Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

MEDICAL FRONTIERS - 17th Conference on Retroviruses and Opportunistic Infections (CROI)

San Francisco, California / February 16-19, 2010

The concept of treating HIV with compounds that can prevent the virus from entering target immune cells, thereby aborting the viral replication cycle, is extremely attractive. The first approved agent to employ this strategy was the entry inhibitor enfuvirtide which requires injection. The second was maraviroc (MVC), an oral agent that blocks the CCR5 receptor, which is by far the most important of the two employed by HIV for infection. Prior to the use of CCR5 antagonists, patients must be screened to confirm CCR5 tropism, which signals the presence of HIV using the CCR5 receptor (R5 virus). New data with improved tropism assays than those employed initially demonstrate extremely durable HIV suppression.

As opposed to virus that employs the CXCR4 co-receptor (X4 virus) or both co-receptors (dual or mixed tropic virus), an estimated 85% of treatment-naïve patients have R5 virus, with rates being lower with very low CD4+ cell counts and climbing to nearly 95% in those with CD4+ cell counts greater than 300 cells/mm3. However, it is important to screen patients for receptor tropism prior to initiating a CCR5 antagonist because these drugs are less effective against virus strains capable of employing the CXCR4 receptor. This has now been demonstrated vividly with initial and later subsequent analyses of the registrational MOTIVATE (Maraviroc versus Placebo) and MERIT (Maraviroc versus Efavirenz Regimens as Initial Therapy) studies. In the MERIT trial, a high proportion of those randomized to the CCR5 antagonist MVC achieved undetectable viremia, but the proportion was less than that achieved in the group randomized to efavirenz (EFV). It is now clear that the assay used in that study failed to adequately screen out virus capable of using the X4 co-receptor.

Virologic Response

In a study led by investigators at the British Columbia (BC) Centre for Excellence in HIV/AIDS, Vancouver, and presented by Dr. Rachel McGovern, the same findings were again generated using a completely different assay for tropism. In this study, plasma samples from patients participating in the MERIT study were re-evaluated using population-based V3-loop sequencing of the HIV env, which involves amplifying and then sequencing the DNA with automated base-calling software that can infer co-receptor tropism. When blinded to the clinical data, the investigators found that the response rates on MVC-based and EFV-based therapy were indistinguishable from those with R5 virus.

“The population-based V3-loop sequencing performed similarly to the enhanced sensitivity Trofile assay (ESTA) in terms of predicting the MVC response,” reported Dr. McGovern. At 48 weeks, the proportion of patients with a viral load <50 copies/mL on MVC compared to EFV was statistically indistinguishable in those with R5 virus, unlike those with non-R5 virus (Figure 1). At least as impressive, a graph of the viral load reduction shows very comparable reductions for EFV and MVC even when MVC was administered once-daily (Figure 2).

Figure 1.

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Figure 2.

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In another study led by Dr. Luke C. Swenson, also of the BC Centre for Excellence in HIV/AIDS, yet another method of tropism screening repeated the conclusion that MVC and EFV cannot be distinguished for relative efficacy when compared in patients effectively selected for having R5 virus. In this study, deep sequencing using 454 technology was employed to determine tropism. Unlike the population-based V3 sequencing used in the study presented by Dr. McGovern, deep sequencing quantifies minority HIV variants on the V3 loop of an individual. This approach was employed to re-evaluate the plasma samples of the MVC treatment arms of the MERIT study, which recruited treatment-naive patients, and the MOTIVATE 1 and 2 (Maraviroc versus Optimized Therapy in Viremic Antiretroviral Treatment-Experienced Patients) trials. Again, the tropism could be reclassified in a substantial number of patients using this more sensitive test.

As in the other studies reported to date in which assay results were discordant with the original Trofile, “Virologic outcomes were better predicted by deep V3 sequencing and ESTA,” noted Dr. Swenson. A substantial number of tropism changes were reported in the original study based on the original Trofile assay. However, a re-analysis with the more sensitive ESTA or deep sequencing assays has demonstrated that changes in co-receptor preference are relatively rare for treatment-naive patients and occur in only a small proportion of treatment-experienced patients even when followed long-term.

Like the data reported by Dr. McGovern, MVC compared well to EFV in the MERIT study when re-evaluated with the deep sequencing tropism assay even among those randomized to q.d. therapy. This suggests that q.d. therapy may remain a viable option for those who want a simplified regimen. “The MVC q.d. arm in MERIT was originally discontinued because it did not meet protocol-defined criteria for non-inferiority to EFV. Re-analysis by deep sequencing appears to give similar results for those two arms [<400 copies/mL in 80% of patients randomized to MVC vs. 78% of patients randomized to EFV at week 16]. This held for the analysis censored to only include patients remaining on MVC q.d. and was similar for the uncensored analysis that included pat
MVC b.i.d.,” Dr. Swenson told delegates (Figure 3).

Figure 3.

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While these results are expected to encourage development of other antiretroviral therapies (ARTs) within this class, faster and cheaper testing for tropism based on blood samples will also encourage more physicians to employ these agents. Such tests are imminent, according to Dr. Richard Harrigan, BC Centre for Excellence in HIV/AIDS, senior author of the studies presented by Drs. McGovern and Swenson. Although testing will still be performed by specialized laboratories, the same facilities that now conduct resistance testing in Canada will be able to classify tropism. When samples are submitted for resistance testing, tropism testing will be included simply by checking the appropriate box.

Of the CCR5 antagonists still in clinical testing, vicriviroc (VCV) is the most advanced, but new data from a phase III study may have set back the release of this agent because of a study design that randomized 857 patients to VCV or placebo after they were placed on an optimized background therapy (OBT) with at least three fully active agents. Although patients were required to be resistant to at least two ART drug classes at entry, the study was perhaps more useful for demonstrating that there is no additional benefit from adding an agent to a fully active three-drug combination than evaluating the efficacy of VCV. According to presenter Dr. Joseph Gathe, Therapeutic Concepts, Houston, Texas, additional studies are now needed to focus on the potential of VCV in those who are on two or fewer active ARTs.

Several studies are also evaluating CCR5 antagonists for their potential to boost immune reconstitution. In one such study presented by investigators from Weill Cornell Medical College, 34 patients on a stable and effective ART regimen were treated with MVC. All had CD4+ cell counts less than 250 cells/mm3. The median count was 153 cells/mm3. After 22 weeks of therapy, the median increase in CD4+ cell count was 11 cells/mm3, which was less than 20 cells/mm3 that the investigators had identified prior to the study as a benchmark for benefit. However, two patients had a CD4+ cell count increase of at least 50 cells/mm3. Further studies appear to be warranted.

The potential for CCR5 antagonists to intensify immune activation is particularly intriguing on the basis of new information that patients with HIV have a higher risk of non-AIDS-defining cancers, including lung cancer and Hodgkin’s lymphoma, than those without HIV. In a large case-control study of 20,277 HIV patients and 202,313 age- and sex-matched controls, there was a strong correlation between CD4+ cell nadir and risk of non-AIDS-defining cancers.

“The impaired immune system in patients with HIV independently increases risk of anal cancer, lung cancer, Hodgkin’s lymphoma and oral/pharynx cancer, suggesting earlier intervention to maintain higher CD4+ cell levels may be important,” reported Dr. Michael Silverberg, Kaiser Permanente HIV Initiative, Oakland, California. Although he did not refer specifically to the role of CCR5 inhibitors, the effect of this class on immunologic defenses is consistent with this potential goal.

Another clinical feature of growing interest is the ability of CCR5 antagonists to reach body compartments not equally well penetrated by other ARTs. In a small study of 12 patients taking an MVC-containing ART regimen, samples from the cerebrospinal fluid (CSF) and semen confirmed high inhibitory concentrations (IC). While high concentrations in semen may prevent spread of infection, high concentrations in the CSF may reduce neurological sequelae, particularly cognitive loss, according to several recent studies evaluating this phenomenon.

“MVC achieves levels in CSF within the range of IC50 [50% inhibitory concentration] or higher, suggesting that regimens containing this agent may be of benefit in treating or preventing HIV-related neurological disorders,” reported Dr. Juan Manuel Tiraboschi, Hospital Universitario Bellvitge, Barcelona, Spain.

Summary

Simpler and more sensitive tropism testing is expected to greatly boost the clinical use of CCR5 antagonists as a tool in the control of HIV. These agents are well tolerated, have a unique resistance profile and have now been shown to provide efficacy commensurate with other highly potent ARTs when administered to patients screened for R5 virus with newer, more advanced assays. The potential for these agents to prevent HIV infection is at a very early stage of analysis, but this avenue of research underscores the unique quality of entry inhibition, which halts HIV replication before it occurs. This mechanism may in part explain the association of these agents with a greater increase in immune reconstitution than has been observed with other potent ARTs.

Questions and Answers

The following section is based on an interview with Dr. Richard Harrigan, BC Centre for Excellence in HIV/AIDS, Vancouver, during the CROI scientific sessions.

Q: Do the studies presented by your group demonstrate that MVC is non-inferior to EFV?

Dr. Harrigan: The studies that have re-evaluated the MERIT study data with more sensitive assays for R5, including ours, have consistently shown that MVC and EFV performed very similarly for standard measures of ART effect, including viral load reductions and the proportion of patients who achieve and sustain undetectable viral loads on treatment. The fact that the same results have been generated using different methods is compelling.

Q: One of the intriguing results is that even q.d. MVC seems to do as well as EFV when patients are better screened for the R5 virus.

Dr. Harrigan: It is unfortunate that we do not have long-term q.d. data so that we could evaluate a sustained effect, but it is true that the q.d. arm seems to be providing the same degree of ART effect as the b.i.d. arm over the 16 weeks for which we have data. Once-daily MVC may be effective based on the data we have, but we need the longer-term follow-up to draw any conclusions about the significance for clinical practice.

Q: Currently, tropism testing requires sending blood samples to the US. Do you think this has been an obstacle to using MVC?

Dr. Harrigan: I don’t know if physicians are less likely to use this agent in a good candidate because they need to send off samples for tropism testing, but it will be easier when the testing can be done by the same laboratories that now do resistance testing. Although this still means sending off a blood sample for most Canadian physicians, we are now routinely performing resistance testing on most patients, so it will be just a matter of asking for the additional result, and physicians will get the tropism result and the resistance back together.

Q: Do you think there is a need to be concerned about pushing more HIV to select for X4 virus by greater use of CCR5 antagonists?

Dr. Harrigan: The resistance associated with MVC has not been generally driven by receptor switches. Even in highly treatment-experienced patients, the new assays for R5 virus have demonstrated that many of the switches reported previously were actually cases of dual or mixed virus at the time treatment was initiated. Tropism change in patients with sustained viral load reductions on these agents does not appear to be an important threat to their efficacy.