Nevirapine Drug Levels in HIV Positive Patients Also Receiving Rifampicin for Tuberculosis
Condition: HIV Infections; Tuberculosis
MeSH terms: Tuberculosis
Study type: Interventional
Phase: Phase 4

Summary: 
      Triomune is the most commonly prescribed treatment for HIV infection in Uganda. Triomune is
      manufactured by a generic drug company and consists of three drugs combined in a single pill
      given twice daily (stavudine 30mg plus lamivudine 150mg plus nevirapine 200mg).

      It is known that the levels of nevirapine in a patient's blood are highest in the first two
      weeks of treatment. Therefore it is recommended that patients starting on nevirapine should
      undergo dose escalation i.e start on 200mg once daily for two weeks and then increase to full
      dose of 200mg twice daily in order to avoid nevirapine related rash. It is not possible to do
      dose escalation with a fixed dose combination pill like Triomune and for the two weeks of the
      dose escalation patients either can buy stavudine plus lamivudine plus nevirapine as separate
      pills or take Triomune in the morning and then take stavudine plus lamivudine as separate
      pills in the evening.

      Rifampicin is used to treat TB and lowers the levels of nevirapine in a patient's blood. This
      raises two questions in routine clinical practice for patients who are co-infected with HIV
      and TB (1) Do we need to put our patients to the trouble of dose escalation of nevirapine if
      they are already on rifampicin? and (2) If we dose escalate nevirapine in patients on
      rifampicin, are we putting them at risk of low drug levels and development of resistance? The
      aim of this study is to compare the plasma concentrations of nevirapine in HIV infected
      patients who are commencing antiretroviral therapy with and without a lead in dose of
      nevirapine and who are also receiving concomitant treatment with antituberculous therapy
      which includes rifampicin to assess whether dose escalation of nevirapine is appropriate in
      this patient population
    

Detailed description: 
      Many patients in Uganda are co-infected with HIV and TB and require simultaneous treatment
      for both diseases. There is a paucity of data on the complex pharmacokinetic interactions
      between antiretroviral and anti-TB drugs and the available data is not representative of the
      African setting, hence it is important that these complex drug interactions be characterized
      fully.

      Rifampicin is a potent inducer of several liver and intestinal enzymes responsible for drug
      metabolism including the cytochrome P450 (CYP450) system, and p-glycoprotein (PgP, a
      multi-drug resistant transport protein). The non-nucleoside reverse transcriptase inhibitors
      (NNRTIs) such as nevirapine are lipophilic drugs which undergo passive diffusion through the
      gastrointestinal lining. Once inside intestinal cells these drugs can be transported back to
      the luminal surface by PgP or oxidatively metabolised by CYP450 enzymes. Thus induction of
      CYP450 and PgP by rifampicin results in accelerated and more extensive presystemic metabolism
      of the NNRTI substrates resulting in decreased oral bioavailability. Available data suggests
      that rifampicin reduces the AUC of the NNRTI, nevirapine by 31% and the Cmin by 21% to 68%
      (Ribera 2001, Robinson 1998) respectively. While minor reductions in levels of the nucleoside
      reverse transcriptase inhibitor (NRTI), zidovudine have been reported (probably due to
      increased glucuronidation; (Burger 1993), it is generally agreed that the efficacy of the
      NRTIs is not affected by concomitant rifampicin use.

      Nevirapine, a dipyridodiazepinone, is an inducer of cytochrome P450 and also induces its own
      metabolism with a reduction in the elimination half life from 45 to 25 hours on repeat dosing
      (Havlir, Murphy). The recommended daily dosing regimen of nevirapine for adults is 200mg
      twice daily. This is preceded by a two week lead in dose of 200mg once daily because of the
      autoinduction of nevirapine hepatic metabolism. This dose escalation strategy reduced
      nevirapine related rash from 48% (in the absence of dose escalation) to 18 %.( Murphy). Dose
      escalation of nevirapine is complex in the resource limited setting where fixed dose
      combinations of generically manufactured drugs are commonly prescribed. It is unclear as to
      whether dose escalation of nevirapine is necessary in patients on rifampicin as they already
      have full induction of their cytochrome P450 system provided that they have been on
      rifampicin for a minimum of two weeks. Furthermore, there is concern that dose escalation of
      nevirapine in this group of patients may expose patients to sub-therapeutic levels of
      nevirapine with the attendant risk of development of drug resistance.
    

Intervention name(s): Nevirapine without dose escalation; Nevirapine initiation with dose escalation
Intervention type(s): Drug; Drug
Intervention description(s): Fixed dose combination tablets of stavudine 30mg,lamivudine 150mg and nevirapine tablets 200mg twice daily at initiation of antiretroviral therapy in patients receiving rifampicin for tuberculosis therapy; Triomune® 30 (according to body weight) one tablet once daily (am) plus Zerit® 30 + Epivir 150mg once daily (pm) for two weeks
Other intervention name(s): Triomune 30
Intervention MeSH terms: Nevirapine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Nevirapine; Rifampicin; Pharmacokinetics