Boosted darunavir monotherapy works well in two studies

Liz Highleyman, Michael Carter
Published: 23 July 2009

Ritonavir-boosted darunavir (Prezista) alone maintains HIV suppression in most patients who achieved an undetectable viral load on combination antiretroviral therapy, according to two studies presented this week at the Fifth International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention in Cape Town, South Africa

MONET

The European MONET study included 256 patients taking a standard triple-drug antiretroviral regimen who had a viral load below 50 copies/ml for at least six months.

Participants were randomly assigned to switch to darunavir/ritonavir at a once-daily dose of 800/100 mg, either alone or in combination with two nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs). They could also optimise their NRTIs at this time.

Patients in the two study arms were generally comparable. About 80% were men, about 90% were white, and the median age was 43 years. Participants had well-controlled HIV disease, with a high median CD4 cell count of 575 cells/mm3. Individuals in the monotherapy arm, however, were more likely to have hepatitis C co-infection. The average duration of antiretroviral use was about seven years.

Treatment failure was defined as two consecutive viral load measurements above 50 copies/ml, stopping the study medication (participants were allowed to switch NRTIs), or re-adding NRTIs in the monotherapy arm. The trial was designed with enough statistical power to demonstrate non-inferiority of darunavir/ritonavir monotherapy compared with darunavir-containing combination therapy.

After 48 weeks, using an analysis called "TLOVR" (time to loss of virological response), in which changing study treatment was regarded as failure, 86% of patients in the darunavir/ritonavir monotherapy arm and 88% of those taking a standard triple-drug regimen maintained a viral load below 50 copies/ml. An intent-to-treat analysis also showed that monotherapy was comparable to triple therapy, with 84% and 85%, respectively, having an undetectable viral load. CD4 cell counts remained stable in both arms.

Furthermore, an analysis that included patients who switched drugs found the two treatment strategies to be equally effective, with 94% in the darunavir/ritonavir monotherapy arm and 95% in the triple therapy arm having undetectable viral load after a year of treatment.

Viral load "blips," or temporary increases, were more common in the monotherapy arm. Most viral load elevations were small (between 50 and 400 copies/ml) and viral load was re-suppressed when NRTIs were restarted. One person in each arm developed HIV mutations conferring resistance to protease inhibitors.

Darunavir/ritonavir monotherapy was generally well tolerated and no new or unexpected safety issues arose during the study. Taking more drugs was not associated with more side-effects overall, but participants in the combination therapy arm were three times more likely than those in the monotherapy arm to have elevated cholesterol. Liver enzymes (ALT and AST) elevations were more common in the monotherapy arm, but this was attributed to the higher rate of viral hepatitis coinfection in this group.

The investigators concluded that darunavir/ritonavir monotherapy was non-inferior to darunavir plus two NRTIs in patients starting with a viral load less than 50 copies/ml.

MONOI-ANRS

The MONOI study, sponsored by the French national AIDS research agency, included 242 participants who also were on combination antiretroviral therapy with viral load below 400 copies/ml for at least six months and below 50 copies/ml at study entry.

Patients in this study were first treated for eight weeks with a standard three-drug regimen containing darunavir/ritonavir plus two NRTIs, but the dose was 600/100 mg twice-daily rather than 800/100 once-daily. After this induction period, participants were randomly assigned to either remain on the combination regimen or drop the NRTIs and continue on darunavir/ritonavir monotherapy. Both the patients and their doctors knew which drugs they were taking.

A total of 225 participants went forward to the randomisation phase of the study. Three-quarters were men, the median age was 46 years and the median CD4 cell count was about 600 cells/mm3. Participants had never experienced treatment failure while using a protease inhibitor and had not previously used darunavir. The average duration of antiretroviral treatment experience was about eight years.

Treatment failure was defined as two consecutive viral load measurements above 400 copies/ml or changing or discontinuing study treatment. Again, the study was statistically powered to be able to show whether darunavir/ritonavir monotherapy was non-inferior to combination therapy.

In an intent-to-treat analysis, 87% of patients taking darunavir/ritonavir monotherapy maintained a viral load below 400 copies/ml through 48 weeks, compared with 92% of those taking standard triple therapy, demonstrating that monotherapy was non-inferior. In a per protocol analysis, 94% of patients taking monotherapy and 99% taking triple combination therapy maintained a viral load below 400 copies/ml, once again demonstrating non-inferiority.

Three patients taking monotherapy experienced virological failure, compared with none of those taking combination therapy. One had a low blood level of darunavir/ritonavir, suggesting inadequate adherence. However, no mutations associated with resistance to darunavir/ritonavir were seen in patients experiencing viral rebound and re-starting NRTIs led to re-suppression of viral load.

Similar proportions of patients changed their treatment during follow-up, and three people in both arms stopped study therapy. Similar numbers of serious adverse events were reported in the monotherapy and combination therapy arms (14 and 15, respectively).

One case of HIV encephalitis and one case of neurological symptoms were observed in the monotherapy arm, which a safety committee classified as possibly related to the treatment regimen under study.

The investigators concluded that darunavir/ritonavir monotherapy is a "viable alternative to standard triple therapy" that is less expensive and avoids NRTI toxicities with "no significant downstream consequences."

"The vast majority did not have even a single blip," MONOI principle investigator Christine Katlama told reporters at a press conference. While a proportion of patients need NRTIs to maintain undetectable viral load, these individuals can easily re-suppress HIV by restarting NRTIs and no resistance developed. However, she added, the effects of less than perfect adherence are more apparent when patients use a single drug.

Asked about the danger of non-AIDS-related events associated with ongoing HIV replication, Katlama suggested that these problems were typically seen in people with a few thousand, not a few hundred, copies/ml. MONET principle investigator Jose Arribas added that occasional viral load blips may not carry the same risk as continuous low-level viral replication.

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