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  18th HIV Drug Resistance Workshop
June 9-12 2009
Ft Myers Florida
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Raltegravir With Unboosted Atazanavir 300 mg Twice Daily in Antiretroviral Treatment-Experienced Participants
 
 
  Shaili Gupta, MD, Max Lataillade, DO, Steven Farber, PA-C, JD, and Michael J. Kozal, MD From the Division of Infectious Diseases, Yale University School of Medicine, New Haven, Connecticut (SG, ML, SF, MJK); VA CT Healthcare System, West Haven, Connecticut (SF, MJK); and UT Southwestern Medical Center, Dallas, Texas (SG).
 
Short Communication
Journal of the International Association of Physicians in AIDS Care
Volume 8 Number 2
March/April 2009 87-92
 
Raltegravir (RAL) is an HIV integrase inhibitor characterized by potent antiretroviral activity, few adverse effects, and lack of cross-resistance to other antiretroviral (ARV) agents. RAL is emerging as a component of effective alternative ARV therapy for those who experience therapeutic failure or intolerance to reverse transcriptase inhibitors (NRTI and NNRTI) and ritonavir (RTV)-boosted protease inhibitor (PI) containing regimens. The combination of RAL with atazanavir (ATV) without a concomitant NRTI-based backbone or the inclusion of RTV may provide an alternative strategy for those unable to tolerate these latter ARV agents. In this report the authors present a case series of treatment-experienced patients managed with RAL + ATV given without a boosting dose of RTV. All patients tolerated this regimen over a course of 25 to 82 weeks, and had good virologic and immunologic outcome with a decrease in HIV RNA levels to <50 copies/mL and a mean CD4 count increase of 234 cells/mm3.
 
Introduction
New antiretroviral (ARV) agents with novel target sites, like the integrase inhibitor (INI) raltegravir (RAL), have provided unique options for the management of HIV infection in highly ARV-experienced individuals. Raltegravir has the advantage of few adverse effects, and lack of cross-resistance to the nucleoside reverse transcriptase inhibitor (NRTI)/ nucleotide reverse transcriptase inhibitor (NtRTI), nonnucleoside reverse transcriptase inhibitor (NNRTI), and protease inhibitor (PI) classes of ARV medications.1 Minimization of adverse effects from ARV medications has now become a major goal of HIV care to ensure better adherence to therapy. The encouraging clinical outcome data achieved with RAL have prompted its use as a component in new ARV strategies that may have relatively lower incidence of adverse effects.
 
Raltegravir inhibits HIV replication by blocking the integration of HIV proviral DNA into the host cell chromosomal DNA.2 Recently published data on the use of RAL in HIV-infected participants infected with drug-resistant strains or those without drug-resistant strains demonstrates that RAL is highly potent, suppressing HIV viral loads in the majority of participants, and having excellent CD4 count responses over 48 weeks of therapy.3,4 Raltegravir is eliminated mainly by metabolism via a uridine diphosphate-glucuronosyl transferase (UGT1A1)-mediated glucuronidation pathway. The PI atazanavir (ATV) is a direct inhibitor of this enzyme. Recent data suggest that coadministration of ATV can increase RAL levels 40% to 55% by inhibition of UGT1A1-mediated clearance of RAL.5 However, current US Department of Health and Human Services (DHHS) HIV treatment guidelines do not recommend a change in the dose of RAL if given with ATV, as persons receiving both agents have demonstrated good tolerability and low side effect profiles.5,6
 
The availability of RAL provides an opportunity to examine alternative ARV strategies that may be equally efficacious and less toxic than those currently recommended in treatment guidelines. Such combinations might include RAL + ATV regimen without a concomitant NRTIs/NtRTIs-based backbone and/or the inclusion of a boosting dose of ritonavir (RTV). However, there is little data available to date regarding such a combination. Atazanavir has been found to have comparable efficacy with or without RTV.7 HIV treatment guidelines list unboosted ATV-based regimen as an alternative option for patients with intolerance or contraindications to RTV.6 Among the 3 dose groups studied for unboosted ATV (200, 300, or 400 mg twice daily [BID]), ATV 300 mg BID is most similar to ATV/RTV 300/100 mg once daily (QD) based on pharmacokinetics and side effect profile.8
 
HIV care providers have begun to use the combination of RAL + unboosted ATV as some patients are intolerant of RTV or have had major side effects/toxicity with NRTIs and NNRTIs. In this report, we present our experience with the combination of RAL + unboosted ATV with or without additional N(t)RTI in HIV-infected individuals who had been placed on the combination for salvage therapy and/ or ARV intolerance/toxicity.
 
Methods
We present a clinical case series of triple-class experienced HIV-infected patients who were receiving RAL + unboosted ATV for >24 weeks, for either prior virological failure, or significant ARV intolerance. Atazanavir was dosed at 300 mg BID in these participants to approach levels attained with ATV/RTV QD dosing.8 Plasma HIV viral load and CD4 counts were determined before and after the switch to an RAL + ATV BID-based regimen. Creatinine clearance (CrCl), liver function tests, and cholesterol levels from baseline and at 24 weeks were documented. Cumulative ARV resistance was derived from Stanford University's HIV Drug Resistance Database (http://hivdb.stanford.edu) for all mutations present historically prior to the switch to an RAL + ATV-based regimen.9,10 Genotypic sensitivity score (GSS) was calculated for highly ARV-experienced patients, with each ARV being assigned a GSS of 1 or 0 for Stanford cumulative mutation score of <30 (susceptible) and >30 (resistant), respectively.11 Relevant comorbidities that played a role in the choice of antiretroviral therapy (ART) were obtained by chart review. Outcomes studied were plasma HIV viral load (copies/mL), CD4 count, resistance profiles, patient-reported adherence, and adverse effects of ARV medications before and after the switch. The minimum and maximum period on RAL 400 mg + unboosted 300 mg ATV BID among these patients was 25 and 82 weeks, respectively.
 
Results
Six patients followed at the HIV clinic at Veterans' Affairs Connecticut Healthcare System had been on RAL + unboosted ATV+N(t)RTI for >24 weeks at the time of clinical review. All participants received RAL 400 mg BID + ATV 300 mg BID as part of their regimens, which had been started between April 2007 and May 2008. Individuals initiated on RAL before the drug became licensed and available for use in December 2008, had obtained the medication via an expanded access program. Median age was 58 (range 50 to 84) years, median time from diagnosis was 14.5 (range 9 to 21) years, and the median time on ART was 10.5 (range 9 to 21) years. Before initiation of RAL + ATV-based therapy, the mean HIV viral load was 115 752 copies/mL, and the mean CD4 count was 309 cells/mm3 (range 32 to 477). After 24 weeks of treatment, the viral load for all participants had become and remained undetectable, while the mean CD4 count was 543 cells/mm3 (range 101 to 1001), with an average gain of 234 CD4 cells/mm3 (Figures 1-6).
 
All 6 patients had relevant comorbidities and had experienced significant adverse effects from NNRTIs, NRTIs, and RTV (Table 1). All 6 patients were highly treatment experienced, with multidrug resistance to NRTIs and NNRTIs. Genotype sequence analysis in these individuals revealed multiple mutations rendering resistance to different classes of ARV medications, with GSS 1/4 0 for all NNRTIs and for most NRTIs. The majority had PI-sensitive virus (1 participant had GSS of 0 for all PIs).
 
The treatment regimen in 3/6 individuals comprised RAL 400 mg BID + ATV 300 mg BID, with no additional ARV agent. In a fourth patient, lamivudine (3TC) was chosen as a third ARV agent. The remaining 2 patients had additional NRTIs in their regimens, with 1 being on saquinavir (SQV) additionally (Table 2). All patients continue tolerating the RAL + ATV regimen well, 25 to 82 weeks after it was started, with no adverse events, and had 100% adherence via electronic prescription refill data. Five participants have been on RAL + ATV for >36 weeks, with 2 reaching >76 weeks, all with viral loads <50 copies/mL.
 
Changes in renal and hepatic function and in total cholesterol levels after 24 weeks of therapy were also documented. Calculated CrCl and cholesterol levels remained essentially unchanged. In all participants, hepatic transaminases (aspartate transaminase/ alanine transaminase [AST/ALT]) showed an overall decline by an average of 25 U/L; however, total bilirubin increased by a mean of 1.3 mg/dL, as is expected with ATV-containing therapy.
 

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Discussion
Raltegravir belongs to a novel class of ARV agents called HIV INIs that act by inhibiting incorporation of HIV proviral DNA into the host cell genome, thereby interrupting production of new HIV particles.12 Raltegravir has been shown to reduce viral replication of HIV including multidrug-resistant HIV strains, independent of concomitant RTIs and RTV boosted PIs.1 Raltegravir has recently been shown to effectively reduce replication in both phases of HIV viral decay, the first reflecting death of productively infected CD4 cells, and the second phase likely arising from decay of cells newly infected by long-lived infected cells as well as that of latently infected cells with unintegrated HIV DNA.2 Lack of cross-resistance to RTIs and PIs, and a good safety and tolerability profile have made RAL a desirable option for salvage therapy in individuals infected with multidrug-resistant virus. Atazanavir as a PI selectively inhibits the virus-specific processing of viral Gag and Gag-Pol polyproteins in HIV-infected cells, preventing formation of mature virions. Compared with other PIs, ATV has little impact on total cholesterol and triglyceride levels.
 
The data presented in our study suggest that the combination of RAL + unboosted ATV may be an effective ARV regimen demonstrating good virologic and immunologic response rates over a 25- to 82-week period. Furthermore, the combination was well tolerated through >24 weeks of therapy in this small cohort of participants. One patient was on SQV additionally, which when used with unboosted ATV has been shown to be equally effective as RTV-boosted SQV, while avoiding RTV-associated hypertriglyceridemia.13 A viral load of <50 copies/mL with a rise in CD4 counts was achieved and has been maintained in all participants over prolonged course of several months, regardless of presence of additional NRTI or PI in the treatment regimen. All patients have tolerated the regimen well, with 100% adherence and demonstable improvement in hepatic transaminase levels and stable cholesterol levels. Although these data are promising, more investigation is required to determine if RAL + ATV is an efficacious and safe alternative to the currently recommended ART strategies. This study is limited, in that it was a case series assembled by retrospective chart review on a small number of patients and was not designed to prospectively follow virologic, laboratory, and clinical parameters in a standardized fashion, thus, the results noted cannot be accepted as expected outcomes without further studies. However, we felt it was important to present these clinical data on this unique ARV combination as many patients cannot tolerate RTV or have had toxicities with N(t)RTIs and clinicians have begun to use novel RAL-based strategies. Future studies comparing RAL-based strategies that include neither N(t)RTIs nor RTV versus traditional ARV class strategies for long-term efficacy and safety outcomes are needed to determine if such combinations are viable alternatives to currently recommended ARV regimens.