Download Ritonavir plus saquinavir versus single protease inhibitor

ß 2002 British HIV Association
HIV Medicine (2002), 3, 247±253
ORIGINAL RESEARCH
Ritonavir plus saquinavir versus single protease inhibitor
therapy in protease inhibitor-naive HIV-infected patients: the
Swiss HIV Cohort Study
HC Bucher,1 M Bichsel,2 P TaffeÂ,3 H Furrer,4 A Telenti,5 B Hirschel,6 R Weber,7 E Bernasconi,8 P Vernazza,9 C Minder2 and
M Battegay1 for the Swiss HIV Cohort Study
1
Basel Center for HIV Research, Internal Medicine Outpatient Clinic University Hospital Basel, 2Department for Social and
Preventive Medicine University Berne, 3Swiss HIV Cohort Data Center, Centre Hospitalier Universitaire Vaudois, Lausanne,
4
Division of Infectious Diseases, Inselspital, Bern, 5Division of Infectious Diseases, Centre Hospitalier Universitaire
Vaudois, Lausanne, 6Division of Infectious Diseases, University Hospital, Geneva, 7Division of Infectious Diseases and
Hospital Epidemiology, University Hospital Zurich, 8Infectious Disease Unit, Ospedale Regionale, Lugano, and 9Infectious
Disease Unit, Cantonal Hospital St. Gall, Switzerland
Objectives
To compare the response to ritonavir (RTV) plus saquinavir (SQV) with single protease inhibitor (PI)
therapies among PI-naive HIV-1 infected individuals.
Methods
Response to treatment was analysed according to the intent-to-treat principle in a prospective
observational cohort study of 177 patients who between May 1995 and March 2000 started a double PI
therapy with RTV and SQV (nonboosting dosages) plus at least one nucleoside reverse transcriptase
inhibitor (NRTI) and 2214 patients with a single PI therapy plus two NRTIs. We used survival analysis
and Cox's proportional hazard regression methods. The primary endpoint was the time to a plasma
viral load of <400 copies/mL. Secondary endpoints were taken as a gain in the CD4 count of
>100 cells/mL, and change of initial PI for any reason.
Results
Baseline characteristics in both treatment groups were balanced. Median follow-up in both groups was
10.4 months. Time to an HIV-1 viral load of <400 copies/mL and an increase in the CD4 count of
>100 106 cells/L was shorter for RTV plus SQV compared with single PI regimens (log rank test for
each endpoint P <0.05). The adjusted hazard ratios of RTV plus SQV compared with single PI regimens
were 1.21 (95% con®dence interval 0.99±1.47) for achieving an HIV-1 viral load of <400 copies/mL,
1.12 (0.88±1.42) for an increase in the CD4 count of >100 cells/mL, and 0.90 (0.73±1.11) for change of
®rst PI regimen.
Conclusions
Treatment with RTV plus SQV compared with single PI regimens appeared to give similar results for
virological or immunological response.
Keywords: antiretroviral therapy, HIV infections, prospective cohort study, protease inhibitors
Received: 28 February 2002, accepted 11 June 2002
[1±3]. Generally, a potent antiretroviral therapy consists of
one protease inhibitor (PI) or nonnucleoside reverse transcriptase inhibitors (NNRTI) combined with at least two
nucleoside reverse transcriptase inhibitors (NRTI). Pharmacokinetic studies have shown that ritonavir (RTV) may boost
serum levels of other PIs such as saquinavir (SQV) and
indinavir (IDV), and has lead to the introduction of dual PI
therapies.
Introduction
The introduction of potent antiretroviral therapy has lead to
a dramatic reduction in HIV-related morbidity and mortality
Correspondence: Heiner C. Bucher, Basel Institute for Clinical Epidemiology,
University Hospital Basel, CH-4031 Basel/Switzerland. e-mail:
[email protected]
247
248 HC Bucher et al.
Several studies have demonstrated that the combination
of RTV plus SQV reduces plasma HIV-1 viral load to a similar
extent to that of a single PI-based regimen [4±9]. These
studies, however, either did not use control groups, reported
only 24 weeks follow-up data, or compared different dosing
or intensi®cation regimens of RTV plus SQV. There is very
little evidence from controlled trials in PI-naive patients
comparing the dual PI therapy of RTV plus SQV with single
PI regimens. In one randomized controlled trial, the dual
combination of RTV plus SQV showed superior short-term
antiretroviral activity when compared with single protease
regimen with either IDV or RTV [10]. However, the limited
number of included patients and the short follow-up period
limit the generalizability of these study ®ndings.
The goal of the present study was to examine the effectiveness of a dual PI therapy based on RTV plus SQV with at
least one additional reverse transcriptase inhibitor compared with a single PI regimen in combination with two
reverse transcriptase inhibitors in a mixed population of
PI-naive HIV-infected patients within the Swiss HIV
Cohort Study.
Method
Study design
Patient selection We searched the database of the Swiss HIV
Cohort Study for PI-naive patients who started a potent
antiretroviral therapy with either a double protease regimen
with RTV plus SQV hard or soft gel capsule in nonboosting
regimens in conjunction with at least one reverse transcriptase inhibitor or a single PI therapy with two reverse transcriptase inhibitors between May 1995 and March 2000.
We included all eligible patients that had had a viral load
and CD4 cell measurement within 3 months prior to start
of therapy and at least two surrogate marker follow-up
measurements, irrespective of whether they were lost to
follow-up, left the cohort for known reasons or died
during follow-up. Pretreated patients were only included
if they were PI naive and if at least one new reverse transcriptase inhibitor was introduced in conjunction with the
PI.
Study endpoints The primary study endpoint was taken as
the probability and time taken to reaching an HIV-1 plasma
viral load of <400 copies/mL. Plasma HIV-1 RNA concentration was determined by the Amplicor HIV-1 Monitor
(Roche Diagnostics, Basel, Switzerland) with a limit of detection of 400 copies/mL. We did not use the ultrasensitive
assay (detection limit <50 copies/mL) because the test was
introduced only in 1999 and was not available in all
patients. The secondary endpoint was the time taken for
an increase in the CD4 count of > 100 cells/mL, and to ®rst
change of a PI regimen. We classi®ed the progression to
AIDS and death as secondary endpoint because we anticipated few events [1]. We used the European classi®cation
of AIDS [11].
Statistics We analysed double and single PI regimens
using the intention-to-treat approach (i.e. all patients were
analysed according to their initial therapy irrespective of
changes of treatment during follow-up). We used the log
rank test to compare the time to undetectable viral load, to
an increase in the CD4 count of >100 cells/mL, to switching
of the initial PI.
To check for differences between the two treatment
groups concerning baseline characteristics we used w2-tests
for categorical variables (i.e. gender, mode of HIV acquisition) and t-tests or rank sum tests for continuous variables
[i.e. CD4 cell count, HIV-1 RNA level, age, time between
entering the cohort and beginning highly active antiretroviral therapy (HAART), date of beginning HAART].
We used proportional Cox regression analysis to adjust for
the difference in baseline characteristics in multivariable
analysis for primary and secondary endpoints. Baseline covariables included in multivariate models were CD4 cell count
(in units of 100 cells/mL), HIV-1 RNA level (log10 transformed), age (in units of 10 years), gender, mode of HIV
acquisition (intravenous drug use or no intravenous drug
use), and whether patients had been pretreated with any
reverse transcriptase inhibitors. Antiretroviral drugs compared in the single and double, respectively, PI therapies in
this study were introduced in sequence as drugs became
available over time. This may introduce a bias and the
bene®cial effect of a given drug may be overestimated because patients who survive longer are more likely to get
treated, irrespective of whether a given treatment is effective
or not. To correct for such bias, we strati®ed the Cox regression by year of start of PI therapy [12]. We excluded preexisting AIDS from the ®nal models because its modifying
effect was depicted by the CD4 cell count. We performed
log rank tests and proportional hazards analyses, as the main
study interest was on average effect differences over a
longer time span. We checked the proportional hazard assumption by splitting the observation period into two time
periods with an approximately equal number of events for
the primary and secondary endpoints, comparing the hazard
ratios in both periods, and by using Schoenfeld residuals. All
probability values stated are two-sided. All analysis was
carried out using Stata 6.0 (Stata Corp., College Station,
TX, USA).
ß 2002 British HIV Association HIV Medicine (2002) 3, 247±253
Double vs. single protease inhibitor in HIV infection 249
Results
Patients' characteristics
From May 1995 to March 2000, 3493 individuals had been
included into the Swiss HIV Cohort Study. Of these individuals, 2870 (82.2%) had initiated either a single or double PI
therapy. We excluded individuals with less than two followup examinations after initiation of a PI-based regimen,
individuals that received a single PI regimen with SQV
hard gel capsule (due to its limited ef®cacy) or a different
double PI regimen other than RTV plus SQV (n ˆ 40), and
patients initiating a potent antiretroviral therapy based on
nonnucleoside reverse transcriptase inhibitor, thus leaving
2391 individuals (83.3%) for analysis. In total, 177 (7.4%)
patients had been treated with a combination of RTV plus
SQV and 2214 with a single PI regimen, and were included
into the present analysis.
Baseline characteristics in both groups were comparable,
though patients with RTV plus SQV double PI compared with
patients with single PI regimens had fewer CD4 cells (median
186 vs. 210 cells/mL, P ˆ 0.47), had a slightly higher
viral load (median 4.6 vs. 4.5 log HIV-1 plasma viral load,
P ˆ 0.07), and included fewer intravenous drug users (25.2%
vs. 31.5%, P ˆ 0.12) (Table 1). The median age in both groups
was 35.5 years and roughly one-quarter of patients were
females. The number of patients who had suffered AIDS
before starting a PI and had had prior treatment with reverse
transcriptase inhibitors was distributed equally in both
groups. Patients treated with RTV plus SQV tended to start
this regimen at a later date compared with single PI regimens, but the time period from inclusion into the cohort to
start of therapy was comparable between groups. Stavudine
(d4T) was the most commonly used reverse transcriptase
inhibitor in the double PI group (82.0%). IDV (41.2%) and
nel®navir (32.1%) were the most used PIs in the single PI
group. Dosages of double PI regimen were RTV 400±600 mg
twice daily and SQV 400±600 mg twice daily. (Exact details
of drug dosing are only available in the Swiss HIV Cohort
Study database since 1999.) Median follow-up was
10.4 months in both groups (Table 2).
Primary endpoint and virological response
The Kaplan±Meier analysis showed that time to a viral load
of <400 copies/mL was shorter with RTV plus SQV compared with single PI regimens (P < 0.01) (Fig. 1). The median
time to a viral load of <400 copies/mL was 93 days for RTV
plus SQV and 111 days for single PI regimens, respectively.
However, at last follow-up the proportion of patients with a
viral load of < 400 copies/mL was similar in both groups, i.e.
63.3% in the RTV plus SQV and 61.4% in the single PI group
ß 2002 British HIV Association HIV Medicine (2002) 3, 247±253
(Table 2). In the adjusted analysis, the hazard ratio for reaching HIV-1 RNA levels of < 400 copies/mL with double RTV
plus SQV compared with single PI regimens was 1.21 (95%
con®dence interval (CI) 0.99±1.47; P ˆ 0.06) (Table 3).
Secondary endpoints
Time to an increase in CD4 count of >100 cells/mL was
statistically signi®cantly shorter for the combination of
RTV plus SQV when compared with single PI regimens (log
rank test P < 0.05) (Fig. 1). Median days to a >100 CD4 cell
increase was 163 days for RTV plus SQV and 212 days for
single PI regimens, respectively. The hazard ratio for an
increase in CD4 count of >100 cells/mL of RTV plus SQV
compared with single PI regimens was 1.12 (0.88±1.42).
A similar proportion of patients in both groups, 67.8% of
patients with the RTV plus SQV combination and 73.3% of
patients with a single PI therapy, changed their initial PI
regimen during follow-up (Table 2). Time to ®rst change and
the hazard for change of double PI-compared with single PIbased regimens was not statistically signi®cantly different.
Fifteen (8.5%) patients in the RTV plus SQV group and 125
(5.6%) patients in the single PI group suffered from AIDS or
died. Analyses for the separate endpoints of AIDS and death
remained inconclusive due to the limited number of events
and, therefore, no further analyses were done.
Discussion
We investigated the most used double PI regimen within the
Swiss HIV Cohort Study. In PI naive individuals, double PI
therapy with RTV plus SQV compared with single PI regimens led to a more rapid decline of HIV-1 RNA levels to
< 400 copies/mL. In multivariable analysis, the hazard ratios
for HIV-1 RNA levels <400 copies/mL were in favour of the
double PI regimen but failed conventional levels of statistical signi®cance (P ˆ 0.06). This difference was not sustained beyond 24 months during extended observation
periods, but these estimates are based on very few observations. At last follow-up, a similar proportion of patients in
both groups (63.3% and 61.4%) had a viral load of <400
copies/mL.
Observational studies such as the Swiss HIV Cohort Study
can provide important insights into the effectiveness of
different antiretroviral drug combinations since they include a large spectrum of patients with a higher proportion
of intravenous drug users and females, two groups of individuals that are more likely to be underrepresented in randomized clinical trials. Results from observational studies of
therapeutic interventions, however, may be prone to bias
due to residual confounding and survival treatment bias
[12,13]. In addition, empirical evidence shows that, in
250 HC Bucher et al.
Table 1 Baseline characteristics
Patients (n)
Median age [years (range)]
Single protease inhibitor
Dual protease inhibitor: RTV/SQV
2214
177
36 (17±82)
P-value*
35 (20±70)
0.51
Female [n (%)]
634 (28.6)
53 (29.9)
0.71
Transmission group [n (%)]
Heterosexual
Homosexual
Intravenous drug user
Other
649 (29.7)
790 (36.2)
689 (31.6)
54 (2.5)
66 (37.9)
59 (33.9)
44 (25.3)
5 (2.9)
Previous AIDS [n (%)]
549 (24.8)
Median CD4 cell count [cells/mL (range)]
Below 50
50±99
100±199
200±349
$ 350
210 (0±1529)
349 (16.5)
239 (11.3)
421 (19.8)
559 (26.3)
554 (26.1)
Log10 HIV-1 RNA (copies/mL)
[median (range)]
< 400
4000±9999
10 000±54 999
55 000±99 999
$ 100 000
4.5 (0.7±6.8)
91 (4.7)
515 (26.7)
559 (29.0)
222 (11.50)
543 (28.1)
Pretreatment with reverse transcriptase
inhibitors [n (%)]
Median time from inclusion to cohort and start
of protease inhibitor [months (range)]
Date for start of protease inhibitor [median (range)]
Protease inhibitor at baseline [n (%)]
Indinavir
Nel®navir
Other protease inhibitor
RTV ‡ SQV hard gel capsule
RTV ‡ SQV soft gel capsule
Reverse transcriptase inhibitor at baseline [n (%)]
Zidovudine/3TC
d4t/3TC
Didanosine/d4T
d4t
Other
41 (23.2)
186 (3±1439)
28 (16.4)
15 (8.8)
46 (26.9)
46 (20.9)
36 (21.1)
4.6 (2.3±6.9)
3 (1.8)
44 (26.4)
46 (27.5)
19 (11.4)
55 (33.0)
1314 (59.3)
101 (57.0)
27.1 (0±140.6)
26.2 (0±145.1)
05/1997 (04/1996±04/1999)
912 (41.2)
710 (32.1)
592 (26.7)
1057 (47.7)
730 (33.0)
300 (13.6)
±
127 (5.7)
0.12
0.62
0.47
0.17
0.07
0.48
0.55
0.64
03/1998 (04/1996±04/1999)
174
3
7 (4.0)
10 (5.6)
6 (3.4)
145 (82.0)
9 (5.1)
*Difference between single protease inhibitor and dual protease inhibitor (RTV/SQV) by w2 and Wilcoxon signed rank tests. RTV, ritonavir; SQV,
saquinavir; d4T, stavudine; 3TC, lamivudine.
general, results from observational studies tend to yield
higher effect sizes when compared with results from randomized controlled trials, though prospective cohort studies
seem to be less prone to this bias [14].
We cannot exclude that our study results are distorted by
residual confounding and our ®ndings should therefore be
interpreted cautiously. There exists only one randomized
controlled trial of a head-to-head comparison of RTV plus
SQV with a single PI, IDV [10], where it was found that at
24 weeks, a higher proportion of patients (82.0%) in the RTV
plus SQV group compared with 71% in the IDV group
achieved a viral load of <200 copies/mL. Our analysis is in
agreement with the ®ndings from this controlled trial, however, our ®gures are considerably lower. In addition, because
our analysis is based on a less rigid cut-off point, we do not
know whether patients with the double PI regimen would
have achieved more favourable results in the ultrasensitive
assay. In the trial by Kirk et al. [10], patients with double PI
therapy were also more likely to reach a viral load of <20
copies/mL compared with the single PIs. In the `Prometheus
study', a randomized trial comparing the intensi®cation of
the double PI therapy of RTV plus SQV with d4T 69% of the
ß 2002 British HIV Association HIV Medicine (2002) 3, 247±253
Double vs. single protease inhibitor in HIV infection 251
Table 2 Clinical course and changes of treatment during follow-up
Median months of follow-up
Viral load < 400 copies/mL
at last follow-up [n (%)]
Viral rebound (> 400 copies/mL) at last
follow-up in patients with a previous viral load
of < 400 copies/mL [n (%)]
CD4 cell increase of >100 cells/mL
ever achieved during follow-up [n (%)]
Switch of initial protease inhibitor [n (%)]
AIDS or death [n (%)]
Single protease inhibitor
(n 5 177)
Dual protease inhibitor:
RTV/SQV
(n 5 2214)
P-value*
10.4
1360 (61.4)
10.4
112 (63.3)
0.90
0.63
632 (31.7)
48 (30)
0.65
1790 (80.8)
149 (84.2)
0.27
1622 (73.3)
125 (5.6)
120 (67.8)
15 (8.5)
0.16
0.13
*Difference between single protease inhibitor and dual protease inhibitor (RTV/SQV) by w2 and Wilcoxon signed rank tests. RTV, ritonavir; SQV,
saquinavir.
Table 3 Relative hazards for reaching a viral load of < 400 copies/mL (primary endpoint), a CD4 cell count increase of >100 cells/mL, and for the ®rst
change of protease inhibitor therapy (secondary endpoint)
Protease
Saquinavir/ritonavir vs. single protease inhibitor
Baseline CD4 cell count per 100 mL increase
Baseline viral load per 1 log10 copies/mL increase
Previous use of reverse transcriptase inhibitor
History of injecting drug use
Female vs. male
Age per 10-year increase
Primary endpoint*
Secondary endpoint*
Relative hazard of
HIV-1 RNA
< 400 copies/mL (95% CI)
Relative hazard of
CD4 cell increase by
> 100 cells/mL (95% CI)
Relative hazard of
®rst change of
inhibitor (95%)
1.21 (0.99±1.47)
1.01 (0.98±1.04)
0.71 (0.65±0.78)
0.62 (0.55±0.71)
0.95 (0.84±1.07)
0.99 (0.84±1.07)
1.04 (0.97±1.10)
1.12 (0.88±1.42)
1.07 (1.03±1.10)
1.27 (1.17±1.38)
0.86 (0.73±0.99)
0.62 (0.53±0.73)
0.82 (0.71±0.96)
0.88 (0.82±0.95)
0.90 (0.73±1.11)
0.99 (0.96±1.02)
1.09 (1.02±1.16)
1.37 (1.21±1.56)
1.10 (0.98±1.24)
0.86 (0.77±0.97)
0.98 (0.92±1.05)
*Adjusted for all variables listed in the table and stratified by year of start of potent antiretroviral therapy with protease inhibitor. CI, confidence interval.
patients reached a viral load of <400 copies/mL at week 48
[8]. In a randomized controlled trial, Cameron et al. [15]
tested different doses of RTV and SQV and found that over
80% of individuals who completed the trial reached a viral
load of <400 copies/mL at 48 weeks. Figures from both trials
are higher than in our analysis. One reason for these discrepant ®ndings could be that over 50% of the patients included
in the present analysis were not antiretroviral drug naive
when starting a potent therapy with PIs. This could explain
the relatively low ®gures of patients in our study that
achieved a viral load of <400 copies/mL in comparison
with other studies where identical dual PI combinations
and dosage regimens were used. The faster decline of HIV1 RNA with RTV plus SQV could indicate a superior antiretroviral effect compared with single PI therapies. However,
given the observational nature of our study, we stress the
need for further data from additional studies to con®rm
these ®ndings. Such studies could particularly evaluate the
ß 2002 British HIV Association HIV Medicine (2002) 3, 247±253
attractiveness of RTV plus SQV for induction therapies
followed by simpli®ed maintenance regiments in selected
patients with high baseline viral loads.
Comparison of our study results with other observational
studies is somewhat limited because most of these studies
included either very small control groups [16,17] or no
controls at all [4±6]. However, compared with our analysis,
the majority of these studies also reported higher proportion
of patients with double PI therapy of RTV plus SQV that
achieved and maintained an HIV-1 plasma viral load of
< 400 copies/mL.
Our data indicated a higher probability for a gain in the
CD4 count of >100 cells/mL in patients with RTV plus SQV
in the survival analysis. Multivariate analysis showed a
trend favouring the double over single PI regimens, though
the hazard ratio failed conventional levels for statistical
signi®cance. Because we could not ®nd a violation of the
proportional hazard assumption in our analysis, we consider
Proportion with CD4 cell increase > 100 per µL
252 HC Bucher et al.
CD4 cell increase >100 per 106/L
P < 0.05
1
0.9
0.8
0.7
0.6
Ritonavir/saquinavir
0.5
0.4
0.3
Single protease inhibitor
0.2
0.1
0
0
6
12
18
24
30
36
42
48
54
60
Proportion with HIV-1 RNA < 400 copies/mL
Time since start of potent antiretroviral therapy (months)
P < 0.04
HIV-1 RNA < 400 copies per mL
1
0.9
0.8
0.7
Ritonavir/saquinavir
0.6
0.5
Single protease inhibitor
0.4
0.3
0.2
0.1
0
0
6
12
18
24
30
36
42
48
54
60
Proportion of change of first protease inhibitor
Time since start of potent antiretroviral therapy (months)
Change of first protease inhibitor for any reason
P = 0.15
1
0.9
0.8
0.7
0.6
Single protease inhibitor
0.5
0.4
Ritonavir/ saquinavir
0.3
0.2
0.1
0
0
6
12
18
24
30
36
42
48
54
60
Time since start of potent antiretroviral therapy (months)
Fig. 1 Cumulative probability of reaching the primary endpoint of an
HIV-1 viral load of <400 copies/mL and secondary endpoints of CD4 cell
count increase of >100 cells/mL, and switch of initial protease inhibitor
for any reason (intention-to-treat analysis).
the lack of power the most likely explanation for this non
signi®cant ®nding. Two smaller, single-centre cohort studies from the UK and the USA found both a similar increase of
CD4 cells with single PI- and RTV plus SQV-treated patients
[16,17].
Time-to-switch from the initial PI regimen due to any
reason was similar in both groups. More than two-thirds of
patients in both groups switched their initial PI during
follow-up. This endpoint de®nition re¯ects the clinical
question `which treatment strategy keeps patients virologically suppressed?' All outcomes other than successful virological suppression with the assigned treatment program are
considered as failure [18]. We had to chose this endpoint
because we lacked detailed information about the reasons
for drug switches since this variable was only introduced
into the Swiss HIV Cohort Study in 1999. This is certainly a
limitation of our study. We suspect, however, that drug
intolerance of the combination therapy of RTV plus SQV
and incommodity of the IDV dosing regimen, the most
frequently used single PI, were the most likely reasons for
the high switch rates in both groups [19]. Evidence from a
cross-sectional survey within the Swiss HIV Cohort Study
supports this hypothesis. Double PI regimens compared with
single PI regimens were twice as likely to be associated with
adverse events [20].
To our knowledge this is the largest existing observational
study for the comparison of RTV plus SQV vs. single PI
regimens. We believe it is unlikely that future randomized
controlled trials will be conducted that compare dual PI
therapy of RTV plus SQV with other PI regimens in PI
naive patients. For this reason, con®rmation of this study's
®ndings from other prospective cohort studies with longer
follow-up times and more detailed information on adverse
effects of RTV plus SQV and exact reasons for drug discontinuation is desirable.
In conclusion, current evidence from this cohort study
suggests that in PI-naive HIV-1-infected patients, the PI
combination of RTV plus SQV plus one reverse transcriptase
inhibitor is as effective as single PI regimens in combination
with two reverse transcriptase inhibitors. These ®ndings
apply only for surrogate marker endpoints and no ®rm
conclusions can be drawn for clinical endpoints. Clinicians
who intend to use a dual regimen of RTV plus SQV should,
however, anticipate that it is highly likely that a large proportion of patients will switch from this combination therapy if treated for a suf®ciently long time span.
Acknowledgements
This study was ®nanced in the framework of the Swiss HIV
Cohort Study, supported by the Swiss National Science
Foundation (grant no. 3345±062041).
The members of the Swiss HIV Cohort Study are:
M. Battegay (Chairman of the Scienti®c Board),
E. Bernasconi, H. Bucher, Ph. BuÈrgisser, M. Egger, P. Erb,
W. Fierz, M. Flepp (Chairman of the Clinical and Laboratory
Committee), P. Francioli (President of the SHCS, Centre
ß 2002 British HIV Association HIV Medicine (2002) 3, 247±253
Double vs. single protease inhibitor in HIV infection 253
Hospitalier Universitaire Vaudois, Lausanne), H.J. Furrer,
M. Gorgievski, H. GuÈnthard, P. Grob, B. Hirschel, C. Kind,
Th. Klimkait, B. Ledergerber, U. Lauper, M. Opravil,
F. Paccaud, G. Pantaleo, L. Perrin, J.-C. Piffaretti,
M. Rickenbach (Head of Data Center), C. Rudin (Chairman of
the Mother & Child Substudy), J. Schupbach, A. Telenti,
P. Vernazza, Th. Wagels and R. Weber.
9 Battegay M, Vernazza PL, Bernasconi E et al. Combined therapy
with saquinavir, ritonavir and stavudine in moderately to
severely immunosuppressed HIV-infected protease
inhibitor-naive patients. HIV Med 2001; 2: 35±42.
10 Kirk O, Katzenstein TL, Gerstoft J et al. Combination therapy
containing ritonavir plus saquinavir has superior short-term
antiretroviral ef®cacy: a randomized trial. AIDS 1999; 13:
F9±F16.
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