Nevirapine Drug Levels in HIV Positive Patients Also Receiving Rifampicin for Tuberculosis

This study has been completed.
Sponsor:
Collaborator:
University of Liverpool
Information provided by:
Makerere University
ClinicalTrials.gov Identifier:
NCT00617643
First received: February 5, 2008
Last updated: December 3, 2010
Last verified: December 2010
  Purpose

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


Condition Intervention Phase
HIV Infections
Tuberculosis
Drug: Nevirapine without dose escalation
Drug: Nevirapine initiation with dose escalation
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacokinetics Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by Makerere University:

Primary Outcome Measures:
  • To compare the pharmacokinetics of nevirapine with dose escalation and without dose escalation of nevirapine on day 7, 14 and 21 in patients who are on rifampicin therapy. [ Time Frame: 12 months ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Safety and tolerability of nevirapine when administered in HIV-TB coinfected patients receiving rifampicin [ Time Frame: 1 month ] [ Designated as safety issue: Yes ]

Estimated Enrollment: 18
Study Start Date: May 2008
Study Completion Date: December 2010
Primary Completion Date: June 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: 2
Triomune® 30 one tablet once daily (am) plus Zerit® 30 + Epivir 150mg once daily (pm) for two weeks
Drug: Nevirapine initiation with dose escalation
Triomune® 30 (according to body weight) one tablet once daily (am) plus Zerit® 30 + Epivir 150mg once daily (pm) for two weeks
Experimental: 1
Triomune® 30 one tablet twice daily for two weeks
Drug: Nevirapine without dose escalation
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
Other Name: Triomune 30

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.

  Eligibility

Ages Eligible for Study:   18 Years to 60 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Ability to provide full informed written consent
  • Confirmed diagnosis of HIV infection
  • On rifampicin therapy for at least two weeks
  • Clinical criteria for commencing antiretroviral therapy

Exclusion Criteria:

  • Hemoglobin < 8g/dl
  • Liver and renal function tests > 3 times the upper limit of normal
  • Pregnancy
  • Use of know inhibitors or inducers of Cytochrome P450 or P-glycoprotein.
  • Use of herbal medications
  • Intercurrent Illness
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00617643

Locations
Uganda
Infectious Diseases Institute, Faculty of Medicine, Makerere University
Kampala, Uganda
Sponsors and Collaborators
Makerere University
University of Liverpool
Investigators
Principal Investigator: Concepta A Merry, PhD Trinity College Dublin
  More Information

No publications provided

Responsible Party: Dr. Concepta Merry, Infectious Diseases Institute, Makerere University
ClinicalTrials.gov Identifier: NCT00617643     History of Changes
Other Study ID Numbers: CPR 004
Study First Received: February 5, 2008
Last Updated: December 3, 2010
Health Authority: Uganda: National Council for Science and Technology

Keywords provided by Makerere University:
Nevirapine
Rifampicin
Pharmacokinetics

Additional relevant MeSH terms:
HIV Infections
Acquired Immunodeficiency Syndrome
Tuberculosis
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Immunologic Deficiency Syndromes
Immune System Diseases
Slow Virus Diseases
Mycobacterium Infections
Actinomycetales Infections
Gram-Positive Bacterial Infections
Bacterial Infections
Rifampin
Nevirapine
Antibiotics, Antitubercular
Anti-Bacterial Agents
Anti-Infective Agents
Therapeutic Uses
Pharmacologic Actions
Antitubercular Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Leprostatic Agents
Nucleic Acid Synthesis Inhibitors
Anti-HIV Agents
Anti-Retroviral Agents

ClinicalTrials.gov processed this record on July 22, 2014