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Management of Treatment-Experienced Patients: darunavir, raltegravir, raltegravir intensification, maraviroc, vicriviroc
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17th Conference on Retroviruses and Opportunistic Infections
San Francisco, California, February 16-19, 2010
Rafael E. Campo, MD
Professor of Clinical Medicine
Division of Infectious Diseases
University of Miami Leonard M. Miller School of Medicine
Miami, Florida
Abbreviations used
CI - confidence interval
c/ml - copies/milliliter
HAART - highly active antiretroviral therapy
ITT - intent to treat
NC=F - non-completer=failure
NRTI - nucleoside reverse transcriptase inhibitor
NNRTI - non-nucleoside reverse transcriptase inhibitor
OBT - optimized background treatment
PI - protease inhibitor
PP - per protocol
TLOVR - time to loss of virologic response
The recently concluded 17th Conference on Retroviruses and Opportunistic Infections had one of the smallest numbers of reports of antiretroviral trials for both naïve and experienced HIV-infected patients in several years. Perhaps this is a reflection of the fact that a large number of antiretroviral agents have been approved in the last few years and, drug discovery being somewhat cyclical, this has left the pipeline relatively empty. It could also be that we have achieved such high level of success with first-line therapies because of so many good options for naïve patients that second-line and subsequent therapies are less critically needed than before. Certainly, our understanding of viral dynamics, drug selection pressures, and the appropriate pairing of new agents with enough other active agents is quite thorough and has led to far fewer and far less complicated cases of antiretroviral resistance. The 2 major themes presented at the conference were standard clinical trials of new and relatively new antiretroviral agents for the management of extensively-experienced patients and intensification studies with a variety of agents for patients with persistent immunologic activation and suboptimal restoration of CD4+ cell counts.
Pedro Cahn and colleagues presented 48-week follow up data of the ODIN trial, a comparison of once daily darunavir/ritonavir (DRV/r; 800/100 mg) vs. twice daily DRV/r (600/100 mg) in treatment-experienced patients who also received an OBT regimen that consisted of at least 2 NRTIs.1 One of the critical entry criteria was the requirement for subjects not to have any DRV resistance associated mutations (V11I, V32I, L33F, I47V, I50V, I54L, I54M, T74P, L76V, I84V, L89V) if they had previously failed a PI-containing regimen. This requirement was met in all patients; in fact, approximately 46% of subjects had not been exposed previously to a PI. The details of the trial have been reviewed on this website by Jules Levin so I will greatly summarize the results. In short, the study found that 48-week response rates (VL <50 c/ml) were similar for the once-daily (72.1%) and the twice-daily (70.9%) arm (difference 1.2%; 95% CI -6.1%, 8.5%) by an ITT-TLOVR analysis. Rates of discontinuation for the usual reasons (adverse events, viral failure, loss to follow-up, etc.) were similar for both arms. Also, the twice-daily and once-daily arms were comparable with regards to the frequency of grade 2-4 gastrointestinal side effects such as nausea, vomiting, and diarrhea. The incidence of grade 2-4 lipid (primarily total cholesterol and triglyceride) elevations with once-daily DRV/r was approximately half of that seen with twice-daily DRV/r. Of the viral failures, only one patient (once-daily arm) developed a primary PI resistance-associated mutation and very low numbers (9.8-11.9%) developed NRTI resistance consistent with what is known about boosted PI failures. I think these results are not unexpected and could be summarized as follows: 1) for uncomplicated failures of first-line ART regimens without significant PI resistance, once-daily DRV/r is adequate; 2) once-daily boosted PI regimens with low ritonavir content are associated with fewer lipid disturbances, and; 3) failure of newer boosted-PI regimens continue to be associated with rare selection of resistance to PIs and much less frequent selection of resistance to NRTIs than failure of an NNRTI-NRTI regimen.
CROI: ODIN: efficacy and safety at 48 weeks of once-daily versus twice-daily darunavir/ritonavir in treatment-experienced HIV-1-infected patients with no darunavir resistance-associated mutations - (02/18/10)
Joe Gathe presented the results of 2 phase 3 trials of vicriviroc (VCV) in treatment-experienced patients.2 This presentation has been nicely summarized on the NATAP website by Mark Mascolini so I will not go into all the details. The consensus of the attendees seemed to be that the results were somewhat disappointing because VCV did not show superior efficacy to an OBT regimen; however, in all honesty the failure to show superior efficacy was most likely not due to poor activity of VCV but rather to a less than optimal design of the study with OBT regimens that were "too potent" (if such a thing is even possible when treating experienced patients). Here is what happened: 30 mg of VCV was compared to placebo in a 2:1 randomization scheme in 2 identical phase 3 trials that included a total of 721 subjects. All subjects who received VCV also received a RTV-boosted PI because VCV needs RTV boosting. A large number of study participants (60%) received at least 3 active drugs as part of their OBT before even counting the VCV, and 30-40% of the OBTs included raltegravir and/or DRV/r. Thus, these were pretty robust OBTs to begin with. In view of this, I do not think the results were very surprising: at 48 weeks, there was no difference in primary outcome (VL <50 c/ml) between the VCV (64%) and placebo (62%) arms (p=0.6). It was only in a secondary analysis of individuals taking ≤2 active drugs that VCV's efficacy was appreciated relative to that of placebo with regards to VL <50 c/ml (70% vs. 55%; p=0.02). Rates of adverse events, CD4+ T-cell gains, and malignancies were comparable for the VCV and placebo arms. What does this all mean? As I stated before, I suspect there is nothing inherently wrong with VCV's potency. The problem with the trial was that the OBT was "too good" and VCV would need to be much more potent than any other ART agent currently available to demonstrate superior efficacy to placebo under those circumstances. This begs the question - why was such a design used? I think the investigators were trying to achieve the right balance between doing what is right for the subjects (giving the placebo plus OBT recipients an ethically acceptable chance of achieving an undetectable viral load) and what is right for the drug (designing a weaker OBT regimen that will allow the study drug to clearly demonstrate its antiviral contribution) and at the end of the day they erred on the side of doing what was right for the subjects. Going forward and with the wide availability of potent drugs that can be used for second and third-line failures, we clearly will need to come up with better trial designs. This is my personal opinion - I think placebo-controlled trials such as this one will no longer be adequate because it will be impossible to strike that right balance, and a better strategy will be to compare the study drug to another active agent (in this case, for instance, VCV could have been compared to maraviroc).
Raltegravir (RAL) has been used for a while in treatment-experienced patients and is now also included in the DHHS guidelines as a recommended component of first-line therapy. Follow-up 156-week data for the phase 3 registrational trials for RAL in treatment-experienced patients (the BENCHMRK studies) were presented at the conference.3 These studies have been extensively described in prior conference updates. Briefly, RAL 400 mg twice daily was compared to placebo and both were given with an OBT regimen. In prior updates the viral suppression rates associated with RAL plus OBT have been consistently superior to those of placebo plus OBT. This continues to be the case at 156 weeks with 47% of RAL recipients with a VL of <50 c/ml compared to 18% of placebo recipients (NC=F analysis). What was new to this particular update was the preliminary study of how viral suppression rates at early timepoints are associated with suppression at later timepoints. For instance, for individuals with continuous viral suppression (<50 c/ml) between weeks 16 and 48, the 48 and 96 week rates of suppression (VL <50 c/ml) were 100% and 90%, respectively. At the other end of the spectrum were individuals without viral suppression (i.e. at least one VL >400 c/ml) between weeks 16 and 48: only 17% at week 48 and 32% at week 96 had VL <50 c/ml. Thus, it would seem that adequate early suppression could be used as an indicator of a favorable long-term outcome.
There were several studies that explored the role that intensification through addition of an antiviral or antiretroviral agent may play in boosting CD4+ T-cell numbers in patients on ART with good viral suppression but a suboptimal CD4+ T-cell response. It is known that persistent T-cell (both CD4+ and CD8+) activation may blunt CD4+ T-cell recovery. Peter Hunt and colleagues presented an intriguing study of valganciclovir in this situation.4 They hypothesized that the treatment of asymptomatic cytomegalovirus (CMV) infections with valganciclovir may lead to a decrease in T-cell activation with a corresponding increase in CD4+ T-cell levels. They treated patients with evidence of CMV infection by serum antibodies with valganciclovir 900 mg or matching placebo if they also had high percentages of activated CD8+ T-cells (CD38+ HLA-DR+) and CD4+ T-cell counts <350 cells/mm3 after 1 year of suppressive ART. When comparing 14 valganciclovir treated patients to 16 placebo recipients they found that after 8 weeks of therapy, the valganciclovir recipients were invariably free of CMV in saliva, plasma, or semen while this was the case in only 44% of the placebo-treated individuals. The valganciclovir-treated individuals had a relative decrease in CD8+ T-cell activation of 23% after 8 weeks of therapy although there was no appreciable change in CD4+ T-cell count or plasma HIV viremia. It is not clear whether longer therapy might lead to a change in CD4+ T-cell counts; it certainly could be argued that 8 weeks is too short a time to really be able to assess changes in T-cell subsets. These findings are very interesting and suggest that this strategy should be pursued in larger clinical trials.
It was noted some time ago that maraviroc (MVC)-treated patients tend to have higher CD4+ T-cell increases when compared to placebo recipients even in the absence of viral suppression. Because of this, ACTG 5256 studied the effect of MVC in CD4+ T-cell values in patients with suboptimal CD4+ recovery despite sustained viral suppression.5 After adding MVC for 24 weeks to the ART regimen of 34 subjects with a median baseline CD4+ T-cell value of 153 cells/mm3, the investigators failed to find the expected rise in CD4+ T-cells despite decreases in CD8+ T-cell activation and improvements in markers of apoptosis. In my view, it is possible that follow-up of only 24 weeks may have been too short a time to appreciate whether these measured changes in activation could eventually lead to clinically relevant changes in CD4+ T-cells values. In my opinion, this is a subject that requires further study.
Lastly, there were several studies looking at the role raltegravir (RAL) intensification may play in this same kind of patient. I think they are very interesting because at first glance they seem to be suggesting different outcomes from the same kind of intensification strategy; however, it may be that the seemingly different outcomes are due to different sensitivities of different tests used to detect viral suppression.
Hatano and colleagues added either RAL 400 mg twice daily or matching placebo for 24 weeks to the ART of 30 subjects with viral suppression for at least one year.6 They intended to assess whether this strategy could lead to further viral suppression using a single copy assay (SCA). They also measured cell-associated RNA and proviral DNA levels and markers of T-cell activation in both peripheral blood and gut-associated lymphoid tissue (GALT). They found no differences in the proportion of subjects with undetectable plasma HIV RNA using the SGA. Likewise, they found no differences in proviral DNA, cell-associated RNA, or blood or GALT CD4+ or CD8+ T-cell activation. This led them to conclude that cryptic, low-level viral replication was unlikely to account for the suboptimal CD4+ T-cell response.
On the other hand, Buzon and colleagues found that addition of RAL to the ART of 45 subjects with undetectable HIV RNA for >1 year was associated with increases of episomes (a byproduct of ineffective chromosomal integration of proviral DNA and thus a marker of ongoing low-grade viral replication) and decreases in CD8+ T-cell activation in 29% of these individuals compared to no changes in these markers in 21 subjects without intensification. Interestingly and in concordance with the Hatano study, neither group had changes in proviral DNA levels or viral loads determined by SCA.
How to interpret these results? It seems to me that the episome assay may be a more sensitive marker of ongoing, low-level viral replication. The SCA may have failed to detect ongoing replication because even the ability to detect up to one viral genome per ml of blood may be too insensitive as a marker of cryptic viral replication. The episomal assay may be a much more sensitive marker. Certainly, these findings are interesting and, in my opinion, justify further intensification studies in these kinds of patients.
1. Cahn P, Fourie J, Grinsztejn B, et al. Efficacy and safety at 48 weeks of once-daily vs. twice daily DRV/r in treatment-experienced HIV-1+ patients with no DRV resistance-associated mutations: the ODIN trial. [Abstract 57]. 17th Conference on Retroviruses and Opportunistic Infections. San Francisco, California, February 16-19, 2010.
2. Gathe J, Diaz R, Fatkenheuer G, et al. Phase 3 trials of vicriviroc in treatment-experienced subjects demonstrate safety but not significantly superior efficacy over potent background regimens alone [Abstract 54LB]. 17th Conference on Retroviruses and Opportunistic Infections. San Francisco, California, February 16-19, 2010.
3. Eron J, Cooper D, Steigbigel R, et al. Sustained antiretroviral effect of raltegravir at week 156 in the BENCHMRK studies and exploratory analysis of late outcomes based on early virologic response [Abstract 515]. 17th Conference on Retroviruses and Opportunistic Infections. San Francisco, California, February 16-19, 2010.
4. Hunt P, Martin J, Sinclair E, et al. Valganciclovir reduces CD8+ T cell activation among HIV-infected patients with suboptimal CD4+ T cell recovery during ART [Abstract 380]. 17th Conference on Retroviruses and Opportunistic Infections. San Francisco, California, February 16-19, 2010.
5. Wilkin T, Lalama C, Tenorio A, et al. Maraviroc intensification for suboptimal CD4+ cell response despite sustained virologic suppression: ACTG 5256 [Abstract 285]. 17th Conference on Retroviruses and Opportunistic Infections. San Francisco, California, February 16-19, 2010.
6. Hatano H, Hayes T, Dahl V, et al. Raltegravir intensification in antiretroviral-treated patients exhibiting a suboptimal CD4+ T cell response [Abstract 101LB]. 17th Conference on Retroviruses and Opportunistic Infections. San Francisco, California, February 16-19, 2010.
7. Buzon MJ, Massanella M, Libre J, et al. HIV-1 replication and immune dynamics are impacted by raltegravir intensification of HAART-suppressed patients [Abstract 100LB]. 17th Conference on Retroviruses and Opportunistic Infections. San Francisco, California, February 16-19, 2010.
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