Differences Between Stavudine and Tenofovir Each Combined With Lamivudine and Efavirenz in SA HIV-infected Patients

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