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Management of Treatment-Experienced Patients
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Conference Reports for NATAP
16th Conference on Retroviruses and Opportunistic Infections
Rafael E. Campo, MD
University of Miami, Jackson Memorial Hospital
The Conference on Retroviruses and Opportunistic Infections has been the premier venue for presenting the most important antiretroviral studies for years. There has always been a good balance of studies in both naïve and treatment-experienced patients. However, it seems as if this year the number of studies in treatment-experienced patients was somewhat smaller both in absolute and relative terms compared to studies in naïve patients and compared to prior years. The most interesting of these studies centered around raltegravir (RAL) substitutions and the use of interleukin (IL)-2. Trying to view this paucity of treatment-experienced studies from an optimistic perspective, it would be tempting to postulate that perhaps we have turned a corner and are doing fewer studies in ART-experienced patients because there is less of a need to undertake these studies. Time will tell, but both anecdotally and in the published literature there is a sense that we are gradually seeing fewer patients fail once they start ART and, just as importantly, finding less resistance among these treatment failures.
Merck's presentation of the SWITCHMRK-1 and -2 (also known as the 032 and 033) studies generated a lot of interest [1]. These were identical studies run simultaneously in different parts of the world as multicenter, double-blind, randomized clinical trials. The patient population consisted of individuals on lopinavir/ritonavir (LPV/r) plus 2 nucleoside reverse transcriptase inhibitors (NRTIs) for at least 3 months with an HIV RNA <50 c/ml. Two critical elements in the trials were that prior virologic failures were not excluded and there was no limit on the number of prior antiretroviral agents. Patients were randomized in a 1:1 fashion to either continue LPV/r or switch to RAL. The primary endpoints were the mean percentage change in lipids at week 12 and the proportion of patients with HIV RNA <50 c/ml at week 24. In protocol 032, 174 patients switched to RAL and 174 remained on LPV/r; the corresponding numbers for protocol 033 were 176 and 178, respectively. Baseline demographic characteristics were similar across treatment arms in both studies. One interesting baseline feature was how heavily experienced some of these patients were: the median number of prior years on ART ranged from 3.3 to 4.6 for the 4 treatment arms (2 per each of 2 studies) but the actual range went from 0.3 all the way up to 22.3 years. Similarly, the median number of prior ART agents ranged from 5-6 but the actual range was 2 to 16. In fact, some of these individuals had been previously treated with enfuvirtide (ENF) and tipranavir and were thus quite heavily experienced; it is not yet clear why they had gone back to a LPV/R-based regimen. While the values of total cholesterol, non-HDL cholesterol, and triglycerides were clearly much better for the patients who switched to RAL, the virologic outcomes were better for the patients who stayed on LPV/r (NC=F analysis): 87% of these subjects remained with HIV RNA <50c/ml vs. 81% of the RAL patients (-6.6%; 95% CI -14.4, 1.2) in the 032 study and 94% of LPV/r patients vs. 88% of RAL patients (-5.8%; 95% CI -12.2, 0.2) in the 033 study. Post-hoc data collection showed that 27 of 32 (84%) of RAL patients with confirmed HIV RNA >50 c/ml were not on their first regimen at study entry and 18 of 27 (66%) had a history of prior virologic failure. At first glance and because of RAL's excellent performance in heavily experienced (BENCHMRK studies) and naïve (STARTMRK) patient studies, these results were to some extent unexpected and disappointing. However, a thoughtful review of the baseline patient characteristics suggests that perhaps the findings are not so surprising since RAL, a drug with a less of a genetic barrier (from Jules: it has been said that NNRTIs have a worse genetic barrier but PIs have a better genetic barrier), may have been paired with an NRTI backbone already compromised by prior failures. This seems to be substantiated by the preliminary observation that the RAL failures, much more so than the LPV/r failures, had many NRTI- and NNRTI-associated resistance mutations. We know from some of Merck's early phase 2 work and the patients in the BENCHMRK studies with fewer active drugs in their optimized background regimens that in such a setting RAL is not as effective as it is when used with at least 2 fully active drugs. It will be interesting to see what future sub-analyses of the SWITCHMRK studies show. It is purely speculative but intriguing to contemplate how the outcome may have been different had RAL been substituted not for the anchor drug of the regimen but rather for its potentially compromised nucleoside backbone.
Switching from Stable Lopinavir/Ritonavir (LPV/r)-Based to Raltegravir (RAL)-Based Combination Antiretroviral Therapy (ART) Resulted In a Superior Lipid Profile at Week 12 but Did Not Demonstrate Non-Inferior Virologic Efficacy at Week 24 (SWITCHMRK) - (02/11/09)
On the other hand, there are settings in which it might be safer to make RAL switches. The French ANRS 138 study randomized 170 patients with triple-class resistant HIV on an ENF-containing regimen for at least 3 months and with HIV RNA <400 c/ml to either stay on ENF (n=85) or substitute the ENF with RAL (n=84) [2]. Baseline patient characteristics were similar for both groups; it should be noted that this was a heavily pre-treated patient population with a median prior HAART and ENF exposure of 13.6 and 2.3 years, respectively. Through week 24 (ITT analysis), only 1 failure (HIV RNA >500 c/ml) occurred in each of the treatment arms and 89% of patients in both arms had HIV RNA <50 c/ml. Why such a big difference in outcome compared to SWITCHMRK? As stated previously, what is critical for RAL's efficacy seems to be its association with enough active drugs. For patients well suppressed on an ENF-containing regimen for a long period of time, it would be logical to assume that the other components of the regimen are substantially contributing to antiretroviral activity. Thus, substitution of active ENF with active RAL would be a safe and effective one-for-one switch.
Results for the RAL BENCHMRK-1 and-2 studies after 96 weeks of follow-up were also presented [3]. The previous data set had been from the 48 week follow-up presented at ICAAC in the fall of 2008. This study has been nicely summarized by Jules Levin at the NATAP website so I will mostly focus on what I believe are the take home messages. The good response observed at 24 and 48 weeks continued to be evident at 96 weeks (NC=F analysis): 57% (RAL) vs. 26% (placebo) and 62% (RAL) vs. 28% (placebo) maintain HIV RNA <50 c/ml (p<0.001) and <400 c/ml (p<0.001), respectively. The change from baseline in CD4+ cell counts also favored RAL (+123) compared to placebo (+49) (p<0.001). Thus, RAL does seem to be a good option for the management of these treatment-experienced patients. However, previous sub-analyses have shown a critical element in all this that bears repeating: the more active agents in the optimized background regimen (with the critical number being at least 2), the more likely the RAL-based regimen will be virologically suppressive.
96-Week Results from BENCHMRK 1&2, Phase III Studies of Raltegravir (RAL) in Patients (pts) Failing Antiretroviral Therapy (ART) with Triple-Class Resistant HIV - (02/12/09)
There is a growing body of evidence that suggests there might be a connection between the use of abacavir (ABC) and cardiovascular disease (discussed at length in a CROI newsletter on cardiovascular and metabolic issues by my colleague Pablo Tebas), and the efficacy of ABC in patients with viral loads >100,000 c/ml has recently come into question. Nonetheless, because there is still considerable controversy surrounding this topic, studies are still being conducted in which ABC is part of the NRTI backbone. One such study was presented by David Cooper and colleagues, the Simplification with fixed-dose Tenofovir/Emtricitabine or Abacavir/Lamivudine (STEAL) study [4]. This switch study has also been nicely summarized at the NATAP website so I will not go into all the details. In short, patients with HIV RNA <50 c/ml were randomized to substitute the NRTIs in their ART regimen with either tenofovir/emtricitabine (TDF/FTC) (n=178) or ABC/lamivudine (3TC) (n=179), both as fixed dose combinations. Baseline characteristics were evenly matched except for smoking that was more prevalent among the patients switching to ABC/3TC (40%) than among those switching to TDF/FTC (29%). After 96 weeks of follow-up, the virologic efficacy and protection against death and progression to AIDS was similar for both treatment arms. However, even in this small number of patients followed for a relatively short period of time there was a trend for fewer ischemic cardiovascular events among the TDF/FTC-treated patients (1 vs. 7 events per 100 patient-years of follow up; HR 0.15 [95% CI 0.02, 1.15]; p=0.067). On the other hand, there was less bone loss as determined by hip T-scores among the ABC/3TC-treated patients (0.09 vs. -0.07; HR 0.16 [95% CI 0.08, 0.23]; p<0.0001). Thus, while these findings are not novel, they reinforce our perception that ABC is associated with a greater frequency of cardiovascular diseases while TDF is associated with disorders of bone metabolism.
SIMPLIFICATION WITH FIXED-DOSE TENOFOVIR-EMTRICITABINE OR ABACAVIRLAMIVUDINE IN ADULTS WITH SUPPRESSED HIV REPLICATION (THE STEAL STUDY): A RANDOMIZED, OPEN-LABEL, 96-WEEK, NON-INFERIORITY TRIAL - (02/18/09)
It is well-known that not all patients who start antiretroviral therapy have adequate immune restoration despite having a good virological response to antiretroviral therapy. The most recent update to the DHHS antiretroviral treatment guidelines for adults define immunologic failure on antiretroviral therapy as the inability to increase CD4+ cell counts by more than 25-50 cells/mm3 over the baseline in the first year of therapy despite having an undetectable viral load. This failure to have adequate immune reconstitution is critical as several studies have shown that such a discordant response is associated with an increased risk of opportunistic diseases, non-AIDS-related serious events, and mortality. In recognition of this, studies were begun almost a decade ago to determine if administration of IL-2, known to be associated with increases in CD4+ cell counts and especially of long-lived naïve and central memory cells, could also be associated with a lower rate of clinical complications.
Results of the Evaluation of Subcutaneous Proleukin in a Randomized International Trial (ESPRIT) were presented at the conference [5]. Over 4,000 patients at 252 sites in 25 countries (two-thirds of them in Europe and North America) who were taking ART with CD4+ counts ≥300 cells/mm3 were randomized to receive IL-2 (n=2071) or serve as control subjects (n=2040). Both groups continued their ART. The individuals in the IL-2 group received 7.5 million IUs subcutaneously twice daily for 5 days. These individuals then went on to receive 3 cycles of IL-2 with a rest period of 8 weeks. Additional cycles could be given in order to maintain a CD4+ cell count twice the baseline level or ≥1000 cells/mm3. The other group did not receive IL-2 but was followed just like the intervention group. The primary endpoint of the study was the number of opportunistic diseases or deaths occurring in each study group. Other key endpoints were grade 4 clinical adverse events, serious non-AIDS events, and death from non-AIDS causes. It was estimated that 320 primary events would have to be observed in order to detect a difference in outcomes by treatment group. The study was opened to enrollment in March of 2000 and closed on November 15th, 2008, after 323 events had been observed over a median follow-up time of 7 years. Baseline demographic and disease characteristics of both groups of patients were evenly matched with a median CD4+ cell count of 457 cells/mm3, a median nadir CD4+ cell count of 197 cells/mm3, 80% of patients with an HIV RNA ≦ 500 c/ml, and 26% of patients with a prior clinical diagnosis of AIDS. The average difference in CD4+ cell count during follow-up was 160 cells/mm3 in favor of the IL-2 recipients. However, the rate of opportunistic disease or death per 100 person-years of follow-up among the IL-2 recipients was 1.13 and among the control subjects was 1.21. Thus, the hazard ratio (HR) for the primary endpoint for the IL-2 recipients was 0.93 (95% CI 0.75, 1.16; p=0.52). In similar fashion, there did not seem to be a statistically significant protective effect for the secondary endpoints. On the other hand, the HR for general and administration site effects (such as fever, malaise, and injection site reactions) and for vascular events (such as deep venous thromboses) were higher (1.92 [p=0.01] and 2.82 [p≦0.001], respectively) for the IL-2 recipients. Thus, while IL-2 administration did produce a substantial and sustained increase in CD4+ cells, there was no clinical benefit to this and there certainly was a higher frequency of side effects. It was not clear to the investigators why this was so, but among the theories postulated was that IL-2 might expand CD4+ cells that are not functionally equivalent to CD4+ cells under different circumstances or that there may be harmful effects of IL-2 that counterbalance its beneficial effects.
The Subcutaneous Interleukin-2 in HIV-Infected Patients with Low CD4+ Counts Under Active Antiretroviral Therapy (SILCAAT) trial was a sister study to the ESPRIT trial begun a year later in March of 2001 [6]. SILCAAT was different in that it was intended for subjects with lower CD4+ cell counts (50-299 cells/mm3) while on ART. Subjects randomized to receive IL-2 (n=849) did so at a dose 4.5 million IUs subcutaneously twice daily for 5 days in 6 cycles, each 8 weeks apart. Additional cycles could be given in order to maintain a target goal of a 150 CD4+ cell increase over the baseline value. Control subjects (n=846) continued ART just like the IL-2 recipients but obviously were not treated with IL-2. Just as in ESPRIT, the main study endpoint was the development of an opportunistic disease or death and secondary endpoints were all cause mortality, fatal and non-fatal opportunistic diseases, and grade 4 clinical adverse events. It was estimated that 300 primary events would have to be observed in order to assess the efficacy of the intervention. However, the study was closed after 227 primary events on November 15, 2008, at the same time ESPRIT was closed. A total of 139 sties in 11 countries participated with almost 80% of the enrollment coming from Europe and North America. As in ESPRIT, baseline characteristics of the 2 study groups were almost identical with a median CD4+ count of 202 cells/mm3, a median nadir CD4+ count of 60 cells/mm3, 81% of patients with HIV RNA ≦500 c/ml, and 33% of patients with a prior diagnosis of AIDS. The median number of cycles received was 7-8. The average difference in CD4+ count during follow-up was 59 cells/mm3 in favor of the IL-2-treated patients (p<0.001). The rate of the primary endpoint was 1.92 vs. 2.12 events per 100 person years of follow-up among the control subjects (HR0.91, 95% CI 0.70-1.18; p =0.47). The most frequent opportunistic diseases were esophageal candidiasis, non-Hodgkin's lymphoma, and Pneumocystis jiroveci pneumonia. The rate of grade 4 events was, once more, higher for the IL-2-treated patients than for the control subjects but only during the first year of follow-up (2.69 vs. 2.32 events per 100 years of follow-up). This led the authors to conclude that while IL-2 raises CD4+ cell counts, it does not reduce the rates of clinical outcomes compared to ART alone suggesting that CD4+ cells expanded under IL-2 are qualitatively different from CD4+ cells generated by ART.
What do these 2 studies mean for the practicing clinician? Unfortunately, it does not seem as if going forward IL-2 will be a viable strategy for the prevention of clinical progression of HIV infection. IL-2 undoubtedly raises CD4+ cell levels and we have known this for many years; however, it is now evident that this comes at a great cost in side effects, patient commitment, and financial investment and, at the end of the day, there is no measurable clinical impact.
1. 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]. 16th Conference on Retroviruses and Opportunistic Infections. Montreal, Quebec, February 8-11, 2009.
2. De Castro N, Braun J, Charreau I, et al. Switch from enfuvirtide to raltegravir in highly treatement experienced HIV-1-infected patients: a randomized open-label non-inferiority trial, EASIER - ANRS 138. [Abstract 572]. 16th Conference on Retroviruses and Opportunistic Infections. Montreal, Quebec, February 8-11, 2009.
3. Steigbigel R, Cooper D, Eron J, et al. 96-week results from BENCHMRK 1 and 2, phase III studies of raltegravir in patients failing ART with triple-class-resistant HIV. [Abstract 571B]. 16th Conference on Retroviruses and Opportunistic Infections. Montreal, Quebec, February 8-11, 2009.
4. Cooper D, Bloch M, Humphries A, et al. Simplification with fixed-dose tenofovir/emtricitabine or abacavir/lamivudine in adults with suppressed HIV replication: the STEAL study, a randomized, open-label, 96-week, non-inferiority trial. [Abstract 576]. 16th Conference on Retroviruses and Opportunistic Infections. Montreal, Quebec, February 8-11, 2009.
5. Losso M, Abrams D, INSIGHT ESPRIT Study Group. Effect of interleukin-2 on clinical outcomes in patients with a CD4+cell count of 300/mm3: Primary results of the ESPRIT study. [Abstract 90aLB]. 16th Conference on Retroviruses and Opportunistic Infections. Montreal, Quebec, February 8-11, 2009.
6. Levy Y, SILCAAT Scientific Committee. Effect of interleukin-2 on clinical outcomes in patients with CD4+ cell count 50 to 299/mm3: Primary results of the SILCAAT study. [Abstract 90bLB]. 16th Conference on Retroviruses and Opportunistic Infections. Montreal, Quebec, February 8-11, 2009.
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