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Boosted Darunavir Monotherapy Maintains Viral Suppression in Most People with HIV

SUMMARY: HIV patients with undetectable viral load on traditional combination antiretroviral 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 similar findings.

By Liz Highleyman

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

darunavir (Prezista)

The 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 failure.

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.

Data 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.


At 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.
17% and 15%, respectively, had HIV RNA levels above 5 but below 50 copies/mL.
7% 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:
50-400 copies/mL: 84% and 83% of detectable samples, respectively;
400-1000 copies/mL: 12% vs 9%, respectively;
>1000 copies/mL: 4% vs 9%, respectively.
Emergence of drug resistance was uncommon, with 3 patients developing new IAS PI resistance mutations (2 on monotherapy, 1 on combination ART).

"In 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.

SARA: 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.


As 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.
At 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:
59% vs 77%, respectively, with HIV RNA < 50 copies/mL;
74% vs 90%, respectively, with HIV RNA < 200 copies/mL;
84% vs 94%, respectively, with HIV RNA < 1000 copies/mL.
Looking 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 randomized treatment.
Among 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 combination arm.

"PI 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."

Monotherapy Meta-analysis

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 darunavir/ritonavir (MONET 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."

Investigator affiliations:

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, Germany.

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, Harare, 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, Rotterdam, Netherlands.



N 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. Abstract O213.

D 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 O214.

WFW 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 O212.




















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