CLINICAL EFFICACY OF ONCE-DAILY EFAVIRENZ + DIDANOSINE + LAMIVUDINE

Odivir Kit is a novel product consisting of efavirenz 600 mg, didanosine 250/400 mg and lamivudine 300 mg in a specially packed kit to be administered once-daily.

Efavirenz is a potent non-nucleoside reverse transcriptase inhibitor. When used in combination with nucleoside reverse transcriptase inhibitors (NRTIs), it provides sustained efficacy (suppression of plasma HIV RNA and increased CD4 cell counts) in both treatment-naïve as well as treatment-experienced patients, regardless of baseline viral load. Data from Study 006 up to 3 years (11th European Conf Clin Microb and Inf Dis, 2001) have clearly demonstrated that a regimen consisting of efavirenz in combination with 2NRTIs is superior, with regard to efficacy, durability and tolerability, when compared with a regimen consisting of a PI (indinavir) and 2 NRTIs. Moreover, data from large observational cohort studies have recently provided evidence of the superiority of efavirenz to nevirapine in the clinical practice setting. These analyses have consistently demonstrated viral suppression in more patients treated with efavirenz versus nevirapine (8th ECCAT, October 2001; 1st International AIDS Society Conf on Op Inf and Treatment; July 2001;
J Infect Dis 2002; 185: 1062-69; 8th Conf Retroviruses and Op Inf, 2001; Poster 324). These data strongly support the role of efavirenz as a component of the first-line antiretroviral regimen.

Didanosine is a potent nucleoside reverse transcriptase inhibitor whose long intracellular half-life supports once-daily dosing. It is now available as a capsule containing enteric-coated beadlets, which is associated with better gastrointestinal tolerability and compliance than the earlier buffered tablet which needed to be chewed or dissolved.

Lamivudine is another nucleoside reverse transcriptase inhibitor which is well tolerated and has been widely used as a key component of the initial antiretroviral regimen.

A few key studies have investigated the efficacy of a once-daily antiretroviral regimen of efavirenz, lamivudine and didanosine in antiretroviral-naïve patients. Findings from these studies are presented below.

The 48-week pilot study by Maggiolo et al (Antiviral Therapy 2002; 6: 249-53) investigated the efficacy of a once-daily regimen of didanosine, lamivudine and efavirenz in 75 antiretroviral-naïve patients. This study used the non-enteric coated formulation of didanosine, with a pill burden of 7 (3=efavirenz; 2=didanosine; 2=lamivudine).

Over the 48-week period, viral load declined sharply, with a median decrease of more than 3.4 log copies/ml. By intention-to-treat analysis, the proportion of patients achieving a plasma HIV RNA level below 50 copies/ml was 77%. The mean CD4 count increased steadily from 251 to 459 cells/ l. The antiviral efficacy was similar in patients with a baseline HIV RNA level above or below 100,000 copies/ml (Figure 1).

In this study, the use of once-daily dosing enabled the investigators to provide directly observed therapy (DOT) to 13 patients belonging to difficult-to-treat categories such as intravenous drug users and mentally handicapped subjects.

ANRS 12 - 04/IMEA 011 Study

In the study by Landman et al (9th Congress on Retroviruses and Opportunistic Infections, 2002, Poster 458 W), 40 antiretroviral-naïve patients in Senegal received efavirenz 600 mg, didanosine tablets (400 mg if > 60 kg and 200 mg if < 60 kg), and lamivudine 300 mg, all dosed once daily at bedtime. Patients with CD4 counts between 50 to 350 cells/mm3 and plasma HIV RNA > 30,000 copies/ml were included. The study duration was 15 months.

Figure 2 depicts the percentage of patients with undetectable viral loads over time, and Figure 3 depicts the mean changes in CD4 cell counts and HIV RNA.

Compliance with therapy was assessed by assaying plasma drug concentrations as well as by a questionnaire. The percentage of patients with adequate plasma concentrations of efavirenz (> 1.1 mg/l) was 95% and 83% at 1 and 6 months, respectively. For lamivudine (adequate plasma concentrations 100-200 ng/ml) these percentages were 97% and 85% at 1 and 6 months, respectively. As expected, plasma didanosine levels were below limit of detection (<10 ng/ml) 12 hours after intake for 95 and 93% of patients at months 1 and 6.

Figure 3 : Mean ± SD changes in plasma HIV RNA and
CD4 cell counts from baseline

Adherence to treatment was judged to be generally good. 95% of patients reported that they took their tablets every day without exception. Only 3 patients interrupted their therapy for more than 3 days.

The mean change in weight from baseline to 6 and 15 months was 4.2 ± 4.2 kg and 5.1 ± 5.3 kg, respectively. At 15 months, 30 patients (77%) had increased their weight, 5 (13%) decreased and 4 (10%) had no change.

Thus, this study demonstrated the long-term efficacy, in terms of both virological and immunological responses, in a patient population with advanced immune deficiency and high viral load. There was a high degree of compliance with this regimen, as assessed by a pharmacokinetic study and patient questionnaire. There were no treatment-limiting toxicities.

The authors concluded that this simple once-a-day HAART regimen may help increase compliance of patients in developed and developing countries.

Another study presented by Maggiolo et al at the 42nd ICAAC, 2002 compared the efficacy of a once-daily regimen of efavirenz + lamivudine + didanosine with that of a twice-daily regimen with a low pill burden and a twice-daily regimen with a high pill burden. The 3 regimens were as follows:
Once-a-day: Efavirenz 600 mg + lamivudine 300 mg + didanosine 250/400 mg (enteric-coated) (6 pills).

B.i.d. low pill burden: Efavirenz 600 mg + lamivudine 300 mg + zidovudine 600 mg (5 pills).

B.i.d. high pill burden: Nelfinavir 2500 mg + lamivudine 300 mg + zidovudine 600 mg (12 pills).

The primary end points for this study were the proportion of patients on therapy at the end of 1 year and proportion of patients with HIV RNA < 50 copies/ml. Secondary endpoints were immunological response and tolerability of study drug combinations.

Figure 4 shows the proportion of patients from each arm on therapy at the end of 1 year. Figures 5 and 6 show the virological and immunological improvements, respectively.

Genotypic analysis of rebounding viruses was also conducted. There was only 1 patient with virologic failure in the o.d. treatment arm, whereas there were 6 patients in the b.i.d. high pill burden arm.

The study concluded that both efavirenz-based therapies showed a better outcome than the PI-based therapy. The efficacy of the once-a-day therapy was equivalent to the efavirenz-containing b.i.d. therapy, and superior to the PI-based b.i.d. therapy (intent-to-treat analysis). The authors felt that treatment with lower pill burden seems to ensure a more prolonged virological success (by intent-to-treat, as-treated and genotypic analysis), and that this was probably attributable to enhanced adherence. Another important aspect of this trial is that this once-daily regimen is the first thymidine analogue-sparing regimen tested in a controlled trial, where the efficacy of a didanosine /lamivudine NRTI backbone was compared with that of zidovudine/lamivudine (zidovudine and stavudine are thymidine analogues; most commonly, therapy is initiated with either zidovudine or stavudine as a component of the triple regimen).

To conclude, a once-a-day combination of efavirenz, didanosine and lamivudine can be a safe and effective alternative in antiretroviral-naïve patients. This regimen is well accepted by patients, results in good adherence to therapy and facilitates directly observed therapy.