CCR5 Antagonists (Maraviroc and Vicriviroc)
CCR5 antagonists block viral binding to the CCR5 chemokine coreceptor. Several CCR5 antagonists have been tested in clinical trials.
In August 2007, maraviroc was approved for use in multidrug-resistant patients with R5-only virus. A phase IIb/III trial of this agent in treatment-experienced patients has been reported.[4,5] A phase IIb/III study of maraviroc in treatment‑naive patients with R5 virus has also been performed, and 48-week results were recently reported.[6]
A second CCR5 antagonist in development is vicriviroc. Week 48 phase IIb data from studies in treatment‑experienced patients with R5 virus have been presented.[7] Phase IIb studies in treatment‑naive patients were stopped by the data and safety monitoring board because of decreased efficacy vs efavirenz‑based therapy and an increased rate of viral tropism change among patients receiving vicriviroc.[8]
Advantages and Disadvantages of CCR5 Antagonists
Based on the data currently available for treatment with CCR5 antagonists, there appear to be certain advantages and disadvantages associated with their use. At this time, efficacy data for these agents show a clear advantage over placebo in treatment-experienced individuals who have R5-only virus detected at entry. Indeed, there are numerous reasons to consider using CCR5 antagonists in the later stages of disease. There will likely be no cross-resistance with other available agents such as NRTIs, NNRTIs, PIs, or enfuvirtide. CCR5 antagonists seem to be well tolerated and are orally administered.
Despite these advantages, data have shown that treatment-experienced patients who are in later stages of disease are more likely to have D/M or X4 virus, a setting in which these drugs have not shown antiretroviral activity. For any individual patient, there may be only a specific window of opportunity to benefit from one of these agents while he or she has R5 virus only, with the chance that D/M or X4-only virus will emerge over time. By contrast, other classes of antiretroviral drugs typically only lose activity when agents from the class are used and resistance develops. It is important to recognize that although short-term safety has been demonstrated in studies to date, it remains possible that pharmacologic blockade of CCR5 may have adverse consequences that become apparent only after long-term use of these drugs. The safety aspects of these drugs as well as the consequences of resistance development need to be assessed with long-term use. There may also be the concern about the emergence of D/M or X4 virus with CCR5 antagonist therapy. Finally, use of these agents will require a test for viral tropism, incurring additional cost.
Integrase Inhibitors
Integrase inhibitors target the viral integrase enzyme, which plays a critical role in the viral life cycle, as discussed in the accompanying module by Daniel R. Kuritzkes, MD. Although integrase inhibitors focus on a novel target enzyme, the principle of enzyme inhibition has been the most commonly used mechanism of antiretroviral therapy. Therefore, evaluating response to these agents should be more straightforward than evaluating agents with other mechanisms of action.
The integrase inhibitors that are the furthest in clinical trial development are raltegravir (formerly MK-0518) and elvitegravir (formerly GS9137). Currently, phase III trials of raltegravir in treatment‑naive and treatment-experienced patients are ongoing, and at the time of writing is being considered by the US Food and Drug Administration (FDA) for approval for use in treatment-experienced patients. Elvitegravir is in phase II development for treatment‑experienced patients.
There are significant differences between these 2 compounds. Raltegravir is metabolized by glucuronidation; therefore, while there are interactions with drugs that are metabolized by the CYP450 system, interactions with that have been observed with other PIs and NNRTIs are not thought to be clinically relevant. By contrast, elvitegravir is metabolized by CYP3A4 and may therefore have significant interactions with other antiretrovirals including PIs, NNRTIs, and possibly CCR5 antagonists. Elvitegravir can be pharmacologically boosted with ritonavir, allowing once-daily dosing, whereas raltegravir must be administered twice daily.
Integrase Inhibitors: Advantages and Disadvantages
The advantages of agents in the integrase inhibitor class are clear. It is a novel class with no known cross‑resistance with other agents. The agents act synergistically in combination with approved agents, at least in vitro. They target the third essential enzyme of HIV. Finally, these drugs can be given orally.
Regarding disadvantages, there are no long‑term data on adverse effects since these agents are relatively new and relatively few patients have been treated to date. Virologic failure appears to be associated with a high likelihood of the emergence of resistance mutations. Moreover, available evidence, although limited to date, suggests that considerable cross-resistance exists between raltegravir and elvitegravir.[20,21] A recent case report described 2 patients who switched from elvitegravir/ritonavir to raltegravir after virologic failure, but experienced no significant reduction in HIV-1 RNA level (Capsule Summary).[22] It is clear that these drugs should be combined with an effective OBR to minimize the risk of resistance and potential cross‑resistance
How Will We Use New Agents in Treatment-Experienced Patients?
Maraviroc has been approved for use in treatment-experienced patients; therefore, candidates for therapy will typically be those with more advanced stages of disease who are more likely to have D/M or X4 virus, a setting in which CCR5 antagonists are likely to have reduced or no activity. Another challenge is that it will be difficult to consider switching to maraviroc as a replacement for other agents in patients whose HIV-1 RNA is suppressed, because testing for viral tropism requires detectable viremia. Therefore, maraviroc is most appropriate for the subset of treatment-experienced patients who are experiencing virologic failure on existing therapy, who have no detectable D/M or X4 virus on a screening test for viral tropism, and who have other active agents available to use as part of an OBR.
Individuals who are treatment naive, on the other hand, are less likely to have a D/M-tropic or X4 virus and, therefore, have a better chance of being candidates for CCR5 antagonist therapy. However, in the recently reported results of the MERIT trial, maraviroc failed to meet criteria for noninferiority to efavirenz for the primary endpoint of HIV-1 RNA < 50 copies/mL. Likewise, a trial of vicriviroc was halted because of inferior efficacy compared with efavirenz in treatment-naive patients. These data suggest that further investigation of the use of maraviroc and vicriviroc in treatment-naive patients maybe needed before they can be considered for use in this patient population Integrase inhibitors will initially be used for treatment-experienced patients because the largest data sets involve this population of patients. Studies in treatment-naive individuals are also under way, and preliminary data certainly suggest that there may be a role for this class of drugs in these patients. Unlike CCR5 antagonists, there appear to be no specific considerations that argue for earlier or later therapy, since agents in this class should be effective regardless of when the agents are used. Dosing issues may affect the use of integrase inhibitors as initial therapy. For example, raltegravir, the drug that is in the most advanced stage of clinical development, is dosed twice daily whereas once‑daily options are generally favored in the earlier stages of disease and, indeed, throughout treatment. Although elvitegravir is a once-daily drug and can be given with ritonavir, the implications of the use of low-dose ritonavir without another PI must be considered. There is little experience with this particular situation, and the potential risk of selecting for PI resistance if virologic failure occurs must be explored in the future. Consistent with general principles, this class of drugs will be most active when used in conjunction with other active drugs. Therefore, strategic thinking is necessary when considering the introduction of novel drugs into treatment regimens. It is crucial to preserve as many active drugs as possible and to combine these with new drugs, hopefully enabling us to achieve undetectable HIV-1 RNA even in the most treatment‑experienced patients, as recommended in the US Department of Health and Human Services and the International AIDS Society-USA guidelines. Etravirine, a new second-generation NNRTI, has demonstrated potent activity when combined with other active agents in patients who have experienced virologic failure while receiving efavirenz or nevirapine. Patients who may benefit most from this drug are those who stopped NNRTI-based therapy in the past after developing only 1 or 2 NNRTI resistance mutations, or patients who were not considered candidates for NNRTI-based therapy because of transmitted NNRTI-resistant virus. Those with a greater number of NNRTI mutations may derive less benefit from this agent. The recently reported mutation score may help in identifying which individual patients are most appropriate for this agent. Furthermore, the resistance data emphasize the importance of discontinuing the use of currently approved NNRTIs in a failing regimen to minimize the risk of accumulating multiple NNRTI resistance mutations and developing cross-resistance to next-generation agents. Finally, studies of etravirine have underscored the importance of having an adequate background regimen when using any new and potentially active drug.