Efficacy and Safety of Concomitant Use of Nevirapine and Rifampicin With HIV-TB
Condition: HIV/TB Co-infection
MeSH terms: Coinfection
Study type: Interventional
Phase: Phase 3

Summary: 
      The purpose of the study is to evaluate the efficacy and safety of Nevarapine and Rifampicin
      vs Efavirenz and Rifampicin in antiretroviral naive patients co-infected with HIV and TB and
      to investigate whether Rifampicin co-administration in clinical practice leads to a
      clinically relevant decrease of Nevirapine plasma concentrations in Indian patients
      co-infected with HIV and Tuberculosis and to characterize drug-associated toxicities
      (especially hepatic).
    

Detailed description: 
      Drug interactions complicate concurrent treatment of HIV and Mycobacterium tuberculosis
      co-infection. Drug therapy for HIV and tuberculosis each consists of combined regimens with
      three or four drugs. Tuberculosis (TB) is the most significant co-infection of HIV patients
      in resource-limited settings. Application of antiretroviral (ARV) therapy in co-infected
      patients will require care providers who are appropriately trained in the use of ARV and TB
      drugs. Over 40 million people worldwide are currently living with HIV/AIDS, of which 90% live
      in the developing world, co-infected with TB. There are an estimated 12 million persons with
      TB/HIV co-infection. According to UNAIDS estimates, 5 million people have acquired HIV/AIDS
      in 2003. India is estimated to have 5.1 million HIV individuals by the end of 2002. TB is
      among the most frequent HIV-related opportunistic infections in developing countries, and is
      associated with substantial morbidity and mortality. In India, there were estimated 1.85
      million HIV individuals co-infected with HIV and TB. In patients infected with both HIV and
      TB, the lifetime risk of developing the active tuberculosis has been estimated to be at least
      60%, compared to approximately 10% in persons infected with TB who do not have HIV infection.
      It is well established that HIV increases the risk for TB (acquisition, reactivation and
      reinfection), alters its clinical presentation, and reduces survival compared to patients
      with TB and no HIV infection. Multiple epidemiologic studies have shown that co-infection
      with TB results in reduced survival, increased risk for opportunistic infections and
      elevations in HIV replication. Increased HIV replication is attributed to activation of
      latently infected cells and promotion of infection in uninfected lymphocytes and macrophages.
      HIV genetic diversity is also increased in the presence of active TB infection. Mortality
      rates in HIV-infected patients with TB are extraordinarily high in resource- limited
      settings. Therefore, it is essential to treat patients with HIV and TB co-infection for both
      infections. In India large numbers of HIV positive patients suffering with HIV/Tuberculosis
      co-infection. However, limited data are available for concomitant use of Nevirapine and
      Rifampicin in patients co-infected with HIV and Tuberculosis in India. No concrete data
      available about whether or not Nevirapine and Rifampicin can be safely co-administered
      without the plasma concentration of Nevirapine falling below therapeutic levels.

      Rifamycins are frequently used for the treatment of tuberculosis. Rifamycins can interact
      with several antiretrovirals. In decreasing order of potency, rifampin, rifapentine and
      rifabutin have an inducing effect on drug metabolism mediated through cytochrome P450
      isoenzyme 3A4 (CYP3A4). Non-nucleoside reverse transcriptase inhibitors and protease
      inhibitors are metabolized through CYP3A4 and thus the plasma concentrations of these
      antiretrovirals may decrease in the presence of rifamycins. Additionally, the non-nucleoside
      reverse transcriptase inhibitors are metabolized by CYP2B6. Drug-drug interactions may lead
      to suboptimal drug exposure, loss of viral suppression and selection of resistant HIV
      strains. Interactions between nucleoside analogue reverse transcriptase inhibitors and
      rifamycins occur at the level of glucuronidation and amination, as was described between
      rifampin or rifabutin and zidovudine, but is not considered to be clinically significant.

      Coinfection of HIV-1 and tuberculosis mainly concerns developing countries like India where
      both infections are epidemic. Access to antiretrovirals may be difficult in developing
      countries because of limited availability or high cost. To improve pricing and accessibility,
      generic antiretroviral agents are manufactured in countries such as Brazil, India, Thailand
      and South Africa. Fixed-dose combinations of these generic agents are widely used as well.
      The most often-used generic fixed-dose combination is a twice-daily regimen with stavudine,
      lamivudine and nevirapine. Fixed-dose combinations are attractive regimens for patient care.
      Adherence to therapy may be improved because of low pill burden and the reduced possibility
      of incorrect dosing. Furthermore, the fixed-dose combinations simplify drug logistics.
      Compact drug quantities facilitate storage and distribution to hospitals, pharmacies and
      patients. Important for resource constraint settings is that fixed-dose combinations make
      improvements in public health care management possible. With respect to treatment of
      HIV/tuberculosis-coinfected patients, a clinically significant drug-drug interaction may be
      expected when nevirapine and rifamycin are co-administered. Treatment with rifabutin is
      preferred because of a more favourable interaction profile, but in most developing countries
      rifabutin is not available or too expensive. Tuberculosis treatment with a regimen that
      includes rifampicin is usually the only option. Reports in the literature have shown
      decreases in nevirapine plasma concentrations ranging from 31% to 58%. Rifampicin plasma
      concentrations are not influenced by nevirapine. Low nevirapine plasma concentrations may
      negatively affect virological outcome of antiretroviral therapy. Previous studies have
      documented higher plasma concentrations of nevirapine in Thai patients compared with patients
      in other countries, suggesting that even though the concomitant use of rifampicin lowers the
      nevirapine levels considerable, still most patients would still retain nevirapine plasma
      concentrations above a concentration of 3.1mg/l. The present study will be performed to
      investigate whether rifampicin co-administration in clinical practice leads to a clinically
      relevant decrease of nevirapine plasma concentrations in North Indian patients co-infected
      with HIV/Tuberculosis.
    

Intervention name(s): Nevirapine; Efavirenz
Intervention type(s): Drug; Drug
Intervention description(s): The regimen containing Nevirapine: 3TC/ZDV 150/300 mg 1 tablet BID + NEVIRAPINE 200 mg qD for 2 weeks then 200mg BID; The regimen containing Efavirenz: 3TC/ZDV 150/300 mg 1 tablet BID + EFAVIRENZ 600 mg qD
Other intervention name(s): NEV-Nevirapine; EFV: Efavirenz
Intervention MeSH terms: Efavirenz; Nevirapine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: India; Nevirapine; Rifampicin; Efavirenz; HIV; TB