Darunavir Monotherapy Maintains Viral Suppression in Most People
HIV patients with undetectable viral load on traditional
therapy (ART) were equally likely to maintain
viral suppression whether they stayed on a 3-drug
regimen or switched to monotherapy using the ritonavir-boosted
protease inhibitor darunavir
(Prezista), researchers reported at the 10th
International Congress on Drug Therapy in HIV Infection
last week in Glasgow. A trial in Africa, however,
found that monotherapy with lopinavir/ritonavir
(Kaletra) was nearly 25% less effective than
combination ART. A 10-trial meta-analysis produced
Standard highly active antiretroviral therapy, or HAART,
consists of a protease inhibitor (PI) or non-nucleoside reverse
transcriptase inhibitor (NNRTI) plus a "backbone"
of 2 nucleoside/nucleotide reverse transcriptase inhibitors
(NRTIs). Multiple drugs means less convenience, higher cost,
and potentially more side effects, however, leading researchers
to explore whether using the most potent boosted PIs alone
might be a equally effective.
MONET: Boosted darunavir in Europe
European MONET study enrolled 256 patients who were taking
a standard 3-drug ART regimen, had maintained viral suppression
for at least 6 months, and had no history of virological treatment
Participants were randomly assigned to switch to 800/100 mg
once-daily darunavir/ritonavir, either alone or in combination
with 2 NRTIs. Most participants (about 80%) were men, about
90% were white, and the median age was 44 years. Patients
had been on ART for an average of about 7 years and had a
median CD4 cell count of 575 cells/mm3.
from a 48-week analysis were published in the January
16, 2010 issue of AIDS, and 96-week
results were presented at the International AIDS Conference
this past summer in Vienna.
Briefly, in a time to loss of virological response (TLOVR)
analysis with treatment failure defined as 2 HIV RNA measurements
> 50 copies/mL or discontinuation of the assigned regimen,
86% of participants in the darunavir/ritonavir monotherapy
arm maintained viral load suppression at week 48 compared
with 88% in the combination ART arm; 75% vs 81%, respectively,
did so at week 96. Rates of serious adverse events were also
similar in both arms.
In the retrospective analysis presented in Glasgow, MONET
investigators evaluated blood samples collected between weeks
4 and 96 to determine whether study participants who appeared
to maintain viral suppression using a standard viral load
test with a limit of 50 copies/mL still had undetectable HIV
RNA when using a more sensitive 5 copies/mL assay.
96 weeks most participants -- 79% in the darunavir/ritonavir
monotherapy arm and 81% in the combination ART arm --
had undetectable HIV RNA < 5 copies/mL.
and 15%, respectively, had HIV RNA levels above 5 but
below 50 copies/mL.
of samples from patients in the darunavir/ritonavir monotherapy
arm and 5% from people in the combination arm had viral
load > 50 copies/mL, most being low-level:
copies/mL: 84% and 83% of detectable samples, respectively;
copies/mL: 12% vs 9%, respectively;
copies/mL: 4% vs 9%, respectively.
of drug resistance was uncommon, with 3 patients developing
new IAS PI resistance mutations (2 on monotherapy, 1 on
this study for patients with HIV RNA < 50 copies/mL at
baseline, switching to darunavir/ritonavir monotherapy showed
similar levels of HIV RNA suppression to darunavir/ritonavir
+ 2NRTIs, using more sensitive PCR assay techniques,"
the researchers concluded.
lopinavir/ritonavir in Africa
Another PI studied as monotherapy -- lopinavir/ritonavir --
appears to be less effective for this purpose, however. Investigators
with the SARA trial conducted one of the first antiretroviral
monotherapy studies in Africa. In resource-limited settings,
reducing the cost of therapy can allow more people to receive
treatment. But monotherapy may be especially risky if frequent
viral load monitoring is unavailable to enable treatment intensification
at the first sign of failure.
SARA was a pilot sub-study of the long-running DART (Developing
AntiRetroviral Therapy) trial in Uganda and Zimbabwe. A total
of 192 eligible DART participants who had received 24 weeks
of second-line combination ART containing lopinavir/ritonavir
-- after experiencing previous treatment failure, intolerance
to therapy, or progression to AIDS -- were randomly assigned
to either maintain the same regimen or drop their NRTIs and
continue on lopinavir/ritonavir alone.
In the DART trial as a whole, some participants were randomly
assigned to have their viral load and CD4 cell counts monitored
regularly in "real time," with results used to guide
therapy. The others did not receive regular monitoring (in
actuality, they did undergo testing, but results were not
made available unless the patient became seriously ill). In
the SARA analysis presented in Glasgow, researchers looked
at virus levels in stored plasma samples, performing genotypic
resistance testing on those with HIV RNA > 1000 copies/mL.
previously reported, CD4 cell gains were similar in both
groups, with increases of 48 cells/mm3 in the lopinavir/ritonavir
monotherapy arm and 42 cells/mm3 in the combination ART
arm 24 weeks after randomization; by 72 weeks, both groups
had a median of 150 cells/mm3.
the same time point, however, participants in the monotherapy
arm were significantly less likely to maintain virological
suppression than those in the combination ART arm:
vs 77%, respectively, with HIV RNA < 50 copies/mL;
vs 90%, respectively, with HIV RNA < 200 copies/mL;
vs 94%, respectively, with HIV RNA < 1000 copies/mL.
only at the subset of patients with viral load < 50
copies/mL at the time of randomization, 66% vs 85%, respectively,
still had HIV RNA < 50 copies/mL after 24 weeks of
participants with HIV RNA > 1000 copies/mL who received
genotypic testing, 4 of 24 in the monotherapy arm developed
major PI resistance mutations, compared with none in the
monotherapy following 24 week second-line induction was associated
with an increase in low level viremia, although generally
in the absence of PI resistance," the researchers concluded.
"Longer-term trials are required before definitive conclusions
can be drawn about the effectiveness of PI monotherapy in
populations without access to virological monitoring."
Finally, Wouter Bierman from University Medical Centre Groningen
and colleagues presented findings from a meta-analysis comparing
the efficacy of boosted PI monotherapy vs combination ART.
The investigators searched electronic medical literature databases
(including Pubmed and EMBASE) from 1996 through 2010, using
keywords such as "protease inhibitor," "antiretroviral,"
"monotherapy," and relevant drug names; studies
in all languages were included. They also searched conference
presentations since 2007 and contacted experts.
Out of 137 citations evaluated, the researchers identified
19 articles for further review (after eliminating duplicates
and obviously unrelated titles); of these, 6 met eligibility
criteria. An additional 4 abstracts were identified from conferences.
The investigators then did a meta-analysis of these 10 randomized
controlled trials (RCTs) -- with a total of 1265 participants
-- comparing viral suppression < 50 copies/mL in patients
using PI/ritonavir monotherapy or combination ART. All were
open-label and both treatment-naive and treatment-experienced
patients were represented. They calculated outcomes using
both intention-to-treat (ITT) analysis with missing data counted
as failure, and on-treatment analysis censoring missing information,
deaths, and drug changes due to adverse events.
Overall, using Mantel-Haenszel methods, in the intention-to-treat
analysis the risk ratio (RR) of using PI monotherapy vs combination
therapy was 0.94, or 6% higher risk. In the on-treatment analysis,
the RR was 0.90, or 10% higher risk.
When the researchers looked only at the 2 studies that used
and MONLI, monotherapy performed as well as combination
therapy (RR 0.97, not a significant difference). After excluding
these 2 studies, the risk ratio for the remaining lopinavir/ritonavir
studies rose to 0.90. Only 1 RCT started patients on monotherapy,
rather than switching after they achieved viral suppression,
but excluding this study did not change the findings.
The meta-analysis "suggests that PI/ritonavir monotherapy
is slightly but significantly less effective than combination
ART," the researchers concluded. "Subgroups of patients,
however, may benefit from this promising alternative treatment
strategy. Future RCTs should focus on these patients."
Clumek study (MONET): CHU Saint-Pierre/Maladies Infectieuses,
Brussels, Belgium; Hospital
la Paz, Madrid, Spain; Hospital for Infectious Diseases, Warsaw,
Poland; Med. Einrichtungen der Universität Köln,
Klinik I für Innere Medizin, Köln, Germany; Pharmacology
Research Laboratories, Liverpool University, Liverpool, UK;
Janssen-Cilag, Tilburg, Netherlands; Janssen-Cilag, Neuss,
Pillay study (SARA): University College London, London, UK;
MRC Clinical Trials Unit, London, UK; Imperial College, London,
UK; Ninewells Hospital and Medical School, Dundee, UK; MRC/UVRI
Uganda Research Unit on AIDS, Entebbe, Uganda; Joint Clinical
Research Centre, Kampala, Uganda; University of Zimbabwe,
Bierman meta-analysis: University Medical Centre Groningen,
Internal Medicine, Groningen, Netherlands; University of California,
San Francisco, Global Health Sciences, San Francisco, CA;
VU University Medical Centre, Internal Medicine, Amsterdam,
Netherlands; University Medical Centre Rotterdam, Virology,
Clumeck, JR Arribas, P Pulick, and others. Low-level viraemia
during treatment with darunavir/r monotherapy versus DRV/r
+ 2NRTIs in the MONET trial. 10th International Congress on
Drug Therapy in HIV Infection. Glasgow, November 7-11, 2010.
Pillay, R Goodall, and CF Gilks. Virological findings from
the SARA trial: boosted PI monotherapy as maintenance second-line
ART in Africa. 10th International Congress on Drug Therapy
in HIV Infection. Glasgow, November 7-11, 2010. Abstract
Bierman, EH Humphreys, MA van Agtmael, and others. Ritonavir-boosted
protease inhibitor monotherapy is 6% less effective than combination
antiretroviral therapy in a meta-analysis. 10th International
Congress on Drug Therapy in HIV Infection. Glasgow, November
7-11, 2010. Abstract