Tuberculosis Clinical Trial
Official title:
Early vs Late Introduction of Antiretroviral Therapy in Naive HIV-infected Patients With Tuberculosis in Cambodia
In Cambodia the prevalence of both tuberculosis (TB) and Human Immunodeficiency Virus (HIV)
infection is high. Data suggest that aggressive management of HIV infection, which includes
Anti-Retroviral Therapy (HAART) during treatment of TB, decreases both morbidity and
mortality. On the other hand, the use of HAART for patients with TB may cause severe
complications due to drug-drug interactions, and occasionally a temporary exacerbation of
symptoms. These reactions may be particularly severe when HAART is started soon after the
start of TB treatment.
The proposed study aims to determine the optimal time to initiate HAART in previously
untreated HIV-infected adult patients with TB and low CD4 cell counts.
In Cambodia the prevalence of both tuberculosis (TB) and Human Immunodeficiency Virus (HIV)
infection is high. In 2000, there were approximately 75.000 newly diagnosed TB cases. In
2003, 1.9% of the population was infected with HIV. TB rates in Cambodia are more than
double those observed in other developing countries and up to 30 times higher than those
currently seen in the USA or Western Europe. It is estimated that over 8% of the newly
diagnosed TB cases are co-infected with HIV, of which approximately 85% are severely
immunosuppressed (CD4+ cell count < 200 x 106 cells/l).
Mortality rates were found to be 2-4 folds higher in HIV/TB co-infected patients than in TB
alone. Data suggest that aggressive management of HIV infection, which includes Highly
Active Anti-Retroviral Therapy (HAART) during treatment of TB decreases both morbidity and
mortality by suppressing viral replication and improving immune function.
On the other hand, the use of HAART for patients with TB may cause severe complications due
to drug-drug interactions, and occasionally a temporary exacerbation of symptoms, signs or
radiographic manifestations of TB. Such events or 'paradoxical reactions' that occur among 7
- 36% of HIV/TB co-infected patients treated with HAART may be secondary to immune
restitution. These reactions may be particularly severe when HAART is started soon after the
start of TB treatment.
Most clinical teams recommend delaying the initiation of HAART to avoid the early side
effects of TB treatment and simplify clinical management of the co-infected patient. However
others argue that early initiation of HAART in TB patients with CD4 cell counts < 100 x 106
cells/l leads to a marked reduction of viral load despite frequent adverse events.
The proposed study aims to determine the optimal time to initiate HAART (defined as d4T +
3TC + efavirenz) in previously untreated HIV-infected adult patients with TB and low CD4
cell counts. The study is a multicentre prospective, randomized, open-label two-armed trial
with no placebo. It is designed as a superiority trial to compare the "early arm" (HAART
initiated 2 weeks after TB treatment onset) with the "late arm" (HAART initiated 2 months
after TB treatment onset). Efficacy will be assessed by the survival rate in the two arms.
Secondary objectives will include evaluation of (1) the safety of an early initiation of
HAART in terms of drug interactions or paradoxical reactions, (2) the occurrence of
opportunistic infections diagnosed during the follow-up period, (3) patients' adherence to
TB treatment and HAART, (4) the rate of hospitalization for any cause during the trial; the
measure of (5) the effectiveness of the TB treatment and HAART and (6) the predictive
factors for the survival, the response to anti-TB therapy and HAART and the paradoxical
reactions.
The total study duration is expected to be 4 years (3 years for enrolment and at least one
year of follow-up) in five study sites: (1) Khmero-Soviet Friendship Hospital, Phnom Penh;
(2) Calmette Hospital, Phnom Penh; (3) Provincial hospital, Svay Rieng province; and (4)
Provincial hospital, Takeo province, (5) Provincial Hospital, Siem Reap.
The study will be carried out in compliance with the protocol and in accordance with the
Declaration of Helsinki approved by the World Health Association and with the
recommendations of the Good Clinical Practice.
;
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
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