Metabolic Complications Clinical Trial
Official title:
Molecular, Biochemical and Clinical Differences Between Stavudine and Tenofovir, Each Combined With Lamivudine and Efavirenz in South African HIV-infected Patients
Even with the benefits of HIV therapy, there is a possibility that HIV-infected individuals
develop metabolic complications once they initiate treatment, which may also ultimately put
them at a risk for impending heart disease in the next decades.
The main mechanism through which the main HIV drugs are thought to cause these metabolic
changes and organ toxicities is mitochondrial toxicity. Most of studies that have been done,
have taken place in the West, but few, if any, have been done in South Africa.
The purpose of this study is to prospectively identify early changes between the two
different drugs, Stavudine and Tenofovir, to assess their virological response, molecular,
biochemical and clinical picture, and the possible associated change in cardiovascular risk
factors, this, in the South African setting, and make recommendations to modify the current
National AIDS role out programme
There has been a major improvement in the survival of HIV-infected individuals with the role
out highly active anti-retroviral therapy (HAART) in the public health sector by the South
African Government in 2004.
Despite the unparalleled benefits of HAART, there is an increasing recognition that adverse
events remain an important source of morbidity and even mortality. Knowledge of the adverse
effects of different therapeutic regimes and understanding genetic factors that modulate the
risk of toxicity, are important in the management of HIV/AIDS patients.
There are two regimens offered in the public sector, these contain a triple drug course,
with either a nucleoside reverse transcriptase inhibitor (NRTI), a non-nucleoside reverse
transcriptase inhibitor (NNRTI) or a protease inhibitor (PI). With adherence to treatment,
it is possible to convert HIV from a fatal infection to a chronic and manageable illness.
But, unfortunately, these therapeutic regimens are associated with the development of
metabolic complications, such as dyslipidaemia, insulin resistance. Occasionally frank
diabetes, and altered fat distribution, such as peripheral lipoatrophy and centripetal fat
accumulation. There is a growing concern that these complications may lead to an increase in
the long-term risk of cardiovascular disease in these individuals.
The first regime which contains stavudine, which is a NRTI. It is cheap and easy to
administer in the short term but however is associated with more side effects, with
relatively higher rates of long term risks of lipoatrophy, and peripheral neuropathy. It is
also associated with an asymptomatic or a sometimes fatal lactic acidosis, it is also
associated with complications such as myopathies and pancreatitis. However, some studies
have suggested that reducing the d4T dose improves the toxicity profile while maintaining
efficacy.
Tenofovir on the other hand, is a nucleotide analogue, it was approved in 2001 in the United
States, and it use has grown since its approval. It is commonly used in initial therapy. It
has shown to have a favourable lipid and mt DNA profile when compared to stavudine, but
however it had no difference in virological response.
Clinical practice is moving increasingly towards the use of regimes that combine high levels
of tolerability and efficacy. HIV-infected individuals develop a pattern similar to that of
the metabolic syndrome once they initiate treatment, ultimately putting them at a risk for
impending cardiovascular disease in the next decades. Most studies have been done in the
West, but there is no data on patients from third world countries including South Africa.
This purpose of this study is to prospectively identify differences between the two
different NRTIs, Stavudine, a nucleoside analogue (in different doses), and Tenofovir, a
nucleotide analogue, to assess their virological response, molecular, biochemical and
clinical pictures, and the possible associated change in cardiovascular risk factors, this,
in the South African setting, and make recommendations to modify the current National AIDS
role out programme
Primary Objectives
The following questions will be addressed:
1. To determine if there are any molecular differences (before and after starting
treatment) between the regimens.
2. To determine the biochemical differences (before and after starting treatment) between
the three regimens.
3. To determine clinical differences in patients in all three arms of treatment.
Secondary Objectives
The following questions will be addressed:
1. To determine the outcome of immune reconstitution by monitoring T-cell subsets changes.
2. To determine virological response by monitoring the viral load changes.
3. To determine which of the three treatment arms results in better adherence.
4. To determine if there are any changes in cardiovascular risk factors after treatment.
Study Design This is a randomised controlled study comparing two NRTIs, a nucleoside
analogue Stavudine (standard dose, and low dose), and a nucleotide analogue Tenofovir, each
combined with Lamivudine and Efavirenz in HIV-infected treatment-naïve patients to be
conducted concurrently.
This study will compare the virologic response, molecular, biochemical and clinical
differences between all treatment arms.
At entry, all participants will be enrolled into either Arm A, B or C after randomization.
Duration:48 weeks after randomization of the final participant.From enrollment, the
participants had a minimum of four study visits.
Sample size:90 participants randomized (1:1:1) to either Arm A (30 participants), Arm B (30
participants) and Arm C (30 participants).
Population:HIV-infected, treatment-naïve patients, at least 18 years of age, with CD4+ cell
count <200 cells/mm3.
At study entry, participants will be randomized (as described above) to one of the following
treatment arms:
Arm A Stavudine (d4T) 30 mg po BD if wt < 60kg, or 40 mg po BD if wt > 60kg PLUS Lamivudine
(3TC) 150mg po BD PLUS Efavirenz 600mg po nocte
OR Arm B Stavudine (d4T) 20 mg po BD if wt < 60kg, or 30 mg po BD if wt > 60kg PLUS
Lamivudine (3TC) 150mg po BD PLUS Efavirenz 600mg po nocte
OR Arm C TDF 300 mg po QD PLUS Lamivudine (3TC) 150mg po BD PLUS Efavirenz 600mg po nocte
;
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
| Status | Clinical Trial | Phase | |
|---|---|---|---|
| Completed |
NCT00143689 -
NRTI-Sparing Pilot Study
|
Phase 4 |