ONCE-DAILY HAART: TOWARDS A NEW TREATMENT PARADIGM

The evidence that patients adhere better to once-daily regimens than to twice-daily or more frequent dosing schedules has first come from therapeutic areas other than HIV.

Dezii et al (5th Annual Meeting of the International Society for Pharmacoeconomics and Outcomes Research, Arlington, VA, May 2000) studied adherence retrospectively in patients receiving glipizide for diabetes and in those receiving venlafaxine for the treatment of depression/ anxiety. Short- and longer-term adherence was evaluated. As determined by filled prescriptions, patients receiving glipizide once-daily were more adherent than those receiving the same medication twice daily at both 6 and 12 months of follow-up (13% and 20% greater adherence, respectively). Similarly, patients receiving venlafaxine once-daily were also more adherent than those receiving it twice daily (14% greater adherence at 6 months, 11% greater at 12 months).

Data from other chronic disease states indicate that not only is once-daily dosing preferred, but adherence and dose timing accuracy are improved with once-daily therapy. Now, an increasing number of antiretrovirals from all approved drug classes are suitable for once-daily dosing, allowing construction of suitable once-daily regimens.

Currently, five antiretroviral drugs are approved by the US Food and Drug Administration (FDA) for once-daily dosing: efavirenz, enteric-coated didanosine, lamivudine, extended-release stavudine and tenofovir (Table 1). In addition, the combination of amprenavir and ritonavir is FDA approved for once-daily dosing. Both efavirenz and tenofovir were designed for once-daily administration.

Enteric-coated didanosine represents a new formulation of didanosine, which was previously approved as a buffered tablet for twice-daily dosing. The enteric-coated formulation of didanosine offers improved gastrointestinal tolerability, less frequent dosing, lower pill burden (one capsule vs. up to four tablets), and fewer buffer-related drug interactions. The intracellular half-life of didanosine is longer than 25 hours, and thus it can be dosed once-daily.

When lamivudine was first developed, the recommended dose was 150 mg twice daily. However, it has been demonstrated that the intracellular half-life of its active triphosphate metabolite is longer than 15 hours, and thus consistent with a once-a-day schedule. Subsequently, a once-daily 300 mg tablet of lamivudine has been introduced. This once-daily formulation of lamivudine is also available in the Indian market.

Previously, efavirenz was dosed as 3 x 200 mg capsules once daily. However, recently, a 600 mg tablet has been approved by the FDA that permits dosing of one tablet once daily. This represents a reduction of 2 pills per day. The once-daily 600 mg efavirenz tablet is also available in our country.

Table 1: Antiretroviral agents approved for once-daily dosing

The concept of once-daily antiretroviral therapy responds to patient preference for simpler regimens that fit better into their daily schedules, a benefit which may improve adherence to therapy. Recently, there have been two studies that have investigated patient preferences vis-à-vis once-daily HAART.

The study by Bass and Smith (14th World AIDS Conference, 2002; Abstract MoPeB3290) surveyed patient awareness and interest in once-daily antiretroviral regimens. 536 patients were interviewed via telephone, internet or paper surveys. 65% of these patients had been or were taking antiretroviral therapy (ART). Only 51% of patients surveyed were aware of any once-daily medications for ART.

80% of patients indicated that they were "most likely" to remember all of their antiretroviral doses on an o.d. regimen compared with 63% on a b.d. regimen (p<0.001) (Figure 1). Moreover, 73% claimed that o.d. regimens would fit better into their daily lives than b.d. regimens (p<0.001) (Figure 2).

Moreover, 68% of patients said they would like to take 4 pills once during the day (either morning or evening), as opposed to 24% who preferred 1 pill in the morning and 2 pills at night, and 5% who would like to take 1 pill in the morning and 4 pills in the evening.

The second study by Moyle et al (6th International Congress on Drug Therapy in HIV Infection, 2002; Poster) was designed to assess patients' preferences for dosing regimens. A total of 504 patients from France, Germany, Italy, Spain and the UK underwent standardized interviews concerning their current ART medication and also their future preferences regarding therapy. 87% had taken ART at some time point. Only 34% were aware of once-daily options.

The majority of patients expressed a high level of interest in once-daily antiretroviral therapy (mean score = 8.6). Once-daily dosing was also seen as giving the best lifestyle fit, regardless of their current therapy schedule.

Moreover, as dosing frequency increased, more patients reported having forgotten to take their medication (Figure 3). Interestingly, patients currently taking once-daily regimens were less likely to report having forgotten to take their medication than those on more frequent regimens. Approximately two-thirds of patients thought that once-daily regimens would make them less likely to forget doses.

Another interesting insight regarding patient preferences was that patients prefer compact regimens, even when pill burden is already low. This is depicted in Figure 4. Furthermore, 73% of patients interviewed across Europe thought that reducing the pill burden by even 2 pills per day would have a positive impact on adherence.

Thus, this study unequivocally demonstrated a patient preference for once-daily ART and compact regimens. The preferred regimen that would positively impact adherence was found to be 3 pills per day.

The study concluded that once-daily regimens are a key advance in the management of HIV, and that the ideal regimen consisted of 3 pills given once-daily.

Today, a number of antiretrovirals are available that can be dosed once-daily. Recent surveys have shown an overwhelming patient response to once-daily regimens. Not only would a once-daily regimen fit in better with their lifestyles, but there would also be less forgetfulness associated with taking doses. Forgetfulness has been shown to be a major impediment to successful ART.

The availability of once-daily antiretrovirals is expected to not only improve options in antiretroviral therapy, but also to open up a new era in improving adherence to antiretroviral therapy.