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| New Classes of Antiretrovirals: The Clinical Role of Integrase Inhi |
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Excellent update on new HIV drugs for those of you who like to read and get details..from clinical care options, a great web site that provides treatment education to clinicians.
Please feel free to email me back if you do not understand any terms or concepts.
When to Use a New Agent
In recent years, clinical management of treatment-experienced HIV-infected patients has changed. Based on the results of trials incorporating newer agents in the treatment of these patients, the goal of undetectable plasma HIV-1 RNA is achievable in an ever-increasing group of treatment-experienced patients. Both the US Department of Health and Human Services and the International AIDS Society-USA guidelines now state that virologic suppression to < 50 copies/mL is the goal of therapy for all patients, regardless of antiretroviral experience.[1,2] Antiretroviral agents currently in clinical development are expanding the selection of possible options for patients with drug-resistant HIV. These include new “second-generation” agents in current classes, as well as those in novel classes with new mechanisms of action.
Several questions should be addressed before considering the use of a new antiretroviral regimen in HIV-infected patients who have detectable viremia on their current regimen
- What is the patient’s overall prognosis if they continue on a nonsuppressive regimen?
- What are the resistance consequences of continuing such a regimen?
- When will new drugs be available? Will these drugs be active against this particular patient’s virus?
- Most importantly, are there partner agents available that could be a part of an optimized regimen capable of regaining virologic suppression?
The decision to use a new agent can be challenging. Combination therapy is always required to prevent resistance; however, multiple active agents may not be available simultaneously. A choice must often be made between the lesser of 2 evils
- Premature use of a new agent in a new regimen that may fail to achieve virologic suppression, which may then result in resistance to that drug and to other agents in the new regimen or
- Remaining on the current nonsuppressive regimen until sufficient active agents are available to construct a new regimen that is likely to be suppressive; however, while waiting, additional resistance to agents in the current regimen may accrue, which may reduce the likelihood of response to subsequent regimens
Generally, patients will require multiple active agents to achieve full viral suppression. When designing a suppressive regimen, it is important to consider all agents—approved and investigational—to which the patient’s virus might be susceptible. |
Antiretroviral Classes and New Agents in These Classes
A number of new antiretroviral agents are now in various stages of clinical development. These include new NRTIs, NNRTIs, PIs, and agents that belong to the “novel classes”—entry inhibitors, integrase inhibitors, and maturation inhibitors. The agents in phase IIb clinical trials and beyond are listed in Table 1. Also included is maraviroc, which was approved for use in multidrug-resistant patients with CCR5-tropic (R5) virus in August 2007. The agents that will be discussed in this review are etravirine, maraviroc, TNX-355, vicriviroc, elvitegravir, and raltegravir.
Table 1. New Agents for Treatment-Experienced Patients
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Entry Inhibitors
Entry is a multistep process that involves binding of the viral gp120 envelope protein to the host cell’s CD4 receptor, followed by secondary interactions with 1 of 2 chemokine receptors, CCR5 or CXCR4. This leads to fusion of the viral and cell membranes, mediated by a rearrangement in the structure of the HIV envelope transmembrane subunit, gp41. The various groups of entry inhibitors, including CD4 antagonists, chemokine receptor antagonists, and fusion inhibitors, act at various points in the entry process. The first approved agent in this class, enfuvirtide, is a fusion inhibitor that was approved for use in treatment-experienced patients in 2003.
Monoclonal Anti-CD4 Antibody
TNX-355 is a humanized monoclonal antibody that belongs to the immunoglobulin G subtype 4 class. It recognizes the second extracellular domain of the CD4 receptor (notably, not the epitope associated with gp120 binding). The exact mechanism of action of TNX-355 is unknown, but it is thought that this antibody may block viral entry through steric hindrance of the binding of gp120 and the CD4 receptor, preventing the interaction of the V3 loop of gp120 with the chemokine coreceptor. This agent is administered by IV infusion.
A phase II randomized study[3] showed that TNX-355 plus an optimized background regimen (OBR) had substantial activity (Capsule Summary). In a last-observation-carried forward analysis, patients who received TNX-355 plus OBR had a decline in HIV-1 RNA up to 0.96 log10 copies/mL at 48 weeks compared with 0.14 log10 copies/mL with placebo plus OBR (P < .001 for TNX-355 compared with placebo). Adverse events in the group that received TNX-355 were similar to placebo.
CCR5 Antagonists
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]
Clinical data on both of these agents will be discussed further in this module.
CXCR4 Antagonists
CXCR4 antagonists block binding to the CXCR4 chemokine coreceptor. There are currently no CXCR4 antagonists in late clinical development
Viral Tropism and CCR5 Antagonists
As described in the accompanying module of this program by Daniel R. Kuritzkes, MD, HIV variants have long been recognized as being either syncytium-inducing (SI) or nonsyncytium-inducing (NSI) in cell culture. The emergence of an NSI viral population to a predominantly SI population has been shown to be temporally associated with immunologic decline.[9] It is now understood that SI viruses are primarily either dual tropic (use both receptors) or use CXCR4 only (X4); NSI viruses are those that primarily use the CCR5 coreceptor (R5 viruses).
As outlined in Dr. Kuritzkes’ module, current tropism assays report the viral population as being R5 only, X4 only, or dual or mixed (D/M) tropic. Although there is no proof that D/M or X4 viruses cause disease progression, the association has raised concerns regarding the possibility that CCR5 antagonists might select for such viruses. Moreover, there have been concerns that using CCR5 antagonists in patients with detectable D/M or X4 virus could enrich these viral populations.
To address these concerns, the safety of using maraviroc in patients with detectable D/M or X4 virus was assessed in a randomized, double-blind, phase IIb safety study, A4001029 (Capsule Summary).[10] Patients who were antiretroviral-experienced and/or had multiclass-resistant virus with detectable D/M or X4 virus at the time of screening received maraviroc (150 mg once or twice daily) or placebo, both with an OBR containing at least 1 active drug. There were approximately 60 patients in each arm.
The results of study A4001029 are summarized in Table 2. The study demonstrated no significant difference in change in mean plasma HIV-1 RNA level between the patients randomized to the 2 maraviroc groups or to placebo. By contrast, maraviroc was associated with a greater increase in CD4+ cell count at Week 24 than placebo, even among those patients who had only X4 virus detected at virologic failure. No major adverse events, including malignancies, were seen.
Table 2. HIV-1 RNA and CD4+ Cell Count Change in Patients With D/M or X4 Virus Treated With Maraviroc or Placebo
Although the clinical relevance of these data is not known, it suggests that CCR5 antagonism in patients with X4 or D/M virus is not associated with adverse immunologic outcomes. These results are not definitive, but they suggest that at least over the short term, there is little risk of harm if a CCR5 antagonist is inadvertently given to a patient who has D/M-tropic virus, although no virologic benefit of the CCR5 antagonist can be expected in this setting. |
Maraviroc: Phase IIb/III Studies
Phase IIb/III Studies of Maraviroc in Treatment-Experienced Patients
In August 2007, the US Food and Drug Administration (FDA) approved maraviroc for use in multidrug-resistant patients with R5-only virus, based on 24-week data from the Maraviroc Plus Optimized Background Therapy in Viremic, ART-Experienced Patients (MOTIVATE) 1 and 2, parallel placebo-controlled phase IIb/III trials. Data from these studies were first presented at the 2007 Conference on Retroviruses and Opportunistic Infections (Capsule Summary).[4,5] MOTIVATE 1 (N = 601) was undertaken in Canada and the United States, and MOTIVATE 2 (N = 475) was performed predominantly in Europe and Australia.
Entry criteria for the study required that patients were triple‑class experienced and did not have detectable X4 or D/M virus by the phenotypic tropism assay at the time of screening. Other inclusion criteria included HIV-1 RNA ≥ 5000 copies/mL, a stable antiretroviral regimen before the study or no antiretroviral therapy for ≥ 4 weeks before enrollment, and resistance to and/or ≥ 6 months of experience with ≥ 1 agent from 3 antiretroviral classes or ≥ 2 PIs. The trial randomized patients either to placebo or to once-daily or twice-daily maraviroc at doses of 150 mg or 300 mg, all with OBR. Because maraviroc is a substrate for CYP450, there are significant drug-drug interactions with other PIs and NNRTIs that serve to increase or decrease the plasma concentration of maraviroc. Consequently, the once-daily or twice-daily 150-mg dose was used if patients were taking any ritonavir-boosted PI-based regimen or delavirdine. The 300-mg dose of maraviroc was used in those patients not receiving ritonavir or in those receiving tipranavir. The OBRs typically included 3-6 antiretroviral agents.
The patients were stratified by HIV-1 RNA < 100,000 or ≥ 100,000 copies/mL and enfuvirtide use. Patients were allowed to use all the available drugs; if they were prescribed efavirenz and nevirapine, they also had to be prescribed a PI. (It should be noted that darunavir was not yet available at the start of this trial.) The primary endpoint was change in HIV-1 RNA at Week 24. The trial is scheduled to continue through 48 weeks.
Baseline characteristics were well balanced across all groups, with median CD4+ cell counts between 150 and 182 cells/mm³; median baseline HIV-1 RNA was between 4.85 and 4.89 log10 copies/mL. Forty-two percent of patients included enfuvirtide as part of their OBRs. Forty-four percent of patients screened had detectable X4 or D/M-tropic virus and were, therefore, not eligible for the trial.
Maraviroc in combination with OBR demonstrated potent activity at each of the doses tested. At Week 24, there was an average decline in HIV-1 RNA of approximately 1.9 log10 copies/mL from baseline in both treatment arms compared with a reduction of 1 log10 copies/mL in the placebo plus OBR arm.
When analyzed for the proportion of patients with HIV-1 RNA < 400 copies/mL in an intent-to-treat, noncompleter-equals-failure analysis, results were very similar across both MOTIVATE 1 and 2, with approximately 60% of patients receiving maraviroc plus OBR achieving this endpoint vs approximately 30% in the placebo arms. There was a slight nonsignificant trend favoring the twice-daily vs once-daily maraviroc arm in this overall analysis. Likewise in both studies, approximately 40% to 50% of the maraviroc-treated patients achieved HIV-1 RNA < 50 copies/mL vs 20% to 25% in the placebo arms (Table 3). The twice-daily maraviroc dose performed slightly better than the once-daily dose but both were significantly better than placebo. The CD4+ cell count increase was also significantly higher in the maraviroc-treated arms than the placebo-treated arms.
Table 3. MOTIVATE 1 and 2: Results at Week 24[4,5]
In a pooled analysis of the 2 studies, stratified by the number of active agents in the OBR as measured by genotype/phenotype analysis at baseline, once-daily and twice-daily maraviroc doses were associated with higher rates of virologic suppression than placebo, except when there were ≥ 3 active agents in the OBR, which resulted in little difference between arms (Figure 1).
Figure 1. MOTIVATE 1 and 2: proportion of patients with HIV-1 RNA < 50 copies/mL stratified by number of active drugs in their OBRs.[4,5]
Slightly better efficacy was observed with twice-daily than with once-daily administration of maraviroc for specific patient subgroups with unfavorable treatment characteristics (Capsule Summary).[11] These subgroups included patients with HIV-1 RNA ≥ 100,000 copies/mL at screening, a CD4+ cell count < 50 cells/mm3 at baseline, or no active agents in the OBR. These results support the twice-daily administration of maraviroc, as indicated in the product labeling.
Among patients with treatment failure in whom the tropism assay was performed, the emergence of detectable D/M or X4 virus was more common among maraviroc than placebo recipients (~ 65% vs 5%, respectively). Using sensitive methods to further characterize baseline and emerging viral populations during therapy, investigators have shown that most D/M or X4 virus present at the time of virologic failure was likely to have pre-existed at low levels prior to the initiation of treatment [12] As noted earlier, one theoretical concern regarding CCR5 antagonist therapy is that selection for D/M-tropic virus in patients with treatment failure might be associated with accelerated CD4+ cell decline and disease progression, as seen in natural history studies. Although the current data are limited to only 24 weeks of follow-up, there was no evidence of a significant decline in CD4+ cell count in patients with treatment failure who had D/M or X4 virus at the time of the analysis.
Approximately 8% of patients initially found to be eligible for the study with R5-only virus at screening subsequently had D/M-tropic virus detected at baseline, before the initiation of maraviroc therapy. Although details have not been presented, investigators have commented that this subset of patients had a limited response to maraviroc therapy, similar to that seen in study A4001029 in patients with D/M-tropic virus.
In addition to the emergence of X4 or D/M virus, HIV-1 can also become resistant to maraviroc and other CCR5 antagonists. The mechanism for resistance to maraviroc has not been clearly defined, but it appears that the virus overcomes the steric hindrance related to drug binding and can use the receptor with maraviroc bound. In patients with R5-only virus who failed treatment, mutations were seen in the V3 loop, but no signature R5 mutations have been identified to date.
Maraviroc in Treatment-Naive Patients
Maraviroc has also been studied in treatment-naive patients in the Maraviroc vs Efavirenz Regimens as Initial Therapy (MERIT) study, a randomized, double-blind, multicenter phase IIb/III trial (Capsule Summary).[6] This study randomized antiretroviral-naive patients with detectable R5-only virus and HIV-1 RNA < 2000 copies/mL in a 1-to-1 fashion to receive maraviroc 300 mg twice daily or efavirenz 600 mg once daily, each combined with tenofovir and lamivudine. A third arm, maraviroc 600 mg once daily plus tenofovir and lamivudine, was discontinued at Week 16 by the data and safety monitoring board when it failed to meet criteria for noninferiority to efavirenz for the coprimary endpoint, HIV-1 RNA < 50 copies/mL.
Patients were well matched at baseline. Mean baseline HIV-1 RNA between the 2 groups was 4.87 log10 copies/mL, and the mean baseline CD4+ cell count was 247 cells/mm3.
The on-treatment noninferiority analysis included all patients who received ≥ 1 dose of study drug, with a noninferiority margin of -10% (lower bound of 1-sided 97.5% confidence interval). The primary endpoints were HIV-1 RNA < 400 and < 50 copies/mL at Week 48. At this time point, noninferiority of twice-daily maraviroc vs efavirenz was shown for the endpoint of HIV-1 RNA < 400 copies/mL (73.1% vs 70.6% [97.5% confidence interval lower bound -9.5%]) but not for the other primary endpoint of HIV-1 RNA < 50 copies/mL (69.3% vs 65.3% [97.5% confidence interval lower bound -10.9%]). Patients in the maraviroc arm had a significantly larger increase in CD4+ cell counts (170 vs 140 cells/mm3). Approximately 25% of patients in each arm discontinued, but the reasons for discontinuation were different: More patients in the efavirenz arm discontinued for adverse events (13.6%), and more in the maraviroc arm discontinued for lack of antiviral efficacy (11.9%).
Additional prespecified analyses evaluated HIV-1 RNA response based on baseline plasma HIV-1 RNA of < 100,000 or > 100,000 copies/mL, and whether the study site was in the Northern or Southern Hemisphere. Although it was reported that a significantly lower proportion of patients with a baseline HIV-1 RNA level > 100,000 achieved a plasma HIV-1 RNA of < 50 copies/mL compared with patients who had a baseline HIV-1 RNA level < 100,000 copies/mL, for reasons yet to be explained, most of the difference was observed in patients from the Southern Hemisphere. | |
Adverse Events With Maraviroc
In the MOTIVATE trials, there was no difference in the rate of adverse events between the maraviroc and placebo groups. Each group had the same low level of hepatotoxicity. With the CCR5 antagonists, there have concerns about the potential for hepatotoxicity, and one investigational CCR5 antagonist, aplaviroc, was withdrawn from development due to this adverse event. One case of maraviroc-induced hepatotoxicity with allergic features was reported in a study in healthy volunteers, and an increase in hepatic adverse events with maraviroc was observed during studies of treatment-experienced HIV-infected patients, although there was no overall increase in ACTG grade 3/4 liver function test abnormalities. Nevertheless, the complete prescribing information for maraviroc includes a black box warning about the potential for hepatotoxicity.
There was also no evidence of an increased incidence of malignancies, a potential concern raised by recent data on vicriviroc. In MOTIVATE 1 and 2, a total of 11 malignancies were reported: 3 cases of Kaposi’s sarcoma and 3 cases of lymphoma in the maraviroc arms, and 3 cases of Kaposi’s sarcoma and 2 cases of lymphoma in the placebo arms. In analyzing these safety data, one should remember that approximately 4 times as many patients were enrolled in the maraviroc arms as placebo, so the incidence of malignancies was lower in the maraviroc arms.
In the MERIT trial of treatment-naive patients, overall rates of adverse events and serious adverse events were similar in both arms, including a similar low incidence of hepatotoxicity. In this trial, malignancies also occurred at a lower rate in the maraviroc-treated patients: 2.8% vs 4.4% in the efavirenz-treated arm. Lipid elevations were more pronounced in the efavirenz arm.
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. |
Phase III Studies of Raltegravir in Treatment-Experienced Patients
The results of Blocking Integrase in Treatment Experienced Patients With a Novel Compound against HIV: MeRcK, MK-0518 (BENCHMRK)-1 and -2, two parallel phase III studies of the integrase inhibitor, raltegravir, were presented at the 2007 Conference on Retroviruses and Opportunistic Infections (Capsule Summary).[13,14] These studies were performed in Europe, Australia, and the Pacific Rim (BENCHMRK-1) and in North, Central, and South America (BENCHMRK-2). Inclusion criteria included genotypic or phenotypic resistance to ≥ 1 drug from the PI, NRTI, and NNRTI classes, and HIV-1 RNA > 1000 copies/mL. Patients were randomized 2 to 1 to receive raltegravir 400 mg twice daily or placebo, each combined with an OBR. The primary endpoint was the proportion of patients with HIV-1 RNA < 400 copies/mL at 16 weeks.
Baseline characteristics were similar across arms, with the exception of a greater racial diversity in the BENCHMRK-2 trial. Mean baseline CD4+ cell count across the arms ranged from 146-163 cells/mm³, and mean baseline HIV-1 RNA ranged from 32,000-48,000 copies/mL. Patients had a median previous treatment duration of 11-12 years of antiretroviral therapy and 12 previous agents.
Approximately 60% of patients in each treatment arm had a genotypic sensitivity score of 0 or 1 for the OBR. For the phenotype assay, it should be noted that in the baseline resistance assessment of the drugs in the OBR, patients were considered resistant to a drug if the fold-change in susceptibility to that drug exceeded the lower cutoff in the phenotypic assay. The lower cutoff marks the transition between full activity and reduced activity, rather than no activity, so drugs that had partial activity could have been assigned a score of 0; in other words, the phenotypic susceptibility scores could have slightly underestimated the activity of the OBR. Approximately 20% of patients were naive to enfuvirtide at study entry. When enfuvirtide was used in a previously enfuvirtide-naive patient, a score of 1 was added to the phenotypic susceptibility score. Phenotypic susceptibility testing for darunavir was not available at the study outset, so darunavir was also assigned an activity score of 1 when administered to a patient who had previously been darunavir naive. This approach may have overestimated the activity of darunavir in some patients. Approximately 25% of patients in BENCHMRK‑1 and nearly 50% in BENCHMRK‑2 were darunavir naive and received darunavir as part of their OBR.
The primary endpoint was the proportion of patients with HIV-1 RNA < 400 copies/mL at Week 16 in an intent-to-treat, missing data or noncompleter-equals-failure analysis. In both trials, 77% of patients receiving raltegravir plus OBR had HIV-1 RNA < 400 copies/mL at Week 16 compared with 41% and 43% of patients (in BENCHMRK-1 and BENCHMRK‑2, respectively) who received the OBR with placebo (P < .001 for comparison of raltegravir vs placebo) (Figure 3). Although 24-week data were also reported for some patients, it should be noted that not all patients had reached the 24-week time point at the time of this analysis.
Figure 3. BENCHMRK-1 and -2: proportion of patients with HIV-1 RNA < 400 copies/mL.[13,14]
The percentage of patients with HIV-1 RNA < 50 copies/mL at Week 16 was also reported. In an intent-to-treat, noncompleter-equals-failure analysis, 61% and 62% of patients in BENCHMRK-1 and BENCHMRK‑2, respectively, in the raltegravir plus OBR arm achieved this endpoint compared with 33% and 36%, respectively, in the placebo arm (P < .001 for comparison of raltegravir vs placebo) (Figure 4). The increase in CD4+ cell count at Week 16 was +83 and +86 cells/mm³ in the raltegravir arms in BENCHMRK-1 and BENCHMRK-2, respectively, compared with +31 and +40 cells/mm³, respectively, in the placebo arms (P < .001 for comparison of raltegravir vs placebo).
Figure 4. BENCHMRK-1 and -2: proportion of patients with HIV-1 RNA < 50 copies/mL.[13,14]
Adverse events in patients treated with raltegravir in the 2 studies were similar to placebo. There also did not appear to be an increased incidence of laboratory abnormalities when compared with the placebo arms.
A subset analysis of virologic efficacy in patients who had received enfuvirtide and/or darunavir for the first time as part of their background regimen was also reported. Among those who received both of these agents for the first time in combination with raltegravir (n = 44), 98% had HIV-1 RNA < 400 copies/mL at 16 weeks in a virologic failure–carried-forward analysis. It should be noted that these 44 subjects represent only a small subset (approximately 10%) of the patients treated with raltegravir in the 2 studies (Figure 5). Among those who received either enfuvirtide or darunavir (but not both) as a new agent combined with raltegravir, 90% achieved HIV-1 RNA < 400 copies/mL at 16 weeks. By contrast, 74% of raltegravir-treated patients who received neither enfuvirtide nor darunavir achieved viral suppression. These results illustrate the importance of combining 2-3 active agents into a new regimen rather than adding these agents in a stepwise fashion, and underscore the very real potential to regain virologic suppression in patients who are naive to 2 or more potent agents.
Figure 5. BENCHMRK-1 and -2: proportion of patients with HIV-1 RNA < 400 copies/mL by selected agents in OBR.[13,14]
In a combined analysis stratified by the number of active drugs in the OBR as determined by resistance testing, the virologic efficacy of raltegravir was especially evident in patients with genotypic or phenotypic sensitivity scores of 0 and 1. The high rates of viral suppression observed when raltegravir was given with an OBR for which the genotypic and phenotypic susceptibility scores were 0 suggest that raltegravir has considerable intrinsic activity, recognizing that some of the drugs in the OBR were likely to have partial activity. However, the 16‑week time point is relatively early, and it will be important to evaluate whether patients experience viral breakthrough during longer-term follow-up.
A total of 76 patients on raltegravir in the BENCHMRK trials (16%) experienced virologic failure. Genotype analyses were available for 41 of those who failed. Thirty two of the 41 had changes in the integrase gene that predominantly followed 1 of 2 pathways, characterized by the presence of either N155H or Q148K/R/H. In general, at least 2 mutations were present when resistance was observed at the time of virologic failure. There was no report on resistance to enfuvirtide, darunavir, or other components of the OBR in patients who experienced viral rebound on therapy or who failed to achieve undetectable HIV-1 RNA.
Use of Raltegravir in Treatment-Naive Patients
Protocol 004 is a phase II trial that randomized 203 treatment-naive patients to therapy involving 4 doses of raltegravir (100 mg, 200 mg, 400 mg, and 600 mg) combined with tenofovir plus lamivudine for 48 weeks, compared with a control arm receiving efavirenz, tenofovir, and lamivudine. By Week 24, approximately 80% of patients in each arm had HIV-1 RNA < 50 copies/mL, with no significant differences in response between any of arms (Capsule Summary).[15] This response was maintained through Week 48.[16]
Although there was no difference between the arms in rates of virologic suppression by Week 24, the reduction in viremia occurred more rapidly with raltegravir than with efavirenz. Viral decay observed in response to efavirenz was typical of that seen in other efavirenz trials. However, more than one half of patients in each of the raltegravir arms had HIV-1 RNA levels < 50 copies/mL by Week 4. A mathematical model of this response suggested that second-phase viral decay may be accelerated with raltegravir (Capsule Summary).[17] However, the clinical relevance of this rapid response (if any) has not been defined at this time.
Week 48 results showed similar rates of virologic suppression as seen at Week 24 in each of the arms (Table 5).[16] No raltegravir dose-related toxicities have been identified at this time. Lipid increases were observed with efavirenz but not with raltegravir.
Table 5. Raltegravir in Treatment-Naive Patients: Week 24 and 48 Results
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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
Etravirine: Second-Generation NNRTI
Recent studies have demonstrated the efficacy of second-generation agents from existing classes that have been designed to retain activity against virus that is resistant to other drugs in that class. The POWER trials[23] and the RESIST trials[24] demonstrated the efficacy of the second-generation PIs darunavir/ritonavir and tipranavir/ritonavir in treatment-experienced patients with multiple protease mutations.
Etravirine is a second-generation NNRTI with demonstrated activity against a wide variety of NNRTI-resistant viruses.[25] In contrast to efavirenz or nevirapine, etravirine has a high genetic barrier to resistance in vitro, and multiple NNRTI resistance mutations are required before significant loss of susceptibility is observed.
In a phase IIb trial, study TMC125-C223, etravirine plus an OBR was associated with significantly greater rates of viral suppression than placebo plus an OBR in highly treatment-experienced patients with a history of at least 1 NNRTI resistance mutation and at least 3 primary protease mutations.[26]
The phase II TMC125-C227 trial compared etravirine vs a PI, each combined with NRTIs, in PI-naive patients with virologic failure on an initial regimen containing efavirenz or nevirapine.[27] Although the etravirine arm had an initial HIV-1 RNA reduction of about 1.5 log10 copies/mL at Week 8, this was not sustained, whereas the PI arm showed sustained viral suppression. Further analysis showed that patients with virologic failure had more NNRTI and NRTI resistance mutations than would be expected in a first-line failure population. A substantial proportion of patients was recruited from resource-limited countries, where these patients had been on their failing regimen for many months, which resulted in the accumulation of multiple NNRTI and NRTI resistance mutations. This study underscores the importance of prompt modification of a failing first-generation NNRTI regimen to avoid the accumulation of mutations that may compromise the activity of a second-generation agent.
The activity of etravirine when combined with active agents in treatment-experienced patients was confirmed by the phase III, randomized, double-blind, placebo-controlled DUET studies, which are evaluating the long-term efficacy, tolerability, and safety of etravirine vs placebo, each combined with a darunavir/ritonavir-containing OBR in treatment-experienced HIV-infected patients (Capsule Summary).[28-31] Inclusion criteria stipulated that the patients be on a stable but virologically failing regimen. The subjects were required to have HIV-1 RNA > 5000 copies/mL at screening, at least 1 documented NNRTI resistance–associated mutation (either at screening or from historical genotype reports), and at least 3 documented primary PI mutations. Patients were randomized in a 1-to-1 ratio to either etravirine (given in the new 200 mg twice-daily formulation) or to placebo, both in combination with darunavir/ritonavir (600/100 mg twice daily), and an investigator-selected OBR of at least 2 antiretroviral medications, consisting of NRTI(s) with or without enfuvirtide. Patients were also stratified by number of active agents in the OBR, enfuvirtide use in the OBR, baseline HIV-1 RNA, and previous darunavir use. The primary endpoint was the proportion of patients achieving HIV-1 RNA < 50 copies/mL at Week 24 by intention-to-treat, time-to-loss-of-virologic-response analysis. Secondary endpoints included proportion of patients with HIV-1 RNA < 400 copies/mL, change in HIV-1 RNA from baseline, change in CD4+ cell count from baseline, safety, and tolerability. Of note, this is the first study in treatment-experienced patients to use viral suppression to < 50 copies/mL as the primary endpoint, consistent with current guidelines that state that this endpoint is an achievable goal of therapy in this patient population.
A total of 612 patients were randomized in DUET-1 (304 in the etravirine group; 308 in the placebo group) and 591 patients were randomized in DUET-2 (295 in the etravirine group; 296 in the placebo group). Baseline characteristics were similar between the treatment groups and between the studies. The mean baseline HIV-1 RNA was approximately 4.8 log10 copies/mL, and the mean CD4+ cell count was approximately 100 cells/mm³. Approximately 65% of patients had ≥ 2 NNRTI mutations at baseline, and a similar proportion had ≥ 5 primary PI mutations. Approximately 5% of subjects were experienced with darunavir, and approximately one third of patients in DUET-1 and one half of patients in DUET-2 had previous experience with enfuvirtide.
A summary of the results of primary and secondary endpoints at Week 24 are shown in Table 6. Significantly more patients in the etravirine arm achieved HIV-1 RNA < 50 copies/mL after 24 weeks compared with those in the placebo group. Higher rates of virologic suppression were seen with etravirine, regardless of the number of active agents in the OBR. Relatively high rates of suppression were seen even among patients receiving etravirine with no active agent in OBR. The difference in virologic suppression between etravirine and placebo was particularly pronounced in those patients with 0 or 1 active agents in the OBR. A greater proportion of patients with a baseline HIV-1 RNA ≥ 100,000 copies/mL achieved HIV-1 RNA < 50 copies/mL in the etravirine arm vs the placebo arm in both DUET-1 (38% vs 27%) and DUET-2 (51% vs 24%). Of interest (and unexplained) is the nonsignificant difference in CD4+ cell count between the arms in DUET-2, although in DUET-1 the immunologic response was significantly superior among etravirine recipients.
Table 6. DUET-1 and -2: Primary and Secondary Endpoint Week 24 Analyses[28,30]
Response was also compared in patients who were enfuvirtide naive and used enfuvirtide in their background regimen (n = 153 in the etravirine arms; n = 160 in the placebo arms) vs those who did not use enfuvirtide or recycled it (n = 446 in the etravirine arms; n = 444 in the placebo arms). Among those who were reusing or not using enfuvirtide, more patients in the etravirine group achieved HIV-1 RNA < 50 copies/mL. Among those who were enfuvirtide naive, there was no significant difference in response to etravirine compared with placebo.
Adverse events were generally mild or moderate and were similar in frequency and severity between the etravirine and placebo groups. Rash was approximately twice as common in the etravirine group vs placebo (14% vs 9% in DUET-1; 20% vs 10% in DUET-2). There was no difference between the arms in the nature, frequency, or severity of neuropsychiatric events.
Etravirine Resistance
Among 406 NNRTI-experienced patients enrolled in the DUET trials, researchers identified 13 NNRTI mutations present at baseline that were associated with reduced response to etravirine¾V90I, A98G, L100I, K101E, K101P, V106I, V179D, V179F, Y181C, Y181I, Y181V, G190A, and G190S.[30] Of interest, K103N, which causes high-level resistance to both efavirenz and nevirapine, was not associated with reduced response to etravirine. The Y181C mutation that frequently occurs in patients failing nevirapine-based therapy was only associated with substantially reduced response to etravirine when accompanied by at least 2 other etravirine-associated mutations. The investigators observed an association between increasing number of etravirine resistance mutations and decreasing virologic response. Study participants with no more than 2 of the 13 identified mutations at baseline did not exhibit a reduced virologic response to etravirine. In subjects with 3 or more of the specified mutations at baseline, however, the rate of virologic response declined to a level similar to that observed in the placebo arm. Of the 406 NNRTI-experienced patients studied, 70% had none or only 1 of the 13 etravirine resistance mutations detected at baseline, and only 14% had 3 or more mutations.
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.
Summary: Implications for Clinical Practice
- Significant advances have been made in the development of new antiretroviral agents in existing and new classes that are active against drug-resistant HIV.
- These drugs have demonstrated enhanced rates of virologic response when combined with other fully and/or partially active agents.
- Nevertheless, in treatment-experienced patients, the ability to achieve the goal of undetectable HIV-1 RNA is often limited by the lack of other active drugs to combine in a new regimen. This obstacle has recently been diminished by the availability of new agents that exploit novel targets in the viral life cycle, such as entry and integrase inhibitors.
- The phase IIb/III MOTIVATE trials of maraviroc in treatment-experienced patients with R5 virus demonstrated superior virologic and immunologic efficacy for maraviroc plus OBR vs placebo plus OBR at Week 24. Both once-daily or twice-daily doses were tested. Safety and tolerability of this agent was similar to placebo; although there were some patients who had D/M or X4 virus on failure, this virus was shown to be present at baseline.
- The MERIT trial of maraviroc vs efavirenz, both with tenofovir plus lamivudine, was not able to demonstrate noninferiority of maraviroc for percentage of patients with suppression of HIV-1 RNA to < 50 copies/mL at Week 48. Noninferiority was demonstrated for HIV-1 RNA < 400 copies/mL. Results of this trial indicate that maraviroc will not immediately be considered for use in treatment-naive patients but will require further investigation.
- ACTG 5211, a phase IIb trial in treatment-experienced patients, has demonstrated superiority of another CCR5 antagonist, vicriviroc, compared with placebo, each combined with an OBR. A greater number of malignancies occurred in the vicriviroc-treated arm than in the placebo arm but it is unclear that the malignancies are related to vicriviroc use. Patients are now being recruited for phase III trials of vicriviroc in the treatment-experienced population.
- Trials of 2 integrase inhibitors, raltegravir and elvitegravir, have yielded results in treatment-experienced patients in 2007. A trial of raltegravir in treatment-naive patients has also reported 48-week results.
- The phase III BENCHMRK trials of raltegravir in treatment-experienced patients demonstrated greater virologic and immunologic efficacy at Week 16 for raltegravir vs placebo, each combined with an OBR. Safety and tolerability were similar to placebo.
- Raltegravir has also been studied in treatment-naive patients. The phase II Protocol 004 has compared several doses of raltegravir vs efavirenz, each with tenofovir and lamivudine. At Week 48, similar proportions of patients treated with all doses of raltegravir or efavirenz achieved HIV-1 RNA < 50 copies/mL. Safety and tolerability were similar to efavirenz.
- Week 24 results were reported for a phase II trial of elvitegravir/ritonavir vs comparator PI, each combined with an OBR, in treatment-experienced patients. In the primary endpoint analysis, both of the higher doses of elvitegravir/ritonavir—50/100 mg or 125/100 mg—were shown to be noninferior to comparator PIs.
- Genotypic data from patients with virologic failure taking raltegravir and elvitegravir, albeit limited, have indicated that there is considerable cross-resistance between these 2 drugs at failure. This may mean that it will not be possible to sequence these 2 integrase inhibitors.
- Etravirine, a second-generation NNRTI which is active against many virus variants that are resistant to efavirenz and nevirapine, has demonstrated superior efficacy vs placebo, each combined with a darunavir/ritonavir-based OBR, in a pair of phase III trials in treatment-experienced patients, DUET-1 and -2. This new agent, available in expanded access, can be used as an active agent with integrase inhibitors and entry inhibitors to build regimens in multidrug-resistant patients.
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References
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22. DeJesus E, Cohen C, Elion R, et al. First report of raltegravir (RAL, MK-0518) use after virologic rebound on elvitegravir (EVT, GS 9137). Program and abstracts of the 4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention; July 22-25, 2007; Sydney, Australia. Abstract TUPEB032. (Capsule Summary)
23. Clotet B, Bellos N, Molina JM, et al. Efficacy and safety of darunavir-ritonavir at week 48 in treatment-experienced patients with HIV-1 infection in POWER 1 and 2: a pooled subgroup analysis of data from two randomised trials. Lancet. 2007;369:1169-1178.
24. Hicks CB, Cahn P, Cooper DA, et al. Durable efficacy of tipranavir-ritonavir in combination with an optimised background regimen of antiretroviral drugs for treatment-experienced HIV-1-infected patients at 48 weeks in the Randomized Evaluation of Strategic Intervention in multidrug reSistant patients with Tipranavir (RESIST) studies: an analysis of combined data from two randomised open-label trials. Lancet. 2006;368:466-475.
25. Vingerhoets J, Azijn H, Fransen E, et al. TMC125 displays a high genetic barrier to the development of resistance: evidence from in vitro selection experiments. J Virol. 2005;79:12773-12782.
26. Cohen C, Steinhart C, Ward D, et al. Efficacy and safety results at 48 weeks with the novel NNRTI, TMC125, and impact of baseline resistance on the virologic response in study TMC125-C223. Program and abstracts of the 16th International AIDS Conference; August 13-18, 2006; Toronto, Canada. Abstract TUPE0061.
27. Woodfall B, Vingerhoets J, Peeters M, et al. Impact of NNRTI and NRTI resistance on the response to the regimen of TMC125 plus two NRTIs in study TMC125-C227. Program and abstracts of the 8th International Congress on Drug Therapy in HIV Infection; November 12-16, 2006; Glasgow, Scotland. Abstract PL5.6.
28. Mills A, Cahn P, Grinsztejn B, et al. DUET-1: 24 week results of a phase III randomised double-blind trial to evaluate the efficacy and safety of TMC125 vs placebo in 612 treatment-experienced HIV-1 infected patients. Program and abstracts of the 4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention; July 22-25, 2007; Sydney, Australia. Abstract WESS204-1. (Capsule Summary)
29. Madruga JV, Cahn P, Grinsztejn B, et al. Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1-infected patients in DUET-1: 24-week results from a randomised, double-blind, placebo-controlled trial. Lancet. 2007;370:29-38.
30. Katlama C, Campbell T, Clotet B, et al. DUET-2: 24-week results of a phase III randomised double-blind trial to evaluate the efficacy and safety of TMC125 vs placebo in 591 treatment-experienced HIV-1 infected patients. Program and abstracts of the 4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention; July 22-25, 2007; Sydney, Australia. Abstract WESS204-2.
31. Lazzarin A, Campbell T, Clotet B, et al. Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1-infected patients in DUET-2: 24-week results from a randomised, double-blind, placebo-controlled trial. Lancet. 2007;370:39-48. | | | | |
Regards,
Nelson Vergel
powerusa dot org
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Sat Sep 22, 2007 11:18 pm
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