By Liz Highleyman

Researchers presented findings from 2 similarly designed studies in which patients with stable undetectable viral load on a standard combination antiretroviral regimen were randomly assigned to either stay on combination therapy or switch to darunavir/ritonavir monotherapy (the small boosting dose of ritonavir is not considered a separate drug).

MONET Study

In the international European MONET study, 256 patients taking a standard 3-drug regimen with a viral load below 50 copies/ml for at least 6 months were randomly assigned to switch to 800/100 mg darunavir/ritonavir once-daily, either alone or in combination with 2 NRTIs.

Most participants were men (81%) and white (91%), with a median age of 43 years. They had been on antiretroviral therapy (ART) for an average of 6-7 years and had well-controlled HIV disease, with a median CD4 cell count of 575 cells/mm3. Hepatitis C coinfection was more common in the monotherapy arm.

Results

	After 48 weeks, in a TLOVR (time to loss of virological response) analysis with switches = failure, 86% of participants in the darunavir/ritonavir monotherapy arm and 88% in the combination therapy arm maintained a viral load below 50 copies/ml.
	An intent-to-treat (ITT) analysis, 84% and 85%, respectively, had undetectable viral load.
	In an as-treated analysis including patients who switched drugs, 94% in the monotherapy arm and 95% in the combination therapy arm had undetectable viral load.
	These results demonstrated that darunavir/ritonavir monotherapy was non-inferior to darunavir-containing combination therapy.
	CD4 cell counts remained stable in both arms.
	Viral load "blips" (transient increases) usually low-level (50-400 copies/ml) occurred more often in the monotherapy arm.
	Viral load was re-suppressed when NRTIs were reintroduced.
	1 person in each arm developed protease inhibitor resistance mutations.
	Darunavir/ritonavir monotherapy was generally well tolerated, with no unexpected safety concerns.
	Participants in the combination therapy arm were 3 times more likely to have elevated cholesterol levels (4.8% vs 1.6%).
	ALT and AST liver enzyme elevations were more common in the monotherapy arm, associated with the higher prevalence of viral hepatitis in this group.

Based on these findings, the investigators concluded that "darunavir/ritonavir monotherapy showed consistently non-inferior efficacy versus triple antiretroviral drug treatment at week 48" in patients with undetectable viral load at baseline.

Hospital La Paz, Madrid, Spain; Centrum Diagnostyki i Terapii AIDS, SPZOZ Wojewodski Szpital, Warsaw, Poland; Rigshospitalet, Epidemiklinikken, Copenhagen, Denmark; Universitat Koln, Koln, Germany; St Stephens Research Centre, Chelsea and Westminster Hospital, London, UK; CHU Saint Pierre, Maladies Infectieuses, Brussels, Belgium; Hosp 12 de Octubre, Unidad VIH, Madrid, Spain; iverpool University, Pharmacology Research Laboratories, Liverpool, UK; Janssen-Cilag, Tilburg, Netherlands and Neuss, Germany.

MONOI Study

The French MONOI-ANRS 136 study included 242 patients on combination ART with viral load below 400 copies/ml for at least 6 months and below 50 copies/ml at study entry.

Participants were first treated with a standard regimen containing 600/100 mg twice-daily darunavir/ritonavir plus 2 NRTIs for 8 weeks, then were randomly assigned to either remain on the combination regimen or stop the NRTIs and continue on darunavir/ritonavir monotherapy. 225 participants entered the randomized part of the study.

Most patients were men, the median age was 46 years, and the median CD4 cell count was about 600 cells/mm3. Participants had been on ART for an average of about 8 years but had never used darunavir and had no history of treatment failure while using a protease inhibitor.

Results

	In an ITT analysis, 87% of patients taking darunavir/ritonavir monotherapy and 92% those taking combination therapy maintained undetectable HIV RNA at week 48.
	In a per protocol analysis, 94% and 99%, respectively, did not experience treatment failure, defined as 2 consecutive viral load measurements above 400 copies/ml.
	Here too, these results demonstrated that darunavir/ritonavir monotherapy was non-inferior to combination therapy.
	3 patients in the monotherapy arm experienced virological failure compared with none in the combination arm.
	No darunavir resistance mutations were detected in patients experiencing viral rebound.
	Again, restarting NRTIs led to re-suppression of viral load.
	3 participants in both arms stopped study treatment prematurely.
	Serious adverse events were reported with similar frequency in the monotherapy and combination therapy arms (14 and 15, respectively).
	1 case of HIV encephalitis and 1 case of neurological symptoms were observed in the monotherapy arm that were considered possibly related to treatment.

"Darunavir monotherapy represents a viable alternative to standard triple therapy," the investigators concluded. Monotherapy is effective, had "no significant downstream consequences" including resistance, avoids long-term NRTI toxicities, and is less expensive, they added.

Christine Katlama and Jose Arribas (Photo: Liz Highleyman)

At a press conference accompanying the presentations, MONOI principle investigator Christine Katlama noted that the effects of suboptimal adherence are more apparent when patients use monotherapy.

With regard to non-AIDS-related events and comorbities associated with ongoing HIV replication, Katlama suggested these problems were typically seen in people with a few thousand, not a few hundred, HIV RNA copies/ml. MONET principle investigator Jose Arribas added that occasional viral load blips may not be associated with the same risks as continuous low-level viral replication.

Pitié-Salpétrière University Hospital and INSERM U 943, Paris, France; INSERM U 943, Paris, France; Necker Hospital, Paris, France; Saint Antoine Hospital, Infectious Disease, Paris, France; Saint Louis Hospital AP HP, Paris, France; Bicetre Hospital, Kremlin-Bicetre, France; Bichat Claude Bernard Hospital, Paris, France.

7/24/09

References

J Arribas, A Horban, J Gerstoft, and others. The MONET trial: darunavir/ritonavir monotherapy shows non-inferior efficacy to standard HAART, for patients with HIV RNA < 50 copies/mL at baseline. 5th International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention (IAS 2009). July 19-22, 2009. Cape Town, South Africa. Abstract TuAb106.

C Katlama, MA Valentin, M Algarte-Genin, and others. Efficacy of darunavir/ritonavir as single-drug maintenance therapy in patients with HIV-1 viral suppression: a randomized open-label non-inferiority trial, MONOI-ANRS 136. IAS 2009. Abstract WeLBB102.

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