The Pharmacology of Nucleoside and Nucleotide Reverse Transcriptase Inhibitors: Implications for Once-Daily Dosing

Once-daily dosing has become the Holy Grail of HIV drug development, and the pharmaceutical industry has canonized it as a highly sought-after and almost required outcome of the ongoing search for new antiretrovirals for the treatment of HIV infection.

Almost everyone –researchers, clinicians, and patients—agree that once-daily dosing has a powerful and beneficial effect on patient adherence, and thus on the effectiveness of the drug regimen.

In an article appearing in the supplement of the August 1, 2005 Journal of Acquired Immune Deficiency Syndromes, researchers have evaluated the pharmacology of nucleoside and nucleotide RTIs and its implications for once daily dosing. Following are excerpts from that document. It is strongly recommended that readers, especially clinicians, review the article in JAIDS in its entirety (see reference below):

Summary

The trend toward once-daily dosing in HIV antiretroviral therapy is based on the association between adherence, treatment outcome, and patient preferences. Patients prefer simpler treatments, fewer pills, less frequent dosing, and no food restrictions. When a regimen meets a patient's preferences, the patient is more likely to be adherent, and with good adherence, the regimen is more likely to be effective.

Nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) have been a prime focus for developing once-daily therapies primarily because they form the backbone of most current regimens. Within the NRTI class, however, drugs differ in their pharmacokinetic properties, such as plasma and intracellular half-lives, and thus in their suitability for once-daily dosing.

For example, newer NRTIs, such as tenofovir [Viread] and emtricitabine [Emtriva], combine longer plasma half-lives with longer intracellular half-lives, prolonging exposure and the period of pharmacologic activity. Of equal importance, the clinical impact of systemic and intracellular interactions between concomitant drugs defines which once-daily drugs may be combined in once-daily regimens.

To construct simplified and effective therapies for individual patients, clinicians require an understanding of the plasma and intracellular pharmacokinetic properties of NRTIs and how these properties determine a drug's appropriateness for once-daily dosing and placement within a once-daily regimen [emphasis added--Ed].

Successful long-term control of HIV replication requires a high degree of adherence to the dosing schedule, such that approaching 100% of doses are taken on time. A recent survey revealed that HIV-positive patients receiving antiretroviral therapy (ART) reported that they would prefer an antiretroviral combination that could be taken once a day, does not involve a large number of pills, and is without dietary requirements. This is supported by a meta-analysis of virologic outcome data from clinical trials of various ART regimens that found a significant correlation between lower pill burden and treatment efficacy.

The pharmaceutical industry is alert to patient preference and its implication on adherence, and therefore has recognized compact once-daily dosing as an important feature of new drug development. With the exception of enfuvirtide [Fuzeon], only once-daily anti-HIV drugs have been launched since 2001 [FDA recently approved tipranavir (Aptivus)/ritonavir, as a twice daily regimen--Ed].

Notably, in August 2004, the US Food and Drug Administration (FDA) approved 2 coformulated nucleoside analogue combinations--abacavir [Ziagen] with lamivudine [Epivir]: Epzicom and tenofovir with emtricitabine: Truvada--intended for once-daily administration. In addition, a coformulation of tenofovir, emtricitabine, and efavirenz [Sustiva] in a single once-daily pill is in development.

This clear emphasis on once-daily drugs is indicative of a trend in ART to simplify treatment regimens by developing drugs and drug combinations that can be taken once daily in an effort to improve not only adherence but treatment outcome.

Despite the emphasis on once-daily drugs, it is not a given that every existing antiretroviral can be re-released in a once-daily form or that every newly developed antiretroviral can routinely be labeled as a once-daily drug [emphasis added—Ed].

As a class, nucleoside reverse transcriptase inhibitors (NRTIs), which include nucleosides and nucleotides, have been a prime focus for developing once-daily therapies, primarily because they form the backbone of virtually all currently used regimens. Within the NRTI class, however, drugs differ in their pharmacokinetic properties, and thus in their suitability for once-daily dosing.

To offer patients the benefit of once-daily drugs and regimens, clinicians must understand the plasma and intracellular pharmacokinetic properties of antiretroviral drugs and how these properties determine a drug's appropriateness for once-daily dosing and place within a once-daily regimen. This understanding is the foundation on which clinicians can construct simplified and effective therapies for individual patients.

Importance of Adherence

Key Messages

* Better adherence is associated with better therapeutic outcome.

* For optimal adherence and patient satisfaction, less frequent dosing is usually better.

* Low pill burden per dose and absence of food restrictions also improve adherence.

* The degree of adherence required for optimal response to once-daily drugs is not yet known and likely varies for different classes of drugs.

* When selecting a once-daily regimen for a particular patient, the clinician must take into account factors that would support optimal adherence within that patient's lifestyle.

Adherence is the primary reason behind the enthusiasm for once-daily dosing among patients and clinicians. Adherence to therapy is significant because of its strong association with successful therapy.

For optimal adherence, once-daily dosing is the best dosing regimen possible with currently available agents. Selection of agents within a once-daily regimen, however, requires knowledge of the pharmacokinetics of the drugs and their suitability for once-daily combinations.

Equivalency between once-daily dosing and more frequent dosing is evaluated by comparing pharmacokinetic parameters. Newer NRTIs, such as tenofovir and emtricitabine, combine longer plasma half-lives with longer intracellular half-lives; thus, they have the advantage of prolonged exposure. Clinicians can use half-life data to decide on dosing frequencies of drugs.

Systemic Nucleoside Reverse Transcriptase Inhibitor Interactions

Key Messages

* Lopinavir/ritonavir [Kaletra] increases tenofovir exposure by approximately 30%. This is considered clinically unimportant, except in patients with impaired renal function.

* Tenofovir increases exposure to didanosine [Videx], resulting in potential didanosine-related clinical consequences. A dose reduction of didanosine, when coadministered with tenofovir, compensates for the increased exposure.

* Atazanavir [Reyataz] should be boosted with ritonavir when used in a tenofovir-containing regimen, because tenofovir reduces atazanavir exposure.

* There are no known systemic drug interactions involving emtricitabine.

Impact of Tenofovir on Atazanavir

Tenofovir coadministered with unboosted atazanavir (400 mg once daily) lowers atazanavir exposure by approximately 25%, requiring boosting of atazanavir. This was shown in a study of healthy volunteers receiving atazanavir, EC-didanosine [Videx EC], and tenofovir. A secondary objective of the study was to evaluate changes in the pharmacokinetics of tenofovir and atazanavir when the 2 drugs were coadministered (n = 36) (Bristol-Myers Squibb Company, data on file).

Kaul et al found atazanavir exposure to be decreased when 400 mg of atazanavir is coadministered with 300 mg of tenofovir and food compared with atazanavir given alone. In some patients, the decrease in atazanavir C_min secondary to tenofovir may result in a suboptimal atazanavir concentration, and thus virologic failure. There are no published data, however, that correlate the drug-drug interaction with virologic outcome.

When coadministering atazanavir and tenofovir, it is necessary to increase the exposure of atazanavir. Boosting a 300-mg dose of atazanavir with 100 mg of ritonavir seems to compensate for the negative impact of tenofovir (Bristol-Myers Squibb Company, data on file).

Trough levels of atazanavir boosted with ritonavir (300 mg/100 mg) are 4 times higher than those of unboosted atazanavir (400 mg). Although the exposure of boosted atazanavir is also decreased by tenofovir, the greater exposure offered by the boosting renders the decrease clinically irrelevant when dealing with PI-susceptible virus infection.

A recent study by Kruse et al, however, does not confirm the decrease in atazanavir exposure by the presence of tenofovir. A total of 178 plasma samples were collected from people taking atazanavir with or without tenofovir, but the timing of the dose of atazanavir in relation to blood collection was not rigorous.

Data showed similar trough levels of boosted atazanavir regardless of tenofovir coadministration. The C_trough, however, varied substantially among these subjects. Despite these observations, most clinicians believe it prudent to give atazanavir only in the boosted form when using it in a tenofovir-containing regimen.

Impact of Tenofovir on Didanosine

Multiple studies have demonstrated the interaction between tenofovir and didanosine. Kearney et al found that the exposure to didanosine increases approximately 44% when the buffered tablet formulation of didanosine is given in the fasting state 1 hour before tenofovir (n = 30).

A similar increase (48%) was observed in a subsequent study by Kearney et al when EC-didanosine was given in the fasting state 2 hours before tenofovir (n = 28). In the same study, EC-didanosine given simultaneously with food and tenofovir further increased the exposure (60%). Because increased exposure to didanosine can result in the development of pancreatitis and/or peripheral neuropathy, this degree of drug-drug interaction can be of concern.

Assessments of didanosine dose reduction instruct that when tenofovir is also included in the regimen, a lower dose of didanosine (250 mg) compensates for the increased exposure. There is debate among clinicians, however, whether patients weighing <60 kg should have an even greater dose reduction (ie, 200 mg). There are no data available yet on this issue. Recent early treatment failures associated with regimens containing tenofovir and didanosine (more detailed discussion to follow) suggest caution in using these 2 agents in combination.

The mechanism for this interaction is believed to involve purine phosphorylase, a key enzyme required for the metabolic breakdown of didanosine. Findings from enzymatic inhibition assays point to inhibition of this enzyme by the phosphorylated metabolites of tenofovir, resulting in increased circulating didanosine. This mechanism is discussed in greater detail in the section on intracellular NRTI interactions.

Cellular toxicity may also result from didanosine-tenofovir coadministration. A retrospective analysis showed a significant decrease in CD4, CD8, and total lymphocyte cell counts, despite an undetectable viral load, in patients receiving didanosine and tenofovir (n = 302).

More than 50% of patients had a decrease of 100 CD4 cells at 48 weeks. Patients not receiving coadministered didanosine and tenofovir did not experience the decrease but instead had a steady increase in cell counts. Data from the study do not point to one drug or the other as the cause of the decrease.

Patients who received only one or the other drug (but not both) did not experience the decline in cell counts. The mechanism for this toxicity is unclear, although a role for guanosine triphosphate has been put forward. The decrease in CD4 cell count suggests worsening immunodeficiency, but there are no clinical data to correlate with this laboratory observation.

Summary

Drug-drug interactions can result in an increase or decrease in exposure to the drugs. Understanding the therapeutic indices of the drugs in question and knowledge of the plasma concentration of the drug necessary for maximal efficacy are important determinants of the significance of these drug-drug interactions. For a drug with a high therapeutic index, like lamivudine [Epivir], a 2-fold increase in exposure is not clinically significant, but for a drug with a low therapeutic index, like didanosine, even small increases in exposure can result in excess toxicity.

Intracellular Nucleoside Reverse Transcriptase Inhibitor Interactions

Key Messages

* Intracellular interactions of clinical impact do occur within the NRTI class of antiviral agents.

* An interaction that decreases a drug's intracellular phosphorylation also decreases its antiviral activity. Such a decrease must be considered when making dosing decisions.

* Ribavirin and didanosine should not be coadministered because of didanosine-related mitochondrial toxicity.

* Although in vitro data suggest a decrease of antiviral activity when ribavirin and zidovudine are coadministered, data from clinical trials show no loss of efficacy.

Nucleoside Reverse Transcriptase Inhibitors: Ribavirin

Potential interactions between NRTIs and ribavirin are of timely interest because of ribavirin's extensive use among the large number of patients coinfected with hepatitis C virus (HCV) and HIV. Worldwide, an estimated 25% of the 40 million individuals infected with HIV are also coinfected with HCV.

Typically, anti-HCV therapy includes up to 48 weeks of peginterferon alfa coadministered with ribavirin. Ribavirin is used with caution in coinfected patients, however. Independent of ART, there is concern for the development of dose-dependent hemolytic anemia, the primary adverse effect of ribavirin. Associated with ART, there is the potential for a ribavirin-NRTI drug interaction, which, in turn, raises concerns about antiviral efficacy and toxicity.

A key large study by Gries et al investigated the effect of ribavirin on intracellular and plasma kinetics of nucleosides in patients who are coinfected with HIV and HCV.

Study data supported the conclusion that ribavirin seemed not to perturb the intracellular metabolism of lamivudine, stavudine [Zerit], or zidovudine [Retrovir] or their corresponding endogenous nucleoside triphosphates. In addition, ribavirin seemed not to modify the plasma concentration-time profile of lamivudine, stavudine, or zidovudine.

The clinical relevance of these findings is that ribavirin, as part of an interferon-based regimen for the treatment of HCV infection, in combination with stavudine, lamivudine, and zidovudine does not have a negative impact on anti-HIV efficacy. This finding is consistent with findings from large trials of coinfected patients receiving treatment with peginterferon and ribavirin. No loss of disease control has been observed in these trials.

A number of questions arise from the study of Gries et al,however. What would be the effect of a higher dose (>800 mg/d) of ribavirin? Would 1200 mg/d produce a toxic effect? With an initial time point of 8 weeks, what happened before the first time point? What happened before the cell's homeostatic mechanism had already returned the state to normal? Indeed, some preliminary data suggest that higher doses of ribavirin may have an impact on intracellular phosphorylation.

Summary

Clinicians must be aware of the interactions between antiretrovirals and between antiretrovirals and other concomitant drugs. Most of the interaction data, however, refer to PIs or NNRTIs-a reflection of the fact that these drugs are extensively metabolized by CYP450 enzymes. Our understanding of interactions involving NRTIs, especially at the phosphorylation level, is more limited and reflects, in part, the difficulty of being able to measure the drug phosphates in patient studies. It is thus vital for the clinician to be aware that interactions may not only theoretically occur but do occur in practice.

More clinical studies are warranted to aid our understanding of NRTI disposition.

Clinical Pharmacologic Perspective on Once-Daily Regimens and NRTI Failures

Key Messages

* The utility of once-daily regimens is different in treatment-naive patients compared with treatment-experienced patients because of resistance.

* The precise mechanism of early failure for some regimens is unclear. It is too early to discard all triple- or quadruple-NRTI regimens; more studies need to be done.

* The pharmacologic principle of symmetry (ie, matching drugs for pharmacokinetic properties) is important when combining antiretroviral drugs, primarily because of resistance concerns.

The potential benefit of once-daily therapy, in terms of simplicity and adherence, makes these regimens appealing to clinicians and patients. It can be a challenge, however, to determine if a once-daily regimen is appropriate for a particular patient, and if so, which regimen. The patient's virus and treatment history as well as the properties of the drugs and regimen must all be considered when deciding if once-daily therapy is appropriate for a particular patient.

Table 1 lists drugs that have pharmacokinetic properties that would support once-daily dosing. The listed drugs are FDA-approved for once-daily administration (indicated with an asterisk) or are in sufficiently advanced clinical development, with published or reported studies, that a clinician might consider prescribing them for once-daily use.

Table 1. Once-Daily Drugs

Tenofovir

Tenofovir [Viread] is the first antiretroviral NRTI developed from the outset and approved by the FDA as a once-daily drug, with plasma and intracellular half-lives of 17 and >60 hours, respectively. Tenofovir is currently approved for treating HIV infection in adults in combination with other antiretroviral agents.

In antiretroviral-experienced patients, the addition of once-daily tenofovir to existing therapy resulted in a further sustained decrease in HIV plasma RNA concentrations of 0.65 to 0.87 log copies/mL compared with placebo after 48 weeks of treatment.

Several large trials have confirmed the antiretroviral activity of tenofovir in 3-drug regimens with other agents, including other NRTIs, PIs, and NNRTIs. In a 3-year randomized, double-blind, comparison trial in which treatment-naive patients also received lamivudine and efavirenz, 300 mg of tenofovir administered once daily was as effective as 40 mg of stavudine administered twice daily and was better tolerated.

Patients receiving tenofovir showed significantly fewer adverse effects associated with mitochondrial toxicity (lactic acidosis, peripheral neuropathy, and lipodystrophy) compared with patients receiving stavudine and had better total fasting lipid profiles.

Emtricitabine

Emtricitabine [Emtriva] was also developed from the outset as a once-daily agent based on its pharmacokinetic properties, including its 10-hour plasma half-life and its >39-hour intracellular half-life. Emtricitabine is FDA approved for treating HIV infection in adults in combination with other antiretroviral agents.

In 2 small monotherapy trials, emtricitabine at a dose of 200 mg administered once daily produced a maximal mean drop in HIV plasma RNA concentration of 1.9 logs. Several large trials have confirmed the antiretroviral activity of emtricitabine in 3-drug regimens with other agents, including NRTIs, PIs, and/or NNRTIs. In 2 randomized comparison studies, emtricitabine- and lamivudine-based triple-combination regimens had similar long-term efficacy.

Lamivudine

Lamivudine [Epivir] was originally marketed as a twice-daily drug with a recommended dose of 150 mg taken twice daily. This dosage was based in part on the short half-life (5-7 hours) of its parent compound in plasma. The intracellular half-life of lamivudine 5′-TP, however, is 15 to 16 hours, and the drug is now approved by the FDA for 300-mg once-daily dosing.

In a large, prospective, randomized trial, 554 treatment-naive patients received 150 mg of lamivudine twice daily or 300 mg once daily in combination with zidovudine and efavirenz. At the end of 48 weeks, these 2 regimens were indistinguishable in terms of virologic efficacy, CD4 cell response, and adverse effects. In 81 treatment-experienced patients who were fully suppressed on a twice-daily lamivudine regimen, a 300-mg once-daily regimen produced a similar magnitude of viral suppression at 24 weeks compared with the twice-daily regimen.

Abacavir

Like lamivudine and didanosine, abacavir [Ziagen] was originally developed as a twice-daily drug based on plasma pharmacokinetics of the parent compound (plasma half-life: 1.54 ± 0.63 hours). Given the much longer half-life of intracellular carbovir 5′-TP (12-21 hours), however, once-daily dosing is pharmacologically rational.

A comparative prospective trial has demonstrated that once-daily dosing of abacavir is as effective as twice-daily dosing, and on the basis of this trial, abacavir is now FDA approved for once-daily dosing. In addition, the FDA recently approved abacavir for once-daily dosing in a coformulation with lamivudine.

One consideration with abacavir in a once-daily regimen is the possibility of abacavir hypersensitivity syndrome, characterized by fever, abdominal pain, and rash. This syndrome occurs in 3% to 5% of recipients but can be fatal, especially if the patient is re-challenged with the drug. Recent data suggest that this syndrome is the consequence of a specific genetic polymorphism linked to HLA-B57 and the heat-shock locus Hsp70-Hom in the white population. There is no evidence that once-daily administration of abacavir alters the incidence of the hypersensitivity syndrome.

Didanosine

The intracellular triphosphate of didanosine [Videx], ddATP, has a half-life of 25 to 40 hours (although this is actually based on limited data), making once-daily dosing of this drug pharmacokinetically rational. In fact, didanosine was the first antiretroviral nucleoside approved for once-daily administration.

Unless coadministered with tenofovir, however, didanosine must be administered in the fasted state, thereby creating at least a twice-daily regimen when combined with any antiretroviral that must be given with food. This is especially true when didanosine is given with most HIV PIs. Toxicity is a major concern with didanosine, particularly the possibility of peripheral neuropathy and pancreatitis, as has been discussed.

Stavudine-extended Release

Stavudine-XR [Zerit XR] has been approved by the FDA as a once-daily NRTI. At the time of this writing, however, it is not yet commercially available because of manufacturing difficulties.

Regimen Considerations

Recent studies have proven the danger of prescribing untested combinations of once-daily antiretroviral drugs. Several once-daily regimens have produced high rates of early virologic nonresponse or rapid failure with the development of drug resistance. To date, most of these failing regimens are triple-NRTI combinations.

Recent Experience with Once-Daily Nucleoside Reverse Transcriptase Inhibitor-Only Combination Regimens

A small pilot study by Farthing et al assessed the efficacy of a once-daily regimen of 600 mg of abacavir, 300 mg of lamivudine, and 300 mg of tenofovir in treatment-naive patients. At week 8, 9 (52%) of 17 patients had viral rebound after initial viral suppression.

The tenofovir/lamivudine/abacavir (ESS30009) trial reported by Gallant et al was a randomized, prospective, open-label, multicenter study evaluating once-daily regimens in 345 treatment-naive patients. The regimens consisted of 600 mg of efavirenz or 300 mg of tenofovir in combination with the fixed dose coformulation of 600 mg of abacavir and 300 mg of lamivudine.

Because of early reports of poor antiviral efficacy from some investigators, an unplanned interim analysis at 8 weeks was conducted after most patients had completed 8 weeks of treatment.

At week 8, 50 (49%) of 102 patients who were receiving the triple-NRTI regimen met the definition of virologic nonresponse (194 patients were at or beyond week 8 at this point). In contrast, only 5 (5.4%) of 92 of those receiving the regimen containing efavirenz met the failure definition. As a result, the triple-NRTI arm of this study was immediately terminated.

A single-site pilot study of 22 treatment-naive patients receiving the triple-NRTI once-daily regimen of 250 mg of EC-didanosine, 300 mg of lamivudine, and 300 mg of tenofovir was also terminated early because of poor efficacy. By week 12, 20 (91%) of 22 patients met the definition of virologic failure.

Landman et al conducted an abacavir/lamivudine/tenofovir (TONUS) pilot study in which treatment-naive patients received once-daily abacavir/lamivudine/tenofovir for 12 months. Like the other triple-NRTI trials discussed, this trial was also stopped after an unplanned interim analysis. Twelve of 36 patients met the definition of virologic failure.

Elion et al reported on an abacavir/lamivudine/zidovudine/tenofovir (COL40263) open-label multicenter trial in which a once-daily regimen of abacavir, lamivudine, zidovudine, and tenofovir was studied. Unlike the previously discussed all-NRTI regimens, this regimen produced virologic failure in only 10 (11%) of 88 treatment-naive patients at week 8, suggesting the possible benefit of a 4-drug regimen or the benefit of using zidovudine with tenofovir.

Conclusions from Recent Experience With Once-Daily Nucleoside Reverse Transcriptase Inhibitor-Only Combination Regimens

Until more is known about the mechanism underlying early virologic treatment failure in these trials, clinicians should probably not administer tenofovir in combination with didanosine and lamivudine or in combination with abacavir and lamivudine for treatment-naive or treatment-experienced patients unless other drugs are added to the regimen. Inclusion of a thymidine analogue is likely to potentiate a tenofovir-containing triple-NRTI regimen.

Recent Experience with Once-Daily Nonnucleoside Reverse Transcriptase Inhibitor Plus Nucleoside Reverse Transcriptase Inhibitor Regimens

Recently (November 2004), a Dear Health Care Provider letter was issued by Bristol-Myers Squibb Company warning of the risk of virologic failure in patients with a high baseline viral load when receiving didanosine, tenofovir, and efavirenz or nevirapine. This warning was based on recently conducted trials by Podzamzcer et al the first reports implicating NNRTIs in combination with NRTIs in early failure (Table 2). Study is ongoing to determine the mechanism and clinical implications of these failures.

Table 2. Once-Daily Regimens

Summary

·         Several NRTIs have pharmacokinetic properties that support once-daily dosing.

·         Unexpected early virologic failure has been seen with the once-daily triple-NRTI combinations of didanosine/lamivudine/tenofovir and abacavir/lamivudine/tenofovir.

·         Combining these agents with a once-daily NNRTI or PI has not been associated with early virologic treatment failure.

Unanswered Questions

There are many issues that need further study:

* What is the optimal adherence threshold for once-daily regimens?

* What is the total pill burden patients are willing to take at a single time?

* What is the extent of increased cell activation associated with HIV infection?

* What is the relation between plasma and intracellular pharmacokinetics for all NRTIs?

* Is there differential phosphorylation in different cell types in vivo?

* Why have some once-daily regimens failed, despite lack of evidence of adverse systemic or intracellular interactions?

* Should tenofovir be routinely combined with a thymidine analogue to prevent emergence of the K65R resistance mutation?

Conclusion

·         Once-daily dosing and regimens improve the convenience and simplicity of treatment.

·         The complexity of the pharmacokinetic parameters and interactions affecting this simplified treatment, however, must first be defined and managed.

·         Each drug is unique, and not all drugs have the appropriate pharmacokinetic properties to qualify for once-daily dosing.

·         Among the current once-daily drugs, tenofovir has the longest plasma and intracellular half-lives, and thus the most prolonged exposure.

·         Until further research is completed, care providers should be cautious in using untested combinations of antiretroviral drugs.

From the *Department of Pharmacology, University of Liverpool, Liverpool, United Kingdom; †Department of Clinical Pharmacology, University Medical Centre Nijmegen, Nijmegen, The Netherlands; ‡Departments of Medicine, Pharmacology, Molecular Sciences, and International Health, The Johns Hopkins University School of Medicine, Bloomberg School of Public Health, Baltimore, MD; and §Departments of Medicine and Pharmacology, University of Colorado Health Sciences Center, Denver, CO.

This independent continuing medical education activity was supported by an educational grant from Gilead Sciences, Inc.

07/06/05

Reference
D J Back and others. The Pharmacology of Antiretroviral Nucleoside and Nucleotide Reverse Transcriptase Inhibitors: Implications for Once-Daily Dosing. Journal of Acquired Immune Deficiency Syndromes 39 (Supp 1): S1-S23.