of new drugs are in development, and to one degree or another, all are expected
to be effective for people with resistance to currently available drugs.
However, problems can occur in drug development, such as unforeseen toxicities
which can derail development. ABT-378 is the furthest along in development, so
there is more information available on it. Abbott Labs, the manufacturer, has
applied to the FDA for accelerated approval, and it should be available before
the end of 2000.
(Kaletra) In Treatment NaÔve: 72 week Update.
One hundred treatment naÔve individuals were randomized to receive one of three
dose levels of ABT-378/r (200/100 mg BID), 400/100 mg BID or 400/200 BID),
together with d4T and 3TC, given either from study entry (group 2) or after 3
weeks (group 1). Enrollment into group 2 began following an evaluation of
preliminary efficacy and safety in group 1. After 48 weeks, all patients began
conversion to open label ABT-378/r (Kaletra) 400/100 BID dosing. Plasma viral
load was measured using Roche Amplicor Monitor 400copy/ml assay, and Abbott Labs
quantitative 50 copy/ml assay.
baseline, there were 32 individuals in group 1; 30 men, two women; 69%
Caucasian, 28% Black, 3% Hispanic. Median viral load was 5 log (100,000
copies/ml) (range 3.7 log-6.0 log). Mean CD4 count was 421. In group 2 (n=68),
two were women; 63% Caucasian, 29% Black, 7% Hispanic. Viral load was 4.9 log
(79,000 copies/ml) (range 3.3 log to 6.7 log; 2000 copies/ml to 500,000
copies/ml). Median CD4 count was 301.
Treatment Analysis: 93% (25/27) in group 1, and 100% (57/57) in group 2 had <400
Analysis (missing values considered as treatment failures): 78%
in group 1 (25/32), and 84% (57/68) in group 2 had <400 copies/ml
Treatment Analysis: 96% (26/27) in group 1, and 96% (54/56) in group 2 had <50 copies/ml
(26/32) in group 1, and 79% (54/68) in group 2 had <50 copies/ml
performed the same, using the 400 copy assay, whether a person's viral load was
<100,000 copies/ml or >100,000 copies/ml. There was no data on performance
regarding <50 when a person was less than or greater than 100,000 copies/ml.
with baseline viral load >100,000 copies/ml generally took longer to reach
<400 copies/ml than patients with <100,000 copies/ml, but response rates
were the same by week 20 and subsequently. At week 72, those with <100,000
copies/ml 100% had <400 copies/ml at week 72 by on treatment analysis, and by
ITT 78% had <400 copies/ml. For those with >100,000 copies/ml at baseline,
95% had <400 copies/ml at week 72 by on treatment analysis, and 87% had
<400 copies/ml by ITT analysis.
count increase was 304 in group 1 by week 72, and 240 in group 2.
Based on patient reported dose interruptions, adherence was reportedly 98% through week 72. The most common adverse events were diarrhea, nausea, and abnormal stools. Abbott reported that at week 72, only one patient discontinued due to an adverse event/lab abnormality related to study drug. (See Table 3)
adverse events of at "least moderate severity, and probable,
4/8 patients with AST/ALT elevations were seropositive for HBV
surface antigen (HbsAg) or HCV antibody at baseline
DISPOSITION- 13 patients discontinued at or before week 72: 1 due to AST/ALT; 4
for noncompliance, 3 lost to follow-up, 1 for personal reasons, 3 for adverse
event; lymphoma, hyperglycemia in diabetic patient, alcohol detoxification.
of Clinically Relevant Phenotypic and Genotypic Breakpoints for ABT-378/r in
Multiple PI-experienced, NNRTI-naÔve Patients.
Dale Kempf & Eugene Sun from Abbott delivered these talks at the Resistance
Workshop. Abbott reports that at a dose of 400/100 ABT-378/r (higher doses are
being explored for salvage), pre-dose mean plasma trough levels are
≥75-fold above its serum adjusted EC50. The high plasma levels of ABT-378
appear to have an important significance. Firstly, the effectiveness of ABT-378
in individuals with PI experience and resistance will likely be associated with
the drug's high blood levels rather than a unique resistance profile, which it
does not appear to have. Second, it appears that due to high blood levels
ABT-378 will have higher phenotypic susceptibility cut-offs or breakpoints than
other protease inhibitors. What does this mean in plain language? For example,
assume for the sake of discussion that 12-fold reduced susceptibility may be
enough for full resistance to a given PI. A similar situation applies to RTV-IDV
and RTV-amprenavir combinations, as there are no defined cut-offs for efficacy.
The amount of reduced susceptibility to ABT-378 may have to be significantly
higher for resistance to develop, since ABT-378 achieves high blood levels. It
is in this context that Abbott has designed and reported at this meeting their
approach to analyzing the response to ABT-378 in PI experienced individuals.
Dale Kempf talked about genotypic and phenotypic correlates of reduced in vitro
susceptibility to ABT-378. He discussed the 11 mutations identified to be
associated with ABT-378 resistance development and their correlations to reduced
phenotypic susceptibility. Then Eugene Sun delivered an oral presentation on how
these geno/pheno correlations relate to virologic response to ABT-378.
analysis is of participants in study M98-957, which was for individuals with
multiple PI experience, NNRTI-naÔve, and HIV-RNA >1000 copies/ml. The number
of median prior protease inhibitors was 3, 4 NRTIs, and 7.5 total antiretroviral
drugs. Individuals received ABT-378, efavirenz, and NRTIs as chosen by a
treating physician. The mean HIV-RNA viral load was 4.5 log (31,600 copies/ml).
All but two individualsí baseline clinical viral isolates were susceptible to
efavirenz. Baseline genotypic and phenotypic resistance tests were performed,
and PK profiles were performed on all participants at week 5. Additional week 24
data was presented at Durban and is reported below.
Susceptibility of Viruses to ABT-378.
In study M97-765, in single PI experienced individuals, the mean reduced
susceptibility was 2.8 fold, while in study M98-957 the mean reduced
susceptibility was 16 fold.
of Mutations: ABT-378 Mutation Score of Baseline Clinical Isolates.
Of the 11 mutations identified and reported to be associated with ABT-378
reduced susceptibility by Dale Kempf, here is a breakdown of the frequency of
mutations. Nearly 80% of patients had at least 4 of the 11 mutations (10, 20,
24, 46, 53, 54, 63, 71, 82, 84, 90) in their clinical viral isolates (blood
samples). There were 0 mutations in 2 isolates, 1 mutation in 6 isolates, 3
mutations in 1 isolate, 4 mutations in 7 isolates, 5 mutations in 9 isolates, 6
mutations in 11 isolates, 7 mutations in 10 isolates, 8 mutations in 3 isolates,
9 mutations in 3 isolates, and 10 mutations in 1 isolate.
Responses. At week
24, 52 of the 57 who enrolled in study M98-957 qualified for the analysis of
week 24 response, with 42 (81%) of these patients having had HIV RNA ≤400
copies/ml at week 24. See below for more details on virologic response.
of Patients (Week 24).
responders (HIV RNA ≤400 copies/ml at week 24)
failures (HIV RNA ≥400 copies/ml at week 24)
failures (discontinued therapy between weeks 8 and 24 with HIV RNA >400
censored (discontinued therapy prior to week 8 for adverse events, all
discontinued by day 17)
censored (baseline genotype and phenotype not available)
of Response with Respect to Baseline Phenotypic Resistance:
with <10-fold reduced baseline phenotypic susceptibility to ABT-378, 27/29
(93%) had ≤400 copies/ml
individuals who had 10-20 fold reduced susceptibility (resistance to ABT-378) at
baseline, 78% had ≤400 copies/ml (n=9)
67% with 20-40
fold reduced susceptibility had ≤400 copies/ml (n=6)
50% with >40
fold reduced susceptibility had ≤400 copies/ml (n=8)
Genotype and Week 24 Virologic Response:
(24/25) of individuals with 0-5 mutations had ≤400 copies/ml at week
(16/21) of those with 6-7 mutations at baseline had ≤400 copies/ml
(2/6) with 8-10 mutations had ≤400 copies/ml
This early ABT-378 data preliminarily suggests a continuum of approximate
phenotypic and genotypic breakpoints that may be useful in estimating the
potential for a positive virologic response by a given person. By the time
ABT-378 receives accelerated approval (expected near the end of 2000), both
phenotypic resistance testing companies (Virco and Virologic) should be able to
integrate this information on breakpoints into their reporting of test results.
The information and research on these cut-offs is preliminary. Continued work by
Abbott is required to confirm and validate this information clinically. The more
data that is collected as the drug is tested and used, the more such validation
attempts can be made. For example, it is possible that there are mutations
associated with ABT-378 resistance that have not been identified yet. The
influence or affect of one mutation may be greater than the others. For example,
maybe the 82 mutation is more influential in causing virologic failure and
reduced susceptibility. This has yet to be determined.
was some discussion about the relative contribution of efavirenz and ABT-378 to
the virologic response of individuals. I think it was generally agreed by many
researchers that ABT-378 is making a substantial contribution, certainly to
those individuals with possibly about 33% reduced susceptibility or less. How
much contribution ABT-378 makes to virologic success for individuals with 40
fold or more reduced susceptibility appears questionable. It was also estimated
by Sun that this triple combination was effective for individuals with up to 7
mutations. These questions need to be continued to be addressed as they cannot
absolutely be answered yet.
Associated With Virologic Response.
stepwise regression models were performed to assess the effect of baseline
phenotype and genotype in the context of other parameters that might impact
virologic response. Baseline phenotype (p=0.016), genotype (p=0.024) and
inhibitory quotient (trough/EC50, p=0.068) were associated independently to be
predictive of virologic response.
first model, baseline phenotypic susceptibility and genotype at baseline were
considered and phenotypic susceptibility remained the most closely associated
with the virologic response at week 24. In model 2, in which the baseline
phenotypic susceptibility was omitted, the ABT-378 mutation score remained a
significant predictor of virologic response at week 24. In the third model,
ABT-378 pharmacokinetic parameters were considered along with the other
parameters considered in models 1 and 2. Baseline phenotype was incorporated as
part of 4 exploratory inhibitory quotients (IQ), representing the ratio of
Ctrough, Cmin, AUC and Cmax to the serum-adjusted EC50 for each baseline isolate
(IQCtrough, IQCmin, IQAUC and IQCmax, respectively). Baseline genotype entered
model 3 first but was ultimately displaced by the IQC trough, which remained
associated with week 24 virologic response. The following parameters also
appeared to indicate a trend towards association with being predictive of
response: NRTI susceptibility, number of new NRTIs, years since HIV diagnosis,
baseline patient weight. Sun concluded that these results provide a framework
for the interpretation of HIV phenotypic and genotypic testing.
(Kaletra) and Efavirenz: 24-Week Safety/Efficacy Evaluation in Multiple
This study reports the percent <400 copies/ml for ABT-378 at week 24. In
Sitges, at the Resistance Workshop, data was broken down by response according
to baseline genotypic and phenotypic resistance. Individuals with 0-5 mutations
responded best. Individuals with >7 mutations may not respond as well to
ABT-378. Individuals with phenotypic resistance <20 fold responded best.
Those with phenotypic resistance >40 fold may not respond well to ABT-378.
a study of 57 patients receiving ABT-378/r 400/100 mg (3 coformulated capsules)
twice daily (BID) in place of their current PI, in combination with efavirenz (Sustiva)
once daily (QD) and NRTIs chosen by the doctor/study investigator, for the first
13 days of the study. On day 14, some patients (n=28) randomly had their
ABT-378/r dose increased to 533/133 (ABT/378/ritonavir); 4 co-formulated
capsules. The remaining (n=29) continued on the 400/100 dose. ABT/378 trough
levels were drawn at week 2l, full PK (drug levels) was performed at week 5;
efavirenz levels were drawn at weeks 2 and 5. Viral load in plasma was measured
with the Roche Amplicor Monitor assay, with a lower limit of quantification of
400 copies/ml. To qualify for this study patients had to be NNRTI-naÔve and had
multiple PI-experience (history of sequential or concurrent treatment with at
least 2 protease inhibitors for at least 3 months each.)
baseline viral load was 4.6 log (39,000 copies/ml) in the group remaining on
400/100 dose; viral load was about 25,000 copies/ml (about the same) in the
533/133 arm. Cd4s in the 400/100 group were 230 and in the 533/133 arm they were
Prior to this study the mean number of HIV drugs were 7 (range 3-10); mean number of prior protease inhibitors was 3 (range 1-4); and the mean number of NRTIs was 2 (range 1-4). The types of drugs previously used in both arms were pretty evenly distributed, but all protease inhibitors and NRTIs were used. For example, 83% in the 400/100 arm had used indinavir, and 89% had used indinavir in the 533/133 arm. 68% (38/56) of patients had baseline viral isolates demonstrating ≥4 fold resistance (increased EC50 relative to wild-type) to at least 3 approved protease inhibitors. 43% of these viral isolates (24/56) showed ≥10-fold resistance (increased EC50 of ABT-378 relative to wild-type virus). (See Table 4)
levels achieved with 400/100 dose are reduced when taken with efavirenz
(C-trough reduced -33%; AUC reduced -25%). Abbott reported that increasing
ABT-378 dose produced similar levels as taking 400/100 without efavirenz. They
also reported efavirenz levels are similar for both ABT-378/r dose levels
studied, so ABT-378 doesn't appear to affect levels.
Discontinuation at Week 24.
In the 400/100 group (n=29), 4 (13.8%) patients discontinued at or before week
24; 2 due to virologic failure, and 2 due to CNS side effects, GI/CNS side
effects, lactic acidosis. In the 533/133 arm, there were 3 patients discontinued
(10.7%); 1 due to virologic failure, and 2 due to drug related side effects
described just above (both discontinuations occurred prior to study day 145 and
initiation of the 533/133 dose).
Load Suppression at 24 Weeks:
(23/25) in the 533/133 arm had <400 copies/ml
the 400/100 arm (20/25) had <400 copies/ml
the 533/133 arm had <400 copies/ml
in the 400/100 arm had <400 copies/ml
dose groups CD4s increased about 45 at week 24.
The most common study drug side effects of at least moderate severity were
diarrhea and asthenia, while the most common lab abnormality was lipid
elevations. Of the 7 patients who discontinued through week 24, 4 were due to
adverse events/lab abnormalities related to study drug. (See
cholesterol/HDL cholesterol ratios were not significantly changed from baseline
at week 24 at either dose level of ABT-378.
Resistance May Respond to Tipranavir, Amprenavir, and Saquinavir. This laboratory study reported at the Resistance
Workshop in Spain suggests that individuals who develop resistance to ABT-378
may respond to tipranavir, amprenavir, and saquinavir. In a small study Abbott
researchers looked at phenotypic resistance to ABT-378 for 3 individuals who had
used ABT-378 and had detectable HIV viral. They had 4 to 112-fold resistance to
ABT-378 and had pre-existing resistance to other protease inhibitors. Using lab
(in vitro) testing, they found that all 3 had no resistance or demonstrated
modest resistance to amprenavir (8.5 fold resistance), while they had
99-resistance to ABT-378. Two of the 3 individuals who had no prior saquinavir
experience had no resistance to saquinavir. A virus that was created to be
resistant to ABT-378 in the lab (34 fold resistant to ABT-378) had no resistance
to tipranavir. Three isolates tested against tipranavir were fully sensitive.
DAPD. From preliminary studies in humans, it appears that
DAPD should be effective for individuals with extensive NRTI experience and
resistance. Viral load results were reported from two preliminary studies of
DAPD at this Workshop. The results of a small study in 30+ individuals with NRTI
experience was reported at Sitges. After receiving 15 days of DAPD monotherapy
in several doses, the individuals receiving the highest dose of 500 mg twice a
day achieved a viral load reduction of -1.1 log. In a study of treatment naÔve
individuals receiving various doses, the individuals receiving the highest dose
of 500 mg twice a day achieved a viral load reduction of -1.6 log. Laboratory
resistance experiments were conducted and reported at this meeting. The
researchers found in these experiments that DAPD can be effective against
viruses with AZT or AZT/3TC resistance. However, DAPD was effective against some
viruses with "multi-nucleoside" resistance mutations and was not
effective against virus with different "multi-nucleoside" mutations. A
virus with mutation associated with multi-NRTI resistance due to SS or SG
insertions between codons 68/69 was sensitive to DAPD. The Q151M
multi-nucleoside mutation in a background of AZT resistance mutations as well as
the Q151M in combination with the 116Y showed moderate resistance (EC50 fold
increase) to DAPD. Larger studies are needed to confirm this information and to
explore how to use DAPD. The most common adverse events were headache, other
pain, nausea and diarrhea. Adverse laboratory events that were moderate or worse
(at least "grade 2") were decreased white cells (neutrophils),
increased glucose, increased creatine kinase (muscle enzyme), increased
triglycerides, increased amylase (pancreas gland enzyme), increased ALT (liver
enzyme), increased bilirubin. No patient discontinued due to toxicity. DAPD is
in phase I/II clinical trials for HIV but has not yet entered clinical trials
This is a once daily PI which appears to have a favorable resistance profile in
early in vitro testing with clinical isolates. At the Resistance Workshop,
Richard Colonna from Bristol Myers Squibb reported sensitivity was often
retained to BMS-232632 by clinical isolates with resistance to one or two of the
approved protease inhibitors. Isolates (patientsí samples) with high
resistance levels to 3 or more protease inhibitors tended to lose sensitivity to
BMS-232632. Clinical studies are planned.
an entry inhibitor.
T-20 is a fusion inhibitor, which is a type of entry inhibitor. Current drugs
act to prevent HIV replication once HIV is in the CD4 cell. Entry inhibitors act
to prevent HIV from entering the CD4 cell. There are several ports of entry for
HIV into the CD4, and researchers are trying to develop many different types of
entry inhibitors. At Durban, Joe Eron reported 48 weeks results from a study
whose primary objective was to evaluate T-20's safety. The secondary objective
was to evaluate the antiviral activity of T-20. The dose was 50 mg twice daily
administered by subcutaneous injection. T-20 is a powder that is reconstituted
with water. Patients with prior T-20 use were allowed to enter this study.
study participants were highly treatment-experienced. 97% were PI experienced,
79% were experienced with all 3 classes of drugs; NRTIs, NNRTIs, and protease
inhibitors. Participants received genotypic & phenotypic resistance testing
to aid in selecting their regimen for this study. Participants received a median
of 5 drugs in their study regimen. The initial indication for use of this drug
is intended for people with resistance to drugs, who have limited treatment
optionsóso-called "salvage therapy."
median CD4 count was 90, and viral load was 100,000 copies/ml. 71 patients were
enrolled The Intent-To-Treat (ITT, non-completer=failure) analysis is based on
70 patients. At week 48, 41 of 71 patients remained on the study. Fourteen
patients discontinued due to virologic failure, defined as plasma viral load
<0.5 log from baseline. Study investigators reported that no one discontinued
the study due to T-20 related toxicity.
were 30 discontinuations: 14 virologic failure; 7 voluntary withdrawal; 4 lost
to follow-up; 3 adverse events; 2 non-compliance. Twenty-three of 70 (ITT)
individuals had decreased viral load of >1 log from baseline and/or <400
copies/ml. Sixteen patients (16/70, ITT) had viral load <400 copies/ml. 13%
of 70 had <50 copies/ml (ITT). For the on-study group, the mean and median
viral load decline was 1.4 log and 1 log, respectively. The study investigators
concluded that T-20 is well tolerated with other HIV drugs. Patients have to be
taught about storage (refrigeration) and reconstituting powder but investigators
said this was able to be done. They also said that these study results suggest
that T-20 contributes to the suppression of viral load in extensively treatment
injection site reactions (mild to moderate). A new formulation in development
and possibly available for upcoming studies may reduce this reaction. 21% had
grade 3 event(s) possibly related to T-20 but these were not reported. 10% had
serious adverse events possibly related to T-20: elevated GGT, altered mental
state, anemia, elevated SGOT (LFT), elevated amylase, neutropenia, elevated SGPT
(LFT). Two large pivotol studies are expected to start this autumn in
anticipation of applying for FDA approval.
In Vitro Resistance Data on a Protease Inhibitor for PI Resistance.
Tipranavir is a non-peptidic dihydropyrone protease inhibitor that has antiviral
activity against broadly PI resistant HIV. At last year's Resistance Workshop in
San Diego, Brendan Larder reported that 96/107 highly PI cross-resistant
clinical isolates were fully sensitive (< 4-fold resistance or a mean of
2-fold resistance) to tipranavir when tested in vitro. Eight of the 107 isolates
had intermediate resistance (4-10 fold resistance), and only 3 clinical isolates
had resistance (>10-fold). He suggested tipranavir's activity against PI
resistant HIV could be due to a flexible mode of binding in the protease active
site. Clinical development of tipranavir has been slow because the drug's rights
were sold from Pharmacia & Upjohn to Boehringer Ingelheim this past
winter/spring. At this year's meeting, Sharon Kemp of Virco reported on
additional in vitro resistance testing of tipranavir.
reported that of 85 clinical isolates that had greater than 10-fold resistance
to at least 4 of the current protease inhibitors in a recombinant phenotypic
assay, and 74 (87%) remained completely susceptible to tipranavir. Limited
phenotypic resistance to tipranavir has been seen. The purpose of Kemp's study
was to define the patterns of PI resistance mutations associated with TPV
constructed 11 site directed mutants containing 6-8 known protease mutations
which were highly cross-resistant to other protease inhibitors, and >4 fold
resistant to TPV. The most common genotypic mutations were at positions 10, 20,
36, 46, 54, 71, and 84, together with 82T and 90M. Twenty site-directed mutants
were constructed, and upon phenotypic testing the site-directed mutant with only
the backbone mutations had a 2 fold tipranavir resistance. When 82T or 90M or
both were added to the secondary mutations a mean 2.4 fold tipranavir resistance
resulted. They constructed a series of site-directed mutants with various
mutations (up to 10 mutations in one mutant) selected from 4 viruses with >10
fold TPV resistance but were unable to create TPV resistance greater than 4
fold. Often TPV had no more than 2 fold increased IC50. One virus they created
included 82A, 54V, and 90M with a background of 10/20/36/71/84. Although these
viruses were resistant, and in a number of cases highly resistant, to other
protease inhibitors, they were sensitive to TPV.
further test for resistance they passaged a pre-existing PI resistant, but
tipranavir sensitive clinical isolate in escalating doses of tipranavir (up to
30uM). This isolate had >10 mutations and was >40 fold resistant to IDV,
RTV, NFV, and SQV but was sensitive to TPV. 13-33 fold tipranavir resistance
developed in culture with the following mutations developed: I47V, V82L, I85V,
and T91A in a background of 10I, 20I, 46I, 77I, 84V, and 90M. Thereupon, Kemp
created a site-directed mutant with a 47V mutation added to 82L and 54V to the
backbone of 10/20/36/71/84. The mean fold increase in IC50 for TPV was about
concluded that there does not appear to be an obvious combination of mutations
associated with tipranavir resistance. Complex combinations of mutations were
observed in PI cross-resistant samples with > 4 fold increase in IC50 to TPV
(n=11). Unusual mutations at codon 82 (T/L) appear to play a role in TPV
resistance. To date, re-constructed virus mutants have failed to show high level
TPV resistance, although resistance development is possible by in vitro
vitro resistance data so far generated suggests tipranavir will be helpful as a
salvage drug for people with PI resistance. But as you know, along the way in
drug development, obstacles can emerge. So enthusiasm should be reserved until
safety and antiviral activity can be further tested in humans with PI
from Clinical Studies.
Tenofovir (PMPA) is a nucleotide RT inhibitor and is currently in phase III
human studies. Study 902 looked at highly NRTI experienced individuals receiving
300 mg once daily PMPA. The 48-week double-blind, dose-ranging study enrolled
189 treatment-experienced patients who were on a stable antiretroviral regimen
of no more than 4 antiretroviral drugs for at least 8 weeks prior to entering
the study. Patients were randomized to receive one of three PMPA doses (300 mg,
150 mg or 75 mg) or placebo in addition to their existing treatment regimen. The
mean change in HIV RNA from baseline for patients receiving the 300 mg dose was
-0.68 log10 copies/mL after 48 weeks of treatment (n=41). In that study the mean
baseline viral load was 3.7 log (5000 copies/ml). In study 901, a 1.06 log
reduction was seen in treatment experienced individuals, and in a 28 day
monotherapy study of treatment-naÔve individuals, a 1.5 log reduction in HIV
RNA was reported. A full report on PMPA in study 902 is available on the NATAP
and Adverse Events.
In the 300 mg arm, 20% (11) patients discontinued through 48 weeks. While 24%
(12), 26% (14), and 25% (7) discontinued in the 150 mg, 75 mg, and placebo arms,
respectively. In the 300 mg arm 4% withdrew for adverse events and 11%
"withdrew consent/lost to follow-up". The percentages were similar in
the other arms. After a minimum of 32 weeks data (n=54), 9% (5) patients
experienced a serious adverse event, compared to 4% (1) in the placebo arm. In
the 300-mg arm, the serious adverse events included 1 depression and 1
pneumonia. In the 300 mg PMPA arm at week 48, 39% (21 of 54) experienced grade 3
or 4 lab abnormalities: 11% triglyceride elevation; 11% creatine kinase; 7% AST
elevation; 7% neutropenia; 6% amylase elevation; 4% ALT elevation, 0% serum
glucose elevation, and 2% each for serum lipase and bilirubin elevations. In the
placebo arm, 29% reported experiencing lab abnormalities of grade 3 or 4.
reported that through 48 weeks, no patients randomized to tenofovir 300 mg had
confirmed elevations (greater than or equal to 0.5 mg/dL) of serum creatinine (a
marker of kidney function). There were two unconfirmed cases (4%) in the 300 mg
dose arm by week 48, and one in the placebo (4%) arm by week 24. Gilead said
that the pattern of phosphate declines <2.0 was different in this study than
with adefovir. Gilead reported that 5 patients (10%) in the TDF 300-mg dose
group and 1 patient (4%) in the placebo group (censored at 24 weeks when they
crossed over to active therapy) had a serum phosphate <2.0 mg/dl through week
48 of the study. The decreases in serum phosphate occurred (by looking at
Kaplan-Meier curves) between weeks 4 and 28. From week 28 to week 72 the rate
remained stable in both arms. At week 76 there was one case of phosphate decline
<2.0 mg/dL in the 300 mg PMPA arm. In the adefovir studies, 47% of patients
treated with the 120 mg dose of adefovir experienced serum phosphate <2.0 mg/dL
by week 48, but didn't occur until after 20 weeks on therapy. As well, phosphate
<2.0 mg/dL was often associated with creatinine abnormalities.
pre-clinical animal studies (rat, dogs, monkeys), decreased bone mineral density
(BMD) has been previously observed at PMPA drug levels 10-30 times the amount
used in humans. Gilead said that in experimenting with giving a dose of 5 times
the human dose (10 mk/kg) to young animals (who Gilead says may be more
susceptible to bone loss), they did not see bone loss out to two years of
dosing. So far (48 weeks) in the human study described here (#902), Gilead
reported a 1-2% BMD loss which Gilead reported was within the assay variability.
Gilead said that clinical significance, in terms of being at risk for bone
fracture, occurs when there is a 10-20% bone loss. Gilead also said there is
data on women for osteoporosis that says if there is 1-2% per year bone loss
that accumulates to 20% over 10 years, there is increased risk for bone
fracture. Gilead reported there were no changes in serum markers of bone disease
(serum calcium, serum phosphate, alkaline phosphatase, parathyroid hormone), and
no clinical reports of bony abnormalities (spontaneous fractures or pain
requiring hospitalization) through 48 weeks. To evaluate the risk of bone loss
associated with PMPA, longer-term studies appear to be required. Gilead will
continue to evaluate bone density changes in their phase 3 program using
standardized methodologies across study centers. Changes in bone mineral density
have recently been preliminarily reported in HIV patients taking HAART therapy
including protease inhibitors.
the BMD observations associated with PMPA, the FDA may be requesting 48 week
safety before granting commercial availability. Accelerated approval is granted
with 24 weeks data. Gilead and the FDA will be meeting for further discussions.
PMPA appears to have utility for salvage therapy, but requiring 48 weeks safety
data will delay availability.
Miller, from Gilead Sciences, reported on this preliminary resistance research.
Miller selected blood samples from the Virco library of resistant viruses.
Seventy-two outpatient samples with the following genotypic resistance patterns
were chosen according to pre-defined resistance genotypic patterns.
Susceptibility to all approved NRTIs and PMPA were assessed using the Virco
Antivirogram phenotypic test. The samples included patient sample viruses with
either 3TC resistance containing the M184 mutation, high level AZT resistance
with & without M184 3TC resistance, or multi-nucleoside resistance mutations
Q151M, or T69S double insertions with and without the 3TC M184 mutation.
PMPA had a
slight hypersensitivity (mean 0.7 EC50 fold change) to the set of viruses with
M184V resistance alone.
PMPA had a mean
3.7 fold reduced susceptibility to the set of viruses with high level AZT
resistance (3.5 AZT mutations), .....and 3/10 of these viruses had intermediate
susceptibility to PMPA (between 4-10 fold reduced susceptibility). These viruses
had a mean 47 fold increase in IC50 (47 fold resistance) to AZT.
All the viruses
with the 3TC M184V mutation added to high level AZT resistance had less than 4
fold resistance to PMPA with a mean fold change in IC50 of 2.4.
to retain almost full antiviral activity (mean 1.7 fold increase in IC50) to
viruses with the Q151M complex (multi-nucleoside resistance) and with the
With or without
the 3TC M184 mutation, PMPA appears resistant to viruses containing the rare
T69S double insertion mutation.
suggests that PMPA should have antiviral activity for people with low level and
high level AZT resistance accompanied by 3TC resistance. High level resistance
was defined by a mean of 3.5 AZT mutations. The amount of antiviral activity may
differ between individuals and may be related to how much AZT/3TC resistance a
When treating a
person with PMPA, you want to retain the presence of the M184V.
NNRTI: DPC 083.
DuPont Pharma first reported on DPC 083, a new second generation NNRTI, at the
Retrovirus Conference this past February. They reported that preliminary data
shows a favorable PK profile in covering NNRTI double mutants. Meaning that they
are hopeful that 083 will have adequate blood levels (above the IC90 for double
mutants) to suppress HIV for individuals with key double NNRTI mutants. Of
course, this remains to be confirmed in human studies.
reported DPC 083 is potent against the single mutant variants such as L100I and
K103N, and against double substitution variants such as K103N + Y181C, K103N +
V108I and K103N + P225H which are observed in nevirapine, delavirdine and
reported on a phase 1 human study in HIV uninfected individuals. Five groups of
male subjects (6 active/2 placebo per cohort) received 50, 100, 200, 300 and 400
mg doses of DPC 083, and one group of female subjects received 100 mg doses of
DPC 083. Two doses were administered on the first day, followed by single daily
doses for the following 8 days, for a total of 10 doses. Plasma samples were
collected during the dosing period and for 3 weeks thereafter. They have also
experimented with up to 1600 mg single doses.
had a very long half-life (>140 hours). The half-life for efavirenz is about
50 hours, and for the other NNRTI DPC-961, 72 hours. But it appears dosing for
083 will be tested once daily. DPC 083 plasma concentrations increased during
the dosing period, and steady-state had not been achieved after 10 doses. After
10 doses of ≥100 mg DPC 083, the average trough concentration (Cmin-24)
exceeded the calculated protein-binding-adjusted concentration needed for 90%
inhibition of wild type viruses by >172-fold, of K103N virus by >11-fold,
of K103N + P225H by >1.9-fold, or K103N + V108I by >2.9-fold, and of K103N
+ Y181C by >1.6-fold. One double mutant, which appears difficult to cover, is
K103N+L100I. It has been seen in 2% of efavirenz failures, mostly in people who
failed efavirenz, switched to nevirapine and remained on the failing regimen for
a while. DuPont reported in Durban that in vitro experiments may not always
select for mutations that may occur in humans. Therefore human studies are
required to see if 083 will suppress NNRTI resistant virus for individuals.
2 study in HIV-infected is planned for later this year. Dosing will be based on
tolerability. The goal is to optimize tolerability.
Durban, DuPont reported on two protease inhibitors in early development. Based
on in vitro studies, DPC 681 and DPC 684 appear potent against wild-type and
resistant viruses, suggesting less drug will go further. In vitro, viruses with
1-5 standard PI mutations appear to retain sensitivity to both 681 & 684.
Further studies are planned.