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HIV and AIDS
of hyperglycaemia and diabetes associated with the use of PIs prompted Darunavir (DRV) is another new PI with potent ARV activity that also
a warning from the US Food and Drug Administration (FDA) in June 1997. displays a high genetic barrier to the development of resistance.
23
In 1998, the first reports of lipodystrophy were published,
15
followed by RTV-boosted darunavir has proved to be effective and well tolerated in
the description of mitochondrial toxicity and its consequences in 1999.
16,17
highly treatment-experienced patients.
24,25
Darunavir was approved by
Physicians now became more reserved with regard to the previously the FDA in June 2006 for use in ARV treatment in patients failing
generous administration of ARV drugs. In view of an expected lifelong previous ARV therapy. Approval in Europe followed in February 2007. In
treatment with multiple drugs that possibly had cumulative toxic effects – the recently published TITAN study, the efficacy of DRV/r was superior
as well as the risk of developing drug resistance in cases of suboptimal to that of LPV/r at 48 weeks of therapy in LPV-naïve HIV-infected
compliance, which limits future treatment options – the concept changed patients in terms of viral suppression.
26
There was no significant
from early initiation of HAART to a new approach: ‘hit hard, but only difference in the occurrence of toxicities and adverse events between
when necessary’, as expressed by Harrington and Carpenter in 2000.
18
the two treatment arms in this trial. Also in the ARTEMIS trial in ARV-
naïve patients, once-daily RTV was not inferior to twice-daily
The possibilities of combining ARV substances in HAART seemed endless. lopinavir–RTV in suppression of HIV viral load to <50c/ml (84 versus
However, high pill burden and the occurrence of undesirable adverse 81%),
27
whereas only 71% patients receiving once-daily lopinavir–RTV
events made systematic and regular application difficult for many reached HIV-RNA <50c/ml.
patients. The development of fixed-dose combination tablets (AZT+3TC in
combivir, TDF+FTC in truvada, ABC+3TC in kivexa, LPV+RTV in kaletra and CCR5 Antagonists – Maraviroc (Celsentri)
AZT+3TC+ABC in trizivir) eased drug administration and improved patient With a hitherto novel mechanism of action, the CCR5 antagonists inhibit
compliance. Moreover, whereas in early HAART days multiple tablets were entry of HIV into the host cell by blocking the host cell’s chemokine
to be taken several times a day, once-daily administration became possible receptor CCR5. The CCR5 receptor antagonist maraviroc is active against
as a result of improved pharmacokinetics. With the combination of current triple-class-resistant R5-tropic HIV-1, but not against CXCR4 or
TDF+FTC+EFV in atripla, a complete HAART is now incorporated in one the dual-tropic virus. Results of clinical trials with maraviroc showed a
single tablet, which is administrated only once a day.
19
In 2006, atripla was significantly greater decline in HIV RNA and CD4 cell increase with
approved for use in HIV treatment in the US and it is expected to reach the maraviroc treatment compared with placebo, with no clinically relevant
European market by the end of 2007 (see Figure 1). differences in safety profile and tolerability.
28,29
In October 2007,
maraviroc was approved in the EU for use in pre-treated CCR5-tropic-
Recent Developments in Antiretroviral Therapy HIV-infected patients.
In an attempt to overcome the increasing levels of worldwide ARV drug
resistance, further studies are continuously being performed in order to Integrase Inhibitors – Raltegravir (Isentress)
create new ARV substances. In the following section, we will briefly discuss Integrase inhibitors target the integration step, in which a strand of HIV
the most recent developments in the previously described ARV classes. genetic material is incorporated into the host cell’s DNA. Raltegravir was
approved by the FDA on 12 October 2007 for use in combination with
Fusion Inhibitors other ARV agents for the treatment of HIV-1 infection in treatment-
The fusion inhibitor enfuvirtid (T20) became available for ARV treatment in experienced patients with HIV-1 strains resistant to multiple ARV agents.
2003. T20 has a new mechanism of action involving disruption of HIV entry In a phase II trial, raltegravir showed safety and efficacy when added to
at the stage of membrane fusion, and is associated with a reduced potential an optimised background regimen in patients with advanced HIV
for cross-resistance with conventional classes of ARV agents. Drug infections that failed previous therapies because of triple-class ARV drug
interactions and intracellular metabolic disturbances are unlikely because of resistance, thereby strengthening the potential of raltegravir to become
its extra-cellular distribution.
20
Downsides of T20 are the need for twice-daily an important component of HAART in heavily pre-treated patients who
subcutaneous injections and a high incidence of injection site reactions. have failed previous therapies as a result of multidrug resistance.
30
New Protease Inhibitors Antiretroviral Substances in Late Stages of
In the PI class, two new substances have been approved for use in ARV Clinical Evaluation
treatment and have shown promising results for use in cases of resistant
HIV strains. New Non-nucleoside Reverse Transcriptase Inhibitors
Etravirine (TMC 125) is a new investigational NNRTI. Development of
Tipranavir (TPV) is a new PI that showed good activity against HIV that is resistance to TMC 125 requires multiple mutations, which is in contrast to
resistant to other PIs. The superiority of RTV-boosted tipranavir in resistance evolution for the existing commercially available NNRTIs. Several
virological and immunological response was reported compared with clinical studies have suggested the efficacy of etravirine in virological and
other currently used PIs after 48 weeks of treatment in patients with immunological response in treatment-naïve individuals.
31,32
The efficacy of
triple-class ARV resistance.
21
However, dyslipidaemia and elevation of etravirine after 48 weeks of treatment was also shown in heavily
liver enzymes occurred significantly more frequently in the tipranavir pre-treated patients with substantial NNRTI and PI resistance.
33
Etravirine
group than in the control PI group. Tipranavir causes significant provided superior efficacy compared with placebo against a background
interactions with other ARV drugs. Plasma concentrations of AZT and regimen comprising RTV-boosted DRV at week 24 in multiple treatment-
ABC may be altered by co-administration of tipranavir, but generally do experienced patients.
34,35
not require dose adaptation. Tipranavir should not be combined with
LPV/r, SQV, ATV or APV.
22
The use of tipranavir in ARV therapy regimens Another new NNRTI in clinical development is rilpivirine (TMC 278),
was first approved in June 2006. which has shown potent short-term activity against most NNRTI-
38 EUROPEAN INFECTIOUS DISEASE 2007
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