HIV/TB Co-infection Clinical Trial
Official title:
Efficacy and Safety of Concomitant Use of Nevirapine and Rifampicin in Antiretroviral Naive Patients Co-infected With HIV and Tuberculosis in India.
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).
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.
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Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment