Hana Vondráčková 1; Marie Staňková 2; Ladislav Machala 3; František Perlík 1; Ondřej Slanař 1
Univerzita Karlova v Praze, 1. lékařská fakulta, Farmakologický ústav
1; Univerzita Karlova v Praze, 1. lékařská fakulta, AIDS centrum FN Na Bulovce, Infekční klinika 1. LF UK a FN Na Bulovce
2; Univerzita Karlova v Praze, 2. lékařská fakulta, AIDS centrum FN Na Bulovce, Infekční klinika FN Na Bulovce
Čas. Lék. čes. 2011; 150: 447-450
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
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).
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
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
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.
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.
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.
Patient demographics and baseline characteristics are summarised in
Table 1. The minimum of durationof the HIV treatment infectionwas 9
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
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;
None of the patients resigned fromthe maraviroc treatment. Neither physicians nor patients reported any adverse effects both 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
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
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
use of maraviroc significantly reduced the
value of viral load and maintained that value throughout the whole period
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
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
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.
study, no patient discontinued treatment due to poor tolerance.
During the treatment,
there were some possible suspected adverse reactions
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
drugs other than maraviroc. According to
the results of clinical trials the
occurrence of diarrhea,
nausea andheadaches was expected.
These side effects occurred frequently,
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
Europe and Australia
(15). We conclude that maraviroc
was effective, generally safe and well
tolerated drug for combination therapy of HIV infection.
acquired immune deficiency syndrome
Combined Antiretroviral Therapy
Food and Drug Administration agency
of the United
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: email@example.com
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