ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, July 2005, p. 2828–2833
Copyright © 2005, American Society for Microbiology. All Rights Reserved.
Vol. 49, No. 7
Safety, Pharmacokinetics, and Efficacy of
(?/?)-?-2?,3?-Dideoxy-5-Fluoro-3?-Thiacytidine with Efavirenz and
Stavudine in Antiretroviral-Naı ¨ve Human Immunodeficiency
C. Herzmann,1K. Araste `h,1R. L. Murphy,2H. Schulbin,1P. Kreckel,1D. Drauz,1R. F. Schinazi,3
A. Beard,4L. Cartee,4and M. J. Otto4*
EPIMED GmbH, Vivantes Auguste-Viktoria-Klinikum, Berlin, Germany1; Northwestern University, Chicago, Illinois2; Emory
University School of Medicine and VA Medical Center, Decatur, Georgia3; and Pharmasset, Inc., Tucker, Georgia4
Received 27 July 2004/Returned for modification 20 September 2004/Accepted 18 March 2005
Racivir [RCV; (?/?)-?-2?,3?-dideoxy-5-fluoro-3?-thiacytidine], a 50:50 racemic mixture of the two ? nucle-
oside enantiomers, is currently in development for the treatment of human immunodeficiency virus type 1
(HIV-1) infections. RCV was administered once a day orally for 14 days at doses of 200, 400, or 600 mg in
combination with stavudine and efavirenz to HIV-1-infected treatment-naı ¨ve male volunteers in a phase Ib/IIa
study. Six volunteers at each dose were monitored for a total of 35 days for tolerance, pharmacokinetics, and
plasma HIV RNA levels. RCV in combination with stavudine and efavirenz was well tolerated at all doses
tested. Pharmacokinetic parameters were dose proportional, and the maximum concentration of drug in serum
at all doses exceeded the 90% effective concentration for wild-type HIV-1. Viral loads dropped as expected in
all dosage groups, with mean reductions from 1.13 to 1.42 log10by day 4 and 2.02 to 2.43 log10by day 14. HIV
RNA levels remained suppressed for more than 2 weeks in the absence of any additional therapy, with mean
viral loads ranging from 2.1 to 2.6 log10below baseline through day 28. By day 35, HIV RNA levels began to
increase but still remained >1 log10below baseline levels.
Racivir [(?/?)-?-2?,3?-dideoxy-5-fluoro-3?-thiacytidine; (?/?)-
FTC; RCV] is a novel drug currently being investigated as a
therapeutic agent for human immunodeficiency virus type 1
(HIV-1) and hepatitis B virus (HBV) infections.
RCV is a 50:50 mixture of the two ? enantiomers. The
chemical properties of the two enantiomers are essentially
identical. As triphosphates, both enantiomers are potent in-
hibitors of HIV-1 reverse transcriptase (11). Interestingly,
studies have shown that they select for different mutations on
the HIV-1 reverse transcriptase gene in vitro, M184V for the
(?) enantiomer and T215Y for the (?) enantiomer (9, 10). In
addition these same studies showed that time to emergence of
resistant virus in peripheral blood mononuclear cell culture
was prolonged with RCV (14 weeks) compared to either lami-
vudine (3TC) (9 weeks) or (?)-FTC (9 weeks) (7, 8; R. F.
Schinazi, personal communication). This could be advanta-
geous for a therapeutic regimen if the emergence of resistance
mutations in patients were also delayed. In vitro studies with
(?)-FTC] is active against HIV (90% effective concentration
[EC90], 0.04 and 0.6 ?M, respectively) as well as HBV (EC90,
0.01 and 0.9 ?M, respectively) (5, 7). A major advantage of
using RCV would be that the virus would be challenged with
two different compounds, which should increase the difficulty
of developing resistance to both enantiomers (10). Both enan-
tiomers are well absorbed orally and have demonstrated low
toxicity in preclinical safety studies (1, 2, 3, 4, 8).
RCV is well tolerated when given orally once a day in rats up
to 1 g/kg of body weight per day for 6 months and dogs up to
100 mg/kg per day for 12 months (unpublished data). This is in
contrast to other racemic nucleoside mixtures in which toxicity
was found to be associated with one of the enantiomers (e.g.,
BCH-189 and 3TC) (2, 3, 6, 12). Pharmacokinetic studies
showed dose-dependent blood plasma levels with mean maxi-
mum concentrations (Cmax) of 19 ?g/ml in dogs (at 100 mg/kg)
and 97 ?g/ml in rats (at 1 g/kg). The only adverse event noted
in either species was emesis in some dogs at 300 mg/kg/day
(unpublished data). At this dose there were no other adverse
events or gross toxicity nor abnormal histopathologic findings.
The primary objective of this study was to explore the safety
and tolerability of RCV in combination with efavirenz and
stavudine (d4T) during a 14-day oral regimen in HIV-infected
male subjects. The secondary objectives of this study were to
determine the pharmacokinetics of RCV in plasma and urine.
Furthermore, a virologic response of HIV to RCV in combi-
nation with efavirenz and stavudine was assessed. CD4 cell
counts were also measured during the trial.
MATERIALS AND METHODS
The study was approved by the ethics committee of the Berlin (Germany)
Chamber of Physicians (Berliner A ¨rztekammer) and conducted under a U.S.
Food and Drug Administration Investigative New Drug Application. Oral and
written information was given to all patients, and written consent was obtained
before trial-specific procedures.
Protocol outline. Participants were aged 25 to 45 years and naı ¨ve to antiret-
roviral therapy. Subjects were required to have a viral load above 5,000 copies/
ml, a CD4 cell count above 50 cells/?l, and a body mass index above 18 kg/m2.
Patients with significantly abnormal laboratory results or electrocardiogram ab-
normalities or a positive urine drug screening or breath alcohol test were ex-
* Corresponding author. Mailing address: Pharmasset, Inc., 1860
Montreal Rd., Tucker, GA 30084. Phone: (678) 395-0047. Fax: (678)
395-0030. E-mail: firstname.lastname@example.org.
cluded. Further exclusion criteria were participation in another clinical trial
within the last 3 months, a history of substance dependency, or any other medical
condition compromising adherence to the protocol. It should be noted that none
of the subjects enrolled in this study needed to be placed on highly active
antiretroviral therapy under current treatment guidelines.
This was a dose escalation study with three groups of six subjects each receiv-
ing a 14-day course of 200 mg, 400 mg, or 600 mg of RCV once daily in
combination with twice-daily stavudine (30 mg twice a day or 40 mg twice a day
for subjects below or above 60 kg of body weight, respectively) and efavirenz (600
mg once daily). Additionally, a control group of six subjects received a 14-day
course of 300 mg 3TC once daily, instead of RCV, in combination with stavudine
and efavirenz. Since monotherapy with RCV may have placed the subjects at risk
of acquiring resistant virus, triple therapy was employed so that multiple-dose
pharmacokinetics, safety, and some measure of efficacy could be assessed. The
200-mg-dose group completed the study prior to initiation of the 400-mg-dose
group, who completed the study prior to the 600-mg-dose group. For approxi-
mately one-half of the subjects, treatment was followed by a 21-day follow-up off
therapy. In order to control for adverse events possibly related to concomitant
medication, six control subjects were treated with lamivudine, stavudine, and
By protocol all subjects discontinued their RCV-containing triple-drug therapy
on day 15. Patients were permitted to start any other antiretroviral therapy
thereafter. In some cases, at the discretion of the treating physician, lamivudine
was given for 5 days and stavudine was continued for 5 days. This 5-day course
of dual therapy was given to prevent the emergence of nonnucleoside reverse
transcriptase inhibitor-associated resistance mutations due to the long plasma
half-life of efavirenz.
On day 1 (baseline) and day 14 (last day of treatment period) 24-h blood
plasma and urine excretion profiles were performed. Intracellular concentrations of
the triphosphate form of RCV in peripheral blood mononuclear cells could not be
assessed due to technical difficulties such as interference from red blood cells.
RCV and (?)-FTU determination. A high-performance liquid chromato-
graphic method was developed and validated by Pharmakologische Forschungs-
gesellschaft Biopharm GmbH, Berlin, Germany. RCV and the deaminated
metabolite (?)-FTU [(?)-?-2?,3?-dideoxy-5-fluoro-3?-thiauridine], were ex-
tracted from human plasma with perchloric acid, neutralized with KOH, and
separated in a Phenomenex Hypersil octadecylsilane (C18) reverse-phase column
with a mobile phase of 50 mM phosphate buffer (pH 2.40):methanol:diethyl-
amine (03:7:0,1, vol/vol/vol) with a flow rate of 0.5 ml/min at 35°C. Injections of
50 ?l were performed by the autosampler, and a run time of 20 min per injection
was used. The pump was programmed to wash the column for approximately 3.0
min by using 25% methanol in water following the elution of the internal
standard. The detector was set at a wavelength of 279 nm and an attenuation of
5. Concentrations were determined using standard curves derived from spiked
For RCV and the deaminated metabolite (?)-FTU the following parameters
FIG. 1. Mean plasma concentrations of RCV following once-daily dosing. Values following the first dose of RCV on day 1 and the 14th dose
on day 14 were determined by high-performance liquid chromatography as described in Materials and Methods. Oral doses of 200 mg (}), 400
mg (■), or 600 mg (Œ) of RCV are plotted.
TABLE 1. Pharmacokinetic parameters for RCV (mean ? standard deviation) in blood plasma
Value for group:
RCV, 200 mg (n ? 6)RCV, 400 mg (n ? 6)RCV, 600 mg (n ? 5)
Day 1Day 14Day 1 Day 14Day 1 Day 14
AUC03tlast(ng ? h/ml)
AUC03?(ng ? h/ml)
1,336 ? 520
0.92 ? 0.59
3,827 ? 1,059
4,002 ? 1,237
5.73 ? 2.71
1,272 ? 602
0.67 ? 0.26
3,519 ? 1,633
3,705 ? 1,794
6.04 ? 3.39
2,597 ? 482
0.92 ? 0.59
10,020 ? 1,746
10,677 ? 1,936
6.67 ? 1.48
2,374 ? 435
0.67 ? 0.26
9,272 ? 1,520
99,923 ? 1,846
6.83 ? 2.38
4,140 ? 1,404
0.7 ? 0.27
11,944 ? 5,014
11,990 ? 5,063
2.93 ? 0.6
4,423 ? 1,709
0.6 ? 0.22
12,707 ? 3,449
12,873 ? 3,568
3.43 ? 1.2
VOL. 49, 2005RACIVIR IN HIV-1-INFECTED INDIVIDUALS2829
were determined for blood plasma: observed maximum concentration (Cmax),
time of observed maximum concentration (tmax), area under the plasma concen-
tration-time curve from time zero until the last quantifiable plasma concentra-
tion (AUC03tlast) (linear trapezoidal rule), area under the plasma concentra-
tion-time curve from time zero to infinity (AUC03?), apparent terminal rate
constant derived from the slope of the log-linear regression of the log-linear
terminal portion of the plasma concentration-time curve (?z), and apparent
terminal plasma half-life (t1/2? ln2/?z). The limit of quantification in plasma was
20 ng/ml (?0.08 ?M). The renally excreted amounts of RCV and (?)-FTU were
determined from concentrations in urine and urine weights on day 1 and day 14.
The following pharmacokinetic parameters were calculated: total amount of
drug excreted into urine (Aeur) and renal clearance (CLR). The limit of quan-
tification in urine was 2 ?g/ml (?8 ?M).
HIV RNA levels. Throughout the study, serum HIV RNA was measured
(Roche Amplicor HIV-1 Monitor test, v1.5-Quantitative). Efficacy was assessed
for all subjects using the following values: change from baseline in log10plasma
HIV RNA and AUC of the plasma HIV RNA curve.
CD4 cell counts, electrocardiograms, adverse events, and significant clinical
and laboratory findings were collected and documented throughout the trial.
All statistical analyses were done using SAS (version 8.1) software. Pharma-
cokinetic data were processed with WinNonlin (Windows Non-Linear PK soft-
ware, version 3.1).
Demographics. Twenty-five subjects were enrolled in this
study. One subject dropped out on day 4 due to adverse events
possibly related to efavirenz and/or RCV. The mean age was
33.2 years (standard deviation, ?5.8; range, 25 to 47), mean
body weight was 72.1 kg (?9.6; range, 52.0 to 93.2), and mean
body mass index was 22.5 kg/m2(?2.4; range, 18.5 to 28.4).
Two subjects were suffering from chronic hepatitis B. No rel-
evant coexisting diseases were found at screening, and no in-
teracting drugs were taken.
No changes in CD4 cell counts were observed during the
trial. Mean baseline values were 662 ? 257 cells/?l, 487 ? 222
cells/?l, 431 ? 295 cells/?l, and 545 ? 432 cells/?l in patients
receiving 200 mg, 400 mg, or 600 mg of RCV or receiving
Dosing regimens. Subjects received stavudine and efavirenz
in combination with 200 mg, 400 mg, or 600 mg RCV once a
day or 150 mg lamivudine twice a day for 14 days. Per the
protocol, from day 15 onward subjects were permitted to
switch their antiretroviral drugs or, in the case of the lamivu-
dine group, to continue their regimen. There were six subjects
in each dosing group with five/six subjects in the 200- and
400-mg groups stopping all antiretroviral drugs after day 14. At
the end of the 14-day treatment phase five/six subjects in the
600-mg-RCV group and five/six subjects in the lamivudine
group received stavudine plus lamivudine for an additional 5
days (days 15 to 19) and then stopped all antiretroviral drugs.
One subject in each group was switched to lamivudine plus
stavudine plus efavirenz on day 15 and remained on this reg-
imen during the follow-up period.
Pharmacokinetics. The plasma pharmacokinetic profiles for
RCV are shown in Fig. 1. Mean peak plasma concentration
(Cmax) values for RCV were 1,336 ? 520 ng/ml, 2,597 ? 482
ng/ml, and 4,140 ? 1,404 ng/ml for the groups taking 200 mg,
400 mg, and 600 mg of RCV on day 1, respectively. Cmaxvalues
on day 14 were similar. A dose-dependent relationship be-
tween mean peak plasma concentrations of RCV was found for
the three treatment groups on days 1 and 14 (Table 1).
RCV reached its maximum plasma concentration in less
than 1 h. Mean tmaxof RCV ranged from 0.7 to 0.92 h on day
1 and from 0.60 to 0.67 h on day 14 and was not related to the
Mean area under the curve (AUC03tlast) and extrapolated
AUC03?were similar on day 1 and day 14 in each group. A
relationship between dose and these parameters was apparent;
however, this relationship was not strictly dose proportional.
t1/2was approximately 6 h for the treatment doses 200 mg
and 400 mg on day 1 as well as on day 14. t1/2for the 600-mg
group was shorter—approximately 3 h on day 1 and day 14.
Mean plasma Cmaxof the metabolite (?)-FTU ranged from
TABLE 2. Pharmacokinetic parameters for (?)-FTU (mean ? standard deviation) in blood plasma
Value for group:
RCV, 200 mg (n ? 6) RCV, 400 mg (n ? 6) RCV, 600 mg (n ? 5)
Day 1Day 14 Day 1Day 14 Day 1Day 14
AUC03tlast(ng ? h/ml)
AUC03?(ng ? h/ml)
1,335 ? 296
0.68 ? 0.26
2,967 ? 416
3,075 ? 411
3.73 ? 0.2
1,946 ? 367
0.58 ? 0.2
3,525 ? 498
3,630 ? 490
3.61 ? 0.36
3,001 ? 994
0.67 ? 0.41
6,394 ? 1,175
6,516 ? 1,244
4.26 ? 2.94
2,446 ? 648
0.58 ? 0.2
6,201 ? 1,390
6,291 ? 1,385
3.09 ? 0.17
2,860 ? 254
0.8 ? 0.27
7,238 ? 696
7,346 ? 680
3.73 ? 1.64
2,776 ? 627
0.7 ? 0.27
6,911 ? 929
7,026 ? 912
3.99 ? 2.19
TABLE 3. Excretion of unchanged RCV into urine
parameter for RCV
Value for group:
RCV, 200 mg (n ? 5)RCV, 400 mg (n ? 6)RCV, 600 mg (n ? 5)
Day 1 Day 14Day 1 Day 14 Day 1Day 14
90 ? 31.4
362 ? 94.4
90.9 ? 31.2
400 ? 154
183 ? 24.8
295 ? 72.1
260 ? 22.8
457 ? 421
249 ? 68.3
373 ? 97.5
242 ? 65.7
329 ? 97.7
aOne subject in this group had unexpectedly high concentrations of RCV in urine (threefold higher than those of other subjects) on day 14. Plasma concentrations
of RCV were in the same range as those in other subjects.
2830HERZMANN ET AL.ANTIMICROB. AGENTS CHEMOTHER.
1,335 to 2,860 ng/ml on day 1 and from 1,946 to 2,776 ng/ml on
day 14. (?)-FTU levels were directly related to the RCV dos-
(?)-FTU reached its maximum concentration in plasma in
less than 1 h on day 1 and day 14 (Table 2). Mean tmaxof
(?)-FTU ranged from 0.58 to 0.8 h for all doses of RCV,
suggesting a fast metabolism of RCV. Mean AUC03tlastand
extrapolated AUC03?of (?)-FTU showed a similar relation-
ship to dosage as that of RCV. The half-life of (?)-FTU (t1/2)
ranged from 3 to 4 h for all treatment doses. No differences
were found between day 1 and day 14.
Approximately 40 to 45% of the drug was excreted as un-
changed RCV (RCV) (Table 3), and 27 to 40% was excreted as
its metabolite (?)-FTU (Table 4) in all groups. It is of interest
that the percentage of the total dose recovered as the metab-
olite actually decreased with the highest dose. Renal clearance
ranged from 295 to 457 ml/min, indicating that the drug was
eliminated by glomerular filtration and active tubular secre-
tion. Nearly the full amount of RCV was excreted renally
within a day.
Safety. The AIDS Clinical Trial Group (ACTG) classifica-
tion for adverse events was used in this study. RCV was well
tolerated with no significant clinical or laboratory adverse
events. The adverse events reported most often during the
14-day treatment period were dizziness (six, seven, nine, and
five episodes in subjects receiving 200 mg, 400 mg, and 600 mg
of RCV or receiving lamivudine, respectively) and headache
(five, two, five, and one episode, respectively). Both were mild
to moderate in intensity and possibly related to study medica-
tion in 85% (dizziness) and 68% (headache). Other adverse
events reported on more than three occasions during the trial
were impaired concentration, nausea, fatigue, common cold,
and ocular discomfort. One subject taking 600 mg of RCV
reported “heartburn” that was possibly related to the trial
drug. It should be noted that the headaches were associated
primarily with common colds that occurred during the autumn
when this study was being conducted. This may account for the
apparently higher level of headaches in the RCV groups.
One subject taking 600 mg of RCV withdrew his consent on
day 4 due to moderate nausea and vomiting associated with
mild dizziness possibly caused by RCV or efavirenz.
No relevant electrocardiographic, biochemical, or hemato-
logical changes were found. One subject, who had chronic
hepatitis B and was taking 400 mg of RCV, had high levels of
liver enzymes aspartate aminotransferase and alanine amino-
transferase during the whole study (ACTG grade ?1). These
values did not decrease during the course of the study. He
showed a significant elevation (ACTG grade 1) of liver
transaminases due to a flare-up of his chronic hepatitis B
infection after cessation of therapy, and these values were
reported by the physician as an adverse event of elevated liver
enzymes severe in intensity on day 28, which was considered to
be possibly related to study drug (82.6-U/liter aspartate ami-
notransferase; normal range, 17 to 59 U/liter; 119.6-U/liter
alanine aminotransferase; normal range, 21 to 72 U/liter).
Other laboratory parameters did not show values of clinical
Another subject taking 200 mg of RCV presented with sig-
nificantly elevated creatinine phosphokinase after physical ex-
ercise. There were no serious adverse events as defined by the
ACTG classification during the trial or follow-up period.
TABLE 4. Excretion of the metabolite (?)-FTU into urine after administration of RCV
parameter for (?)-FTU
Value for group:
RCV, 200 mg (n ? 5) RCV, 400 mg (n ? 6) RCV, 600 mg (n ? 5)
Day 1 Day 14 Day 1Day 14Day 1Day 14
79.2 ? 21.2
427 ? 103
80.5 ? 31
367 ? 166
172 ? 32.2
450 ? 103
234 ? 23
735 ? 908
183 ? 52.3
423 ? 141
162 ? 27
393 ? 101
aOne subject in this group had unexpectantly high concentrations of (?)-FTU in urine (threefold higher than those of other subjects) on day 14. Plasma
concentrations of RCV and FTU were in the same range as those in other subjects.
TABLE 5. HIV RNA levels in individual subjects during and
Viral load (log10copies/ml)
Day 0 Day 14
On last day of
3.85 2.75 (19)
3.53 2.52 (20)
aSubject 4 switched to 3TC plus abacavir plus efavirenz on day 15 and con-
tinued. Subject 7 switched to 3TC plus zidovudine plus efavirenz on day 15 and
continued. Subject 26 switched to d4T plus efavirenz plus Combivir on day 15
and continued. Subject 27 remained on 3TC plus d4T plus efavirenz. Subjects 13,
14, 15, 16, 20, 21, 22, 24, and 29 switched to 3TC only for 5 days. Subject 28
remained on 3TC plus d4T for 6 days.
VOL. 49, 2005RACIVIR IN HIV-1-INFECTED INDIVIDUALS2831
Virologic response. Virologic response was estimated as the
change of plasma HIV RNA copies/ml. All tested treatment
combinations and doses were effective (Fig. 1). On day 14,
mean decreases in plasma HIV RNA were 1.92 log10, 2.03
log10, 2.17 log10, and 2.25 log10for the groups treated with 200
mg, 400 mg, and 600 mg RCV and with lamivudine, respec-
tively. The effect was not related to the RCV dose. The mean
reduction in plasma HIV RNA on day 28, 14 days after ces-
sation of RCV, compared to baseline was 2.15 log10, 2.18 log10,
2.06 log10, and 2.19 log10for the groups as listed above. It is
important to note that in the 200- and 400-mg-RCV groups the
HIV RNA levels remained suppressed in those subjects who
received no antiretroviral drugs from day 15 to day 35 (Table
5). The mean HIV RNA levels on day 35 for these subjects
were still 1.57 log10and 1.26 log10below baseline for the 200-
and 400-mg groups, respectively.
This phase Ib/IIa study demonstrated a profile of RCV as
safe and well tolerated when taken over 14 days. The doses
chosen for this study were based on the “no adverse effect dose
level” in dogs, i.e., 100 mg/kg for 12 months. In this trial,
weight-related doses ranged from approximately 3 mg/kg (200
mg of RCV) to 8 mg/kg (600 mg of RCV). Based on previous
studies we expected a clinically effective and safe dose of RCV
to be between 200 mg and 600 mg once daily. With the possible
exception of headaches the tolerability of RCV seemed to be
comparable with those of lamivudine and emtricitabine. With
respect to the possible flare-up of chronic hepatitis B in a
subject receiving 400 mg RCV, further investigations are re-
quired for this coinfected group of patients. It was noted that
plasma HBV DNA levels, in this subject, dropped approxi-
mately 2 log10over the 14-day treatment period. Unfortunately
no samples were available to determine HBV DNA levels
during the follow-up period. The other HBV-coinfected sub-
ject who was in the 3TC group showed no evidence of a
flare-up, most probably due to the fact that 3TC dosing was not
stopped after 14 days. The change in HBV viral load in this
subject was not measured due to the unavailability of samples
Maximum plasma concentrations of both RCV and its me-
tabolite (?)-FTU were reached rapidly and were proportional
to the administered dose. The areas under the plasma concen-
tration curve for both compounds were directly related to
dosage of RCV, indicating linear pharmacokinetics.
Most of the total dose (70% to 80%) was excreted into urine
over 24 h, 40 to 45% as unchanged RCV and 27 to 40% as
(?)-FTU. The plasma half-life of RCV was several hours, thus
encouraging further trials assessing the once-daily regimen.
The percentage of dose metabolized to (?)-FTU actually de-
creased as the dose of RCV was increased, suggesting that
metabolism may be saturable.
Virologic response was good in all groups (Fig. 2). Viral
suppression was not dose dependent, indicating that the lowest
dose of RCV (200 mg twice daily) was safe with regards to the
potential for emergence of resistance. These results are not
unexpected given the fact that each group received three po-
tent antiretroviral drugs and that the mean plasma concentra-
tion of RCV at 24 h (approximately 0.1 ?M) remained at or
FIG. 2. Change in plasma HIV RNA in all subjects. Subjects received stavudine and efavirenz in combination with 200 mg (}), 400 mg (■),
or 600 mg (Œ) RCV once a day or 150 mg lamivudine (?) twice a day for 14 days. There were six subjects in each dosing group with five/six subjects
in the 200- and 400-mg groups stopping all antiretroviral drugs. One subject in each group was switched to lamivudine plus stavudine plus efavirenz
on day 15 and remained on this regimen during the follow-up period. All other subjects in the 600-mg-RCV group and in the lamivudine group
received stavudine plus efavirenz for 5 days (days 15 to 19) in the follow-up phase and then stopped all antiretroviral drugs.
2832 HERZMANN ET AL.ANTIMICROB. AGENTS CHEMOTHER.
above the in vitro EC90(0.04 to 0.1 ?M). However, this issue Download full-text
will be addressed in long-term safety and efficacy studies. Viral
suppression was maintained up to 2 weeks after cessation of
therapy with these combinations of antiretroviral drugs most
probably due to the long plasma half-life of efavirenz. Based
on all these data a once-daily regimen with RCV will be in-
In conclusion, RCV is a safe and novel nucleoside reverse
transcriptase inhibitor with promising antiviral features for the
treatment of HIV-1. Phase II and III trials are currently
planned in treatment-naı ¨ve and experienced patients.
Raymond F. Schinazi is a founder, director, and consultant of Phar-
masset and as such holds equity interest in the company. His particu-
lars have been reviewed by Emory University’s Conflict of Interest
Committee. The Schinazi laboratory received no funding from Phar-
masset. Robert Murphy is a consultant to Pharmasset and assisted in
the design of the study including review of safety and efficacy data.
1. Abobo, C. V., L. Ni, R. F. Schinazi, D. C. Liotta, and F. D. Boudinot. 1994.
Pharmacokinetics of 2?,3?-dideoxy-5-fluoro-3?-thiacytidine in rats. J. Pharm.
2. Chang, C. N., S. L. Doong, J. H. Zhou, J. W. Beach, L. S. Jeong, C. K. Chu,
C. H. Tsai, Y. C. Cheng, D. Liotta, and R. Schinazi. 1992. Deoxycytidine
deaminase-resistant stereoisomer is the active form of (?/?)-2?,3?-dideoxy-
3?-thiacytidine in the inhibition of hepatitis B virus replication. J. Biol. Chem.
3. Cui, L., R. F. Schinazi, G. Gosselin, J. L. Imbach, C. K. Chu, R. F. Rando,
G. R. Revankar, and J. P. Sommadossi. 1996. Effect of ?-enantiomeric and
racemic nucleoside analogues on mitochondrial functions in HepG2 cells.
Biochem. Pharmacol. 52:1577–1584.
4. Frick, L. W., L. St. John, L. C. Taylor, G. R. Painter, P. A. Furman, D. C.
Liotta, E. S. Furfine, and D. J. Nelson 1993. Pharmacokinetics, oral bioavail-
ability, and metabolic disposition in rats of (?)-cis-5-fluoro-1-[2-(hydroxy-
methyl)-1,3-oxathiolan-5-yl]cytosine, a nucleoside analog active against hu-
man immunodeficiency virus and hepatitis B virus. Antimicrob. Agents
5. Furman, P. A., M. Davis, D. C. Liotta, M. Paff, L. W. Frick, D. J. Nelson,
R. E. Dornsife, J. A. Wurster, L. J. Wilson, J. A. Fyfe, J. V. Tuttle, W. H.
Miller, L. Condreay, D. R. Averett, R. F. Schinazi, and G. R. Painter. 1992.
The anti-hepatitis B virus activities, cytotoxicities, and anabolic profiles of
the (?) and (?) enantiomers of cis-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxa-
thiolan-5-yl]cytosine. Antimicrob. Agents Chemother. 36:2686–2692.
6. Mansour, T. S., H. Jin, W. Wang, E. U. Hooker, C. Ashman, N. Cammack,
H. Salomon, A. R. Belmonte, and M. A. Wainberg. 1995. Anti-human im-
munodeficiency virus and anti-hepatitis-B virus activities and toxicities of the
enantiomers of 2?-deoxy-3?-oxa-4?-thiocytidine and their 5-fluoro analogues
in vitro. J. Med. Chem. 38:1–4.
7. Schinazi, R. F., A. McMillan, D. Cannon, R. Mathis, R. M. Lloyd, A. Peck,
J. P. Sommadossi, M. St. Clair, J. Wilson, P. A. Furman, G. Painter, W.-B.
Choi, and D. C. Liotta. 1992. Selective inhibition of human immunodefi-
ciency viruses by racemates and enantiomers of cis-5-fluoro-1-[2-(hydroxy-
8. Schinazi, R. F., F. D. Boudinot, S. S. Ibrahim, C. Manning, H. M. McClure,
and D. C. Liotta. 1992. Pharmacokinetics and metabolism of racemic 2?,3?-
dideoxy-5-fluoro-3?-thiacytidine in rhesus monkeys. Antimicrob. Agents
9. Schinazi, R. F., R. M. Lloyd, Jr., M. H. Nguyen, D. L. Cannon, A. McMillan,
N. Ilksoy, C. K. Chu, D. C. Liotta, H. Z. Bazmi, and J. W. Mellors. 1993.
Characterization of human immunodeficiency viruses resistant to oxathio-
lane-cytosine nucleosides. Antimicrob. Agents Chemother. 37:875–881.
10. Schinazi, R. F., A. McMillan, R. L. Lloyd, Jr., S. Schlueter-Wirtz, D. C.
Liotta, and C. K. Chu. 1997. Molecular properties of HIV-1 resistant to
(?)-enantiomers and racemates of oxathiolane cytosine nucleosides and
their potential for the treatment of HIV and HBV infections. Antivir. Res.
11. Shewach, D. S., D. C. Liotta, and R. F. Schinazi. 1993. Affinity of the antiviral
enantiomers of oxathiolane cytosine nucleosides for human 2?-deoxycytidine
kinase. Biochem. Pharmacol. 45:1540–1543.
12. Styrt, B. A., T. D. Piazza-Hepp, and G. K. Chikami. 1996. Clinical toxicity of
antiretroviral nucleoside analogs. Antivir. Res. 31:121–135.
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