Antiretroviral therapy with the integrase inhibitor

raltegravir alters decay kinetics of HIV, significantly

reducing the second phase
John M. Murraya,b, Sean Emerya, Anthony D. Kellehera, Matthew Lawa,
Joshua Chenc, Daria J. Hazudac, Bach-Yen T. Nguyenc,
Hedy Tepplerc and David A. Coopera

Objective: Raltegravir (MK-0518) belongs to the new class of HIV integrase inhibitors.
To date, there have been no reports investigating the potential for differential effects on
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viral dynamics with integrase inhibitors relative to current antiretroviral drugs.

Methods: Patients in this phase II study (P004) were antiretroviral treatment naive.
Part 1 of this study compared monotherapy with raltegravir (100 mg, 200 mg, 400 mg, or
600 mg twice daily) with placebo over 10 days. In part 2, patients were enrolled for
48 weeks of combination therapy, with randomization to one of the four dosages of
raltegravir or to efavirenz, in addition to tenofovir and lamivudine. Mathematical
models were used to investigate processes underlying viral dynamics.
Results: From day 15 through to day 57, individuals in the raltegravir arm were
significantly more likely to have HIV RNA < 50 copies/ml (P
0.047). Plasma viral
loads were 70% lower at initiation of second-phase decay for individuals taking
raltegravir than for those taking efavirenz (P < 0.0001). This challenges the current
hypothesis that second-phase virus originates from infected long-lived cells, as an
integrase inhibitor should not impact on viral production from this cell population.
Mathematical modeling supported two hypotheses as consistent with these obser-
vations: (i) that second-phase virus arises from cells newly infected by long-lived
infected cells and (2) that it arises from activation of latently infected cells with full-
length unintegrated HIV DNA.
Conclusions: These observations challenge the current understanding of HIV-1 turn-
over and compartmentalization. They also indicate the promise of this new integrase
inhibitor raltegravir. ß 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins

AIDS 2007, 21:2315–2321

Keywords: antiviral therapy, HIV-1, integrase inhibitors, mathematical models,

raltegravir, viral load

Introduction requires integration of HIV DNA, an integrase inhibitor

HIV integrase inhibitors are a new class of antiretroviral
drugs that target a crucial process in the life cycle of HIV
[1–3]. They act by blocking incorporation of the proviral
HIV DNA into the host cell DNA. As productive infection
prevents an infectious virion that has progressed through
reverse transcription from successfully infecting the cell.
This class of drugs has a mode of action that is independent
of reverse transcriptase and protease inhibitors and has the
capacity to assist in control of HIV replication.

From the aNational Centre in HIV Epidemiology and Clinical Research, the bSchool of Mathematics and Statistics, University of
New South Wales, Sydney, Australia, and the cMerck Research Laboratories, North Wales, Pennsylvania, USA.
Correspondence to Dr J. Murray, School of Mathematics and Statistics, University of New South Wales, Sydney, NSW 2052,
Australia.
E-mail: J.Murray@unsw.edu.au
Received: 14 June 2007; revised: 10 August 2007; accepted: 13 August 2007.

ISSN 0269-9370 Q 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins 2315
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
2316 AIDS 2007, Vol 21 No 17
Ten-day monotherapy trials investigating dosing levels
and tolerability of integrase inhibitors have been reported
[1,3], and preliminary results from phase II studies suggest
that this new class of drugs can be effective in controlling
HIV replication even in individuals infected with
multiclass drug-resistant virus [4]. To date, however,
there have been no reports investigating the potential for
differential effects on viral dynamics with integrase
inhibitors relative to current antiretroviral drugs.
Classically, the reduction in HIV replication under
antiretroviral therapy (ART) is characterized by a biphasic
decay pattern of HIV RNA in blood. The first phase
exhibits a mean half-life of between 0.9 and 1.6 days and
occurs over the first 7 to 10 days [5–7]. The second phase
has a mean half-life of 14 days and successful therapy
reduces plasma HIV RNA below standard limits of
detection [6]. Analysis of HIV RNA < 50 copies/ml
suggests that HIV RNA stabilizes at low but detectable
levels in plasma, with 50% of patients who have been
taking ART for at least 6 months having HIV RNA
> 2.5 copies/ml [8].
It is generally believed that virus observed during the
first-phase decay arises from productively infected CD4
T cells, and that this phase of viral decay tracks their death
[9,10]. The origins of HIV RNA during the second phase
are not clearly defined. It has been hypothesized the virus
may arise from long-lived infected cells [6], from
dissociation of virus from follicular dendritic cells [11]
or from productively infected CD4 T cells that are not
subject to clearance by the host immune responses given
the waning levels of HIV antigen [12].
The addition of an integrase inhibitor such as raltegravir
(formerly known as MK-0518) to antiretroviral drugs
from other classes may be expected to provide at least an
additive effect on inhibition of HIV replication.
However, it would not be expected to interfere with
production of progeny virus from the above sources since
the cells that are hypothesized to be responsible for the
observed second-phase virus are already infected or, in
the case of dissociation from dendritic cells, these virions
have already been produced.
To investigate these matters, viral dynamics were analyzed
from treatment-naive patients enrolled in a phase II dose-
ranging study of raltegravir over 10 days of monotherapy
and then in comparison over 48 weeks with efavirenz,
each in combination with two other antiretroviral drugs.
Methods
Patients were naive to ARTor had received less than 7 days
total ART. Patients were at least 18 years of age with a
positive HIV enzyme-linked immunosorbent test, had
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
HIV RNA of  5000 copies/ml and a CD4 cell count
of  100 cells/ml. HIV RNA was assessed by the
AMPLICOR HIV-1 Monitor Standard Assay version
1.5 (limit of detection, 400 copies/ml; Roche Molecular
Systems, Branchburg, New Jersey, USA); those samples
below the limit of detection were reassessed by the
AMPLICOR HIV-1 Monitor UltraSensitive Assay version
1.5 (limit of detection, 50 copies/ml).
The mathematical models are described in the supple-
mentary text. Statistical comparisons for continuously
distributed variables between groups were performed with
the Wilcoxon rank sum test, while comparisons for
proportions of patients above or below detection limits
were performed using Fisher’s exact test. Nominal P values
< 0.05 were considered significant and all tests were two
sided. In this exploratory analysis, no adjustments were
made to P values for multiple testing. Mathematical
modeling and statistical analyses were conducted within
Matlab, version 7, The MathWorks.
Results
Patients in this study were naive for ART, had baseline
plasma HIV RNA of  5000 copies/ml and CD4 T cell
counts  100 cells/ml. This phase II dose ranging study of
raltegravir was conducted in two parts. Part 1 compared
monotherapy with raltegravir against placebo over 10 days
[3]. Patients entering part 1 were randomized to one of four
different dosages of raltegravir (100, 200, 400 and 600 mg),
each taken twice daily, or matched placebo. In Part 1 there
were approximately eight patients in each of the
five groups. At the end of Part 1 therapy was stopped
before commencement of Part 2. In Part 2, an additional
150 patients were enrolled for 48 weeks of combination
therapy, with randomization to one of the four dosages of
raltegravir or to efavirenz (600 mg every night), in addition
to tenofovir (300 mg once a day) and lamivudine (300 mg
once a day) for all individuals.
First-phase decay with raltegravir monotherapy
Monotherapy with raltegravir over 10 days produced
extensive monophasic decay for all dosage groups, with a
median 2.2 log10 copies/ml decrease. Linear regression
analysis determined no significant differences in the first-
phase half-lives between the dosage groups (P  0.18).
Mean half-lives were 1.3, 1.1, 1.3, and 1.2 days for the 100,
200, 400 and 600 mg raltegravir groups, respectively,
with an overall mean of 1.2 days (SD, 0.26). The first-phase
half-lives were consistent with the ranges previously
observed [5–7].
Combination therapy with raltegravir
Under combination therapy, each of the raltegravir
treatment groups achieved undetectable HIV RNA
(<50 copies/ml), faster than the efavirenz group. From
 Raltegravir reduces second-phase virus Murray et al. 2317

Table 1. Numbers of individuals in each treatment group with HIV RNA/ml < 50 copies/ml.

Raltegravir (mg) twice daily

a
Efavirenz (600 mg every night) b
Time (days) 100 (n ¼ 39) 200 (n ¼ 40) 400 (n ¼ 41) 600 (n ¼ 40) (n ¼ 38) P value

1 0 0 0 0 0 1
15 12 12 19 12 4
0.047
29 25 22 31 25 8
0.003
57 33 34 37 28 14
0.006
85 35 34 36 35 26 0.03
P
0.10
112 29 31 35 36 27 0.02
P
1.0
168 31 34 36 38 33 0.30
P
1.0
223 28 31 34 33 31 0.40
P
1.0
280 29 29 34 34 32 0.30
P
1.0
335 24 27 31 29 29 0.20
P
1.0
a
Mean time over all patients.
b
Probability that the efavirenz treatment group was significantly different to each of the raltegravir treatment groups.

the second (day 15 of therapy, on average) to the fourth
time point (day 57), patients in the raltegravir groups
were more likely to be below the level of HIV detection
(Table 1). Since first-phase monotherapy decay rates were
indistinguishable for each of the dosage groups, and all
raltegravir dosages achieved undetectable RNA at similar
rates with combination therapy, subsequent analysis was
performed on the combined raltegravir patients. Plasma
HIV RNA was significantly lower for the combined
raltegravir group until day 168 (Fig. 1). From day 1 to day
15, median HIV RNA fell from 58 350 to 98 copies/ml
for the combined raltegravir patients, while those in the
efavirenz group decreased from 70 200 to 537 copies/ml.
second-phase half-life for raltegravir individuals was
15.5 days [interquartile range (IQR), 14], whereas it was
18.3 days (IQR, 10) for those on efavirenz, but these half-
lives were not significantly different (P ¼ 0.2). The slightly
numerically faster second-phase dynamics for the ralte-
gravir group may be because some of these individuals had
a first-phase decline that was prolonged beyond day 15.
This appears likely given the extended first-phase decline
exhibited under monotherapy. Including only those
individuals on raltegravir who had detectable HIV
RNA at days 15 and 29 (n ¼ 42), gave a median
second-phase half-life of 19.6 days, which also was not
significantly different to the efavirenz group (P ¼ 0.6).

Second-phase half-lives were calculated using linear Although the rate of decline during the second phase did
regression on HIV RNA log10 copies/ml from the second not differ between the raltegravir and efavirenz regimens,
time point (day 15 on average), until the first point where the point at which this decline initiated did differ.
HIV RNA fell below the 50 copies/ml limit. The median The significantly lower viral levels in plasma from day 15

(a) (c)
HIV RNA (log10 copies/ml)

6 6
HIV RNA (log10 copies/ml)

5 5

4 4

3 3

2 2

1 1
0 50 100 150 200 250 300 350 0 50 100
Days
(b)
HIV RNA (log10 copies/ml)

1
0 50 100 150 200 250 300 350
Days

Fig. 1. Combination therapy starting at day 1 for patients taking all dosages of (a) raltegravir (160 patients at day 1 to 121 at final
time) or (b) efavirenz (36 patients at day 1 to 30 at final time). At each time point, the central horizontal line depicts the median,
with the box extending over the interquartile range. Outliers, more than 1.5 times the interquartile range away from the box
extremities, are depicted as ‘þ’. (c) Median HIV RNA for raltegravir (squares) and efavirenz (diamonds) arms.

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
2318 AIDS 2007, Vol 21 No 17
onwards for the raltegravir group meant that the first
phase of viral decay was more extensive, thereby reducing
the viral level at which the second phase commenced
(Fig. 1). Estimation of the size of the viral compartment
contributing to second-phase viral decay was calculated
by extrapolating the regression line of this second phase
back to baseline. The ratio of this baseline second-phase
value to baseline HIV RNA (‘M ratio’), has been listed for
six individuals in Perelson et al. [6] (Table 1, pM0/cV0).
In that study combination therapy with nelfinavir,
zidovudine and lamividine resulted in M ratios with a
mean of 0.04 and median of 0.03. The lower the M ratio
the more extensive was first phase decline. In the present
study, M ratios for the efavirenz group were lower but not
statistically different to values reported in the literature,
with the higher literature values perhaps arising from a
slightly different method where a viral load curve was
fitted to the data in that study [6] (P ¼ 0.08). The M ratio
was 70% lower for individuals taking raltegravir than
efavirenz (median 0.0042 versus 0.014; P < 0.0001),
implying that raltegravir reduces viral production from
the second-phase source by this amount over and above
standard regimens.
The decrease in the second-phase viral production with the
addition of raltegravir necessitates rethinking current
theories of the source of virus responsible for the second
phase. Current hypotheses are that second-phase viral load
arises through production by long-lived infected cells [6],
release from follicular dendritic cells [11] or decreased
cytotoxic lymphocyte response [12]. None of these
theories can explain the effects produced by raltegravir,
if it is acting as a pure integrase inhibitor, since they suggest
that second-phase viral load originates from sources that an
integrase inhibitor would not affect: previously infected
cells or virus already produced but bound to dendritic cells.
Hypotheses for second-phase virus
If an integrase inhibitor is to influence viral levels in the
second phase, the virus at that stage must arise from (i) cells
that are either newly infected and where the integrase
inhibitor provides an additional benefit above that of
reverse transcriptase and protease inhibitors, (ii) cells that
have been previously infected but where the proviral DNA
has yet to be integrated into the host cell genome, or (iii) a
sanctuary site where the integrase inhibitor has improved
penetration. To investigate the viability of these hypotheses
as explanations of the reduced second phase under an
integrase inhibitor, three mathematical models were
developed and applied to the median data derived from
the monotherapy and combination trials with raltegravir
and efavirenz. Model 1 simulated the first hypothesis
above, model 2 simulated the second, and model 3
simulated the third (supplementary text). A cartoon of the
effects of raltegravir in these models is displayed in Fig. 2.
In model 1, new productive infection (I), which generates
virus (V) in the second phase, originates from long-lived
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Sanctuary
site
IS
M
Ra
lte
gr
3
av
ir
D
1
Ralteg
ravir
V
ir
av
2 I
gr
lte
Ra
Fig. 2. A cartoon representation of the effects of raltegravir
in the three models shown as numbered circles. Long-lived
infected cells are denoted with M, latently infected cells with
unintegrated virus as D, productively infected cells as I, and
productively infected cells in a sanctuary site as IS, with virus
as V. HIV DNA is denoted by a solid red bar in each cell.
infected cells (M). These latter cells decay at the slow rate
observed in this phase, thereby providing this same
dynamic to newly infected cells and second-phase virus
(Fig. 3a,b). The integrase inhibitor provides an additional
effect to reverse transcriptase and protease inhibitors in
their inhibition of new productive infection from long-
lived infected cells, decreasing second-phase viral levels
more (solid lines Fig. 3a,b) than with efavirenz (dashed
lines).
The results achieved with the integrase inhibitor in model
1 could theoretically be achieved through more potent
reverse transcriptase or protease inhibitors. By comparison,
model 2 simulates a process of infection that is not
susceptible to traditional drugs, where virus from the
second phase arises from latently infected cells that contain
proviral DNA in a full-length unintegrated form, which
has been estimated to form the vast majority of latent
infection [13]. In this model, second-phase virus originates
from latently infected cells with unintegrated viral DNA
(D) that are activated and converted to productively
infected cells (I). Increased potency of traditional drugs will
reduce the replenishment of the latent pool D but will not
stop its conversion to productive infection. Model 2 also
provides a consistent explanation for the effect achieved by
the integrase inhibitor (Fig. 3c,d).
The third model, where the differential effects of the
integrase inhibitor are achieved through better penetration
of a sanctuary site, was less successful in duplicating the data
(Fig. 3e,f). Although it achieved lower second-phase viral
 Raltegravir reduces second-phase virus Murray et al. 2319

(a) (c) (e)

5 5 5
10 10 10

HIV RNA (copies/ml)

0 0 0
10 10 10
0 20 40 60 0 20 40 60 0 20 40 60
Days Days Days
(b) (d) (f)
0 0 0
10 10 10
Cell count (cells/µl)

0 20 40 60 0 20 40 60 0 20 40 60
Days Days Days

Fig. 3. Simulations for model 1 (a,b), model 2 (c,d) and model 3 (e,f). (a,c,e) Simulations versus median HIV RNA data from part 1
and part 2 with raltegravir (squares) and part 2 data for the efavirenz arm (diamonds). (b,d,f) Simulations of underlying cell types.
Simulations with an integrase inhibitor are depicted as solid lines and those without an integrase inhibitor are depicted as dashed
lines. Some cell population simulations show no difference whether an integrase inhibitor is included or not, and for these cases
the solid line overlays the dashed line. (b) Model 1 simulations for long-lived infected cells M (green lines) and productively
infected cells I (blue lines). (d) Model 2 simulations for long-lived infected cells M (green lines), productively infected cells I
(blue lines), and latently infected cells D (red lines). (f) Model 3 simulations for productively infected cells in a sanctuary site
IS (green lines) and productively infected cells I in a site susceptible to conventional antiretroviral therapy (blue lines).

load, the slope of this second phase was significantly faster raltegravir arm with those on the efavirenz arm,
for the integrase inhibitor (solid line Fig. 3e) than for the raltegravir achieved a 70% reduction of second-phase
efavirenz arm (dashed line Fig. 3e). This was at odds with viral levels.
the results described above, where there was no significant
difference. The second-phase virus in this model traffics The effect of raltegravir on the second phase of viral decay
from the sanctuary site, where it is produced by was unexpected given current hypotheses for the processes
productively infected cells. In order to achieve this underlying this phase [6,11,12] and the mechanism by
differential effect for the integrase inhibitor, the efavirenz which the drug is thought to work. We proposed three
arm must have extremely low efficacy, 6%, in order for the hypotheses to explain the observed effects and compared
additional efficacy provided by the integrase inhibitor to simulations of mathematical models for these hypotheses to
significantly perturb the decay rate of productively infected median data for ART with or without an integrase
cells in the sanctuary site (green solid line versus green inhibitor. Models 1 and 2 successfully reproduced the
dashed line Fig. 3f). clinical data (Fig. 3).

The effect of adding an integrase inhibitor to model 1 is to

provide an additional effect to that of the reverse
Discussion transcriptase inhibitors (and any protease inhibitors that
act in the model through decreasing infectivity), thereby
Raltegravir significantly extended the first phase of viral decreasing new infection from virus associated with long-
decay and reduced the plasma HIV RNA level at which lived infected cells. Hence under these assumptions, the
the second phase commenced (Fig. 1). It enabled integrase inhibitor does not target new infection mech-
individuals to suppress HIV RNA to below detection anisms but reduces the success of transmission from long-
limits significantly faster than current regimens (Table 1). lived infected cells to productively infected cells. Model 2,
The 50 copies/ml assay limit did not allow investigation of where the second phase is assumed to arise from activation
any effects this may have on subsequent viral levels. By of latently infected cells that have HIV DNA in a
comparing M ratios for individuals enrolled on the predominantly unintegrated form, provides a mechanism

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
2320 AIDS 2007, Vol 21 No 17
that is completely resistant to any additional benefit from
improvements in reverse transcriptase inhibition. For this
second model, the integrase inhibitor provides a protective
mechanism that cannot be replaced by reverse transcriptase
or protease inhibitors, no matter their potency, since for
reverse transcriptase and protease inhibitors new virions
will be produced, although these will be mostly
noninfectious in the presence of protease inhibitors [14].
Under each of these models, there may be an increase in
aborted HIV DNA integration and a resulting rise in
extrachromosomal viral DNA in circular forms containing
one or two long terminal repeats (2LTR circles), as
observed in vitro [2]. In those experiments, cell viability was
not affected, and clinical trials with raltegravir have not
shown toxicities higher than with current antiretroviral
drugs [3,4]. Therefore, any resulting increases in
unintegrated HIV DNA would not be expected to be
detrimental to these cells. Although not conclusive, the
simulations of model 3 suggest that second-phase virus does
not originate from a sanctuary site where raltegravir is more
successful in penetrating than standard antiretroviral drugs.
Availability of protease inhibitors in the 1990s and their
combination with reverse transcriptase inhibitors evoked
hopes that this new potent ART would at last allow
clearance of HIV infection. Estimates were made on the
length of treatment needed before this could be achieved
[6]. Although plasma levels of HIV RNA fall below
detection limits within several months of ART, it was
soon realized that latent infection provided a lower bound
on the rate at which HIV infection could be removed
from the body. This component is established early in
infection [15] and consists of both unintegrated and
integrated HIV DNA even under ART [13]. The high
levels under ART of unintegrated HIV DNA in resting
CD4 T cells [13], and proviral sequence evolution in
individuals with undetectable HIV RNA [16], suggest
that there is persistent viral replication even in the
presence of seemingly successful ART. Regardless of
whether ongoing infection or the slow turnover of resting
CD4 T cells is primarily responsible, the latent pool
decreases slowly under standard ART, with a half-life of
anywhere between 6 months [16,17] and 44 months [18].
This leads to estimates of between 8 years [16,18] and
more than 60 years for clearance of infection. The rate of
decrease is dependent on residual viral replication [17],
and hence drugs like raltegravir that increase the
effectiveness of ART, especially for viral components
such as unintegrated HIV DNA that are immune to
current drugs, may improve this rate of decay.
There is considerable uncertainty as to the prevalence of
unintegrated HIV DNA in resting CD4 T cells during
ART, and the impact this component makes to renewing
the integrated pool. In-vitro experiments have established
that HIV can enter resting CD4 T cells with high
efficiency, but that productive infection does not ensue.
The cause of this failure seems dependent on the cell
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
culture conditions, as infection of resting cells can fail
during reverse transcription [19,20] or through the
lability of the full-length unintegrated HIV DNA
transcript [20], or it can lead to stable infection that is
transcriptionally inactive without cellular activation [21].
The in-vivo situation under ART is equally unclear. Total
HIV DNA exceeds integrated HIV DNA in resting CD4
T cells by 100-fold, yet does not seem to contribute
significantly to replication competent virus [13]. The
presence of unintegrated HIV DNA under ART,
however, indicates either that there is substantial ongoing
infection, if this molecule is labile, or that it is long lived.
If it is the latter, then integrase inhibitors can provide
an effective block in new productive infection upon
activation of this latent component, as hypothesized in
model 2. Regardless, integrated HIV DNA must undergo
some replenishment since it decays slowly under ART but
rebounds within weeks upon cessation of therapy [13]. It
is difficult to reconcile these very different dynamics if
there is no compensatory loss in this compartment, and
hence continual replacement. Detailed analysis of
integrated and unintegrated HIV DNA in resting CD4
T cells, in the presence and absence of an integrase
inhibitor, would provide valuable information on this
matter.
Acknowledgements
We thank the patients and investigators who participated
in this study.
Sponsorship: The National Centre in HIV Epidemiology
and Clinical Research is funded by the Australian
Commonwealth Department of Health and Ageing and
is affiliated with the Faculty of Medicine at the
University of New South Wales. AK is supported by a
Practitioner Fellowship from the NHMRC.
Note: The P004 study is registered at ClinicalTrials.gov
under identifier NCT00100048.
Note: Supplementary material can be accessed online.
References
1. DeJesus E, Berger D, Markowitz M, Cohen C, Hawkins T, Ruane
P, et al. Antiviral activity, pharmacokinetics, and dose response
of the HIV-1 integrase inhibitor GS-9137 (JTK-303) in
treatment-naive and treatment-experienced patients. J Acquir
Immune Defic Syndr 2006; 43:1–5.
2. Hazuda DJ, Felock P, Witmer M, Wolfe A, Stillmock K, Grobler
JA, et al. Inhibitors of strand transfer that prevent integration
and inhibit HIV-1 replication in cells. Science 2000; 287:646–
650.
3. Markowitz M, Morales-Ramirez JO, Nguyen BY, Kovacs CM,
Steigbigel RT, Cooper DA, et al. Antiretroviral Activity,
pharmacokinetics, and tolerability of MK-0518, a novel inhi-
bitor of HIV-1 integrase, dosed as monotherapy for 10 days in
treatment-naive HIV-1-infected individuals. J Acquir Immune
Defic Syndr 2006; 43:509–515.

4. Grinsztejn B, Nguyen BY, Katlama C, Gatell JM, Lazzarin A,
Vittecoq D, et al. Safety and efficacy of the HIV-1 integrase
inhibitor raltegravir (MK-0518) in treatment-experienced
patients with multidrug-resistant virus: a phase II randomised
controlled trial. Lancet 2007; 369:1261–1269.
5. Plipat N, Ruan PK, Fenton T, Yogev R. Rapid Human immu-
nodeficiency virus decay in highly active antiretroviral therapy
(HAART)-experienced children after starting mega-HAART.
J Virol 2004; 78:11272–11275.
6. Perelson AS, Essunger P, Cao Y, Vesanen M, Hurley A, Saksela
K, et al. Decay characteristics of HIV-1-infected compartments
during combination therapy. Nature 1997; 387:188–191.
7. Kuritzkes DR, Ribaudo HJ, Squires KE, Koletar SL, Santana J,
Riddler SA, et al. Plasma HIV-1 RNA dynamics in antiretroviral-
naive subjects receiving either triple-nucleoside or efavirenz-
containing regimens: ACTG A5166s. J Infect Dis 2007;
195:1169–1176.
8. Palmisano L, Giuliano M, Nicastri E, Pirillo MF, Andreotti M,
Galluzzo CM, et al. Residual viraemia in subjects with chronic
HIV infection and viral load < 50 copies/ml: the impact of
highly active antiretroviral therapy. AIDS 2005; 19:1843–
1847.
9. Ho DD, Neumann AU, Perelson AS, Chen W, Leonard JM,
Markowitz M. Rapid turnover of plasma virions and CD4
lymphocytes in HIV-1 infection. Nature 1995; 373:123–126.
10. Wei X, Ghosh SK, Taylor ME, Johnson VA, Emini EA, Deutsch P,
et al. Viral dynamics in human immunodeficiency virus type 1
infection. Nature 1995; 373:117–122.
11. Hlavacek WS, Stilianakis NI, Notermans DW, Danner SA,
Perelson AS. Influence of follicular dendritic cells on decay
of HIV during antiretroviral therapy. Proc Natl Acad Sci USA
2000; 97:10966–10971.
12. Arnaout RA, Nowak MA, Wodarz D. HIV-1 dynamics revisited:
biphasic decay by cytotoxic T lymphocyte killing? Proc R Soc
Lond, Ser B Biol Sci 2000; 267:1347–1354.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Raltegravir reduces second-phase virus Murray et al. 2321
13. Chun TW, Stuyver L, Mizell SB, Ehler LA, Mican JA, Baseler M,
et al. Presence of an inducible HIV-1 latent reservoir during
highly active antiretroviral therapy. Proc Natl Acad Sci USA
1997; 94:13193–13197.
14. Ashorn P, McQuade TJ, Thaisrivongs S, Tomasselli AG, Tarpley
WG, Moss B. An inhibitor of the protease blocks maturation of
human and simian immunodeficiency viruses and spread of
infection. Proc Natl Acad Sci USA 1990; 87:7472–7476.
15. Chun TW, Engel D, Berrey MM, Shea T, Corey L, Fauci AS. Early
establishment of a pool of latently infected, resting CD4(R)
T cells during primary HIV-1 infection. Proc Natl Acad Sci USA
1998; 95:8869–8873.
16. Zhang L, Ramratnam B, Tenner-Racz K, He Y, Vesanen M,
Lewin S, et al. Quantifying residual HIV-1 replication in
patients receiving combination antiretroviral therapy. N Engl
J Med 1999; 340:1605–1613.
17. Ramratnam B, Mittler JE, Zhang L, Boden D, Hurley A, Fang F,
et al. The decay of the latent reservoir of replication-competent
HIV-1 is inversely correlated with the extent of residual viral
replication during prolonged antiretroviral therapy. Nat Med
2000; 6:82–85.
18. Finzi D, Blankson J, Siliciano JD, Margolick JB, Chadwick K,
Pierson T, et al. Latent infection of CD4R T cells provides a
mechanism for lifelong persistence of HIV-1, even in patients
on effective combination therapy. Nat Med 1999; 5:512–517.
19. Zack JA. The role of the cell cycle in HIV-1 infection. Adv Exp
Med Biol 1995; 374:27–31.
20. Zhou Y, Zhang H, Siliciano JD, Siliciano RF. Kinetics of human
immunodeficiency virus type 1 decay following entry into
resting CD4R T cells. J Virol 2005; 79:2199–2210.
21. Spina CA, Guatelli JC, Richman DD. Establishment of a stable,
inducible form of human immunodeficiency virus type 1 DNA
in quiescent CD4 lymphocytes in vitro. J Virol 1995; 69:2977–
2988.