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Once-A-Day Dosing: Balancing Convenience and Effectiveness

Winter 2002/2003

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 As a result, parts of this article may be outdated.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!

The era of once-a-day anti-HIV therapy is upon us with five antiretrovirals approved for once-a-day use and more on the way. It is now possible to construct a first- and even second-line once-a-day anti-HIV regimen. A number of surveys have reported that people with HIV want once-a-day therapy. Adherence would probably be better -- clinical data from a number of different diseases suggest that adherence is better on once-a-day compared to twice-a-day medications, although not dramatically so. But are once-a-day regimens the best therapeutic option? We need to be certain that convenience does not come at the cost of effectiveness.

Study results support using some antiretrovirals as once-a-day drugs. Even so, there are reasons to carefully scrutinize the data:

  • Most of the studies were conducted over only 48 weeks, although some have gone on longer.
  • Most were in patients who had never taken any antiretrovirals before and tend to have wild-type virus, which has no mutations and is, therefore, most responsive to the drugs.
  • Some of the studies were "switch" studies -- in which people whose viral loads were suppressed by the drug when used twice a day, continued to respond when they switched to taking the drug once a day. This is not the same as demonstrating that taking the drug once a day to start with would have suppressed HIV as well.
  • In the clinical trials designed to win once-a-day approval, the study drug is generally administered with other antivirals that are given twice daily. The effect of twice-daily drugs could mask slight weaknesses of the once-a-day drug. This is particularly worrisome if people want to try to take all their antiretrovirals once a day, because there is very little data to show that using allthe drugs together once a day works. In fact, it will be years before there are results from large trials comparing each of these once-a-day regimens to today's standard twice-a-day therapy.

It helps to understand the strengths and weaknesses of each individual drug's pharmacokinetic (PK) profile -- what happens to the drug in the body after it's been absorbed. However, what is true about a drug in the bloodstream may not explain what's happening inside an infected cell, and drug concentrations can differ from one cell type to another. For example, less frequent dosing could mean insufficient concentrations of drug in harder to reach "sanctuary" sites such as the brain and testes. Cells such as HIV-infected macrophages require more drug than CD4 cells to keep the virus in check. HIV in sanctuary sites and macrophages may develop resistance sooner on once-a-day than on twice-a-day therapy. Once-a-day dosing may look fine the first year or two on therapy, but not necessarily with longer follow-up.

Finally, what's true for the majority may not be true for the individual. Even if trials demonstrate that most people can use these drugs successfully once a day, a sizable minority may not be able to. Pharmacokinetics may vary from person to person, and people with different genetic backgrounds, diets, co-infections, or more or less sensitive virus may respond very differently. Of course this is all true for twice-daily dosing, too, but these theoretical concerns deserve consideration and continued research.

Nucleoside/tide Analogs

The pharmacokinetics of nucleoside and nucleotide analogs differ from most other drugs. Cellular enzymes must change these drugs into their active form inside the cell. With the exception of Viread (tenofovir), they have very short half-lives in the bloodstream. The half-life is the amount of time that it takes the body to eliminate half of the absorbed drug. The nucleoside analogs' half-life in the bloodstream is generally less than an hour -- but their active forms have much longer half-lives within the cell (intracellularly). In some cases, the intracellular half-life appears to be long enough for once-a-day dosing.

Videx (ddI): Videx EC (enteric-coated) has an intracellular half-life ranging between 25-40 hours. Clinical trial data have demonstrated equivalence of once and twice-a-day dosing when given with other drugs taken twice a day. Videx is only absorbed in an empty stomach, which poses a problem for use in once-a-day combinations with drugs that have to be taken with food. When taken with Viread (even with a light meal), blood levels of Videx may be dangerously high in some patients -- a case of pancreatitis and several cases of lactic acidemia have been reported. If the two drugs are used together, Bristol Myers-Squibb recommends that the Videx dose be reduced and patients be monitored closely.

Epivir (3TC): Epivir has an intracellular half-life of 16-19 hours. It has been approved for once-a-day use on the basis of clinical trials that demonstrated the equivalence of 300 mg once daily to 150 mg twice daily when used with other drugs taken twice-a-day. 300 mg tablets are now available.

Sustained release Zerit (d4T): A new once-a-day formulation of Zerit has been approved in the U.S. and is expected to be on the market early this year. Zerit's intracellular half-life is only seven hours, so the pills had to be improved to make this drug once-a-day. The extended release formulation is absorbed as the pill passes through the colon. It continues to deliver drug to the bloodstream over the course of several hours. Clinical data to support use of this once-a-day formulation include a large study in 783 patients comparing the new formulation to the old twice-daily formulation. There were no statistically significant differences in activity or toxicity up to week 48. The once-a-day dose is 100 mg or 75 mg depending on body weight.

Viread (tenofovir): Viread is distinguished by having a long half-life in the bloodstream (about 17 hours). Its intracellular half-life is between 10-50 hours. Every study of Viread has used it as a once-a-day drug. However, it needs to be taken with food.

Ziagen (abacavir): Early data suggested that the intracellular half-life of Ziagen was only 3.3 hours. Recently, however, more advanced lab techniques suggest that the half-life is much longer, perhaps long enough for once-a-day dosing. There is little clinical data as of yet, but studies are underway.

Nucleoside analogs in development with once-a-day potential include Coviracil (FTC, emtricitabine) and amdoxovir (DADP). A combined once-a-day formulation of Viread and Coviracil is also planned.

Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

The case seems strong for using Sustiva (efavirenz) and Viramune (nevirapine) as once-daily drugs. Though only Sustiva is approved as a once-a-day drug, both of these NNRTIs have such long half-lives (over 24 hours) and consistently high blood concentrations that they can be given once a day, just by taking the pills all at once. These drugs offer more "forgiveness" than other antivirals -- if you're late taking your next dose, blood concentrations should remain above the levels needed to suppress viral replication.

Sustiva: Now available in a single 600 mg tablet, Sustiva's half-life is 40-55 hours. Food slightly increases absorption and thus possibly toxicity as well, so the label recommends taking the drug on an empty stomach. Also, higher than normal blood levels of Sustiva have been associated with more central nervous system toxicity -- although it is not clear whether higher peak concentration of drug in the bloodstream after once-daily dosing increases the incidence of side effects.

Viramune: Although not yet approved for once-daily dosing, Viramune's long half-life (30-40 hours) should allow for it. Several studies have used Viramune once a day - the first one that should be large enough to win approval from the Food and Drug Administration (FDA) is ongoing.

Protease Inhibitors (PIs)

Protease inhibitors have borderline pharmacokinetics. Even after swallowing many large pills, only a small amount of drug is absorbed into the bloodstream and this is usually rapidly broken down by the body. Although PIs are potent, there is a wealth of data demonstrating that they stop working when blood concentrations fall too low.

Norvir (ritonavir), however, was discovered to improve the pharmacokinetics of other PIs by slowing down their metabolism and, in some cases, improving their absorption. With the addition of low-doses of ritonavir -- called ritonavir-boosting -- Crixivan (indinavir) and Fortovase (saquinavir) can be comfortably taken twice a day. The pill count is lower, and there are no dietary restrictions. Total exposure to drug is higher, sometimes high enough to treat resistant HIV or virus in sanctuary sites in the body, with improved concentrations of drug persisting at the next dosing.

But can ritonavir-boosting make PIs once-a-day drugs? The data are mixed. Ritonavir-boosting of some PIs achieves adequate drug concentrations for most people. For others, drug levels in the blood fall below those necessary to suppress the virus. So it's worth questioning whether this is the best way to take PIs.

Agenerase (amprenavir)/ritonavir: Agenerase has the longest half-life of the approved PIs (around 7.1-9.5 hours) and is a twice-a-day drug without ritonavir. With Agenerase/ritonavir (1200 mg/200 mg) once daily, blood levels of Agenerase are six times higher 24 hours after dosing than seen with standard dosing after twelve hours. But there is at least one problem -- ten pills. A high pill count can lead to adherence problems, especially when coupled with Agenerase-related nausea.

In one study, patients with undetectable viral loads on Agenerase were switched to Agenerase plus ritonavir taken either once or twice daily. Thirty-two weeks after the switch, three-quarters of the participants still had viral loads below 50 copies/mL; however, the CD4 cell rise was much higher in the twice-a-day arm -- 314 vs. 100 cells.

The FDA has amended Agenerase's package insert to include data on once-a-day usage. Once-a-day use is now an approved option, although not necessarily the best way to take the drug.

Kaletra (lopinavir/ritonavir): In initial once-a-day studies with Kaletra, Abbott found that long before a day had passed, the remaining levels of lopinavir were inadequate. However, another study has reported more promising results comparing twice-daily to once-daily (double-dosed) Kaletra in combination with Zerit and Epivir taken twice a day. Although blood concentrations of lopinavir just before the next dose were found to be 56% lower as well as more variable from patient to patient in the once-a-day arm, the antiviral effect in both arms was similar. This was a small study, however -- only 17 patients took once-daily Kaletra. Abbott is conducting a larger follow-up study.

Saquinavir (Fortovase or Invirase)/ritonavir: On its own, saquinavir's half-life is one to two hours. However, ritonavir dramatically improves the elimination (and absorption) of saquinavir. Studies in patients who had never taken any antiretrovirals before have used Fortovase (saquinavir soft gel capsules) (1600 mg) plus low-dose ritonavir (100 mg) given once daily for a total of nine pills. The blood levels of saquinavir were within targeted levels in most subjects but not in all.

The high pill count and gastrointestinal side effects are also a problem for Fortovase/ritonavir. One study of once-daily Fortovase/ritonavir (in combination with nucleoside analogs) reported a high discontinuation rate: 25 out of 81 patients. Tolerance may be improved by using the old Invirase formulation (saquinavir hard gel capsules), which, when given with ritonavir, achieves similar saquinavir concentrations without the gastrointestinal side effects.

Crixivan (indinavir)/ritonavir: Ritonavir slows the metabolism of Crixivan but does not improve its absorption. Thus the dose of ritonavir given with Crixivan is sometimes higher than with the other PIs, which may make it harder to tolerate. A trial of Crixivan (1200 mg) plus ritonavir (400 mg), in combination with Videx and Epivir, all given once daily, reported successful responses out to week 24 in seven of nine patients. Two patients had blood in the urine (associated with kidney problems), and one was diagnosed with kidney stones. Another study of Crixivan (1200 mg) plus ritonavir (200 mg), given once daily in combination with Zerit and Epivir both given twice daily, has reported success out to week 24. The small size and short length of these studies is worrisome. Like saquinavir, minimum blood concentrations of Crixivan fall below targeted levels in a percentage of patients.

Once-Daily Combination Regimens

Even if a drug is effective once a day when given with other antivirals taken twice a day, it may not perform adequately as part of an all once-a-day regimen. The antiretroviral coverage with an all once-daily regimen might be weak at hour 24, and, if the next dose is delayed or missed, virtually non-existent. These regimens haven't been compared to standard therapy in any large study.

A couple of studies have evaluated a once-a-day combination of Sustiva/Videx EC/Epivir. One enrolled 75 patients with an average CD4 cell count of 251 and an average viral load of 123,000 copies/mL. After 48 weeks, 77% of those who started treatment had a viral load below 50 copies/mL. There was no difference in response between patients with higher or lower viral loads at study entry. The regimen was well tolerated, but Videx was given at a 300 mg dose to all patients regardless of weight. [300 mg is only recommended for adults who weigh less than 132 pounds; heavier patients are given 400 mg.]

Another study used the same combination in 40 patients in Senegal, with Videx EC weight adjusted. At the end of 24 weeks, 78% had viral loads below 50 copies/mL and the average increase in CD4 cell count was 153 cells. Similar responses have been reported with Sustiva and Videx in combination with Coviracil (FTC).

The controversial combination of Sustiva plus Viramune (plus Videx), all once-a-day, was successful in one study, both in people who had taken antiretrovirals before and those who hadn't. Viramune anchored the once-a-day regimen in a few small studies where dosing was directly observed by a nurse or social worker. One reported comparable responses whether using once-a-day (mainly Viramune-based plus Epivir/Videx) or twice-a-day antiretroviral regimens (mainly protease inhibitor-based) in 54 people enrolled at a methadone clinic. 65% of the participants achieved viral loads less than 400 copies/mL at 24 months. This is despite a high viral load at study entry of 210,000 copies/mL and despite the fact that all patients were on methadone. [Viramune reduces methadone blood levels, so the methadone dose must be increased by about 45% to avoid withdrawal.]

Once-a-day Agenerase (1200 mg), ritonavir (200 mg), plus Videx (400 mg) and Epivir (300 mg) worked well in adherent patients from a similar population, although the researchers excluded many patients for skipping doses.

The Variable Patient

Drug pharmacokinetics vary from person to person due to differences in metabolism (sometimes inherited), diet, smoking, alcohol or recreational drug use, gender, other medications, and infections such as viral hepatitis. The best solution is to tailor the combination, whether once or twice daily, to the individual.

For most patients, plasma and intracellular concentrations of drug and therapeutic efficacy might be similar on a once-a-day or twice-a-day regimen. But a minority can represent many people and could possibly include you. For the time being, there are many theoretical concerns about starting with or switching to a once-a-day regimen, particularly the protease inhibitor-based combinations, and little reassuring clinical data to guide individual treatment decisions. Two types of laboratory tests that aren't yet used in clinical practice -- therapeutic drug level monitoring and gene screening -- could someday help determine whether a person has adequate levels of drug on a regimen.

In the meantime, it makes sense to choose regimens that are tried and tested, or at least those drugs with pharmacokinetic profiles that aren't stretched thin by once-a-day usage. Or stick with a twice-a-day regimen. Either way, staying on treatment requires commitment, hard work and a support network. Even if an all-in-one, once-daily small pill is developed, people will still have to take it every day. The struggle to do that consistently should not be underestimated.

Theo Smart works with SAFE-T, the Southern African Fund to Enable Treatment, in Cape Town, South Africa.

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 AIDS Community Research Initiative of America. It is a part of the publication ACRIA Update. Visit ACRIA's website to find out more about their activities, publications and services.
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