HIV Clinical Studies
ìSwitchî or
ìSubstitution Studies
There were several ìswitchî or drug ìsubstitutionî
studies reported at the 40th ICAAC.
Most of them involved substituting a PI (protease inhibitor) drug with a
NNRTI (non-nucleoside reverse transcriptase inhibitor) drug or the NRTI drug
abacavir (Ziagen). In general, the
following trends occurred: (1) some
metabolic changes (blood cholesterol, triglycerides [fats]) tended to improve;
(2) fat redistribution usually was not improved; (3) HIV RNA viral load remained
undetectable for the vast majority (a few patients had rebound, as did a few in
the ìcontrolî arms that continued their PI drug and did not switch) and in
one study remained undetectable for a higher percentage of patients who switched
than those who did not switch; and (4) CD4 counts continued to increase when the
viral load remained undetectable. Those
who had prior experience with a regimen that contained only one or two NRTI
drugs did not fare as well when switching to abacavir and therefore switching to
a triple NRTI combination.
Anita Rachlis, MD of Sunnybrook and Womenís College
Health Sciences Centre in Toronto, Ontario presented the interim 24-week results
of Study DMP 266-049. In this trial efavirenz (Sustiva, NNRTI drug) was substituted for 1-2 PI drugs in
a triple regimen with 2 NRTI drugs. At
baseline, all patients were required to have an undetectable viral load (lower
limit 50 copies per milliliter). A
total of 226 patients were randomized to the switch arm. This included 10% women, 20% Blacks, 8%
Hispanics and a history of injection drug use among 6%. The mean baseline CD4 count was 578
cells per microliter. The mean
duration of the prior PI drug regimen was 20 months. The prior PI drug was indinavir (Crixivan)
in 44% and nelfinavir (Viracept) in 30%, and 12% had taken two PI drugs in the
prior regimen. The most common dual
NRTI drug combinations were lamivudine (3TC, Epivir) with either zidovudine
(AZT, Retrovir) or stavudine (d4T, Zerit); both NRTI combinations represented
90%.
The results after
24 weeks showed the following. A significantly greater percentage maintained
viral undetectability (89%) than those who remained on their PI drug regimen
(81%) (strict ìnon-completer equals failureî analysis). Also, the time to virologic rebound was
significantly longer in the ìswitchî arm than in the ìno switchî arm. There were no significant differences in
CD4 count increases, approximately 40 cells per microliter in both arms. The only significant difference in blood
cholesterol between the two arms was a mild increase in the ìHDLî
(ìgoodî or high density lipoprotein) cholesterol in the ìswitchî group. However, those measurements were not
ìfastingî (empty stomach for 12 hours).
The only significant change in liver enzymes was an increase in the
ìGGTî (ìgammaglutamyl transpeptidaseî) in the switch arm. Adverse events (moderate or worse) were
higher in the switch arm (30%) than in the no-switch arm (17%). Most of those were known side effects
due to efavirenz, including CNS (central nervous system, brain) side effects and
rash. Potential changes in fat
redistribution were not reported. Adherence
questionnaires completed by participants revealed a significantly lower
percentage who reported missed doses at several clinic visits in the switch arm
(8%) than in the no-switch arm (20%). Discontinuation
rates were slightly lower in the ìswitchî arm (7%) than in the no switch arm
(12%). The authors concluded that
substituting efavirenz for 1-2 PI drugs in combination maintains viral
undetectability in a significantly greater proportion than those who continue
their PI drug-based regimen. Also,
CD4 counts continue to increase. And,
that the improved benefits are likely associated with improved adherence.
Reference
Rachlis A and others. Successful substitution of protease
inhibitors with Sustiva (efavirenz) in patients with undetectable plasma HIV-1
RNA levels: results of a prospective, randomized, multicenter, open-label study
(DMP 266-049). Abstract and
presentation 473.
Bonaventura Clotet, MD of Germans Trias I Pujol Hospital in
Barcelona, Spain presented the interim results of a similar study to DMP 266-049
above. However, in this study,
patients were randomized to one of three arms:
(1) switch to nevirapine (Viramune,
NNRTI drug); (2) switch to efavirenz (Sustiva,
NNRTI drug); or maintain the PI drug-based regimen. All 77 patients (29% women) who enrolled had an undetectable
viral load (lower limit 80 copies per milliliter) for at least 9 months. None had previously taken an NNRTI drug. The mean baseline CD4 count was rather
similar in all three arms, 595-660 cells per microliter. The mean time on prior anti-HIV therapy
was just over 5 years; 25% had taken HAART as their first regimen. The results after 9 months showed the
following. Viral rebound occurred at the same low rate: one or two patients in
each arm. CD4 counts continued to
increase in all arms. Adverse
events occurred among 2-3 patients in each arm due to known side effects of the
drugs used. Arm 1 (switch to
nevirapine) had a significant decrease in the total cholesterol level from an
abnormally high level at baseline and had a significant increase in liver
enzymes (ìALTî and ìGGTî). However,
the other two study arms also had mild increases in those liver enzymes (only an
increase in the GGT was significant in the efavirenz arm). Increases in liver enzymes trended among
those with HCV (hepatitis C virus) co-infection.
Total cholesterol, ìLDLî (low density lipoprotein or ìbadî)
cholesterol and triglycerides (fats) decreased significantly in the nevirapine
arm after 9 months. Switch
medications were stopped in the nevirapine arm in two patients (due to liver
enzymes or rash) and in the efavirenz arm in three patients due to ìCNSî
(brain) side effects that occurred among 32%.
Fat redistribution was unchanged, and was measured by ìDEXAî
(ìdual energy x-ray absorptiometryî). Quality-of-life
questionnaires indicated a significant improvement in both ìswitchî arms
after 9 months. The conclusions of
this small study indicate that viral undetectability is maintained in nearly all
patients, but there is a somewhat different side effect profile when comparing
patients who switch to either nevirapine or efavirenz to those who remain on a
PI drug regimen. Dr. Clotet said that monthly testing of liver enzymes among
those patients starting nevirapine ìis required mainly in HCV-co-infected
patients.î
(Editorial comment:
The FDA is issuing label changes related to NVP and potential liver/LFT related
toxicities. The new label will recommend close monitoring of liver function
tests during the first 12 weeks after initiation of therapy. Monitoring should
continue after that as well. Also, a Dear
Health Care Provider letter is being mailed by the maker of NVP (Boerhinger
Ingleheim) to doctors. At the European AIDS Conference in Glasgow in October
there were 3 studies related to this question, and they can be read on the NATAP
web site).
Reference
Negredo E, Clotet B and
others. Impact of switching from
protease inhibitors to nevirapine or efavirenz in patients with viral
suppression. Abstract and
presentation 473.
A similar study was
presented by Francois Raffi, MD of University Hospital in Nantes, France, called
The Maintavir Study. A total of 73 patients (21% women) switched to either nevirapine (86%) or efavirenz (14%) after having an
undetectable viral load (lower limit 400 copies per milliliter) for at least six
months while taking a PI drug-based regimen. NRTI drugs were continued.
None had ever taken an NNRTI drug. The
desire to switch was due to one or more of several reasonsósimplifying the
regimen was the most common. The median baseline CD4 count was 473 cells per microliter
with a median 22 months of prior PI drug therapy.
95% had a baseline viral load less than 50 copies per milliliter. There were 20 months of follow-up results. Virologic rebound occurred among 14% of the nevirapine arm
and 10% of the efavirenz arm, a non-significant difference. The rate of virological rebound also was
reported based upon a history of anti-HIV drug therapy prior to the HAART
(highly active antiretroviral therapy) regimen taken before entry into the
current study. For those with no
prior therapy, viral rebound occurred among 7% (58% of the 73 patients),
compared to 19% among those with prior anti-HIV therapy (42% of all patients). All 10 patients with viral rebound later
became undetectable after switching back to a PI drug regimen within 6 weeks. CD4 counts continued to increase in both
arms. Adverse events at six months
showed a significant decrease in blood triglycerides and no significant change
in cholesterol. (Note the somewhat
different results regarding triglycerides and cholesterol in this study compared
to the one above.) Fat
redistribution improved in some by ìsubjective assessment.î Discontinuations occurred among 7%.
Reference
Raffi F and others. The Maintavir Study, substitution of a
non-nucleoside reverse transcriptase inhibitor (NNRTI) for a protease inhibitor
(PI) in patients with undetectable plasma HIV-1 RNA: 18 months follow-up. Abstract and presentation 474.
There were two
presentations about switching from
a PI drug-based HAART to an abacavir (Ziagen, NRTI drug)-based triple NRTI drug regimen. The first was presented by Milos Opravil,
MD of University Hospital in Zurich, Switzerland.
In that study, the switch arm took abacavir plus zidovudine (AZT,
Retrovir) and lamivudine (3TC, Zerit) as the one pill formulation Combivir. When the new formulation Trizivir was
available (all three drugs in one pill), it was substituted. This represents a regimen with one pill
every twelve hours. A total of 163
patients (20% women) were randomized to abacavir/AZT/3TC or to continue their
current PI-based regimen. Requirements
for entering the study included an undetectable HIV viral load (lower limit 50
copies per milliliter) for at least six months and not having the AZT ì215î
gene mutation in DNA of blood immune cells.
The mean baseline CD4 count was 512 cells per microliter. The mean duration of the previous
PI-based HAART regimen at baseline was 20 months.
Pre-HAART treatment with 1 or 2 NRTI drugs had occurred among 46% of
patients.
The results were
as follows. The median (average)
follow-up was 68 weeks. The switch arm had 15% with viral rebound,
compared to 6% of the no-switch arm (strict ìintent-to-treatî analysis,
all patients included). However,
the total ìtreatment failureî rate was slightly higher in the
ìno-switchî arm (29%) than in the switch arm (25%). This opposite outcome was due to a
higher rate of changing drug(s) due to adverse events and a higher rate of
ìlost to follow-upî in the ìno-switchî arm. In a separate analysis, Dr. Opravil
reported that viral rebound was 5-times
more likely (ìodds ratioî) to
occur in either treatment arm if there had been exposure to AZT before HAART. This finding was statistically
significant for the ìswitchî arm. Virologic
rebound also was associated with 1- or 2-drug NRTI treatment before HAART. There was a significant decrease in the
blood cholesterol in the ìswitchî arm.
Virologic rebound in the ìswitchî arm still allowed for constructing
a new regimen with a NNRTI or PI drug(s) in combination therapy. The authors conclude, ìSimplified
maintenance therapy with abacavir/Combivir (Trizivir) is an effective option if
prior treatment history indicates [an] absence of archived [saved from the past]
resistance mutations [to NRTI drugs] and adherence is maintained.î The study also suggests that this triple
NRTI combination might be less effective among those patients with prior 1- or
2-drug NRTI treatment regimens.
Reference
Opravil M and others. Simplified maintenance therapy with
abacavir + lamivudine + zidovudine in patients with HAART-induced long-term
suppression of HIV-1 RNA: final results. Abstract
and presentation 476.
A similar study was
presented by Julio Montaner, MD of the St. Paulís Hospital in Vancouver,
British Columbia (CNA 30017). However, this study had different
results than the one above, due to a much lower
rate of prior NRTI drug experience at baseline (9%). In this larger study of 211 patients
(approximately 18% women), patients must have had an undetectable viral load
(lower limit 50 copies per milliliter) for at least six months on a triple
regimen with a PI plus 2 NRTI drugs. Patients
were randomized to continue their regimen or switch the PI drug to abacavir in a
ìsimplifiedî regimen. Note that
in this study, the switch arm could have continued with any two NRTI drugs, not
necessarily AZT plus 3TC as Combivir that occurred in the study above. The median CD4 count was approximately
505 cells per microliter. The
follow-up period in this study was somewhat shorter at 48 weeks.
The results showed
that 11% in both arms had virologic
rebound at 48 weeks using a lower limit of 50 copies per milliliter (strict
ìintent-to-treatî analysis). Using
a lower limit of 400 copies per milliliter, 4% in the switch arm and 2% in the
no-switch \arm had virologic ìfailure.î
Among those with rebound in the ìswitchî arm who did not have drug
resistance at baseline, 2 of 3 patients developed only one mutation, allowing
for a wide range of options for the next drug regimen. However, ìtreatment failureî (discontinuation due to any reason) was twice as high in the no-switch arm (26%) than
in the switch arm (13%), a statistically significant difference. Most of the difference was due to
discontinuation resulting from adverse
events in the no-switch arm. The
switch arm also had a significantly longer time until treatment failure than the
no-switch arm. Serious adverse
events were nearly equal in both arms, 10% in the switch and 12% in the
no-switch arms. There was a
significantly greater decrease in blood cholesterol in the ìswitchî arm than
in the ìno-switchî arm. CD4
counts increased mildly in both arms.
These two studies about switching to an abacavir, triple
NRTI regimen indicate significant potency with this ìsimplifiedî regimen
that has a lower number of daily pills. However,
this may not be the best regimen for those with prior single or dual NRTI
regimens due to a higher rate of virologic rebound. The impending availability of the triple
formulation Trizivir with all three drugs as a regimen of one pill twice daily
also allows for easier adherence. For
some patients, this would be associated with a greater likelihood of maintaining
virologic suppression.
(Editorial comment:
At Durban, Pedro Cahn reported a triple NRTI regimen of abacavir+AZT/3TC
performed as well as IDV+AZT/3TC in treatment-naÔve patients with viral load
>100,000. These were, however, 24 weeks data from an open-label study. Longer
term data will confirm if these results will hold up over time. Cahn reported
the good performance by the abacavir regimen was due to better adherence and
tolerability than the indinavir arm. The NATAP Durban reports contain details of
this study).
An additional report on Switching Studies at ICAAC
written by Jules Levin is available on the NATAP web site:
Reference
Montaner J and others. A novel use of abacavir to simplify
therapy and reduce toxicity in PI experienced patients successfully treated with
HAART: 48-week results (CNA30017). Abstract
and presentation 477.
Does Adding a 4th
Drug Lead to Virologic Benefits?
There was an interesting presentation about the number of
anti-HIV drugs in a regimen that was authored by W. Jeffrey Fessel, MD of Kaiser
Foundation Hospital in San Francisco, California.
In that study, 53 patients had a stable, undetectable viral load (lower
limit 50 copies per milliliter) with a triple drug regimen of a PI and 2 NRTI
drugs. Patients were then
randomized to continue the regimen or add efavirenz (Sustiva, NNRTI drug). The two groups were comparable in
baseline characteristics. After
follow-up of 20 weeks, 17% in the 3-drug arm and none in the 4-drug arm had
viral rebound to greater than 50 copies per milliliter, a significant
difference. There were another five
patients with a baseline viral load greater than 50 but less than 500 copies per
milliliter that were a part of the arm that maintained 3 drugs. Two of them decreased their load to less
than 50 while the other 3 maintained a level greater than 50 copies per
milliliter. There was a 14%
discontinuation rate in the 4-drug arm, due to efavirenz side effects. While adding efavirenz did show
virologic benefits, there are other considerations. First is the fact that the
4-drug arm included all three-drug classes, which limits future options if
virologic rebound occurs. Second,
as Dr. Fessel points out, the potential negative long-term adverse events
associated with four drugs must be weighed against the potential increase in
sustained virologic benefits.
Reference
Fessel WJ and others. Four drugs are better than three drugs
to maintain existing HIV suppression and reduce productive infection. Abstract 535.
Comparing Different
NNRTI Regimens and NNRTI with PI Drug Regimens
There were several presentations that compared several drug
regimens in randomized studies with HIV patients who had not had previous
anti-HIV treatment (ìnaÔveî). In
the Spanish SENC Trial, nevirapine
(Viramune, NNRTI drug) was compared to efavirenz (Sustiva) when combined with
the 2 NRTI drugs didanosine (ddI, Videx) and stavudine (Zerit, d4T). The small study of 54 HIV positive
patients (approximately 75% men) was randomized and prospective (planned
beforehand). The two study arms
were comparable at baseline. The
median baseline HIV RNA viral load was approximately 4.3 log (21,000) copies per
milliliter and the CD4 count was approximately 360 cells per microliter. Approximately 1/3 was HCV (hepatitis C
virus) positive.
(Editorial comment:
This study drew sharp criticism because the presenter concluded that the study
showed that EFV & NVP were equivalent. The criticism was that a much larger
study is needed to show equivalence than to show a difference between regimens.
The smaller a study is the less likely it is to show a difference between 2
arms. As well, the baseline viral load was low, maybe too low to detect
differences between the 2 arms).
The interim results were
after a median of 9 months. Outcome measurements were generally similar
in both arms. An undetectable
viral load (lower limit 50 copies per milliliter) was achieved by 79% of the
nevirapine arm and 85% of the efavirenz arm (strict ìintent-to-treatî
analysis). Achieving
undetectability occurred at the same rate in both arms. Rash, a common side effect in the NNRTI
drug class occurred among 17% of the nevirapine arm and 12% of the efavirenz
arm; however, no one discontinued due to rash.
Increases in liver enzymes (ìALT, ASTî) were generally mild and were
more common in the nevirapine arm (59%) than in the efavirenz arm (35%);
although, the difference was not statistically different. Liver toxicity was significantly
associated with HCV positivity. The total discontinuation rate was 22%, although only two
patients did so due to adverse events related to study drugs (both efavirenz). The lead author, M. Nunez, MD, concluded
that there was a similar virologic outcome when ddI and d4T are combined with
either nevirapine or efavirenz. A
much larger study called 2NN with 1,200 patients has begun and will compare the
two NNRTI drugs in combination therapy. The 4-arm study will have a NRTI backbone of d4T plus 3TC. The other drugs will be: (1) nevirapine
dosed once daily; (2) nevirapine twice daily; (3) efavirenz once daily; or (4)
efavirenz plus nevirapine.
The Combine Study
compared the results of a nevirapine (Viramune,
NNRTI drug)-based regimen with a nelfinavir (Viracept, PI drug)-based regimen in a randomized trial. Daniel Podzamczer, MD of Hospital de
Bellvitge in Barcelona, Spain presented the interim 9-month results. Either drug was combined with the
double NRTI drug formulation Combivir (AZT plus 3TC) in HIV patients without
previous anti-HIV treatment. The
twice-daily dose of nelfinavir was used (1,250 mg). A total of 142 patients were in the
randomized study. Women represented
25% of participants, although there were significantly more women randomized to
the nelfinavir arm (18%) than the nevirapine arm (33%). Race-ethnicity was not reported. The median baseline viral load was 4.8
log (63,095) copies per milliliter with a CD4 count of approximately 356 cells
per microliter.
The interim results were
presented after 9 months. Using a lower limit of 20 copies per milliliter,
significantly more patients achieved an
undetectable viral load in the nevirapine arm (67%) than in the nelfinavir arm
(39%, strict ìintent-to-treatî analysis).
The viral load results had less of a difference using a lower limit of
200 copies: 71% in the nevirapine arm and 56% in the nelfinavir arm. A superior trend in the nevirapine arm
also occurred among those with a high baseline viral load, greater than 100,000
copies per milliliter (approximately 1/3 of patients). However, the nelfinavir arm achieved a
greater increase in the CD4 count (increase of 172 cells per microliter) than
the nevirapine arm (increase of 116 cells per microliter)óthis difference was
not statistically significant. Discontinuation
due to adverse events was similar in both arms: 22% in the nevirapine arm and
19% in the nelfinavir arm. Adverse
events were similar to what has been reported for these drugs in the past. The study did have a somewhat high rate of ìlost-to-follow-up:î 24% in
the nelfinavir arm and 14% in the nevirapine arm. The interim results suggest that a combination of
nevirapine/Combivir shows virologic benefits over a nelfinavir/Combivir
combination. The higher rate of
ìlost-to-follow-upî in the nelfinavir arm is one limiting factor of the
results. The nevirapine/Combivir
regimen represents only three pills twice daily. The study is ongoing for 48 weeks.
(Editorial note:
nelfinavir performed less well than it usually does, so this raises questions
about the results. It's possible there was more non-adherence in the NFV arm and
it didn't appear as though there was a method to collect that information.
Investigators also reported 39% (56/142) total patients stopped therapy: 45%
(32/70) in NFV arm and 33% (24/72) in the NVP arm. About 20% stopped due to
intolerance).
Reference
Podzamczer D and others. A randomized, open, multicenter trial
comparing Combivir plus nelfinavir or nevirapine in HIV-infected naÔve patients
(The Combine Study). Abstract and
presentation 694.
In a study comparing
nevirapine combination therapy to indinavir
(Crixivan, PI drug) combination therapy, the results after 36 weeks revealed
nearly similar outcomes. J.
Guardiola, MD of Sant Pau Hospital in Barcelona, Spain presented the study. The dual NRTI backbone was stavudine
(d4T, Zerit) and didanosine (ddI, Videx). A
total of 50 HIV patients (27% women) were enrolled with no previous anti-HIV
therapy. Nevirapine was dosed twice
daily, 200 mg, while indinavir had a standard dose of 800 mg 3-times daily. The median baseline viral load was
approximately 5.3 log (199,526) copies per milliliter with a CD4 count of 370
(nevirapine) and 337 cells per microliter (indinavir). The results after 9 months revealed an equal
percentage with an undetectable viral load (50%, lower limit 50 copies per
milliliter) for both arms (strict ìintent-to-treatî analysis). There also were similar results for
those with a high baseline viral load. The CD4 count increase was 223 (nevirapine) and 166 cells per
microliter (indinavir) arm. Adverse
events likewise occurred at similar rates in the two arms, not all of which were
due to nevirapine or indinavir. Changes
in lipids and cholesterol also were very similar when comparing the two arms. This small study reports a near
equivalence comparing nevirapine to indinavir in combination therapy, a
different result than the study above, comparing nevirapine to nelfinavir. (Note the NRTI backbone was different in
the two studies.
(Editorial Note: there
appears to be no adherence data reported. The no difference between the two arms
could be related to adherence. In addition, I think similar criticisms could be
raised for this study as raised for the SENC study above. Concluding equivalence
would require a considerably larger study
(NVP RASH: At Glasgow,
P Barreiro and a Spanish research group reported results from a
comparison
of
several methods for preventing NVP-related rash. The authors concluded, the
incidence of rash complicating the first few weeks of treatment with NVP can be
diminished adding corticosteroids or antihista-minics for two weeks to the
standard recommendation, or using a slow escalating dosing. This third approach
is proven to be pharma-cokinetically safe. They reported the rate of rash is cut
in half--187% vs 8.8-7.7%).
You can read details of the presentation at Glasgow:
Prevention
of nevirapine-associated rash using slow dose escalation, antihistaminics or
corticosteroids
Reference
Guardiola J and others. An open-label, randomized, comparative
study of stavudine (d4T) + didanosine (ddI) + indinavir versus d4T + ddI +
nevirapine in treatment of HIV-infected naÔve patients. Abstract 539.
Lopinavir/Ritonavir (Kaletra) Update
There were several presentations about lopinavir/ritonavir
(Kaletra) at the 40th ICAAC. This double protease (PI) drug
formulation was approved by the FDA a few days before the Conference began.
Treatment ìnaÔveî
A 96-week update of lopinavir/ritonavir (LVP/RTV) in Study
M97-720 was authored by Constance Benson, MD of the University of Colorado at
Denver. The study enrolled 100 HIV
positive patients without previous treatment (ìtreatment-naÔveî). The group was composed of 4% women, 29%
Blacks and 6% Hispanics. The dosing
was lopinavir 200-400 mg plus ritonavir 100-200 mg, twice daily plus stavudine
(d4T, Zerit) and lamivudine (3TC, Epivir).
After week 48, all patients took the FDA-approved dose of lopinavir 400
mg plus ritonavir 100 mg in a fixed formulation twice daily. The median baseline HIV RNA viral load
was 4.8 log (63,095) copies per milliliter with a CD4 count of 326 cells per
microliter. The results after 96 weeks showed that 78% had an undetectable viral
load (lower limit 50 copies per milliliter) using a strict ìintent-to-treatî
analysis (all patients included). The mean increase in the CD4 count was 290
cells per microliter. The most
common adverse events (side effects, moderate or worse) were diarrhea 23%,
nausea 15%, stomach-area pain 8%, weakness 7%, headache 7%, and vomiting 5%. The most common abnormal laboratory
tests were increased cholesterol (greater than 300 mg per deciliter) 14%,
increased triglycerides (fats, greater than 750 mg per deciliter), increased
liver enzymes (greater than 5-times the upper normal limit) 10%, and increased
amylase (pancreas gland enzyme, greater than twice the upper normal limit) 4%. Yet, only 2% discontinued due to adverse
events. The total discontinuation
rate was 14%, due to dosing non-adherence, medical problems unrelated to study
drugs, lost to follow-up and others. The
overall results indicate that the combination of lopinavir/ritonavir, stavudine
and lamivudine is quite potent in treatment-naÔve patients.
(Editorial note: Week
96 <400 data was about the same for <100,000 or >100,000 copies/ml at
baseline. Week 96 <50 copy data
was not reported. Median time to first VL <50 copies was 113 days for the
group with baseline VL <100,000 copies/ml and 140 days for the group with
baseline VL >100,000 copies/ml (p<0.001). Of note, 12/43 (28%) of patients
in the group with baseline VL >100,000 had their first VL measure <50 at
week 36 or later. Compared to 1/51 (2%) of the group with baseline VL
<100,000).
Treatment-ìExperiencedî
An update of the 24-week results of Study M98-957 was
presented by Steven Becker, MD of Horizon Medical Group in San Francisco,
California. A total of 57 HIV
positive patients with a detectable HIV RNA viral load after at least two PI
(protease inhibitor) drugs (at least 3 months each) were enrolled. None had ever taken a NNRTI drug. Women represented 21% and non-Caucasians
12%. The median baseline viral load
was 4.5 log (31,622) copies per milliliter with a median CD4 count of 218-271
cells per microliter. Patients were
randomized to receive the FDA-approved dose of lopinavir 400 mg/ ritonavir 100
mg twice daily or 533 mg/ 133 mg twice daily.
Also in the regimen were efavirenz (Sustiva, NNRTI drug) and two NRTI
drugs. Patients had taken a mean 3
previous PI drugs and 7 total anti-HIV drugs.
The mean baseline susceptibility to lopinavir was decreased 16-fold
(relative ìresistanceî) when compared to ìwild-typeî without mutations. After 24 weeks, the results were as follows. An
undetectable HIV RNA was achieved by 62% in the 400 mg arm and 64% of the 533 mg
arm (strict ìintent-to-treatî analysis, 50 copies per milliliter lower
limit). The mean CD4 cell increase
was 46 cells and 41 cells per microliter in the 400 mg and 533 mg arms,
respectively. The most common
adverse effects were quite similar to Study M97-720 above: diarrhea, weakness,
increased cholesterol, triglycerides, amylase and liver enzymes. Seven patients discontinued (12%, four
patients in 400 mg and three in 533 mg arms), including four due to adverse
events and three due to ìvirologic failure.î
Both categories of discontinuation reasons occurred among both dosing
arms. The patients are still being
followed, although taking the higher dose of lopinavir/ritonavir. The results show that the 5-drug
combination of lopinavir/ritonavir, efavirenz and 2 NRTI drugs is quite
effective as a ìthird-lineî regimen for those who have taken at least two PI
drugs in the past but not any NNRTI drugsóeven with significant PI drug
resistance at baseline. Dr. Becker
also concluded that lopinavir/ritonavir
ìshould be increased to 533/133 mg BID [twice daily] when co-administered with
efavirenz in patients with extensive prior PI [drug] use.î
(Editorial note: 24
week <400 data ITT reported 69%
and 82% for 400/100 and 533/133 doses, respectively. Week 48 data reported at
Glasgow for ITT <400 was 59% and 71%, for 400/100 and 533/133, respectively.
All patients in Arm A began conversion to 533/133 bid dose after week 24 and completed process prior to week
48).
Also
see Glasgow report: ABT-378 (Kaletra) in Multiple PI Experienced: 48 Week Update
Interaction with Cholesterol-Lowering Drugs
Lopinavir/ritonavir (Kaletra) should not be combined with
atorvastatin (Lipitor) due to 5-fold increased blood levels of the latter drug. However, it is safe to combine
lopinavir/ritonavir with pravastatin (Pravachol). The drug levels of pravastatin are increased by approximately
30% and are unlikely to represent a problem for most patients. Neither of the two ì-statinî drugs
affected the blood levels of lopinavir/ritonavir.
Both atorvastatin and pravastatin are members of the ì-statinî drug
class to lower blood cholesterol levels. High
cholesterol levels represent a common side effect of most PI (protease
inhibitor) drugs and some NNRTI drugs. High cholesterol is one risk factor for blood vessel disease
that can lead to a ìheart attackî or ìstrokeî (ìbrain attackî).
Interaction with Efavirenz (Sustiva)
The dosing of lopinavir/ritonavir (Kaletra) might need to
be increased when combined with the NNRTI drug efavirenz (Sustiva). The blood concentrations of lopinavir
were reduced when lopinavir/ritonavir and efavirenz were combined in HIV
positive patients. Specifically,
the minimal concentration was reduced 44% and the total concentration
(ìarea-under-the-curveî) was decreased by 25%. In healthy volunteers, the combination
decreased all blood concentration measurements of efavirenz by less than 16%,
suggesting that no dose adjustment for efavirenz is needed. Ritonavir blood levels were not
affected. If the twice daily
dose of lopinavir 400mg /ritonavir 100 mg is increased to 533/133 mg twice daily
when combined with efavirenz, then the blood levels of lopinavir are nearly the
same as when lopinavir/ritonavir is taken alone.
This would mean four capsules twice daily of lopinavir/ritonavir, plus
the other medications in the regimen.
ìGenotypeî resistance testing at baseline in this study was
presented by Dale Kempf, PhD of Abbott Laboratories. He expanded his previous findings and proposed a new
categorization for lopinavir resistance. If
there were zero to five genotype mutations to lopinavir, this would be called
ìsensitiveî (no resistance). If
there were 6-7 mutations, this would be called ìintermediate resistance.î Only if there were 8 or more mutations
would this be called ìresistant.î
At the Resistance Workshop (summer 2000), additional data
on response based on baseline resistance was reported up to the week 24 point.
Link to the NATAP Report:
Report 1 - 4th International Workshop
on HIV Drug Resistance and Treatment Strategies
Lopinavir Combination Compared to Viracept Combination
The interim results of the first phase III study comparing
lopinavir/ritonavir combination therapy to another PI drug-based combination
were presented. Sharon Walmsley, MD
of Toronto General Hospital in Ontario, Canada discussed the results of the
randomized, ìblindedî (medications unknown to patients) study of 653
patients. Women represented 20% of
patients, Blacks 27% and Hispanics 13%. No
patient had ever taken more than 14 days of anti-HIV drug, without any previous
d4T or 3TC. The mean baseline HIV
RNA viral load was 4.9 log (79,432) copies per milliliter with a CD4 count of
259 cells per microliter. Patients
were randomized to receive lopinavir 400 mg/ ritonavir 100 mg twice daily or
nelfinavir (Viracept, PI drug) 750 mg 3-times daily. (The nelfinavir dose was changed later
to 1,250 mg twice daily.) All also
took stavudine (d4T, Zerit) and lamivudine (3TC, Epivir), both twice daily (both
NRTI drugs). In order for the study
to be ìblinded,î patients also took ìplaceboî (inactive) pills of the PI
drug to which they were not randomized. This
led to a high number of daily pills.
The results after
40 weeks showed that the lopinavir arm had a significantly higher rate of viral
undetectability (79%, lower 400 copies per milliliter) compared to a 64% rate in
the nelfinavir arm (strict ìintent-to-treatî analysis, all patients
included). Using a lower limit of
50 copies per milliliter, the undetectability rates were 70% and 54%,
respectively for the same two arms. The
CD4 count increases were 190 and 177 cells per microliter for the lopinavir and
nelfinavir arms, respectively. Adverse
events (side effects) were similar in both groups: diarrhea, nausea, weakness,
stomach-area pain, vomiting, and headache.
The lopinavir arm had a higher rate of ìgrade 3-4î (severe or
life-threatening) increase in blood cholesterol (8%) than the nelfinavir arm
(4%). Similarly, the lopinavir arm
had a higher rate of grade 3-4 increase in blood triglycerides (fats, 7%) when
compared to the nelfinavir arm (1%). The
discontinuation rate after 40 weeks was 15% in the lopinavir arm and 20% in the
nelfinavir arm; although only 2-3% in each arm was due to adverse effects
related to study drugs. These
preliminary results suggest that the lopinavir combination therapy arm may be
more potent than the nelfinavir combination therapy arm. However, the number of pills required to
make this a study placebo-controlled and the fact that a middle of the day
dosing was required initially both limit the results. The study is ongoing.
Additional information was reported at Glasgow in
October, and here's the link to NATAP Report: ABT-378 vs
Nelfinavir (+d4T/3TC)
Food Interaction
The total blood concentration (ìarea-under-the-curveî)
of lopinavir from the soft capsule formulation was increased 26% when taken with
a high fat meal (56% of calories from fat) than when taken with a moderate fat
meal (25-30% of calories from fat). The
same experiment using the liquid formulation led to a 37% increase in blood
levels of lopinavir. When taken
without food (fasting), the capsule formulation led to 36% lower blood levels
than with a moderate fat meal. The
same test with the liquid formulation led to a 44% lower level. The results indicate that lopinavir/ritonavir should be taken
with food and preferably, a high fat meal.
References
Becker S and others. ABT-378/ritonavir and efavirenz: 24 week
safety/efficacy evaluation in multiple PI experienced patients. Abstract and oral presentation 697.
Benson C and others. ABT-378/ritonavir (ABT-378/r) in
antiretroviral naÔve HIV + patients: 96 weeks.
Abstract and poster 546.
Bertz R and others. Assessment of the pharmacokinetic
interaction between ABT-378/ritonavir and efavirenz in healthy volunteers and
HIV+ subjects. Abstract 424.
Carr RA and others. Concomitant administration of
ABT-378/ritonavir results in a clinically important pharmacokinetic interaction
with atorvastatin but not pravastatin. Abstract
and presentation 1644.
Gustavson LE and others. Assessment of the bioequivalence and
food effects for liquid and soft elastic capsule co-formulations of
ABT-378/ritonavir in healthy subjects. Abstract
and presentation 1659.
Kempf D and others. Definition of genotypic breakpoints for
ABT-378/ritonavir for use in the interpretation of HIV resistance testing. Abstract and presentation 1264.
Walmsley S and others. Efficacy of ABT-378/ritonavir versus
nelfinavir in antiretroviral-naÔve subjects: results of a phase III blinded
randomized clinical trial. Abstract
and presentation 693.