To the Editors:
In the BENCHMRK-1 and BENCHMRK-2 studies (the blocking integrase in treatment-experienced patients with a novel compound against HIV, Merck studies), the entry criteria included patients with documented resistance to 3 classes of antiretrovirals.1,2 In those randomized studies, patients were assigned to receive an optimized antiretroviral regimen either alone or in conjunction with raltegravir (RGV), also known as MK-0518 or Isentress, and the antiretroviral regimens were individually designed on the basis of previous antiretroviral history and results of drug-resistance testing. Individuals who received RGV had higher rates of virologic suppression than those who received placebo, and the overall rates of viral suppression are among the highest reported for patients infected with HIV with triple-class resistance. Increases in the CD4-cell count were more pronounced in the RGV group than in the placebo group; the overall adverse-event profile did not differ between the 2 groups. Rates of cancer were higher in the RGV group; however, the rates of adverse events were low, and differences in the rates from the combined BENCHMRK studies and from a larger data set including other studies of RGV3 were not significant. One could speculate that the earlier occurrence of clinical events in the RGV group reflects a more robust immunologic response and unmasking of underlying conditions. Continued monitoring for these and other adverse events in patients receiving RGV are therefore important during its expanded use.
To study this further, 57 triple-class experienced individuals (47 males and 10 females) received RGV 400 mg twice a day in addition to optimized background therapy (OBT) at the Chelsea and Westminster Hospital, London, United Kingdom, as part of an expanded access study. A total of 31 individuals received RGV in combination with OBT because of virological failure on their prior regiment. A total of 26 individuals switched to RGV with an undetectable viral load from T-20 or a poorly tolerated boosted protease inhibitor.
In those individuals starting on RGV with virological failure, the median number of prior antiretroviral regimens was 10 (range 3-20). As part of OBT, 21 patients received darunavir; 23, etravirine; and 3, T20 of which 2 were naive. The median number of active drugs per patient being 2, the mean baseline CD4 count measured 206 cells per microliter, and the baseline viral load was 55,000 copies per milliliter. By 4 weeks, all patients achieved a > 1 log decrease in viral load, and by week 48, the mean rise in CD4 count was 80 cells per microliter (Fig. 1). By week 48, 2 individuals died of preexisting complications of cardiovascular disease, 1 patient stopped all antiretrovirals due to adherence issues, and 1 patient was lost to follow-up. No patients stopped because of RGV toxicity; of those who remained on RGV, all apart from 1 achieved an HIV-1 viral load <50 copies per milliliter and the patient who failed to suppress had additional adherence support and subsequently became undetectable.
In those individuals who switched to RGV with an undetectable viral load, as part of the OBT, 11 patients received darunavir and 9 etravirine. One patient died of preexisting progressive multifocal luekoencephalopathy; 1 patient stopped all therapy because of preexisting liver function test abnormalities at week 8, and the same combination retroviral therapy was recommenced at week 12 and full virological suppression was achieved by week 24. All remaining patients maintained an undetectable viral load up to week 48, with a mean rise in CD4 cells at this point being 73 cells per milliliter, and no malignancies were observed in either group.
A concern with RGV is the low genetic barrier to drug resistance, its major point of vulnerability4-8; however, even in our heavily treated triple-class resistant cohort, the use of RGV in combination with other active agents led to excellent virological responses through to week 48.
Switching to RGV from T20 with an undetectable viral load has proven to be a successful strategy in clinical practice and randomized studies,9 maintaining virological suppression, negating the need for twice daily injections, and therefore simplifying a patient's combination therapy. However, concern that this switch may have the effect of lowering the Cmax and Cmin of certain protease inhibitors warrants further study.10
The use of RGV to replace a poorly tolerated protease inhibitor was a successful strategy in our patient cohort; however, randomized studies have shown switching from boosted lopinavir to RGV led to more virological failures when compared with patients who did not switch. In this case, the proposed mechanism has been the “unmasking” of archived nucleoside reverse transcriptase inhibitor resistance mutations; careful selection of supporting agents may therefore help to overcome this effect.11
Alastair Teague, MD
Chris Scott, MD
Mark Bower, PhD, FRCPath, FRCP
Brian Gazzard, MD, FRCP
Mark Nelson, MD, FRCP
Justin Stebbing, PhD, MRCP, FRCPath
Department of HN Medicine
Imperial College, London
1. Cooper DA, Steigbigel RT, Gatell JM, et al. Subgroup and resistance analyses of raltegravir for resistant HIV-1 infection. N Engl J Med
2. Steigbigel RT, Cooper DA, Kumar PN, et al. Raltegravir with optimized background therapy for resistant HIV-1 infection. N Engl J Med
3. Markowitz M, Morales-Ramirez JO, Nguyen BY, et al. Antiretroviral activity, pharmacokinetics, and tolerability of MK-0518, a novel inhibitor of HIV-1 integrase, dosed as monotherapy for 10 days in treatment-naive HIV-1-infected individuals. J Acquir Immune Defic Syndr
4. Maiga AI, Malet I, Soulie C, et al. Genetic barriers for integrase inhibitor drug resistance in HIV type-1 B and CRF02_AG subtypes. Antivir Ther
5. Ceccherini-Silberstein F, Malet I, D'Arrigo R, et al. Characterization and structural analysis of HIV-1 integrase conservation. AIDS Rev
6. Malet I, Delelis O, Soulie C, et al. Quasispecies variant dynamics during emergence of resistance to raltegravir in HIV-1-infected patients. J Antimicrob Chemother
7. Delelis O, Malet I, Na L, et al. The G140S mutation in HIV integrases from raltegravir-resistant patients rescues catalytic defect due to the resistance Q148H mutation. Nucleic Acids Res
8. Malet I, Delelis O, Valantin MA, et al. Mutations associated with failure of raltegravir treatment affect integrase sensitivity to the inhibitor in vitro. Antimicrob Agents Chemother
9. De Castro I, Braun J, Charreau I, et al; and the ANRS 138 Study Group. Switch from enfuvirtide to raltegravir in highly treatment experienced HIV-1 infected patients: a ramdomised open-label non-inferiority trial. Presented at: 16th Conference on Retroviruses and Opportunistic Infections; February 8-11, 2009; Montreal, Canada.
10. Goldwirt L, Braun J, de Castro N, et al. Tipranavir and darunavir pharmacokinetics in patients switching from enfuvirtide to raltegravir: a sub-study of the ANRS 138 EASIER trial [abstract 0-12]. Presented at: 10th International Workshop on Clinical Pharmacology of HIV Therapy; April 15-17, 2009; Amsterdam, The Netherlands.
11. Eron J, Andrade J, Zajdenverg R, et al. Switching from stable lopinavir/ritonavir-based to raltegravir-based combination ART resulted in a superior lipid profile at week 12 but did not demonstrate non-inferior virologic efficacy at week 24 [abstract 70aLB, 2009]. Presented at: Sixteenth Conference on Retroviruses and Opportunistic Infections, February 5, 2009; Montreal, Canada.