Our experience with maraviroc treatment in HIV positive patients

Summary

Background:
Although antiretroviral therapy has changed the clinical course of HIV infection, AIDS remains an incurable disease. Virus entry inhibitors, including maraviroc as the only registered representative of the class, represent a newly emerged group of anti-retrovirals with novel mechanism of action. The primary endpoint is to evaluate the clinical efficacy parameter of maraviroc by measuring viral load at the end of the 4 week treatment period. The secondary endpoint is to evaluate the effectiveness of the drug by monitoring the changes of the viral load values and CD4 + cell counts during the period of 125 weeks. Drug safety was also assessed.

Methods and results:
Data of 23 subjects were collected, 21 patients were from the Czech Republic and 2 patients from France. Decrease in viral load in the 4th, 24th and 48th week was more than two orders of magnitude (-2.136; -2.448; -2.452 log₁₀ copies/ml). The CD4 + cells led to an increase of values (71.71, 143.00, 196.43 cells/mm³). Drug safety was assessed by monitoring the frequency of adverse effects. The data obtained were compared with the III. phase of clinical trials.

Conclusions:
Our experience with maraviroc was positive. Maraviroc proved to be an effective antiretroviral agent for a combination therapy of HIV infection.

Key words:
maraviroc, CCR5 inhibitors, HIV, AIDS.

Acquired Immune Deficiency Syndrome (AIDS) is a set of symptoms and infections resulting from the escalating damage to the humann immune system with Human immunodeficiency virus (HIV). This progression and the associated clinical picture was divided into six stages according to the Walter-Reed classification system. HIV infection can be classified into 3 phases: phase of primary infection, chronic phase and advanced stages of AIDS (1). The virus belongs to a group of lentiviruses, which is a subgroup of retroviruses. There are two major families of the HIV virus: the predominant HIV-1 and less pathogenic HIV-2. Family HIV-1 is further comprised from seven groups. Geographically, the family of HIV-1 is worldwide extended. HIV-1 class B dominates especially in North America and Europe. Among the different classes of HIV-1, biological differences are apparent. A person, as well as a cell can be infected simultaneously by more types of HIV (2).

There has been a great progress in the development of therapies for HIV infection, which have brought benefits for many patients. However, despite those achievements,viral resistance and tolerance remain the limiting factors of treatment (3). Modern group of anti-retrovirals with new mechanisms of actions are entering the drug market. One of these emerging groups are the inhibitors of HIV entry into the cells. Currently maraviroc is the first-in-class of CCR5 anatgonists and the only registered representative drug at the moment. Maraviroc selectively binds to the human chemokine receptor CCR5 (4). The rationale behind the use of CCR5-antagonists in treatment of HIV infection is based on the fact that HIV requires the binding to both the CD4-receptor and a co-receptor to enter a cell (5,6). The two relevant co-receptors are CCR5 and CXCR4. HIV can be either CCR5-tropic or CXCR4-tropic, so called tropism. Virus isolates replicating on both CCR5- and CXCR4-positive cells may do so either because they contain a mixture of R5- and X4-tropic virus, or they use both CCR5 andCXCR4. If the CCR5 receptor is blocked by CCR5-antagonists, CCR5-tropic HIV cannot enter the cell (7).

Maraviroc has been registered in the European Union in October 2008. (8). Maraviroc, in combination with other antiretroviral medicinal products, is indicated for treatment-experienced adult patients infected with only detectable CCR5-tropic HIV-1. In November 2009, The U.S. Food and Drug Administration (FDA) approved maraviroc for treatment-naïve adult HIV patients with exclusively CCR5-tropic virus (4). Maraviroc is a substrate of cytochrome P450 CYP3A4. Dose adjustment of maraviroc is recommended when co-administered with CYP3A4 inhibitors and/or inducers. Renal clearance accounts for approximately 23 % of the total clearance. The most frequently reported adverse reactions in the 3rd phase clinical trials were nausea, diarrhea and headache. These adverse reactions were frequent (≥ 1/100 to < 1/10). Although the HIV-1 clinical isolates resistant to standard antiretroviral therapy were all susceptible to maraviroc in pre-registration studies, it can be assumed that resistance to maraviroc will appear in the future (9).

Patients and methods

Twenty-three subjects were enrolled in the group of patients receiving maraviroc as a part of their antiretroviral therapy. Two patients were followed at the AIDS center at the Prague University Hospital in Bulovka and 21 patients were treated at Centre Hospitalier Universitaire Montpellier Lapeyronie in Montpellier. The main inclusion criteria were preceeding treatement or therapeutic failure in the anamnesis (viral load greater than 5,000 RNA copies/ml or the need for discontinuation), stable treatement (or no treatement) for a minimum of 4 weeks prior to screening, age over 16 years, CCR5 tropic HIV-1 at baseline. Viral load was evaluated before the maraviroc treatment and subsequently during the therapy. Trofile assay was conducted in San Francisco and the results were available in 3-4 weeks.

Treatment efficacy was evidenced by viral load that is a measure of the severity of a viral infection. It was given in RNA copies per milliliter of blood plasma. Detection method for measuring levels of viral load had a sensitivity of 20 copiesof RNA/ml. We transferred the viral load values to logarithmic values and we followed the decrease of viral load in the hundreds. Secondary efficacy parameter was the number of CD4 + cells. It reflects the immunological status of the patient. Both efficacy parameters were recorded at fixed time intervals, immediately before treatment and approximately in the 4th, 24th and 48th week of maravirocem treatment. Primary efficacy parameter was set to be viral load at week 4 of maraviroc treatment, other time-points were considered as secondary. Safety and tolerance to maraviroc were observed too. All un desirable effects during the treatment were identified and compared to the SPC data and conclusions of the 3rd phase of clinical trials MOTIVATE 1 and MOTIVATE 2.

Statistical methods

The nonparametric paired Wilcoxon test (statistical software Unistat 5.1.) was used for statistical evaluation of the changes in viral load and number of CD4 + cells. The p-values less than 0.05 were considered significant.

Results

Patient demographics and baseline characteristics are summarised in Table 1. The minimum of durationof the HIV treatment infectionwas 9 years.

Table 2 outlines changes in viral load including the proportion of patients with HIV-RNA < 50 copies/mL and the proportion of patients with HIV-RNA < 400 copies/mL. Differencesbetweenbaselineand values at other time intervals were statistically highly significant (p-values<0.01). Percentage of patients achieving viral load values below 400 copies/ml during treatment increased significantly (p-values<0.01). Also, the percentage of patients achieving values of viral load below 50 copies/ml at the time grew significantly (p-values < 0.01).

Change in CD4+ cells in the time intervals is presented in Table 3. The values of viral load and numbers of CD4 +cells during the study are captured in Figure 1 and Figure 2. A two-eponential pattern of decline in viral load was observed. Rapid decrease of viral load with therapeutic half-life of 1.7 weeks was noted up to week 8, followed by a slow decrease phase with therapeutic half-life of 404.9 weeks. Increase in CD4+ lymphocytes was negatively related to viral load values (r = -0,80; p<0.01).

None of the patients resigned fromthe maraviroc treatment. Neither physicians nor patients reported any adverse effects both at the French and at the Czech AIDS centers. Even patients intolerant to the prior antiretroviral treatment had no adverese reactions to maraviroc. There were 11 suspected adverse reactions in 8 patients. Neurological reactions, acute obstructive renal insufficiency, cardiac ischemia and bone pain, elevated uric acid, hypercholsterolemia, hypertriglyceridemia and immune reconstitution inflammatory syndrome were noted.

Discussion

HIV/AIDS is still a serious public health problem (10). Evident increase in transmission of the virus is regularly recorded in many countries including the Czech Republic, where 1536 new HIV cases were reported in the period of October, 1985 to January, 2011 (11). Moreover, prevalence is increasing annually. Despite the decrease in morbidity and mortality due to AIDS following the introduction of combined antiretroviral therapy (cART), the efficacy of the treatment is still significantly limited by several factors. The three most common reasons for treatment failure are poor compliance, bad tolerance of treatment and lack of efficacy. Moreover, all available antiretroviral-drug only provide a temporary suppression of viral load (12).

There was a marked decrease inviral load by about two orders (2.136). For the vast majority of patients the use of maraviroc significantly reduced the value of viral load and maintained that value throughout the whole period (ie. to the 125th week). We noted continuous decreasing trend after 8 weeks of treatment, but there is substantial interindividual variability also affected by a number of factors such as compliance of the patient and his general health conditions and incidence of superinfections. A positive outcome is also a high percentage of patients achieving viral load below 400 RNA copies/ml of blood very early after starting the therapy. Further, in time increasing percentage of patients that reach values of less than 50 copies RNA/ml suggests good therapeutic efficacy. Our results confirm the results obtained during the phase III clinical trials. The maximum reduction in viral load for as long as possible is one of the major therapeutic targets, because it stops or delays the progression of the disease and helps to prevent the development of resistance (13). According to the current clinical guidelines, after a month of treatment, the viral load should decline by at least one order of magnitude, to declare a successful drug therapy (12).

The second main parameter – the CD4+ count is a predictor of progression to AIDS and that shows patient's immunological status. It reflects the imbalance between production and destruction of CD4 + T lymphocytes (12). For individual patients, the increase is slow and fluctuating. This can be explained by the difficulty to restore normal functioning of the human immune system, compliance of the patients and also a various health condition of each patient. Immune reconstitution inflammatory syndrome (IRIS) is another complication of the improvement of the immune system. IRIS occurs in 10-32% of patiens after the introduction of antiretroviral therapy or after a temporary interruption. The clinical condition worsens and patients develop symptoms compatible with infectious diseases (14). One patient in our study was suspected to have a presence of this syndrome. He experienced symptoms of acute influenza illness shortly after initiation of treatment. This complication did not require pharmacological treatment. Even in the case of CD4 + count, our results confirm the results of clinical trials of Maraviroc.

During this study, no patient discontinued treatment due to poor tolerance. During the treatment, there were some possible suspected adverse reactions of maraviroc, but none of them have proven causal relation with maraviroc. Patients received a combination of several antiretroviral drugs at the same time, and the experienced adverse effects could therefore be associated with drugs other than maraviroc. According to the results of clinical trials the occurrence of diarrhea, nausea andheadaches was expected. These side effects occurred frequently, ie in 0.01 - 0.1% of cases inthe 3rd phase studies. Out of the three before mentioned expected adverse effects, headache was the only adverse event experienced in our group of patients.

Our work generally confirms the results of clinical studies A4001027 and A4001028 held, in the U.S., Canada, Europe and Australia (15). We conclude that maraviroc was effective, generally safe and well tolerated drug for combination therapy of HIV infection.

Abbreviations

• AIDS – acquired immune deficiency syndrome
• cART – Combined Antiretroviral Therapy
• FDA – Food and Drug Administration agency of the United States
• HIV – human immunodeficiency virus
• IRIS – immune reconstitution inflammatory syndrome
• OBT – optimized background theraoy
• RNA – ribonucleic acid
• SD – standard deviation
• SPC – summary of product characteristics
• T_1/2 – therapeutic half-life
• VL – viral load

Acknowledgements

We thank  Sylvie Hansel-Esteller a Nicolas Terrail from collaborating Centre Hospitalier Universitaire Montpellier.

PharmDr. Hana Vondráčková
Farmakologický ústav 1. LF UK
Albertov 4
128 00 Praha 2
Email: hana.vondrackova@centrum.cz