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PI MONOTHERAPY - Darunavir Monotherapy
Equivalent to Triple Therapy in Meta-Analysis
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Tenth International Congress on Drug Therapy in HIV Infection, November 7-11, 2010, Glasgow
Mark Mascolini
Boosted darunavir/ritonavir monotherapy proved virologically equivalent to triple therapy in a meta-analysis by Dutch and US investigators [1]. But lopinavir/ritonavir monotherapy was less effective than triple therapy in the same analysis, and a combined analysis of both monotherapies showed significant inferiority to triple therapy.
Wouter Bierman (University Medical Center Groningen) and colleagues in Rotterdam and San Francisco scoured electronic databases and hand-searched meeting reports for studies that compared boosted protease inhibitor (PI) monotherapy with triple therapy from 1996 to March 22, 2010. They did not include observational studies, single-arm trials, or review articles. This exercise yielded 10 comparative trials, two testing darunavir/ritonavir and eight testing lopinavir/ritonavir; all trials were open label. Two reviewers extracted relevant data, and original investigators supplied additional findings.
Bierman used random effects Mantel-Haenszel methods to figure risk ratios (RR) for virologic failure comparing monotherapy arms with triple-therapy arms. Virologic response in an intent-to-treat analysis meant reaching a viral load below 50 copies, with missing data or adding nucleosides back to the PIs counted as failure. In an on-treatment sub-50-copy analysis, adding back nucleosides counted as failure, but missing data, deaths, and drug changes due to side effects were censored from the analysis. Follow-up in the two darunavir trials, MONET and MONOI, lasted 48 weeks in the meta-analysis. Follow-up in four lopinavir trials ran to 96 weeks, while three lopinavir trials had 48-week data and one had 24-week results.
In the primary intent-to-treat analysis of all 10 trials, risk of virologic failure was 6% higher with PI monotherapy than with triple therapy (RR 0.94, 95% confidence interval [CI] 0.89 to 0.99). Analyzing the two darunavir trials separately, Bierman calculated a 0.97 risk ratio favoring triple therapy, but the confidence interval crossed 1.0 (0.90 to 1.03), a result indicating that darunavir/ritonavir monotherapy was not virologically inferior to triple therapy in combined MONET and MONOI results. Looking only at the eight lopinavir monotherapy trials, the investigators found a significant 10% higher risk of virologic failure with monotherapy than with triple therapy (RR 0.90, 95% CI 0.84 to 0.98).
Only one trial, a 96-week lopinavir trial (Delfraissy 2008) did not have an induction phase with triple therapy before participants started monotherapy. When Bierman eliminated this trial from the overall intent-to-treat analysis, results favoring triple therapy did not change.
In the 10-trial on-treatment analysis, the risk of virologic failure was 10% greater with monotherapy than with triple therapy (RR 0.90, 95% CI 0.85 to 0.94). When Bierman analyzed only the two darunavir trials, he found a 4% greater risk of virologic failure with monotherapy, with a confidence interval that touched 1.0 (RR 0.96, 95% CI 0.92 to 1.00). In the eight lopinavir monotherapy trials, the risk of virologic failure was 13% greater with monotherapy than with triple therapy (RR 0.87, 95% CI 0.80 to 0.94).
The investigators concluded that PI monotherapy is "slightly but significantly" less effective than triple therapy in virologically suppressed patients with no record of PI failure or resistance. But in the two darunavir trials, PI monotherapy and standard therapy "are equally effective."
European antiretroviral guidelines now say lopinavir/ritonavir or darunavir/ritonavir monotherapy "might be an option in patients with intolerance to NRTIs or for therapeutic simplification." US Department of Health and Human Services guidelines do not support monotherapy as an option, saying it is "somewhat less effective" than standard therapy.
In a PI monotherapy overview before the meta-analysis, monotherapy researcher Jose Arribas noted that concerns about this strategy have not been resolved to the satisfaction of all, including central nervous system penetration and the risk of acute retroviral syndrome when two nucleosides are added back to monotherapy [2]. He called the acute retroviral syndrome finding in four patients taking lopinavir/ritonavir monotherapy "an alarming result," but he added that he has never seen that happen in his lopinavir or darunavir trials. The 60-person lopinavir trial [2] stopped early after six virologic failures in the monotherapy arm. Four of the six people with virologic failure had neurologic symptoms.
Monotherapy is often mentioned as a nucleoside-sparing option in low-income countries with high HIV burdens. But a 192-person African study presented at the conference found a higher failure rate with lopinavir/ritonavir monotherapy than with continued lopinavir-based triple therapy following first-line nonnucleoside failure [3]. Twenty-four weeks after randomization, 56 of 94 people on monotherapy (60%) versus 70 of 91 (77%) on triple therapy maintained virologic suppression (P = 0.007).
References
1. Bierman WFW, Humphreys EH, van Agtmael MA, Boucher CA, Rutherford GW. Ritonavir-boosted protease inhibitor monotherapy is 6% less effective than combination antiretroviral therapy in meta-analysis. Tenth International Congress on Drug Therapy in HIV Infection. November 7-11, 2010. Glasgow. Abstract O212.
2. Gutmann C, Cusini A, Gunthard HF, et al. Randomized controlled study demonstrating failure of LPV/r monotherapy in HIV: the role of compartment and CD4-nadir. AIDS. 2010;24:2347-2354.
3. Pillay D, Goodall R, Gilks GF, et al. Virological findings from the SARA trial: boosted PI monotherapy as maintenance second-line ART in Africa. Tenth International Congress on Drug Therapy in HIV Infection. November 7-11, 2010. Glasgow. Abstract O214.
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