Lopinavir/Ritonavir as Single-Drug Therapy for Maintenance of HIV-1 Viral Suppression

To the Editor: Highly active antiretroviral therapy (HAART) typically comprises 2 nucleoside reverse transcriptase inhibitors (NRTIs) and either a protease inhibitor (PI) or a nonnucleoside reverse transcriptase inhibitor (NNRTI).1,2 Many factors, including medication nonadherence, drug toxicities, lack of drug potency, and drug resistance, contribute to treatment failure. Treatment failure results in persistent viremia, development of resistance, and disease progression. The favorable pharmacokinetics, high anti-HIV potency, high genetic threshold to resistance, and fixed-dose formulation of lopinavir/ritonavir (LPV/r) have generated interest in its use as single-drug therapy.3-15 In 1 pilot study, LPV/r has been used as initial therapy, thereby deferring the use of NRTIs and their potential mitochondrial toxicities and deferring the use of NNRTIs and their low genetic threshold to resistance. However, virologic outcomes (18/30 patients with viral load [VL] of <50 copies/mL at 48 weeks) are inferior compared with triple-drug HAART.16 LPV/r monotherapy has also been explored as maintenance therapy after virologic suppression has been achieved with the current standard of triple-drug HAART (Table 1).17-20 Patients in these 4 pilot studies are PI naive, have no history of virologic failure with PIs, or have no protease mutations as suggested by resistance testing or by treatment history. These studies are small and have different designs, and follow-up is short. In fact, 2 of these studies are not yet completed.19,20 In the November 2005 issue of the Journal of Acquired Immune Deficiency Syndromes, Arribas et al17 reported the 48-week results of the "Only Kaletra Study." To date, this is the only randomized controlled trial to evaluate maintenance therapy with LPV/r monotherapy against triple-drug HAART (LPV/r + 2 NRTIs [or 1 NRTI + tenofovir disoproxil fumarate]). The authors should be commended for their careful study design and close monitoring. By intention-to-treat, noncompleter-equals-failure analysis, 20 (95%) of 21 patients on triple-drug HAART and 17 (81%) of 21 patients on LPV/r had VL of less than 50 copies/mL at week 48 (P = 0.34). The 4 LPV/r treatment failures had low-level viremia, and no primary protease mutations developed with viral rebound. Suboptimal adherence was associated with treatment failure. LPV/r monotherapy was well tolerated, and no patient discontinued LPV/r because ''''''of adverse events. No statistically significant differences in lipids were seen between the 2 study arms.TABLE 1: Summary of the Efficacy, Safety, and Tolerability of LPV/r Monotherapy for Maintenance of HIV-1 Viral SuppressionArribas et al17 highlight that most patients in the LPV/r arm maintained viral suppression. They note that the sample size was too small to compare the efficacy of LPV/r monotherapy against triple-drug HAART but also suggest that the LPV/r 48-week efficacy rate might be acceptable for a maintenance strategy. Several problems exist with these inferences. The small number of patients certainly limits the depth and rigor of statistical analyses. Because of the small sample size and hence the risk of making a type II error, the difference in virologic efficacy was not statistically significant but, conversely, these findings do not rule out that such a difference is real. Another concern is the high risk of viral rebound in the LPV/r arm (4 rebounds/19.4 person-years of follow-up = 21%). Interestingly, the 4LPV/r treatment failures had a significantly shorter period with VL of less than 50 copies/mL before LPV/r monotherapy (median, 40 weeks; range, 30-84 weeks) than the 17 LPV/r treatment successes (median, 132 weeks; range, 40-331 weeks). This suggests that lengthy induction courses may be necessary before attempting to simplify to LPV/r monotherapy. However, if patients are virologically suppressed and tolerating triple-drug HAART, one might question the rationale for simplification at all. If these observations are confirmed by larger randomized controlled trials, they would argue against LPV/r monotherapy as an acceptable maintenance approach. In addition, the relatively short duration of follow-up for these patients does not allow adequate evaluation of the long-term efficacy and safety of LPV/r monotherapy. Some patients in other LPV/r monotherapy studies have developed severe gastrointestinal side effects (requiring LPV/r discontinuation), hyperlipidemia, and diabetes.16-20 The efficacy, safety, tolerability, and durability of LPV/r monotherapy for HIV infection remain unclear and much more data are needed. ACKNOWLEDGMENTS The authors thank the staff of the InSite safer injecting facility (SIF) and Vancouver Coastal Health (Chris Buchner, Heather Hay, and David Marsh, MD). We also thank Bonnie Devlin, Evelyn King, Aaron Eddie, Peter Vann, Dave Isham, Daniel Kane, Steve Gaspar, Carl Bognar, Megan Oleson, Deborah Graham, and Suzy Coulter for their research and administrative assistance. This study was made possible through a financial contribution from Health Canada. Kirk M. Chan-Tack Anthony Edozien Institute of Human Virology University of Maryland School of Medicine Baltimore, MD

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