ReviewMaraviroc, risks and benefits: a review of the clinical literature
Jetske M Emmelkamp & Jürgen K Rockstroh†
University Clinic Bonn, Department of Medicine I, Sigmund-Freud-Str. 25, 53105 Bonn, Germany

Background: Maraviroc represents the first licensed CCR5 co-receptor antagonist from the new antiretroviral (ARV) drug-class of entry inhibitors. Results: Results of Phase III clinical trials in three-drug-class experienced patients have presented maraviroc as a promising new agent for treatment of HIV-1-infection. Maraviroc (b.i.d./q.d.) + optimised background therapy (OBT) provided significantly superior virological control and CD4+ increases compared with placebo + OBT at 48 weeks, with no clinically relevant differences in the safety profile between the maraviroc and the placebo groups. Conclusion: Its proven efficacy in cases of virological failure and three-class ARV-drug resistance is a major benefit of maraviroc compared to the so far commercially available drugs from existing (non-) nucleoside reverse transcriptase inhibitors ([N]NRTI) and protease inhibitors drug-classes, particularly in times of increasing ARV drug resistance. Moreover, the tolerability profile of the drug makes maraviroc particularly appealing as a combination partner in ARV therapy. As maraviroc however is only effective against CCR5-tropic HIV-1, tropism testing is required before initiation of treatment. Tropism-testing possibilities are still limited, and presently only possible at high costs. The main constraints to be considered in the clinical use of maraviroc are the declining number of CCR5-tropic patients with advanced HIV-1 disease owing to tropism-shifting and the occurrence of drug–drug interactions, requiring regular dose adaptations. The true clinical value of this new substance and its future role in the treatment of HIV-1-infection remains to be defined by further data from clinical studies and by future experiences of practitioners.
Keywords: antiretroviral therapy, CCR5 co-receptor antagonist, CCR5 inhibitors, drug–drug interactions, HIV-1, maraviroc, tropism

Expert Opin. Drug Saf. (2008) 7(5):559-569

1.Introduction
Over the past 20 years, development of antiretroviral (ARV) therapy for HIV- infection has been dynamic, with continuous development in existing new ARV drug-classes as well as the introduction of new ARV drug-classes with a new mode of action. Recently, CCR5 co-receptor antagonists have been added to the HIV-specific therapeutic armamentarium. Highly selective, small-molecule CCR5 antagonists with good bioavailability have been developed, using the CCR5 receptor on the host cell membrane as an extracellular target for treatment intervention [1]. Although challenges for clinical use of these new drugs still remain, results of pharmacological and early clinical trials have been encouraging, especially for patients with resistant HIV disease [2]. In October 2007, CCR5 co-receptor antagonists were introduced as a new drug-class for treatment of HIV-1-infection with the approval of maraviroc for use in treatment experienced patients with CCR5-tropic HIV-1-viral strains (Selzentry™ in the US, Celsentri™ in Europe and Canada, manufactured by Pfizer).

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After ARV activity against CCR5-tropic HIV-1 from various clades and geographic origin, as well as the potential for an excellent safety profile were shown in preclinical and early clinical studies [3], the introduction of this extracellular mechanism of action for inhibition of HIV-1-replication was associated with increased expectations and optimism. In the following review, we summarise the clinical data generated with maraviroc so far and discuss the most important challenges and benefits of this new CCR5 co-receptor antagonist, and give our view regarding its possible use in clinical practise.

2.Mode of action

HIV uses the CD4 receptor on T cells of the host for cell fusion. In addition to binding to the CD4 receptor, HIV gp120 uses either the CCR5 or CXCR4 co-receptor that is also expressed on the host cell membrane to fuse cell membranes and enter the CD4+ T lymphocyte. Mutations of CCR5-Δ32 lead to reduced appearance of CCR5 chemokine receptors on the T cell. Decreased CCR5 expression on the CD4 cell membrane in individuals heterozygous for the CCR5-Δ32 mutation (an estimated 20% of Caucasians [4]) has been associated with delayed progression of HIV-1 disease [5,6]. Moreover, individuals homozygous for this deletion (an estimated 1% of Caucasians) even seem to have a certain degree of protection for acquiring HIV-1-infection, owing to complete absence of CCR5 expression on the CD4 cell-surface [4].
Unlike the existing ARV drugs that inhibit HIV replication
once the virus has entered immune system cells, CCR5 receptor antagonists inhibit the initiation step when HIV-1 binds to the CCR5 co-receptor of the host cell by blocking the CCR5 chemokine receptor on its cell-surface and thus mimicking the results of CCR5-Δ32 mutation. Ideally, preventing entry of HIV-1 into the cell will then inhibit further viral replication.

3.Tropism: CCR5/CXCR4

In the majority of patients with early stage HIV-1-disease, viral strains use CCR5 co-receptors to enter the T cell (CCR5-tropic virus). In advanced immunosuppression however, approximately one-half of viral strains enter through either the CXCR4 co-receptor alone, or both the CCR5 and the CXCR4 receptors (‘dual or mixed’ tropic viruses) [7]. Approximately 80% of ARV-naive patients are infected with CCR5-tropic HIV-1, whereas an estimated 50% of pretreated patients show exclusively CCR5-tropic viral strains. Maraviroc has been approved only for use in patients who are exclusively infected with CCR5-tropic HIV-1, based on its proven efficacy against CCR5-tropic HIV-1. In patients with CXCR4 or dual-tropic virus, maraviroc did not lead to further declines in HIV-1 RNA levels compared to optimised background therapy (OBT) alone [8].
4.
Results of early clinical trials

ARV efficacy was first shown in a Phase IIa, 10-day monotherapy study in 63 asymptomatic, HIV-1 positive patients who were prescreened for R5-tropism. In this study at the nadir maraviroc reduced the mean HIV-1 RNA by  1.6 log with 300 mg/day and 1.8 log with 300 mg b.i.d. [9]. Mean decline of viral load in this study was greater in all maraviroc treatment arms compared to placebo on day 11. In contrast, the non-effectiveness of maraviroc in cases of mixed X4/R5-tropic virus was demonstrated in a Phase IIb exploratory trial, which evaluated the efficacy of maraviroc as an add-on to an OBT in pretreated patients. Here, no significant decline in viral load reduction was shown in patients with dual- or mixed-tropic infection in maraviroc treated patients compared to placebo [8], confirming efficient antiviral activity of maraviroc only in R5-tropic HIV-1-infection.

5.Clinical evaluation of maraviroc in treatment experienced patients: the MOTIVATE trials

5.1Study design and baseline characteristics
The safety and efficacy of maraviroc in heavily pretreated HIV-1-infected patients with virological failure owing to multiple class ARV drug resistance were evaluated in the two identically designed large double-blind, placebo-controlled, randomised clinical MOTIVATE trials (Phase IIb – III). MOTIVATE I was performed in the US and Canada [10] and enrolled 601 individuals; in MOTIVATE II, 475 patients from Europe, Australia and North America were randomised and 464 received more than one dose of the study drug [11]. In both trials, maraviroc q.d. and maraviroc b.i.d. were compared with placebo against an investigator selected OBT on the basis of previous resistance testing. Primary end points in both MOTIVATE studies were mean decline in HIV-viral load after 24 and 48 weeks of therapy. Baseline characteristics were comparable between maraviroc and placebo treatment groups, with the included participants being predominantly white males with a mean age of 46 years. All patients included had triple-class drug resistance and/or triple-class drug experience. Table 1 lists the baseline characteristics of patients in all three study arms.

5.2Efficacy in pretreated patients
In both MOTIVATE studies proof of clinical efficacy of maraviroc was obtained, as maraviroc + OBT showed superior efficacy compared to placebo + OBT in terms of viral suppression and immunological response. Table 2 shows the percentage of patients achieving undetectable viral loads (< 50 copies/ml) for the pooled MOTIVATE 1 and 2 analyses. In the following segment the specific results for MOTIVATE 1 and 2 will be provided, respectively.

Table 1. Baseline characteristics, pooled analysis of the MOTIVATE 1 and 2 studies.

Maraviroc q.d. (n  414) Maraviroc b.i.d. (n  426) Placebo (n  209)
 2 active drugs in OBT 66.0 69.7 66.0
Enfuvirtide in OBT, percentage 42.7% 43.5% 40.6%
Tipranavir in OBT, percentage 15.9% 14.8% 13.9%
Mean HIV-1 RNA, log10c/ml 4.86 4.85 4.86
Mean CD4+ count, cells/mm3 195.7 189.2 187.2
Female, n (percentage) 51 (12.3%) 44 (10.3%) 24 (11.5%)
White, n (percentage) 336 (81.2%) 363 (85.2%) 178 (85.2%)
Mean age, years (range) 45.6 (17 – 75) 46.3 (21 – 73) 45.7 (29 – 72)
Modified from Hardy et al. [16]. OBT: Optimised background therapy.

Table 2. Percentage of patients with undetectable HIV-1 RNA after 48 weeks of treatment with maraviroc (pooled data from the MOTIVATE 1 and 2 studies).

HIV-1 RNA Maraviroc q.d. + OBT (n  414) Maraviroc b.i.d. + OBT (n  426) Placebo + OBT (n  209)
< 400 c/ml 51.7%* 56.1%* 22.5%
< 50 c/ml 43.2%* 45.5%* 16.7%
*p < 0.0001 versus placebo + OBT. HIV-1 RNA value imputed as baseline if missing or if patient discontinued before 48 weeks. Includes all patients who received at least one dose of study medication; pooled analysis of MOTIVATE 1 and 2 (adapted from Hardy et al. [16]).
OBT: Optimised background therapy.

In MOTIVATE 1 [10], patients were randomised 1:2:2 to treatment with placebo, maraviroc q.d. or maraviroc b.i.d. The primary end point, mean change in HIV-1 RNA from baseline, was -0.80 log10c/ml in the placebo group compared to
-1.66 log10c/ml (-0.85 log10c/ml difference to placebo) and
-1.82 log10c/c/ml (-1.02 log10c/ml difference to placebo) in the maraviroc groups, respectively. As for the secondary end points, 42 and 47% of patients randomised to receive maraviroc
q.d. and maraviroc b.i.d. reached a decline of HIV-1 RNA
< 50 c/ml, compared to 16% of patients receiving OBT alone. Mean change in CD4-count from baseline was also greater in the maraviroc groups, with +113 cells/mm3 (maraviroc q.d.) and +122 cells/mm3 (maraviroc b.i.d.) against +54 cells/mm3 in the placebo group.
In the identically designed MOTIVATE 2 study [11], mean change of HIV-1 RNA after 48 weeks of treatment compared to baseline was -0.76 log10c/ml in the placebo group, -1.72 log10c/ml in individuals treated with maraviroc
q.d. (-0.96 log10c/ml treatment difference to placebo) and
-1.87 log10c/ml in the group receiving maraviroc b.i.d. (-1.11 log10c/ml difference to placebo). In the study, 45.1 and 44.5% of patients receiving maraviroc reached optimal viral suppression defined as HIV-1 RNA < 50 c/ml, against only 17.6% of the placebo cohort. Mean change in CD4-count from baseline was +121 and +128 cells/mm3 in both maraviroc treatment groups and +69 cells/mm3 in the placebo group.
In summary, both clinical trials demonstrated that treatment with maraviroc q.d./b.i.d. + OBT provided

significantly superior virological control and CD4+ increases compared to placebo + OBT after 48 weeks of treatment.

5.3Tolerability in early clinical evaluation and in pretreated patients
In Phase I – II maraviroc was well tolerated in multiple doses tested  900 mg/day [12,13]. Most frequently reported adverse effects included headache, asthenia, dizziness, gingivitis and nausea [8].
In the MOTIVATE trials among pretreated patients, the most frequently reported side effects were diarrhoea, nausea, headache and fatigue in both maraviroc and placebo treatment groups. A slightly higher incidence of respiratory infections and drowsiness was reported in the maraviroc arms after 24 weeks follow-up [14,15]. Table 3 shows the frequency of adverse events reported in the pooled data of the MOTIVATE 1 and 2 studies after 24 weeks of treatment. Also in the analysis of pooled data after 24 weeks follow-up, there was no clinically significant difference in safety profile between maraviroc and placebo, with most common adverse events being diarrhoea, nausea, fatigue and headache [16]. More deaths occurred in the maraviroc study arms but none was considered treatment related. Discontinuation of treatment due to adverse events in MOTIVATE 1 occurred in 7% of patients in the group ran- domised to placebo, and in 14 and 11% of patients treated with maraviroc q.d. and b.i.d., respectively [10]. In MOTIVATE 2, ARV treatment was discontinued in 4.4% of patients taking

Table 3. Maraviroc, adverse events in Phase III (MOTIVATE pooled data after 24 weeks).

Adverse events Maraviroc b.i.d. + OBT OBT alone
(n  426) (n  209)
Diarrhoea 89 (20.9%) 45 (21.5%)
Nausea 73 (17.1%) 39 (18.7%)
Headache 54 (12.7%) 32 (15.3%)
Fatigue 54 (12.7%) 31 (14.8%)
Fever 51 (12%) 17 (8.1%)
Cough 48 (11.3%) 10 (4.8%)
Total AE 383 (89.9%) 175 (83.7%)
Any grade 3 AE 92 (21.6%) 43 (20.6%)
Any grade 4 AE 42 (9.9%) 13 (6.2%)
AE: Adverse event; OBT: Optimised background therapy.

placebo, in 5.5% of those treated with maraviroc q.d. and in 5.2% of those receiving maraviroc b.i.d. [11].

5.4Laboratory abnormalities in pretreated patients In the Phase III MOTIVATE studies in pretreated subjects, there were no differences between the maraviroc and placebo arms regarding significant abnormalities of liver enzymes, nor were alterations in amylase, lipase and neutrophil-count described with higher frequency in the maraviroc arm than in the placebo arms. Table 4 lists the occurrence of hepatotoxicity as described in the pooled data from the MOTIVATE 1 and 2 studies at 48 weeks.

6.Clinical evaluation of maraviroc in ARV-naive patients: the MERIT trial

Assessment of the efficacy and safety of maraviroc among ARV-naive individuals was investigated in the MERIT trial [17]. This trial included 917 HIV-1 infected patients and compared maraviroc q.d. and maraviroc b.i.d. with efavirenz against a nucleoside reverse transcriptase inhibitor (NRTI)-backbone consisting of zidovudin and lamivudin (Combivir). The primary end point of the MERIT study was a reduction of HIV-1 RNA < 400/< 50 c/ml after 48 and 96 weeks, respectively.

6.1Efficacy in ARV-naive patients
The q.d. arm of the MERIT trial was stopped prematurely because of lack of antiviral efficacy. After 48 weeks of follow-up of the remaining b.i.d. and efavirenz arms in this trial, non- inferiority of maraviroc could be shown for a reduction of HIV-1 RNA < 400 c/ml but not for the primary end point
< 50 c/ml [17]. Mean CD4-count rise was +170 cells/mm3 for
maraviroc and thereby significantly higher than for efavirenz with +144 cells/mm3. Differences in virological response rates were however small (65.3% of patients in the maraviroc arm reached VL < 50 c/ml versus 69.3% in the efavirenz study arm

at week 48), and although all study participants had R5-tropic virus at the date of study-screening, 25 (3.5%) had changed to dual/mixed or X4-tropic virus on the first day of treatment. When these patients showing a tropism-shift from screening to baseline were excluded, non-inferiority of maraviroc was reached. Further follow-up is at present being performed and 96-weeks results of the MERIT study are awaited.

6.2Tolerability in ARV-naive patients
Maraviroc showed overall good tolerability and no maraviroc specific adverse events were found in comparison to the efavirenz arm. Indeed, fewer patients in the maraviroc arm than with efavirenz experienced grade 3 adverse events, grade 4 adverse events or category C events. ARV treatment in the MERIT trial was discontinued due to adverse events in 13.6% of patients randomised to efavirenz but only in 4.2% of those randomised to maraviroc. Adverse events in the efavirenz arm leading to discontinuation were mainly associ- ated with CNS toxicity [17].

6.3Laboratory abnormalities in ARV-naive patients Clinically significant elevations of transaminases occurred with a similar rate in both treatment arms of the study. Grade 3 hyperbilirubinaemia occurred in none of the patients in the efavirenz arm and in 3 out of 352 (0.9%) patients receiving maraviroc + OBT. In all three patients hyperbilirubinaemia was not associated with transaminase elevations; two were associated with Gilbert’s syndrome. In ARV-naive patients treated with maraviroc + Combivir or with efavirenz + Combivir, median maximum change in fasting lipid levels from baseline (total cholesterol, HDL–cholesterol, LDL–cholesterol and triglycerides) were even greater in the efavirenz arm [17]. Therewith, no higher incidence of clinically significant laboratory alterations of maraviroc compared to placebo or to efavirenz could be detected in different clinical trials.

7.Resistance barrier

As maraviroc uses a hitherto new mechanism of action with its extracellular inhibition of viral entry, its effectiveness is not influenced by possible pre-existing (N)NRTI- or protease inhibitor-mutations. Therefore, maraviroc retains efficacy in extensively pretreated patients also in cases of three-class ARV drug resistance when multiple previous ARV-regimens have failed. Virological mechanisms by which maraviroc treatment can fail are viral escape owing to a tropism shift from R5- to dual/mixed- or X4-tropic virus, and second, the development of maraviroc-specific resistance-associated mutations. A combination of A316T- and I323V-mutations has been shown to be associated with resistance against maraviroc [18].
Yet, mechanisms of resistance development are presently still poorly understood and continue to be subject of further virological research [19].

Table 4. Reported toxicities with maraviroc in Phase III (MOTIVATE pooled data after 48 weeks).

Toxicities at week 48 (%) Maraviroc q.d. + OBT (n  414) Maraviroc b.i.d. + OBT (n  426) OBT alone (n  209)
Aspartate aminotransferase
Grade 3 > 5.0 – 10.0  ULN 2.9 3.3 2.9
Grade 4 > 10.0  ULN 1.0 1.4 0
Alanine aminotransferase
Grade 3 > 5.0 – 10.0  ULN 3.9 1.7 2.9
Grade 4 > 10.0  ULN 0.5 1.0 0.5
Total bilirubin
Grade 3 > 2.5 – 5.0  ULN 6.9 5.0 3.9
Grade 4 > 5.0  ULN 1.2 0.5 1.5
OBT: Optimised background therapy; ULN: Upper limit of normal.

8.Challenges of maraviroc

8.1Receptor/tropism shift
Maraviroc is only effective against CCR5-tropic HIV-1. No virological efficacy has been shown against CXCR4- or dual/mixed tropic viral strains. Viral receptor-tropism is however variable and may shift in the course of disease, mostly evolving from CCR5 towards CXCR4 over time. Whereas  80% of asymptomatic HIV-infected patients without need for HIV therapy harbour CCR5-tropic virus, tropism change to CXCR4 or mixed-tropic virus may occur with further disease progression [5], hampering the impact of maraviroc and thus creating a need for tropism-testing before treatment initiation. This phenomenon was illustrated in the MOTIVATE and MERIT trials, in which 8 and 3% of patients expressed such a tropism shift in the time span from screening to baseline, respectively. Further to co-receptor shifting in course of disease, tropism change can also be caused under co-receptor antagonist-exposure (drug pressure) by expansion of previously minor CXCR4-tropic viral populations, overgrowing the CCR5-tropic viral strains [20]. Tropism testing is at present available in the US with the phenotypic Trofile® assay (Monogram) at a cost of about $1500 – 2000. The turnaround time for the results of the test is on average 3 weeks.

8.2Toxicity/adverse events
8.2.1Laboratory abnormalities of maraviroc
In a review of six short-term multiple dose studies in which maraviroc was administered alone, clinically significant elevation of liver function tests occurred in 7 of 195 patients receiving varying doses of maraviroc. These alterations were independent from drug-dosage (4 patients had > 3  the upper limit of normal (ULN) transaminases and 3 patients had > 1.25 – < 2  ULN bilirubin). Mild-to-moderate elevations in creatinine (< 2  ULN) were reported in one study at 1200 mg single dose [13]. In further follow-up

in the MOTIVATE studies, these differences in biochemic laboratory parameters were not confirmed to be of significance. The safety and efficacy of maraviroc has not yet been studied in pregnant women. Also, there are no data available yet on possible long-term tolerability and toxicities of maraviroc, so that the occurrence of these long-term adverse events cannot be excluded until the data available so far on tolerability- and toxicity-profiles are confirmed by further clinical experience with maraviroc in the future.

8.2.2Concerns about a possible class-specific hepatotoxicity
As clinical development of the first CCR5 antagonist aplaviroc had to be terminated in October 2005 owing to severe hepatotoxicity [21], concerns were raised regarding possible class specific hepatotoxic effects of this new ARV drug-class. In 2005, from 1300 patients enrolled in Phase III, one case of hepatic failure and subsequent liver transplantation was reported in a patient treated with maraviroc and with concomitant use of isoniazid and trimethoprim-sulfamethoxazole. Which of these three possible hepatotoxic agents eventually caused failure of liver function in this patient could not be defined [22]. In subsequent clinical studies, no higher incidence of hepatotoxicity was reported in maraviroc arms as compared to placebo [23]. Given the early occurrence of toxicities in clinical evaluation of aplaviroc and as a higher frequency of elevated liver enzymes could not be detected in individuals treated with the other two CCR5 receptor antagonists tested (maraviroc, vicriviroc) compared to those receiving placebo even after 48 weeks of treatment, the possibility of a class specific hepatotoxic effect is unlikely. Nevertheless, in lack of long-term data on hepatotoxic effects of CCR5 inhibitors, strict and regular evaluation of liver enzymes in the course of treatment with maraviroc or with other CCR5 antagonists in development remains indicated.

8.2.3QT-prolongation
Preclinical testing of CCR5 co-receptor antagonists revealed a potential for QT prolongation. In early investigational stages, the CCR5 inhibitor ‘SCH-C’ caused QT prolongation when administered in high doses [24]. Most probably, this effect was caused by the relatively low degree of specifity of the examined substances, blocking not only CCR5 but also pharmacologically relevant enzymes and ion channels such as the cardiac K+ channel hERG [3]. This potential adverse event was further examined in healthy subjects receiving single doses of maraviroc,  900 mg. No clinically relevant effect on QTcF or QTcI was detected. Also, no relationship between QT interval and maraviroc plasma concentration
 2363 ng/ml was seen in both male and female
subjects, nor was there evidence of a change in the QT/RR relationship with concentration [25].

8.2.4Concerns about a class-specific risk on the occurrence of malignancies
In 2006, the ACTG 5211 trial evaluating vicriviroc, another CCR5 antagonist, was unblinded early owing to the unexpected occurrence of malignant lymphomas in the vicriviroc arm of the study [26]. In this trial among ARV therapy experienced adults with R5-tropic HIV-1, malignancies occurred in six subjects randomised to vicriviroc and in only two patients receiving placebo, from which one had been exposed to vicriviroc for a period of 3 months. From the six patients in the vicriviroc group, one was diagnosed with gastric adenoma, one patient developed HPV-related squamous cell carcinoma, two patients developed m. Hodgkin (one of whom had a history of treated Hodgkin’s disease) and two patients developed non-Hodgkin’s lymphoma (one of whom also had a history of Hodgkin’s disease) [27]. This is remarkable as prevalence of non-Hodgkin’s lymphoma is usually lower in individuals heterozygous for CCR5-Δ32 than in the population without this genetic mutation [28]. The association of vicriviroc treatment and the occurrence of malignancies remains uncertain but seems to be not drug related. Indeed, recently published data of the ACTG 5211 study showed no further development of malignancies and a sustained ARV activity of vicriviroc over 48 weeks when added to OBT [29]. Further follow-up on this possible association of vicriviroc use and malignant development is needed. As for maraviroc, the pooled data of MOTIVATE 1 and MOTIVATE 2 showed no significant difference in the occurrence of malignant disease between maraviroc-treated individuals and the placebo group after 24 and 48 weeks of follow-up [16]. CDC category C cancers occurred in 0.7% of patients treated with maraviroc q.d., in 0.9% of patients treated with maraviroc b.i.d. and in 2.4% of patients in the placebo group. Non HIV-related cancers occurred in 2.9% of the patients treated with maraviroc q.d., in 4.5% of those receiving maraviroc b.i.d. and in 5.3% of the patients in the placebo group [16]. As for the concerns regarding an increased risk

for development of malignancies under CCR5 antagonist containing HAART, the not forthcoming appearance of malignancies in 48 weeks of follow-up in the vicriviroc trials as well as no corresponding signal from the maraviroc trials, lessens the suspicion of a direct association between the two.

8.2.5Other consequences of CCR5 receptor blockade Primary (congenital) CCR5 receptor-deficiency has been shown to be associated with delayed progression of HIV-1 disease. Individuals with detected CCR5-Δ32-mutation are otherwise healthy. Nevertheless, secondary consequences of acquired CCR5 receptor blockade, for example regarding cellular immune modulation, can be imagined [2]. In a retrospective analysis performed in two independent cohorts of symptomatic individuals with West Nile virus in the US, CCR5 has been shown to play an important role in the pathogenesis of West Nile virus. According to this analysis, a homozygous defective allele CCR5-Δ32 is a risk factor for symptomatic West Nile virus infection [30], In a summary of possible effects of CCR5-Δ32-mutations on other human diseases, Ahlenstiel et al. report a milder course of disease in CCR5-Δ32 carriers with rheumatoid arthritis but an increased disease-susceptibility and severity for sarcoidosis and systemic lupus erythematosus [31]. Ayoub et al. performed a review of immune function markers from several multiple dose studies and described no such effects [32]. Neither were there any reports of negative effects of CCR5 receptor blockade in simian studies [33].

8.3Blood–brain barrier
HIV-1-tropism may diverge between blood and cerebrospinal fluid (CSF). In a Swedish study comparing tropism in plasma and CSF from 28 HIV-positive patients, 36% (10 of 28 patients) showed discordant co-receptor tropism in plasma and CSF [34,35]. This discordance has to be considered in treatment with CCR5 antagonists, especially in clinical settings in which a neurological penetration of ARV substances is imminent. A subsequent clinical trial compared the antiviral effects of the CCR5 antagonist D-Ala1-peptide T-amide. The authors reported an inferior antiviral activity in CSF compared to plasma, suggesting a non-penetrability of the blood–brain barrier for the study drug [36]. Further evaluation on the antiviral efficacy of the CCR5 inhibitors maraviroc and vicriviroc is herewith strongly supported.

8.4Frequent drug–drug interactions
Dosing of maraviroc depends on whether or not it is being administered with inducers or inhibitors of cytochrome P450. Maraviroc is primarily metabolised by CYP3A4, an enzyme that is part of the cytochrome P450 (CYP450) system. As a CYP3A4 substrate its drug levels may decrease when coadministered with strong CYP3A4 inducers and increase when coadministered with CYP3A4 inhibitors. Therefore, drug–drug interactions can be expected particularly

Table 5. Summary of important drug–drug interactions with maraviroc.

Drug name Effect on maraviroc levels Recommended dose adjustments
Atazanavir/r Increased maraviroc exposure (fivefold) Reduce maraviroc dose by 50%
Darunavir/r Increased maraviroc (fourfold) Reduce maraviroc dose by 50%
Efavirenz Reduced maraviroc exposure by a half Double maraviroc dose (in the absence of PIs) Reduce maraviroc dose by 50% in the presence of a boosting dose of ritonavir
Ketoconazole Increased maraviroc exposure (fivefold) Reduce maraviroc dose by 50%
Lopinavir/r Increased maraviroc exposure (fourfold) Reduce maraviroc dose by 50%
Rifampin Reduced maraviroc exposure by one third Double maraviroc dose (in the absence of PIs)
Ritonavir (full dose) Increased maraviroc exposure (2.6-fold) Reduce maraviroc dose by 50%
Tipranavir/r No change in maraviroc exposure No dose modification required
PI: Protease inhibitor.

with HIV protease inhibitors. A reduction of maraviroc dose by 50% (to 150 mg b.i.d.) in the presence of protease inhibitors/potent CYP3A4 inhibitors is, therefore, recom- mended. An exception is made for the protease inhibitor tipranavir, which in healthy subjects did not lead to any significant changes in maraviroc exposure [37]. On the contrary, when administering maraviroc with efavirenz or rifampin (in the absence of protease inhibitors), the maraviroc dose should be doubled (to 600 mg b.i.d.) [38]. Table 5 summarises the clinically relevant drug–drug interactions and possible dose adaptations for maraviroc (further in development). Maraviroc has no significant inhibitory effect on any major CYP450 enzyme, thereby making it unlikely that the substance can alter the metabolism of coadministered drugs that are metabolised by CYP450 enzymes [39].
Data obtained from healthy volunteer pharmacokinetic studies indicate that maraviroc does not affect the pharmaco- kinetics of the N(t)RTIs zidovudin, lamivudin or tenofovir. Data from clinical studies further confirmed that maraviroc had no effect on components of the oral contraceptive pill (ethinylestradiol and levonorgestrel) or the renal clearance of zidovudin and lamivudin. Effects of coadministration with midazolam were not clinically significant and within pharmacokinetic variability [38,40,41].
CYP3A4 inducers decrease maraviroc exposure, with reductions in AUC and Cmax of 50 – 70% seen in studies with efavirenz and rifampin [42,43]. Significant decreases in systemic exposure with CYP3A4 inducers can be corrected by increasing the maraviroc dosage (Table 5). CYP3A4 inhibitors increase maraviroc exposure; ketoconazole, the protease inhibitors (with the exception of tipranavir/r) and delavirdine are associated with increases in AUC (3 – 10 ) and Cmax (2 – 5 ) [41]. Significant increases in systemic exposure with CYP3A4 inhibitors can be corrected by reductions in the maraviroc dose (Table 5).
9.
Expert opinion

As the first available CCR5 co-receptor antagonist, maraviroc represents a new ARV drug-class of entry inhibitors and therewith another instrument in the clinical management of HIV-infection. Although long-term data on efficacy and tolerability are still pending, first results of several Phase III clinical trials have presented maraviroc as an interesting new tool in the treatment of HIV-1-infection. Its proven efficacy in cases of virological failure owing to three-class ARV drug resistance is the major benefit of this new drug compared to the so far commercially available drugs from the existing ARV drug-classes of (N)NRTI and protease inhibitor, particularly in times of increasing ARV drug resistance and of rising life expectancy of HIV-infected individuals (and therewith expected years of HAART use per person). However, the true clinical value of this new substance and its future role in the treatment of HIV-1-infection remain to be determined by further data from clinical trials. Although maraviroc has been approved only for treatment of advanced HIV-1-infection, its efficacy paradoxically seems to decline with progression of infection, because a receptor shift may take place in advanced stages of HIV-1 disease and indeed CXCR4 viral strains can be increasingly found in these more advanced patient populations. As in early stages of HIV-1-infection CCR5-tropic strains are dominating, the potential for maraviroc use also in earlier stages of disease should not be neglected. Furthermore, based on its excellent tolerability and resistance-profile, a future role for maraviroc can for example be imagined in situations without the presence of three-class ARV drug resistance or experience but in which a change of ARV regimen is needed due to individual drug related intolerabilities or toxicities. A new challenge that will arise in such situations is that tropism testing may not be possible because HIV-viral load lies below 50 c/ml under the actual HAART. Whether tropism testing from stored

samples will be possible before starting a new regimen achieving undetectable viral loads or from proviral DNA remains uncertain at this point of time.
Although maraviroc failed to prove its non-inferiority against efavirenz in patients naive to ARV therapy after
48 weeks of follow-up in the MERIT trial, differences between the studies groups were small and non-inferiority was reached when tropism shifts from screening to baseline were excluded. Clinical evaluation in the MERIT trial is still continuing and 96 weeks results are awaited. Because of lack of further data on the use of maraviroc in earlier therapeutic settings or in ARV-naive individuals, there is an urgent need for further trials evaluating its safety and efficacy also in earlier stages of HIV-1 disease.

9.1Further issues to be kept in mind when considering treatment with maraviroc
No more than an estimated 40 – 50% of pretreated patients are infected solely with CCR5-tropic virus and are possible candidates for treatment with maraviroc treatment [44]. The remaining 50 – 60% of patients with virological failure owing to three-class ARV drug resistance are not expected to benefit from maraviroc treatment. To differentiate between CCR5-tropic and CXCR4-tropic HIV-1, tropism testing before initiation of therapy is needed. Presently, the only commercially available test is the phenotypic Trofile assay. This test requires a high intensity viral load > 500 c/ml, and with costs of  $1500 – 2000 per single test, it carries a financial burden that is not to be underestimated. Moreover blood samples need to be shipped to the US causing further logistical impediments. Alternative tropism assays are at present in development but not yet available for use in clinical practice. A cost-effective analysis of maraviroc use has not yet been performed.

9.2Maraviroc in comparison with other new ARV agents
Recently other new ARV drugs have been introduced, such as the integrase inhibitor raltegravir (Isentress™) or the new second generation non-nucleoside reverse transcriptase inhibitor (NNRTI) etravirine (Intelence), from which likewise enthusiastic reports have been published, indicating important roles in future ARV-therapy. Owing to the different modes of action, these agents do not require previous tropism testing. A comparison of maraviroc with these concurrent new developments in terms of viral suppression shows an equal benefit for the new integrase inhibitor raltegravir that was approved by the FDA in October 2007 for use in combination with other ARV agents for the treatment of HIV-1-infection in treatment-experienced patients with HIV-1 strains resistant to multiple ARV agents, followed by European approval in December 2007 [45]. Raltegravir targets the integration step, in which a strand of HIV genetic material is incorporated into the host cell’s DNA. Approval of

raltegravir was based on the outcome of two large clinical trials, showing safety and efficacy when added to an optimised background regimen in patients with advanced HIV infections that failed previous therapies owing to triple-class ARV drug resistance [46]. The BENCHMRK studies compared raltegravir 400 mg b.i.d. + OBT and demonstrated superior ARV and immunological responses compared to OBT alone that were sustained to 48 weeks [47,48].
In BENCHMRK-1 [47], suppression of HIV RNA
< 50 c/ml was achieved in 65% of raltegravir patients and in 31% of placebo patients at 48 weeks (in comparison: 46% maraviroc b.i.d.; 17% placebo, at 48 weeks, pooled
data [16]).
CD4-count increased to +120 cells/mm3 with raltegravir and
+49 cells/mm3 with placebo (in comparison: +124 cells/mm3 after 48 weeks maraviroc b.i.d. [pooled data] versus
+61 cells/mm3 in the placebo arm [16]).
Another new substance to be compared with maraviroc in the context of resistant HIV-infection is etravirine, a new investigational second generation NNRTI, which obtained accelerated FDA approval on 18 January 2008 for use with other ARV agents for the treatment of HIV-1-infection in treatment-experienced adult patients who have evidence of viral replication and HIV-1 strains resistant to an NNRTI and other ARV agents. Approval was based on the 24-week data from two continuing double-blind, placebo-controlled Phase III studies (Duet-1 and Duet-2), which included 1203 patients [49,50]. Analysis of pooled data from the Duet studies revealed significant superiority of etravirine 200 mg b.i.d. + OBT regarding viral and immunological response. In these studies 74 and 60% of patients on etravirine reached viral loads of < 400 and 50 c/ml respectively, versus 52 and 40% of those receiving background therapy alone (in comparison: viral load < 50 was achieved in 45.5% maraviroc b.i.d. and in 16.7% placebo, at 48 weeks [16]). Increase of CD4-count was also significantly higher in the etravirine group (+81 versus +64 cells/mm3 in the placebo group) [51]. Development of resistance to TMC 125 requires multiple mutations, which is in contrast to resistance evolution for the so far commercially available NNRTIs, making this a promising candidate for use in cases of advanced infection due to ARV drug resistance. Several clinical studies have also suggested the efficacy of etravirine in virological and immunological response in treatment-naive individuals [52,53].

9.3Conclusion
With a hitherto new mechanism of action, maraviroc inhibits entry of HIV-1 into the host cell by blocking the host cell’s chemokine receptor CCR5. Maraviroc is active against current three-drug-class-resistant R5-tropic HIV-1 but not against CXCR4- or dual-tropic virus. Results of clinical trials showed a significant greater decline in HIV-1 RNA and CD4 cell increase with maraviroc treatment compared

to placebo, with an excellent safety profile and tolerability. In August and October 2007, maraviroc was approved in the US and in the EU, respectively, for use in pretreated CCR5-tropic-HIV-1-infected patients. As with all newly approved drugs, long-term data on toxicity are missing, and the clinical role of maraviroc still requires validation in future clinical practice. Challenges of maraviroc are its need for tropism testing, which is associated with high costs and logistical impediments, as well as its frequent interactions with other ARV substances, requiring regular dose adaptations. Despite these constraints and despite the declining number

of CCR5-tropic patients in salvage situations, future role for maraviroc could also be imagined in earlier therapeutic settings, particularly if its safety profile remains as clean as first results from Phase III trials have indicated.

Declaration of interest

J Rockstroh has received lecture fees and advisory honoraria from Abbott, Bristol-Myers Squibb, Boehringer Ingelheim, Gilead, GlaxoSmithKline, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Schering-Plough, Tibotec and Vertex.

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Affiliation
Jetske M Emmelkamp & Jürgen K Rockstroh†
†Author for correspondence University Clinic Bonn, Department of Medicine I, Sigmund-Freud-Str. 25,
53105 Bonn, Germany
Tel: +49 228 287 16558;
Fax: +49 228 287 15034;
E-mail: [email protected]