It
is widely accepted that there is a pressing need for new antiretrovirals that
are safe, potent and effective against HIV-1 strains that are resistant to currently
available therapies. There are increasing numbers of treatment-experienced HIV
patients worldwide with extensive drug resistance
that severely restricts their treatment options and therefore threatens effective
management of their HIV infection. [1]
Darunavir
(Prezista; formerly TMC114) is a second generation HIV protease inhibitor
(PI) that has demonstrated potent activity in vitro against both wild-type
and multidrug-resistant HIV-1 strains [2]. In June 2006, the U.S. Food and Drug
Administration (FDA) granted "fast track" (accelerated) approval to
darunavir for use with 100 mg ritonavir plus other antiretroviral agents for the
treatment of HIV infection in adults.
The
multinational POWER
1 and 2 studies (Performance of TMC114/ritonavir When Evaluated
in Treatment-experienced Patients with PI Resistance) compared the
safety and efficacy of darunavir when used in combination with low-dose ritonavir
with that of the available PIs in treatment-experienced HIV-1 patients. These
are randomized Phase IIb trials.
The
24-week analyses of POWER
1 and 2 showed that darunavir/ritonavir treatment plus an optimized background
regimen resulted in greater virological and immunological responses in antiretroviral-experienced
patients compared with those who received investigator-selected control PIs plus
an optimized background regimen [3, 4].
The
use of darunavir/ritonavir 600/100 mg twice daily demonstrated the greatest efficacy:
53% of patients in POWER 1 vs 39% in POWER 2 experienced HIV RNA levels less than
50 copies/mL compared with 18% and 7% of patients receiving control PIs, respectively.
Drug regulatory
agencies in the U.S. and in other countries have recently approved the 600/100
mg dose of darunavir/ritonavir for use by treatment-experienced adults, including
those with HIV-1 strains resistant to more than one PI.
Because
so many aspects of the POWER 1 and 2 trials were the same (e.g., study design,
objectives), in the current report, the study authors combined 48 week safety
and efficacy data from the two trials for patients receiving the recommended dose
of darunavir-ritonavir 600/100 mg compared with those receiving other PIs. Results
of the pooled 48-week data collected by the POWER 1 and 2 study group appear in
the April 4, 2007 issue of the Lancet, and are summarized in the following
text:
Results
•
At week
48, 67 of 110 (61%) darunavir-ritonavir patients compared with 18 of 120 (15%)
of control PI patients had viral load reductions of 1 log10 copies per mL or greater
from baseline (p<0·0001).
•
The
proportion of patients with viral load less than 50 copies/mL (ITT-TLOVR) [primary
endpoint] was greater in the darunavir-ritonavir group than in the control PI
group at all time points; this difference was sustained to week 48, when 50 (45%)
patients receiving darunavir/ritonavir reached a viral load of less than 50 copies/mL,
compared with 12 (10%) patients receiving control PIs (p<0·0001).
•
In
total, 46% (60) of the darunavir-ritonavir patients and 81% (100) of the control
PI patients never achieved a confirmed viral load of less than 50 copies/ mL during
study treatment.
•
Mean
changes from baseline in CD4 cell count were greater in the darunavir-ritonavir
group than in the control PI group at all time points (102 cells/microliter compared
with 19 cells/microliter at week 48; p<0·0001), in parallel with the
virological responses.
•
No
specific safety concerns relative to the overall darunavir-ritonavir patient population
were identified for hepatitis B or C coinfected patients after 48 weeks of darunavir-ritonavir
treatment.
•
In
the darunavir-ritonavir group, rates of adverse events were mostly lower than
or similar to those in the control group when corrected for treatment exposure.
No unexpected safety concerns were identified.
•
The
overall discontinuation rate was lower in the darunavir-ritonavir group than the
control PI group.
Adverse
Events
The
most common adverse events (>/= 10%) in patients receiving darunavir/ritonavir
were diarrhea (26, 20%), nausea (24, 18%), headache (19, 15%), nasopharyngitis
(18, 14%), fatigue (16, 12%), upper respiratory tract infection (16, 12%) and
herpes simplex (16, 12%). This excludes injection site reactions related to use
of enfuvirtide (Fuzeon).
The
majority of adverse events were grade 1 or 2. The investigators reported a low
incidence of grade 3 and 4 adverse events in both groups.
Overall,
26 (20%) darunavir-ritonavir patients and 17 (14%) control PI patients reported
at least one serious adverse event. The majority of serious adverse events did
not lead to treatment discontinuation. No particular serious adverse event was
associated with either treatment group.
In
the darunavir-ritonavir group, five (4%) patients died during the study. The causes
of death were pulmonary embolism, overdose (illicit drug), anal cancer, death
associated with peripheral neuropathy and pain management, and sepsis. The investigators
judged all deaths as unrelated or doubtfully related to study medication. The
data and safety monitoring board (DSMD) confirmed this finding.
The
most common treatment-emergent grade 3 and 4 laboratory abnormalities were increased
triglycerides: 15% [20] of darunavir-ritonavir
patients, 7% [8] of control PI patients), increased pancreatic amylase (>2×
upper limit of normal (ULN); 6% [8], 5% [6]), increased total
cholesterol (>7·7 mmol/L; 7% [9], 2% [3]) and increased pancreatic
lipase (>2×ULN; 5% [6], 1% [1]).
No
cases of clinical pancreatitis were observed in patients with lipase abnormalities.
Grade 3-4 increases in alanine aminotransferase (>5×ULN) and aspartate
aminotransferase (>5×ULN) were noted in 2% [3] and 3% [4], respectively,
of patients in the darunavir-ritonavir group, and 2% [3] and 4% [5], respectively,
of patients in the control PI group.
The
investigators noted no cases of hepatotoxicity.
B
Clotet and others. Lancet online. April 5, 2007
Discussion
The
pooled analysis shows that after 48 weeks of twice daily treatment with darunavir/ritonavir
600/100 mg, patients in POWER 1 and 2 experienced greater virological and immunological
results compared to those using currently available PIs. These 48-week response
rates confirm and extend the 24-week primary efficacy analysis, according to the
study authors.
In
addition, note the authors, because the CD4 cell increases observed in this analysis
correlate with a decrease in AIDS-related
events or death, the patients receiving darunavir/ritonavir may experience
slower disease progression than those in the control group.
According
to the study authors, the results of the 48 week analysis demonstrate that experiencing
a viral load of <50 copies/mL "is an appropriate treatment goal."
In this trial, 45% of patients reached a viral load <50 copies/mL from week
24 to week 48. These results are significant and encouraging in this patient population,
and suggest that they may be able to prevent or delay the development of resistance,
say the authors.
The
authors suggest that including active drugs in the background regimen should always
be a priority, especially drugs from new drug classes. The POWER studies demonstrate
that in treatment-experienced patients, use of darunavir/ritonavir combined with
enfuvirtide produced a "substantial effect." In the future, with access
to oral drugs from other new classes, the combination of darunavir/ritonavir with
these agents "should also provide potent alternatives expected to increase
the likelihood of achieving a durable response."
The
analysis did not reveal any new safety concerns about darunavir/ritonavir. Of
note, however, the incidence of herpes
simplex was higher in the darunavir/ritonavir group than in the control group.
The authors point out that about 30% of these events took place within the first
12 weeks of therapy, at the same time they observed immunological improvement.
Therefore, they theorize that, similar to other antiretroviral combination regimens,
"darunavir/ritonavir might cause an inflammatory reaction to asymptomatic
or residual opportunistic
pathogens."
Although
the sample sizes of the POWER studies are relatively small, the authors emphasize
that the darunavir/ritonavir combination produced results indicating that a relatively
large proportion of patients were able to achieve an undetectable viral load after
48 weeks of treatment: "The consistent magnitudes of differences in responses
over time to week 48 between the groups suggest the potential value of darunavir-ritonavir
as a new antiretroviral agent."
In
conclusion, the authors stated that this pooled analysis suggests that darunavir/ritonavir
600/100 mg twice daily, when used in combination with an "individually-optimized"
antiretroviral regimen, "is effective and well-tolerated."
Further
they wrote in closing, "This treatment is expected to fulfill the clinical
need for a new PI capable of expanding the treatment options available for a treatment-experienced,
drug-resistant population of patients."
Researchers
are now evaluating darunavir/ritonavir in phase III trials among patient populations
with less or no prior treatment experience.
04-06-07
Source
B
Clotet, N Bellos, J-M Molina and others (the Power 1 and 2 study group). Efficacy
and safety of darunavir-ritonavir at week 48 in treatment-experienced patients
with HIV-1 infection in POWER 1 and 2: a pooled subgroup analysis of data from
two randomised trials. The Lancet. Early Online Publication. April 5, 2007.
References
1.
US Department of Health and Human Services (DHHS): Guidelines for the use of antiretroviral
agents in HIV-1-infected adults and adolescents. Oct 10, 2006: www,aidsinfo.nih.gov
(accessed March 5, 2007).
2.
S De Meyer, H Azijn, D Surleraux, and others. TMC114, a novel human immunodeficiency
virus type 1 protease inhibitor active against protease inhibitor-resistant viruses,
including a broad range of clinical isolates. Antimicrobial Agents and Chemotherapy
49: 2314-2321. 2005.
3.
C Katlama, R Esposito, J M Gatell JM, and others. Efficacy and safety of TMC114/ritonavir
in treatment-experienced HIV patients: 24-week results of POWER 1. AIDS 21: 395-402.
2007.
4.
R Haubrich, D Berger, P Chiliade, and others. Week 24 efficacy and safety of TMC114/ritonavir
in treatment-experienced HIV patients: POWER 2. AIDS 21: F11-F18. 2007.
