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Once-Daily Antiretroviral Options

Fall 2002

A note from The field of medicine is constantly evolving. As a result, parts of this article may be outdated. Please keep this in mind, and be sure to visit other parts of our site for more recent information!

Article: Once-Daily Antiretroviral Options

Numerous studies have now shown that very high levels of adherence to medication regimens are necessary for adequate HIV suppression. The ideal antiretroviral (ARV) regimen is simple, effective, and well tolerated. An increasing number of approved once-daily regimens are being used to minimize pill burden and optimize adherence. There is already data showing the efficacy of once-daily dosing of Videx, Epivir, Viread, Viramune, Sustiva, Fortovase/Norvir and Agenerase/Norvir.

The long half-life of the active breakdown product of both Videx and Epivir favors a once-a-day dosing regimen. The plasma half-life of Videx is only 1.5 hours, but its intracellular half-life is approximately 25 to 40 hours. The clinical studies of these two nucleoside reverse transcriptase inhibitors (NRTIs) show that the effectiveness and side effects of a once-daily regimen are equivalent to twice-daily dosing. Once-daily (with a 400 mg dose) and twice-daily (with a 200 mg dose) Videx are equally effective in reducing viral loads and increasing CD4+ cell counts. Epivir once daily (300 mg) compared to twice daily (150 mg) also had similar clinical results and has been approved in Europe. There are also ongoing trials for once-a-day Abacavir.

Viread belongs to a new class of antiretroviral drugs, the nucleotide (as opposed to a nucleoside) reverse transcriptase inhibitors. It is given in a single daily dose of 300 mg. The main advantage of Viread is that it does not appear to have cross-resistance with the other available classes of antiretrovirals and therefore can often be used in individuals with HIV that has many resistance mutations due to prior highly active antiretroviral therapy (HAART) exposure.

The non-nucleoside reverse transcriptase inhibitors (NNRTIs) Viramune (400 mg) and Sustiva (600 mg) are both given once daily with good clinical results. The once-daily dosing regimen for Viramune has yet to be approved by the FDA. Although Sustiva has always been marketed as a once-a-day drug, the only formulation available was a 200 mg pill. The FDA has just approved a 600 mg version of Sustiva (which is about the same size as the 200 mg pill), decreasing the pill burden from three 200 mg tabs to a single 600 mg pill.

The addition of low-dose Norvir to many of the protease inhibitors (PIs) often increases the blood levels of effective drug, allowing for once-daily drug dosing. Peter Cardiello et al. recently published promising data for once-daily dosing of Fortovase (saquinavir) soft gelatin capsules in combination with Norvir (Fortovase 1,600 mg/Norvir 100 mg). HIV-infected individuals with an undetectable viral load on a stable HAART regimen of twice-daily Fortovase/Norvir and two NRTIs were switched to once-daily Fortovase/Norvir while continuing the NRTIs. Once-daily Fortovase was well tolerated and after 24 weeks; 93 percent of the participants still had a viral load less than 50 copies/mL. CD4 cell counts improved significantly on once-daily Fortovase/Norvir therapy as well. The data supports the use of once-daily Fortovase/Norvir with two NRTIs as a convenient regimen in HIV-positive people with a viral load less than 50 copies/mL. Agenerase and likely indinavir (studies ongoing) when combined with Norvir also allow for effective treatment of patients with once-daily dosing. The borderline levels of the drug in the bloodstream achieved by the PIs, however, do not allow much room for error in when the pills are taken. In addition, some of these once-daily PI regimens have a hefty pill burden -- up to 10 pills at a time.

Posters at the Ninth Retrovirus Conference supplied data in support of once-daily dosing for a new formulation of Zerit (d4T) (Abstracts 411 and 416), additional support of once-daily Fortovase/Norvir (Abstract 441), and new data on once-daily dosing of Kaletra (Abstract 409). There were also several studies using newer, not yet approved, antiretrovirals such as atazanavir (a PI) and DPC 083 (an investigational NNRTI) as part of a once-daily HAART regimen. Bristol-Myers Squibb just submitted its application for approval of atazanavir in Europe.

A large, Phase II, placebo-controlled, prospective study of 783 people compared an extended-release formulation of Zerit (d4T XR) dosed at 100 mg once daily to the currently available formulation of immediate-release Zerit (Zerit IR) dosed at 40 mg twice daily (Abstract 411). The Zerit was used as part of a HAART regimen of Epivir (150 mg twice daily) and Sustiva (600 mg once daily). At the start of the study, it was determined that Zerit XR blood levels were just as high as those seen with Zerit IR (Abstract 416). A 24-week interim analysis of the planned 48-week study was reported at the Retrovirus Conference. Virologic and immunologic responses were nearly identical in the Zerit XR and IR groups. The safety, tolerability and efficacy profiles of Zerit XR also appear comparable to that of Zerit IR. Since the results were maintained at the 48-week analysis, this data will likely result in the approval of once-daily Zerit XR in late 2002.

Once-daily regimens using the combination of Fortovase and Norvir (at 1,600 mg and 100 mg) have been previously studied with promising results. However, the combination of Fortovase with Sustiva once daily is discouraged because of the increased metabolism of Fortovase resulting in lower drug levels. L. López-Cortéz studied the safety, efficacy and blood levels of Fortovase (1,200 mg) with Sustiva (600 mg) with the addition of Norvir (100 mg) to see if a once-daily NRT-sparing regimen, using these drugs, was feasible in people in whom NRTIs were withdrawn because of adverse events (Abstract 441). All people were NRTI and PI experienced. All 22 people who entered the study with an undetectable viral load remained undetectable, and 13 of the 20 people with a high viral load became undetectable. At 52 weeks, a total of 71 percent of the people had a viral load below 50 copies/mL with a median CD4 cell count increase of 215 cells. Treatment had to be withdrawn in only one case, due to hepatitis. This regimen may be an effective once-daily alternative for people for whom NRTIs are no longer a good option.

Although once-daily regimens have been shown to be effective for the Fortovase-with-Norvir and Agenerase-with-Norvir combinations, additional once-daily PI regimens are needed. Kaletra (Lopinavir 133 mg / Norvir 33 mg) is currently being prescribed at a dose of 400 mg / 100 mg (3 pills) twice daily. In a pilot study of 38 people, a once-daily Kaletra dose of 800 mg / 200 mg (6 pills) was compared with the standard twice-daily dose as part of a HAART regimen with Zerit and Epivir (Abstract 409). Comparable virologic responses were achieved in the once-daily and twice-daily arms and there were similar CD4+ cell count increases of approximately 240 cells, as well. Although the efficacy and safety results were similar in both groups, there were less consistent Kaletra drug levels with once-daily dosing (Abstract 126). Larger studies are needed before this once-daily regimen is accepted.

One major concern about once-a-day dosing is that if a person skips a dose, they go a whole day without sufficient drugs in the blood to suppress HIV replication, whereas if they miss one dose of a twice-a-day regimen, they go only 12 hours before the next dose. Additional data is needed to determine if missing one dose of a once-daily HAART regimen will allow HIV replication and more frequent failure rates.

DrugOriginal DosingOnce-Daily Dosing
Videx200 mg (1 pill) twice a day400 mg (1 pill) once a day
Epivir150 mg (1 pill) twice a day300 mg (2 pills) once a day
Zerit 40 mg1 pill; Zerit IR twice a day100 mg (1 pill; Zerit XR) once a day*
Viread300 mg (1 pill) once a day 
Viramune200 mg (1 pill) twice a day400 mg (2 pills) once a day
Sustiva600 mg (3 pills) once a day600 mg (1 pill) once a day
Fortovase1,200 mg (6 pills) 3 times a day1,600 mg with 100 mg Norvir (9 pills) once a day
Agenerase1,200 mg (8 pills) twice a day1,200 mg with 200 mg Norvir (10 pills) once a day
400 mg/100 mg (3 pills) twice a day800 mg/200 mg (6 pills) once a day
Atazanavir*400 mg (2 pills) once a day 
* Zerit XR and atazanavir are not yet FDA approved, but likely will be in the near future.

A note from The field of medicine is constantly evolving. As a result, parts of this article may be outdated. Please keep this in mind, and be sure to visit other parts of our site for more recent information!

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This article was provided by Seattle Treatment Education Project. It is a part of the publication STEP Perspective.
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