Folks, if you haven't read Dr. Joseph Eron's review of the Sustiva data from HealthCG's website, well worth your time. See below:
A couple of key points, from memory, after reading the article:
- Sustiva is for real
- It's hard to get apples to apples comparisons between studies. Crixivan is a highly potent compound, in vitro and in vivo. Eron speculates the difference in the results between Crix + 2 NRTI and Sustiva + 2 NRTI may be traceable to tolerability. Btw, there were significantly greater drop-outs on Crix
- Don't know how this data squares with the information Margie posted about changes in patients dosing regimens while on study ... that's not apparent from this presentation of the data
- prelimary data from a small study shows Viracept a little less potent in combo than Sustiva (may be just noise in the numbers), and both together more potent than either alone (Rick's point)
- This may not have made it in the article but was on the website. There's a trial that's already begun that compares Viracept + 2 NRTIs with Sustiva + 2 NRTIs. Watch for this one!
Peter
healthcg.com
Day 1 - June 29, 1998
Antiretroviral Therapy
Efavirenz and the Prospect for Protease Sparing
Author: Joseph Eron, M.D.
Efavirenz - A Promising Beginning
In one of the most clinically important presentations that will occur at
this World AIDS Conference, Schlomo Staszewski presented the results of
a clinical trial comparing:
_efavirenz plus zidovudine and 3TC
_indinavir plus zidovudine and 3TC
_indinavir plus efavirenz
among subjects with asymptomatic or minimally symptomatic HIV disease
who were naive to 3TC, NNRTIs and protease inhibitors [1]. Four hundred
and fifty subjects were randomized and the results after 24 weeks were
presented. In the intent-to-treat analysis the efavirenz/3TC/ZDV regimen
was statistically significantly superior to both indinavir-containing
arms when the proportion of subjects with HIV-1 RNA levels below 400
copies were compared (74.7% for EFV/3TC/ZDV versus 56.2% for IDV/3TC/ZDV
at 24 weeks).
In the intent-to-treat analysis of the proportion of subjects achieving
viral load less than 50 copies/mL, EFV/3TC/ZDV was also superior. The
on-treatment analysis for EFV/3TC/ZDV showed an eye-popping 94.5% of
subjects below 400 copies at 24 weeks though this was not significantly
better than the 88.6% seen with IDV/3TC/ZDV.
Adverse events rates leading to discontinuation were substantially
higher in the IDV/3TC/ZDV arm with 38% of subjects discontinuing for all
causes, compared with only 21% of subjects discontinued from the
EFV/3TC/ZDV arm.
Central nervous system effects predominated in the efavirenz-containing
arms, although these side-effects rarely led to discontinuation of
treatment.
This study is one of the first large clinical trials to compare two
types of three-drug (or HAART therapy) head-to-head. The apparent
superiority of the efavirenz plus nucleoside regimen over either
protease inhibitor-containing regimen demonstrates that a combination
regimen based on a NNRTI and two nucleosides can be at least equipotent
and potentially more efficacious than PI-containing regimens over a
24-week period. A sub-analysis showed that even in subjects who began
the study with HIV RNA levels greater than 100,000 copies/mL the
EFV/3TC/ZDV arm retained its potency, with the on-treatment analysis
showing 90% of subjects below 400 copies/mL at 24 weeks.
Reasons for the observed difference in this trial may be in part due to
the agent itself, as efavirenz has marked potency in vitro against HIV.
However IDV/3TC/ZDV and IDV/EFV have demonstrated very potent
antiretroviral activity in this and other studies. The ease of
administration and tolerability of the EFV/3TC/ZDV regimen cannot be
underestimated. Efavirenz has a long-half life, in the range of 40-55
hours, and is therefore dosed only once daily. When given with 3TC/ZDV
subjects can receive two medication doses per day, while subjects
receiving IDV/ZDV/3TC or IDV/EFV take at least three doses of medication
per day. Although data on adherence were not presented, this may be one
of the driving forces behind these results. Intolerance to indinavir was
higher in this study than in many other reported and published studies.
The results of this sentinel study should be interpreted with a bit of
caution. First, the fact that it was not a blinded study may be a flaw.
Follow-up at this presentation was only 24 weeks, and differences
between these regimens may become greater or less distinct over time.
Durability of treatment effect is an important outcome of all clinical
trials, given the knowledge that HIV can persist at very low levels in a
latent state even after prolonged periods of "successful" therapy [2].
The genetic barrier to resistance of a regimen containing efavirenz and
3TC may be somewhat lower than regimens containing indinavir. However
most studies to date have shown that subjects who reach and maintain HIV
RNA levels below quantifiable limits over 24 weeks, especially if they
are below the limit of more sensitive assays, are very likely to remain
below quantifiable limits over more prolonged periods [3]. Therefore the
effects of efavirenz, 3TC and ZDV are likely to persist especially if
subjects are able to maintain adherence.
Efavirenz, Nelfinavir or Both in Experienced Patients
In another presentation comparing efavirenz (EFV) and a protease
inhibitor, this time nelfinavir (NFV), Mary Albrecht and colleagues
looked at the utility of efavirenz, nelfinavir or both agents in
combination with at least one and preferably two new nucleoside analogs
in subjects who were already nucleoside analog treatment experienced
(ACTG 364) [5]. Subjects on this study were highly selected as the vast
majority had already completed two previous ACTG protocols including
ACTG 175, the results of which were published two years ago [6,7].
Subjects were randomized to one of three arms:
_NFV plus new NRTIs (plus EFV placebo)
_EFV plus new NRTIs (plus NFV placebo)
_EFV plus NFV plus new NRTIs.
The proportion of subjects below the limit of detection (500 copies/mL)
at 16 weeks was the primary endpoint of the study. The median CD4+ cell
count of the entire group at baseline was 388 cell/æL and the median RNA
was 7626 copies/mL, reflecting the general stability over time of this
group of highly studied subjects. Overall only 72% of subjects achieved
HIV-1 RNA levels below 500 copies/mL at 16 weeks despite the very low
baseline RNA level. At 16 weeks, 64% of subjects on the NFV, 69% on EFV
and 81% on EFV plus NFV were below 500 copies. Although the three way
comparison between the arms did not reach statistical significant (P =
0.09) the two-way comparison between NFV/EFV with NRTI versus NFV with
NRTI did (P = 0.03) favoring the NFV/EFV combination. There were no
significant differences in the CD4+ cells rises and no major differences
in toxicity between the three arms.
The study is on going and remains blinded to assess durability of these
regimens for subjects who were below 500 copies at 16 weeks. Of note,
20% of subjects had already experienced virologic failure which was
defined as an HIV-1 RNA level greater than 2,000 copies/mL at 16 weeks.
46% of these subjects had five or more RTI resistance mutations at
baseline, though some had none. Of the 24 subjects who failed, six
acquired the D30N protease mutation associated with NFV resistance and
seven acquired the K103N RT substitution associated with EFV resistance.
Remarkably 11/24 had neither mutation.
Overall, these results suggest but do not prove that subjects who are
nucleoside experienced, even if they have relatively low viral loads,
will not have dramatic response to the addition of new nucleosides and
only one new drug from a different class (i.e., NNRTIs or protease
inhibitors). The best response may require the addition of two new
agents outside the NRTI class.
Discussion
While there is general acceptance that most HIV-1 infected subjects who
have some threshold of HIV-1 RNA detectable in their plasma should be
treated with a potent combination of antiretrovirals, there is certainly
no consensus as to which drug regimen should be instituted. The
Staszewski et al. study presented above offers HIV care providers and
HIV infected individuals another very attractive treatment regimen to be
used as initial potent therapy. (By the way, bravo to Dr Staszewski and
the DuPont-Pharma team for going head-to-head against a "gold-standard"
regimen as opposed to a two-nucleoside straw man).
Which PI Combination?
For those individuals and providers who choose to initiate therapy with
a protease inhibitor-containing regimen, the data continue to roll in.
However, until now there have been few large (i.e. appropriately
powered) trials comparing different PIs in protease inhibitor-containing
three drug regimens as initial therapy.
A study presented by a group from Denmark attempted to compare
ritonavir/saquinavir versus indinavir versus ritonavir as part of
initial therapy in protease-inhibitor individuals [8]. All subjects
received two additional nucleosides, although some of subjects were
nucleoside experienced at the start of the study. Two-hundred and
fifty-seven subjects were randomized in an unblinded fashion and the
vast majority had completed six months of therapy at the time of
analysis for this presentation. In the oral presentation, only subjects
naive to therapy at the start of the study were presented.
The authors presented an intent-to-treat analysis showing that at 48
weeks 92%, 90% and 70% of the IDV, RTV/SQV and RTV-treated subjects were
below 200 copies/mL, respectively. Clearly there was no significance to
the difference between RTV/SQV and IDV but both appeared superior to RTV
alone, which had the highest drop-out rate due to toxicity.
Approximately 35% of subjects discontinued the ritonavir arm compared to
7% on indinavir and 8% on RTV/SQV.
The Danes also looked at the proportion of subjects achieving viral load
below 20 copies/mL at 48 weeks. Although approximately 80% of the
RTV/SQV group had reached this level compared to 60% of the IDV-treated
group, the comparison did not reach statistical significance because the
number of subjects at this time-point was small. The striking difference
in on-treatment rates for the IDV-containing regimen in this study (93%
at 48 weeks) versus the study presented by Staszewski et al (63% at 24
weeks) have to be noted. What becomes clear is that in studies that use
a pure intent-to-treat analysis plan, on-treatment rates may greatly
effect the interpretation of the results.
Abacavir as Initial Therapy
Continuing the theme of protease-sparing treatments, Dr Margaret Fischl
presented data comparing ZDV/3TC plus abacavir (1592, ABC) with a
two-drug straw man (3TC/ZDV) in antiretroviral naive subjects [9].
Subjects were allowed to switch to open-label abacavir plus other
approved drugs if their HIV RNA levels were greater than 400 copies/mL
after 16 weeks.
In general the abacavir -containing regimen was well tolerated with only
two subjects having syndromes consistent with abacavir hypersensitivity.
HIV-1 RNA levels were below 400 copies/mL in 75% of subjects treated
with the three drugs at 16 weeks, at which point the three-drug regimen
was superior to ZDV/3TC alone (35% < 400 copies/mL). Dr Fischl also
present the proportion of subjects less than 50 copies/mL which was 54%
in an intent-to-treat analysis and 67% in the on-treatment analysis for
the three-drug arm at 16 weeks. The CD4+ responses were virtually
indistinguishable between the two and three-drug arms over this short
period.
The overall message of this study is that the PI-sparing and
NNRTI-sparing regimen of abacavir/3TC/ZDV is likely to have similar
potency and efficacy to other three-drug regimens that contain either a
PI or an NNRTI. These results must be considered preliminary, however.
The bottom line data will come from a Glaxo-Wellcome sponsored study
that compares abacavir/3TC/ZDV with indinavir/3TC/ZDV in a head-to-head
comparison. This pivotal study is enrolled though the data may not be
available for several months. The potential up-side of an abacavir
containing three-drug regimen is that it spares two classes of agents
and therefore may be very amenable to salvage therapy. The down-side may
be the predictable occurrence of abacavir hypersensitivity reactions
that occur in two to three percent of subjects and if recognized can be
managed appropriately with little harm to the individual. At present
management includes discontinuing abacavir and STRICTLY AVOIDING
RECHALLENGE!
References
1. Staszewski S, Morales-Ramirez J, Flanigan T, et al. A phase II,
multicenter, randomized, open-label study to compare the antiretroviral
activity and tolerability of efavirenz (EFV) + indinavir (IDV), versus
EFV + zidovudine (ZDV) + lamivudine (3TC) versus IDV + ZDV + 3TC at 24
weeks [DMP-266-006] [Abstract 22336]. 12th World AIDS Conference,
Geneva, Switzerland, 1998.
2. Wong J, et al. Recovery of replication-competent HIV despite
prolonged suppression of plasma viremia. Science 1997; 278:1291-1295.
3. Gulick R, Mellors J, Havlir D, et al. Indinavir (IDV), zidovudine
(ZDV) and lamivudine (3TC): concurrent or sequential therapy in
ZDV-experienced patients. 37th ICAAC, Toronto, Canada, 1997.
4. Albrecht M, Katzenstein D, Bosch RJ, et al. ACTG 364: Virologic
efficacy of nelfinavir (NFV) and/or efavirenz (EFV) in combination with
new nucleoside analogs in nucleoside experienced subjects [Abstract
12203]. 12th World AIDS Conference Geneva, Switzerland, 1998.
5. Hammer S, Katzenstein D, Hughes M, et al. A trial comparing
nucleoside monotherapy with combination therapy in HIV-infected adults
with CD4+ cell counts from 200 to 500 per cubic millimeter. N Engl J Med
1996; 335:1081-1090.
6. Katzenstein D, Hammer S, Hughes M, et al. The relation of virologic
and immunologic markers to clinical outcomes after nucleoside therapy in
HIV-infected adults with 200 to 500 CD4+ cells per cubic millimeter. N
Engl J Med 1996; 335:1091-1098.
7. Pederson C, Gerstoft J, Lunnogren JO, et al. Saquinavir/ritonavir may
have better antiretroviral efficacy than either ritonavir or indinavir
in HIV-infected antiretroviral naive patients [Abstract 12221]. 12th
World AIDS Conference, Geneva, Switzerland, 1998.
8. Fischl M, Greenberg S, Clumeck N, et al. Safety and activity of
abacavir (1592, ABC) with 3TC/ZDV in antiretroviral naive subjects
[Abstract 12230]. 12th World AIDS Conference, Geneva, Switzerland, 1998. |
