In Epzicom, the components Epivir and Ziagen are well known as antiretroviral agents from the nucleoside reverse transcriptase (NRTI) class. Epivir (lamivudine) was first approved in November 1995 and Ziagen (abacavir) in December of 1998. Both have long track records of use, originally administered as twice-daily drugs.
In Truvada's ingredients, Viread (tenofovir DF) was uniquely developed as the first nucleotide and is administered as a one pill, once daily; it was observed to be uniquely effective against Epivir-resistant virus. Approval of Emtriva (emtricitabine) followed last year, another once-a-day pill. Emtriva (emtricitabine) is a nucleoside analog that is similar to 3TC (Epivir) with advantages of having favorable pharmacokinetic (PK) profile (for discussion on PK, see below) that permits once-daily dosing and its' potency was a little stronger than Epivir. In HIV-infected volunteers, 200 mg once daily of Emtriva compared with twice-daily 3TC 150 mg showed a more potent viral load drop after 11 days of treatment (-1.7 compared to -1.45 log10 c/ml; 6th CROI, 1999).
Ziagen HSR is a systemic allergic reaction often manifesting as flu-like symptoms. When it takes place, it is associated with at least two of various side effects occurring simultaneously including: skin rash, fever, body aches, malaise, headaches, abdominal symptoms, shortness of breath. One should know that this HSR only occurs in 5-9% of patients starting Ziagen and usually occurs within the first two-three weeks of treatment. Once a person experiences this HSR, they can never attempt taking Ziagen again. Because Ziagen is a component of Epzicom, the vigilance regarding HSR is also needed with Epzicom.
Both pharmaceutical companies would like physicians to choose their products for newly diagnosed and antiretroviral experienced patients. Consider the mounting competition in the marketplace for companies involved in the development of HIV drugs. Now that there are several once-daily antivirals, competition is heating up and companies are vying for market share and leadership. Experienced physicians following the progress and research regarding these agents should understand the scientific attributes of each and tailor regimens to specific individual patient needs.
Different PK considerations must be taken into account for the nucleoside reverse transcriptase inhibitor (NRTI) class because these agents are phosphorylated intracellularly (chemically altered within the cell) to become active. Thus, a drug effect is dependent on dose, plasma (blood) half-life, rate of intracellular phosphorylation and intracellular half-life.
When first approved, Viread and Emtriva were both developed and approved to be administered once-daily, in contrast to Epivir and Ziagen which were originally developed and administered twice per day. As newer techniques to study cellular half-lives were used (PBMCs, as opposed to cancer cells) the actual PKs of Epivir and Ziagen became better understood. These recent studies of the pharmacokinetic properties and clinical efficacy made it possible to consider reducing dosing frequency of Epivir and Ziagen (abacavir) to once daily.
As illustrated in Table 1 below, Ziagen's (abacavir) active drug metabolite (carbovir triphosphate) has an intracellular half-life (longevity within the cell) of 12 to 19 hours, while its serum half-life (blood longevity) is only 1.5 hours. Epivir has an intracellular half-life of the active (phosphorylated) forms of 11 to 16 hours; its activity in plasma is only 3-6 hours. Both components of Truvada have much longer longevity, however. Viread (Tenofovir) has an intracellular half life (intracellular longevity) of more than 60 hours and serum half life being at 17 hours; Emtriva (emtricitabine) intracellularly is 39 hours and serum half life is 10 hours. Patients being human, may miss dosing by several hours from time to time. Drugs with longer half lives, while remaining longer within body cells may be more forgiving and less apt to promote resistance.
|Half Lives of the Epivir Plus Ziagen (Epzicom) and Viread Plus Emtriva (Truvada)|
Longer half lives may be more practical and forgiving, especially for patients who have difficulty taking daily medications promptly, every 12 hours.
|Drug||Intracellular Half-Life||Serum Half-Life|
|Ziagen||12-14 hours||1.5 hours|
|Epivir||14-18 hours||3-6 hours|
|Viread||>50 hours||17 hours|
|Emtriva||39 hours||10 hours|
Importantly, the clinical research supports once-daily dosing of Ziagen (abacavir) and Epivir. One recent clinical study of naive patients (patients not previously treated) evaluated once-daily administrations of both Epivir and Ziagen combined with Sustiva (efavirenz). The Ziagen/Epivir once-daily arm was randomly compared to Ziagen administered twice daily for 48 weeks. (ZODIAC -- CNA30021, 43rd ICAAC, Sept 2003). Both groups of patients had identical antiviral benefit with no increased side effects observed in the once-daily group.
In contrast, preliminary results from a recent trial (study 934) may have also illustrated how PK and tolerability can impact on treatment success. This study compared the components of Truvada, Viread plus Epivir once daily, to treatment with twice-daily Combivir or AZT plus Epivir. AZT's intracellular half life is very short and only 3 hours; its plasma half life is 1.1 hour. Preliminary data at 24 weeks showed superiority in the Viread/Emtriva once daily vs. Combivir (88% vs. 80% had viral loads
Moreover, a clinical study demonstrated once-daily dosing of HAART was better than multi-dosed treatment and was presented at the 10th CROI in 2003 (Molina JM et al). Individuals who had suppressed viral load levels were switched randomly to a new once-daily regimen of emtricitabine (Emtriva), didanosine (ddI-EC), and efavirenz (Sustiva) versus continuation of their old multi-dose protease inhibitor regimens. There was a significant difference favoring the once-daily arm, as 95% vs. 87%, once daily vs. protease inhibitor arms, had undetectable viral loads below 50 copies. The once-daily regimen resulted in improvements in adherence. As more data from large randomized trials become available, once-daily HAART may demonstrate better durability in treatment throughout.
Combining these agents into one pill provide the practicality of lower bill burden and ease of administration. In contrast, pushing individuals to once-daily drug regimens may have other implications. Agents that do not provide full coverage for 24 hours and missing doses while on a once-daily HAART can potentially be a danger for subtherapeutic blood levels during delayed dosing. As an example, in twice-daily regimens, one missed dose a week translates to one out of 14 doses or 8% missed. One missed dose of once-a-day regimen equals missed for a complete 24 hour period or 15% missed. In this situation, more time without antiviral coverage means suboptimal viral suppression. This usually results in lowered antiretroviral plasma (blood) levels leading to development of resistant strains.
Despite the missed dosing drawback, it is generally agreed that once-daily dosing is more practical and patient friendly; ultimately it should improve durability through better adherence. Because there are other factors that influence adherence, seasoned HIV physicians understand that there is no magical answer for all patients.
Various mutations are associated with resistance to specific antiviral agents. For example, mutations such as the M184V is associated with Epivir resistance and K65R can be associated with Ziagen, ddI and /or Viread. If Epivir resistance develops during treatment with Epzicom (M184V mutation), then later treatment with Viread continues to remain a treatment option. However, if Epzicom selects for the L74V mutant, a recent study showed this to potentially result in the eventual emergence of the K65R which can potentially block an option for later treatment with Viread.
During phase 2 and 3 trials (studies 902 & 907), Viread was given to highly treatment experienced patients. The infrequent presence of K65R was associated with only low grade resistance to Viread. The few patients during these trials who had this mutation also had a history of Ziagen or ddI treatment (previously), which was implicated as the cause of the K65R. Moreover, the K65R mutation is associated with a low-grade resistance to ddI and Ziagen, and moderate resistance to Epivir. In a real world clinic, resistance to Viread occurs relatively infrequently and patients who have the K65R often respond to Viread treatment (and is often sensitive by phenotypic testing).
To make things more complicated, if a patient takes Truvada and develops both K65R and M184V, there is the potential to eliminate later options for treatment with Ziagen and Epzicom. However, if one developed resistance with Combivir or AZT, the mutations are generally of the TAMS variety or thymidine-associated mutations. This also blocks one's potential options with Viread later on as well as other agents.
Thus one can see how complicated drug sequencing becomes, especially when newer treatments come to market. We usually don't have all the answers at first.
Daniel S. Berger, M.D., is Medical Director of Chicago's largest private HIV treatment and research center, NorthStar Healthcare and Clinical Assistant Professor of Medicine at the University of Illinois at Chicago. He serves as medical consultant and columnist for Positively Aware and serves on the HIV Medical Issues Committee for the Illinois AIDS Drug Assistance Program, the Board of Directors for the AIDS Foundation of Chicago and the Editorial Board of Contagion, Reports, Cases, and Commentaries in HIV and Infectious Disease Research. Dr. Berger can be reached at DSBergerMD@aol.com or (773) 296-2400.
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