U.S.
government-sanctioned guidelines for the use of antiretroviral
drugs for HIV infection recommend combining three anti-HIV
agents. However, toxicities, cost, and the complexity of these regimens have
spurred a search for other options.
MONARK is a pilot, prospective, open-label,
randomized, 96-week trial comparing the safety and efficacy of lopinavir/ritonavir
(Kaletra) monotherapy to the standard
lopinavir/ritonavir + AZT/3TC (Combivir)
regimen.
In MONARK, treatment-naive study participants without baseline
resistance to study drugs, viral load (VL) greater than 100,000 copies/mL, and
CD4 cell count greater than 100 cells/mm3, were randomized to receive either Kaletra
monotherapy or Kaletra plus Combivir.
The primary endpoint was VL less
than 400 copies/mL at week 24 and VL less than 50 copies/mL at week 48. Sub-optimal
virologic response was defined as:
•
Less than 1 log VL decrease by week 24;
•
VL greater than 400 copies/mL by week 24;
or
•
VL rebound after being less than 400 copies/mL,
confirmed in a second specimen.
Results
of the MONARK trial were first presented at the 16th International AIDS Conference
(IAS 2006) in Toronto, Canada (August 13-18, 2006) [1],
and more recently, were published in the January 30, 2008 issue of AIDS
[2].
Results
•
83 and 53 patients, respectively, were randomly
assigned and started drugs in the monotherapy and triple-drug groups.
•
At week 48, by an intent-to-treat analysis,
53 of 83 patients (64%) in the monotherapy group and 40 of 53 patients (75%) in
the triple-drug group achieved the primary endpoint (P = 0.19).
•
The on-treatment analysis indicated that 80%
and 95% of patients reached the primary endpoint in the monotherapy and triple-drug
groups, respectively (P = 0.02).
•
In the monotherapy arm, protease inhibitor-associated
resistance mutations were seen in three of the 21 patients qualifying for genotypic
resistance testing, with a modest impact on lopinavir susceptibility.
•
None of the serious reported adverse events
were considered to be related to study treatment.
In
conclusion, the study authors wrote, "Our results suggest that lopinavir/ritonavir
monotherapy demonstrates lower rates of virological suppression when compared
with lopinavir/ritonavir triple therapy and therefore should not be considered
as a preferred treatment option for widespread use in antiretroviral-naive patients."
Despite
this conclusion, in the discussion section of their article, the authors wrote,
"Interestingly, 90% of patients randomly assigned to the lopinavir/ritonavir
monotherapy group with HIV RNA below 400 copies/mL at week 4 reached the protocol-defined
virological response. Therefore, an early decrease in the plasma viral load below
400 copies/mL might enable clinicians to predict potential responders to lopinavir/ritonavir
monotherapy."
Further they stated, "We conclude that first-line
monotherapy with lopinavir/ritonavir soft gel capsules is virologically less effective
than the current standard-of-care triple combination with two NRTI and lopinavir/ritonavir
soft gel capsules. Given the requirement for chronic therapy with current antiretroviral
treatments, however, and the long-term toxicities associated with all antiretroviral
therapies, long-term strategies that limit exposure while providing adequate
virological efficacy deserve further study." [emphasis added--Ed].
They
continued, "Future monotherapy studies utilizing the more convenient lopinavir/ritonavir
tablet formulation should focus on select patient populations, such as those with
extensive reverse transcriptase inhibitor resistance (for example in developing
countries where first to second-line switch is often driven by clinical failure
and results in extensive NRTI resistance).
Finally, they stated, "Taking
into account the long-term rates of lipoatrophy, viral resistance, patient satisfaction,
and the cost of therapy are also critical to identify clinical scenarios in which
lopinavir/ritonavir monotherapy might yet play a significant role in the treatment
of HIV infection."
Following publication of 48-week results of the
MONARK study, some researchers and clinicians expressed concern that these results
cast serious doubts about the ability of Kaletra monotherapy to effectively and
durably suppress HIV.
Effect of Kaletra Monotherapy on Cellular HIV
DNA Reservoir
The impact of protease inhibitor monotherapy on the
reservoirs of HIV-1 infected cells is unknown and remains a concern. At the recent
15th Conference on retroviruses and Opportunistic Infections (CROI 2008) in Boston
(February 2-7, 2008), French researchers presented results of their analysis of
the effect on the cellular HIV DNA reservoir of Kaletra monotherapy compared with
the Kaletra plus Combivir triple-drug regimen in the MONARK trial [3].
As
a reminder, they noted that in MONARK, by on-treatment analysis, 56 of 67 (84%)
patients in the lopinavir/ritonavir monotherapy arm had a plasma viral load less
than 50 copies /mL at week 48.
In
their analysis, the French researchers also noted that HIV DNA levels in blood
cells were measured both at baseline and week 48 in both arms. It was quantified
in whole blood samples, using the real time PCR HIV-1 DNA assay of ANRS AC11;
the cut-off value was at 6 copies by PCR.
Results
•
Overall, HIV-1 DNA samples were available
for 102 and 72 patients at baseline and week 48, respectively.
•
Both arms were balanced at baseline, with
4.26 and 4.21 log copies/million CD4 cells in the monotherapy and triple-drug
groups, respectively.
•
A similar median decrease was observed at
Week 48 in both arms: -0.75 log copies/million CD4 cells in the lopinavir/ritonavir
arm versus -0.77 in the triple arm (P = 0.88).
•
There was no correlation between early HIV
RNA decrease and HIV DNA decrease in both groups.
The
French team noted, "Our results show a very similar effect of 48 weeks lopinavir/ritonavir
monotherapy, versus a lopinavir/ritonavir-based triple regimen, on the level of
the HIV circulating reservoir expressed by HIV-DNA level in blood cells in naive
patients."
They
concluded, "These data suggest that, at the cellular level, this lopinavir/ritonavir
monotherapy regimen is potent, in comparison to a standard-of-care HAART."
Where Now
for Ritonavir-boosted Protease Inhibitor Monotherapy?
The most recently
published opinions voiced in the ongoing discussion of the potential effectiveness
of ritonavir-boosted protease inhibitor monotherapy as demonstrated in the MONARK
trial appears in an editorial published in the current (March 30, 2008) issue
of the online edition of AIDS [4].
Authored by Andrew Hill, Bernard Hirschel, and Christine Katlama, the editorial
is entitled "The MONARK Trial: Where Now for Boosted Protease Inhibitor Monotherapy?
Following is the text of their editorial:
Minimizing
the long-term toxicity profile of HAART is a high priority, as HIV-infected individuals
will need to be treated with HAART for life, and the majority of discontinuations
of HAART are for adverse events. The strategy of ritonavir-boosted protease inhibitor
(PI) monotherapy aims to use the high genetic barrier of this treatment class
to suppress HIV RNA fully without the need for nucleoside analogue reverse transcriptase
inhibitors (NRTI), which have been associated with a range of mitochondrial toxicities
such as lipoatrophy, lactic acidosis, renal abnormalities and lipid elevations.
In
[the January 30, 2008] issue of AIDS, Delfraissy and colleagues present the 48-week
results from the MONARK trial: 136 naive patients were randomly assigned to receive
lopinavir/ritonavir (LPV/r) either as monotherapy or with the two NRTI zidovudine
and lamivudine. At week 48, the rates of full HIV-RNA suppression less than 50
copies/ml were 67% for the LPV/r monotherapy arm and 75% for the LPV/r plus two
NRTI arm in the intent to treat 'switch equals failure' analysis. The lower rate
of full HIV-RNA suppression for LPV/r monotherapy was driven mainly by higher
numbers of patients with 50-400 HIV-RNA copies/ml in the LPV/r monotherapy arm.
Interestingly,
of the 21 patients genotyped for resistance at virological failure in the LPV/r
monotherapy arm, only three showed evidence of PI resistance. Two of these patients
already harbored PI mutations at baseline (K20I and M36I) known to lead to a loss
of virological response to lopinavir in the most recent resistance algorithm,
and the third patient had the L63P and V77I mutations at baseline, which are more
weakly associated with lopinavir resistance. One patient in the two NRTI plus
LPV/r arm also failed virologically, with emergence of the M184V mutation, but
showed the L63P and A71T mutations at baseline, also known to be associated with
lopinavir resistance. These findings suggest that more strict entry criteria in
terms of baseline genotypic PI resistance might have lessened the difference in
efficacy between the arms.
Another feature of the MONARK trial is that
three patients with incomplete suppression of HIV RNA on LPV/r monotherapy intensified
their treatment by adding zidovudine and lamivudine. Patients intensifying with
NRTI in the LPV/r arm can be analyzed either as failures ('switch equals failure'
analysis) or their HIV-RNA data can be included after intensification ('switch
included' analysis).
In the MONARK trial, the three patients intensified
with NRTI then showed full HIV-RNA suppression, but were classified as treatment
failures in the 'switch equals failure' analysis. In a 'switch included' analysis,
these patients would be classified as successes, raising the efficacy of the LPV/r
arm from 67 to 71%. Three other randomized trials have compared LPV/r monotherapy
with standard HAART, and can be analyzed with the two methods.
In the
Abbott M03-613 trial [D Cameron and others. IAS 2006. Abstract THLB0201],
155 naive patients were randomly assigned to either LPV/r monotherapy or two NRTI
plus efavirenz: 18 of 23 patients (78%) with viral breakthrough on LPV/r monotherapy
showed re-suppression below 50 copies/ml after intensification with NRTI. At virological
failure, there were three patients with PI resistance and two patients with M184V
at failure in the LPV/r arm, versus one patient with NRTI resistance and one with
non-nucleoside reverse transcriptase inhibitor resistance in the two NRTI plus
efavirenz arm.
In the OK-04 trial [J Arribas and others. EACS 2007.
Abstract PS3.1], 200 patients with full HIV-RNA suppression at baseline were
randomly assigned to either LPV/r monotherapy or two NRTI plus LPV/r: 5% of the
LPV/r monotherapy group showed persistent, low-level HIV-RNA rebound without obvious
non-adherence, and this group could be re-suppressed by intensifying with NRTI.
At virological failure, two patients in each arm had evidence of PI resistance.
In
the Kalmo trial, 60 patients with full HIV-RNA suppression were randomly assigned
either to start LPV/r monotherapy or continue current HAART. The one patient with
virological failure in the LPV/r monotherapy arm showed no PI or NRTI resistance
at failure and was then re-suppressed after intensification with NRTI [EACS
2007. Abstract P7.5/04].
Across the four trials, LPV/r tended to show
lower rates of efficacy than standard HAART in a standard 'switch equals failure'
analysis. If re-intensification with NRTI was allowed in a 'switch included' analysis,
however, longer-term HIV-RNA suppression rates were similar albeit with a slightly
higher risk of accumulating drug resistance.
How do we interpret the results
from the different analyses? The 'switch equals failure' approach examines the
intrinsic efficacy and safety profile of a fixed treatment, allowing no modifications.
The 'switch included' analysis allows the clinician to modify treatment according
to ongoing laboratory monitoring, and assesses long-term outcomes.
In the
MONARK trial, those with HIV-RNA suppression below 400 copies after 4 weeks of
treatment had a 90% chance of full HIV-RNA suppression by week 48. A strategy
of using a short-term interval of boosted PI monotherapy, with a rule used to
decide on intensification, could be used in future trials and might lower the
risk of accumulating drug resistance.
There are several new trials evaluating
the efficacy of PI monotherapy in patients with full HIV-RNA suppression at baseline:
the MOST trial in Switzerland is re-evaluating LPV/r monotherapy, with a special
focus on effects in the central nervous system. The MONOI and MONET trials are
evaluating ritonavir-boosted darunavir. These new trials might show improved efficacy
and tolerability for boosted PI monotherapy, either by the use of the new formulation
of LPV/r with its lower pill count or the use of once-daily boosted darunavir,
with its relatively long half life.
The potential advantages of boosted
PI monotherapy include lower pill counts, lower costs of treatment, the prevention
of long-term mitochondrial toxicities, and sparing other treatment classes for
later use. The main disadvantage of boosted PI monotherapy is the potential for
accumulating drug resistance from ongoing low-level virus replication. Only a
low percentage of patients have, however, developed drug resistance on PI monotherapy
to date, the correlation between HIV-RNA suppression between 50-400 copies/ml
and the development of drug resistance is unclear, and there are increasing treatment
options becoming available for those with virological failure.
A strategy
of PI monotherapy for most patients, with intensification for the few who need
it, may be attractive for many patients and clinicians. Current trials are concentrating
on patients with full HIV-RNA suppression at baseline. To demonstrate that this
treatment strategy provides the same efficacy as standard HAART, however, the
use of a more pragmatic 'switch included' approach to the design and analysis
of clinical trials will be needed.
Conflicts
of interest: Andrew Hill has received consultancy payments from Tibotec. Bernard
Hirschel has received travel grants and speakers honoraria from Abbott, Bristol
Myers Squibb, Gilead, GlaxoSmithKline, Merck, and Roche and has participated in
advisory boards for Merck, Tibotec and Pfizer. Christine Katlama has no declared
conflicts of interest.
4/01/08
References
1.
F Delfraissy, P Flandre, C Delaugerre, and others. MONARK Trial (MONotherapy AntiRetroviral
Kaletra): 48-Week Analysis of Lopinavir/Ritonavir (LPV/r) Monotherapy compared
to LPV/r + Zidovudine/Lamivudine (AZT/3TC) in Antiretroviral-Naïve Patients.
16th International AIDS Conference (IAS 2006). August 13-18, 2006. Toronto, Canada.
Abstract THLB0202.
2. J-F Delfraissy,
P Flandre, C Delaugerre, and others. Lopinavir/ritonavir monotherapy or plus zidovudine
and lamivudine in antiretroviral-naive HIV-infected patients. AIDS 22(3):
385-393. January 30, 2008.
3. V Avettand-Fenoel.
PhFlandre, ML Chaix, and others. Impact of 48-week Lopinavir/r Monotherapy on
HIV1-DNA in Blood Cells in the MONARK Trial. CROI 2008. February 2-7, 2008. Boston,
MA. Abstract 781.
4.
A Hill, B Hirschel, C Katlama. The MONARK trial: where now for boosted protease
inhibitor monotherapy? AIDS 22(6): 777-779. March 30, 2008.
Results
