HIV Infections Clinical Trial
Official title:
Comparison of Nevirapine Levels With and Without Dose Escalation in HIV-infected Patients Commencing Antiretroviral Therapy Who Are Also Receiving Rifampicin Based Anti-tuberculous Therapy
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
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.
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Allocation: Randomized, Endpoint Classification: Pharmacokinetics Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
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