2 PIs or > or =1 PI with efavirenz), and for noninteracting HAART (>1 nucleoside reverse-transcriptase inhibitor or no HAART) without rifabutin dose adjustments. Low rifabutin concentrations occurred in 9% of those receiving noninteracting HAART, compared with 19% of those receiving single-interacting and 29% of those receiving multi-interacting HAART (chi2, 3.76; P=.05). Of 225 contacts treated with rifabutin-pyrazinamide, 158 (70%) completed treatment while incarcerated. Rifabutin-pyrazinamide therapy was difficult to implement, because of the need for dosage adjustments and expert clinical management.

Clinical Relevance of Drug Interactions in HIV-Infected Patients Receiving Antiretroviral Therapy

“…In general, for a patient using more than one drug with differential capacity to modify CYP3A4 and/or P-gp enzymatic activity (some induce while some others inhibit), it is difficult to predict the net effect on the levels and effects of a drug whose metabolism is affected. (Spradling et al, 2002) Therefore, it is necessary, from a theoretical perspective, to avoid the use of such schemes, which is difficult in patients with HIV/AIDS. In this context, some studies conducted to establish the influence of several antiretroviral drugs on CYP3A activity show that ritonavir/nelfinavir inhibitory effect is maintained and it counteracts efavirenz/nevirapine inducing effect, when they are administered in combination.…”

“…(Blumberg et al, 2003;Finch et al, 2002;Sekar et al, 2010;Spradling et al, 2002) In general, the use of rifampicin (rifabutin is preferred due to their lesser inductive effect than rifabutin) with a single PI, including the most recent, such as amprenavir and atazanavir, is considered contraindicated (level 1: very high risk), because in most cases, rifampicin produces non-efficacy PIs concentrations. Besides, most treatment guidelines for HIV/AIDS patients extend this contraindication even to PIs combined with ritonavir used as a pharmacokinetic extension agent (enhancer).…”

“…(Kashuba, 2005) Combined administration of antacids does not seem to significantly affect the amount absorbed of fosamprenavir, (Ford et al, 2005) or raltegravir; however it is recommended to separate the taking of the two drugs when they are used in pharmacological therapy. (Kiser et al, 2010) Aaron et al, 2004;Benator et al, 2007;Blumberg et al, 2003;DeJong et al 2004;Finch et al, 2002;Hamzeh et al, 2003;Kraft et al, 2004;La Porte et al, 2004;Polk et al, 2001;Ribera et al, 2007;Rolla et al, 2006;Spradling et al, 2002) Ritonavir (Aaron et al, 2004;Blumberg et al, 2003;DeJong et al 2004;Finch et al, 2002;Spradling et al, 2002) 1: very high risk 2: high risk Adjust rifabutin dose 150 mg/48 hours, with no change in ritonavir Indinavir (Hamzeh et al, 2003, Kraft et al, 2004 1: very high risk 2: high risk Adjust the dose of rifabutin 150 mg/24 hours and indinavir at 1,000 mg/8 hours Saquinavir (Aaron et al, 2004;Blumberg et al, 2003;DeJong et al 2004;Finch et al, 2002;Ribera et al, 2007;Rolla et al, 2006;Spradling et al, 2002) 1: very high risk 2: high risk Use usual dose of rifabutin (300 mg/day), with no change in saquinavir Nelfinavir (Aaron et al, 2004;Benator et al, 2007;Blumberg et al, 2003;DeJong et al 2004;…”

“…This combination is considered absolutely contraindicated McCance-Katz et al, 2006;Matteelli et al, 2007a;Ramachandran et al, 2006;Ribera et al, 2001) Delavirdine (Borin et al, 1997;DeJong et al 2004;McCance-Katz et al, 2006;Spradling et al, 2002) Nevirapine (Benator et al, 2007;Blumberg et al, 2003;Borin et al, 1997;Burger et al, 2006;Hamzeh et al, 2003;Kraft et al, 2004;La Porte et al, 2004;Polk et al, 2001;Ramachandran et al, 2006;Ribera et al, 2001Ribera et al, , 2007Rolla et al, 2006) 2: high risk 3: medium risk…”

Updated guidelines for the use of rifamycins for the treatment of tuberculosis in HIV-infected patients taking protease inhibitors or non-nucleoside reverse transcriptase inhibitors

“…One observational study found that the use of rifabutin with such complex ARV regimens was associated with low serum concentrations of rifabutin, particularly when the rifabutin dose was reduced to 150 mg twice weekly for use with ritonavir-containing regimens. 21 The NRTIs, which include zidovudine, didanosine, zalcitabine, stavudine, lamivudine, abacavir and emtricitabine, are not metabolised by CYP3A4, so NRTIs and rifampicins may be co-administered without dose adjustments. However, ARV therapy consisting exclusively of NRTIs appears to have reduced potency compared with regimens that contain either a PI or an NNRTI, and current guidelines recommend NRTI-based regimens only if PIbased or NNRTI-based regimens cannot be used.…”