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HIV Medicine 2007 818 pages Download PDF, 3.7 MB Collaborators About  Other Languages 2007 Portuguese 2005 Russian Spanisch 2003 Persian (Farsi) Copyright Removal Mailing List Privacy
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HIV Therapy 2007 back 5.3: ART 2007/2008 - The horizon and beyond by Christian Hoffmann and Fiona Mulcahy
Refurbished old drugs
Several currently available drugs are under further development, the most important goals being the
reduction of pill burden, and easier dosing. Three such preparations to have recently entered the
market are Invirase 500™, Truvada™ and Kivexa™; Atripla™ will arrive soon. New improvements are
being developed.
Atripla™ is the combination of tenofovir+FTC (Truvada™) and efavirenz (Sustiva™). This preparation
is unique in that it is the first in the history of HIV medicine in which companies have come
together to produce a combination tablet: TDF+FTC come from Gilead; efavirenz comes from BMS.
Atripla™ is regarded (together, Truvada™ and Sustiva™ are just two tablets, anyway) as
psychologically important for patients and clinicians. One tablet a day is a complete and effective
therapy! Some experts, who remember the early HAART regimens with six tablets three times a day,
will be very pleased. The production of the combination was not easy, and a two-layer film-coated
tablet was decided upon, in which both preparations - Truvada™ and Sustiva™ - are simply pressed
together. Bioequivalence to the individual agents has been shown (Mathias 2006). Atripla™ was
licensed by the FDA in July 2006. and is expected in Europe at the end of 2007.
Nelfinavir 625 mg - this new formulation was approved in the US in April 2003. It reduces the
nelfinavir dose to 2 tablets bid. One study has shown that this formulation is better tolerated,
particularly with respect to gastrointestinal side effects - despite the fact that plasma levels are
around 30 % higher than with the previous nelfinavir formulation (Johnson 2003, Kaeser 2003). In
Europe, where nelfinavir is produced and sold by Roche instead of Pfizer, the 625 mg tablet is not
available.
Zerit PRC™ (PRC = "prolonged release capsule", or XR = "extended release") is a capsulated
formulation of d4T (Baril 2002), which was approved in Europe in October 2002, but which never
reached or will reach the market. D4T is definitely "out". Instead, other attempts are currently
underway to improve d4T through modifications to its molecular structure (Haraguchi 2003, Dutschman
2004).
Viramune™ Extended-Release is an improved formulation of conventional nevirapine. It should allow
once daily dosing of nevirapine in one tablet. Boehringer is currently conducting extensive studies
on this formulation.
Norvir™ tablets are actually the bioequivalent to the capsules used until now, as shown in an
initial study on a healthy proband (Cai 2007). When this has been confirmed on larger patient
numbers the bothersome refrigeration of ritonavir could finally become superfluous.
Generic combinations are not so difficult to produce, as experience in Africa, India or Thailand has
shown. Bioequivalence can also usually be demonstrated (Laurent 2004). Fixed combinations such as
Triomune from Cipla (d4T+3TC+nevirapine), GPO (d4T+3TC+nevirapine) or Zidovex-LN from Imunus
(AZT+3TC+nevirapine) are just a few examples. These preparations are not currently as important in
industrialized countries,but this may change in the future as patents for several agents run out.
References
1. Baril JG, Pollard RB, Raffi FM, et al. Stavudine extended/prolonged release (XR/PRC) vs.
stavudine immediate release in combination with lamivudine and efavirenz: 48 week efficacy and
safety. Abstract LbPeB9014, 14th Int AIDS Conf 2002, Barcelona.
2. Cai Y, Klein C, Roggatz U, et al. Bioequivalence of pilot tablet formulations of ritonavir to the
marketed soft gel capsule at a dose of 100 mg. Abstract 52LB, 14th CROI 2007, Los Angeles. Abstract:
http://www.retroconference.org/2007/Abstracts/30518.htm
3. Dutschman GE, Grill SP, Gullen EA, et al. Novel 4'-substituted stavudine analog with improved
anti-HIV activity and decreased cytotoxicity. Antimicrob Agents Chemother 2004, 48:1640-6.
http://amedeo.com/lit.php?id=15105115
4. Haraguchi K, Takeda S, Tanaka H, et al. Synthesis of a highly active new anti-HIV agent
2',3'-didehydro-3'-deoxy-4'-ethynylthymidine. Bioorg Med Chem Lett 2003, 13:3775-7.
http://amedeo.com/lit.php?id=14552777
5. Johnson M, Nieto-Cisneros L, Horban A, et al. Viracept (Nelfinavir) 625 mg film-coated tablets:
investigation of safety and gastrointestinal tolerability of this new formulation in comparison with
250 mg film-coated tablets (Viracept) in HIV patients. Abstract 548, 2nd IAS 2003, Paris.
6. Kaeser B, Akintola DJ, Saifulanwar A, et al. Improved gastrointestinal tolerability of Roche
nelfinavir 625 mg film-coated tablets. Abstract 6.4, 4th Int Worksh Clin Pharma HIV Ther 2003,
Cannes.
7. Laurent C, Kouanfack C, Koulla-Shiro S, et al. Effectiveness and safety of a generic fixed-dose
combination of nevirapine, stavudine, and lamivudine in HIV-1-infected adults in Cameroon:
open-label multicentre trial. Lancet 2004, 364:29-34. http://amedeo.com/lit.php?id=15234853
8. Mathias A, Plummer A, Skillington J, et al. Bioequivalence of the coformulation of
efavirenz/emtricitabine/tenofovir DF. Abstract TUE0098, XVI IAC 2006, Toronto.
New nucleoside analogs
Since the development of DAPD and dexelvucitabine (reverset) came to a halt, hopes are now limited
that there will be new nucleoside analogs on the market in the near future. At the moment, nothing
has past Phase II studies in the development - it seems to be difficult to find new NRTIs, which
have a reduced mitochondrial toxicity and efficacy against resistant viruses.
Apricitabine (AVX-754, earlier SPD-754) is a heterocyclic cytidine analog that was sold by Shire
Biochem to Avexa at the beginning of 2005. In vitro, Apricitabine, which is chemically similar to
3TC, is active against a broad spectrum of TAMs, and up to 5 NRTI mutations do not significantly
impair its activity (Bethell 2005, Gu 2006). In a placebo-controlled study, the viral load decreased
on a 10-day monotherapy by 1.2 to 1.4 logs - good potency for a NRTI (Cahn 2006). Apricitabine has
been well tolerated and has good oral bioavailability (Francis 2003). What about long-term toxicity?
In monkeys, there were minor skin problems, usually hyperpigmentation, after 52 weeks of exposure.
Apricitabine was thus significantly less toxic than its racemate BCH-10652, which caused severe
degenerative dermatopathy in the monkeys (Locas 2004). 3TC and FTC lower intracellular levels of
apricitabine, and the combination with other cytidine analogs is therefore problematic. Avexa is
currently planning Phase IIb studies, and Apricitabine is expected to come onto the market in 2009.
Dioxolanthymidine (DOT) is a new thymidine analog - one of the few new substances in this sub-group.
Dioxolanthymidine appears relatively good in preclinical trials (Chung 2005, Liang 2006) - now
clinical studies have to show what is possible with DOT. Phase I studies are underway.
Elvucitabine (or ACH-126,443) is a nucleoside analog developed by Achillion Pharmaceuticals. It is
an enantiomer of dexelvucitabine, with the chemical name beta-L-D4FC, and is also effective against
HIV and HBV. In vitro studies show potency even in the presence of numerous NRTI mutations, and
viruses with completely unique resistances, such as M184I or the so far unknown mutant D237E, are
selected for (Fabrycki 2003). It is also of interest because it seems to have low mitochondrial
toxicity, as well as an extremely long half-life of 150 hours (Dunkle 2001, Colucci 2005). Phase II
studies are underway on HIV and HBV. A small, double blind study showed a reduction in viral load of
between 0.7 - 0.8 logs after 28 days in HIV patients with the M184V mutation. However, this study
had to be terminated, as 6/56 patients developed leukopenia on a dose of 100 mg elvucitabine (Dunkle
2003). Several patients also developed rashes. In vitro, mitochondrial toxicity is less than with
dexelvucitabine, and the binding affinity to reverse transcriptase resistant viruses may also be
less (Murakami 2004). Does the improved tolerability compromise the efficacy? At the moment, studies
are being conducted with a low dose (10 mg) on patients with the M184V mutation.
Fosalvudine, produced by Heidelberg Pharma, is a NRTI, which consists of a carrier molecule coupled
to an intermediate stage (= "enhanced pro-drug principle") of fluorothymidine alovudine. The active
portion is only released after enzymatic cleavage in the tissue. The idea is that the usual
toxicities are thus reduced. Fosalvudine is currently in Phase I/II trials.
Fozivudine has also been developed from AZT on the "enhanced pro-drug principle" by Heidelberg
Pharma. In Phase I/II studies (Bogner 1997, Girard 2000), fozivudine was well tolerated, but only
moderately virologically effective - after 4 weeks on the highest dose, the viral load fell by just
0.7 logs (Girard 2000). According to the company, they are currently looking for a partner to enter
into Phase IIb/III studies.
KP-1461 from Koronis is an oral pro-drug from KP-1212, an NRTI that remains clearly effective in the
presence of numerous NRTI resistances. The method of action (selective viral mutagenesis)
distinguishes it from classical NRTIs, which induce interruption of the chain (Harris 2005). There
are no cross-resistances to other NRTIs and also no mitochondrial toxicity. In Phase Ia studies,
this exciting agent was well tolerated by a healthy proband. At the end of 2006, the first Phase Ib
study on HIV-infected patients was completed.
MIV-210 is a precursor of the guanosine analog FLG from Medivir, which also has HBV efficacy and
maintains its efficacy in vitro against diverse NRTI resistances (multiple TAMs, as well as
T69-insertions) (Zhang 2002). In 2003, a collaboration between Medivir and GSK was agreed upon,
although GSK have since withdrawn again - the development of MIV-210 should go ahead nevertheless.
In September 2005, a Phase IIa study was started on HIV-infected patients. Because similar
(fluoridated) agents, such as lodenosine were above all hepatotoxic, one of the main foci is on
tolerability.
Phosphazide (Nicavir), which is very similar to AZT, is a nucleoside analog that was developed (and
is already marketed) in Russia. After 12 weeks of phosphazide monotherapy (400 mg), viral load
dropped by median 0.7 logs. Since phosphazide is a prodrug of AZT, it requires an additional
activation step. The D67N mutation seems to reduce efficacy (Machado 1999). further studies have
shown potency in combination with ddI and nevirapine (Kravtchenko 2000), or saquinavir (Sitdykova
2003). It is hard to see the advantage over AZT - although better tolerability had been presumed,
this has not been proven.
Racivir is a cytidine analog produced by Pharmasset. It is a mixture of FTC and its enantiomer.
Possibly, both enantiomers have different resistance profiles so that, theoretically, the
development of resistance is impeded (Hurwitz 2005). It has shown good antiviral activity in
combination with d4T and efavirenz after two weeks (Herzmann 2005). A double blind, randomized study
on 42 patients with the M184V mutation still showed an effect of 0.4 logs at 28 days (Cahn 2007).
Stampidine is a nucleoside analog developed by the American Parker Hughes Institute. It resembles
d4T and is apparently 100 times more potent than AZT in vitro (Uckun 2002). It also has activity
against HIV mutants with up to 5 TAMs (Uckun 2006). It could potentially also be used as a
microbicide (D'Cruz 2004). Studies on HIV patients were announced some time ago, but data are not
yet available.
Out of sight, out of mind: the following NRTIs are not being pursued:
· Adefovir dipivoxil from Gilead, hardly any activity against HIV, nephrotoxicity
· FddA (Lodenosine™) from Bioscience, 1999, severe liver/kidney damage
· dOTC from Biochem Pharma, toxicity in monkeys
· Lobucavir from BMS, carcinogenicity
· GS 7340 from Gilead, stopped at the beginning of 2004 due to changes in the eye lenses.
Development may possibly be resumed ?
· DAPD (Amdoxovir) from Gilead, beginning of 2004, changes to the lenses in the eyes, possibly being
developed further (?)
· SPD-756 (BCH-13520) and SPD-761
· MIV-310 (Alovudin, FLT) from Boehringer, March 2005, disappointing Phase II study.
· Dexelvucitabine (Reverset) from Incyte, 2006, pancreatitis
References
1. Bethell RC, Lie YS, Parkin NT. In vitro activity of SPD754, a new deoxycytidine nucleoside
reverse transcriptase inhibitor (NRTI), against 215 HIV-1 isolates resistant to other NRTIs. Antivir
Chem Chemother 2005, 16:295-302. http://amedeo.com/lit.php?id=16245645
2. Bogner JR, Roecken M, Herrmann DB, Boerner D, Kaufmann B, Gurtler L, Plewig G, Goebel FD. Phase
I/II trial with fozivudine tidoxil (BM 21.1290): a 7 day randomized, placebo-controlled
dose-escalating trial. Antivir Ther 1997, 2:257-64. http://amedeo.com/lit.php?id=11327445
3. Cahn P, Cassetti I, Wood R, et al. Efficacy and tolerability of 10-day monotherapy with
apricitabine in antiretroviral-naive, HIV-infected patients. AIDS 2006, 20:1261-8.
http://amedeo.com/lit.php?id=16816554
4. Cahn P, Sosa N, Wiznia A, et al. Racivir demonstrates safety and efficacy in patients harbouring
HIV with the M184V mutation and > 3 TAM. Abstract 488, 14th CROI 2007, Los Angeles. Abstract:
http://www.retroconference.org/2007/Abstracts/30151.htm
5. Chung KC, Yadav V, Rapp K, Chong Y, Schinazi R. Dioxolane thymine nucleoside is active against a
variety of NRTI-resistant mutants. Abstract 554, 12th CROI 2005, Boston.
6. Colucci P, Pottage J, Robison H, et al. The different clinical pharmacology of elvucitabine
(beta-L-Fd4C) enables the drug to be given in a safe and effective manner with innovative drug
dosing. Abstract LB-27, 45th ICAAC 2005, Washington.
7. D'Cruz OJ, Uckun FM. Stampidine is a potential nonspermicidal broad-spectrum anti-HIV
microbicide. Fertil Steril 2004, 1:831-41. http://amedeo.com/lit.php?id=15019817
8. Dunkle LM, Gathe JC, Pedevillano DE, et al. Elvucitabine: potent antiviral activity demonstrated
in multidrug-resistant HIV infection. Antiviral Therapy 2003, 8:S5.
9. Dunkle LM, Oshana1 SC, Cheng YC, et al. ACH-126,443: a new nucleoside analog with potent activity
against wild type and resistant HIV-1 and a promising pharmacokinetic and mitochondrial safety
profile. Abstract 303, 8th CROI 2001, Chicago.
http://www.retroconference.org/2001/abstracts/abstracts/abstracts/303.htm
10. Fabrycki J, Zhoa Y, Wearne J, et al. In vitro induction of HIV variants with reduced
susceptibility to elvucitabine (ACH-126,443,beta-L-Fd4C). Antiviral Therapy 2003, 8:S8.
11. Francis RJ, Lanclos L, Shiveley L, Sawyer J. Pharmacokinetics of SPD-754, a new cytidine analog
in healthy volunteers. Abstract 528, 2nd IAS 2003, Paris.
12. Girard PM, Pegram PS, Diquet B, et al. Phase II placebo-controlled trial of fozivudine tidoxil
for HIV infection: pharmacokinetics, tolerability, and efficacy. J AIDS 2000, 23:227-35.
http://amedeo.com/lit.php?id=10839658
13. Gu Z, Allard B, de Muys JM, et al. In vitro antiretroviral activity and in vitro toxicity
profile of SPD754, a new deoxycytidine nucleoside reverse transcriptase inhibitor for treatment of
human immunodeficiency virus infection. Antimicrob Agents Chemother 2006, 50:625-31.
http://amedeo.com/lit.php?id=16436719
14. Harris KS, Brabant W, Styrchak S, Gall A, Daifuku R. KP-1212/1461, a nucleoside designed for the
treatment of HIV by viral mutagenesis. Antiviral Res 2005, 67:1-9.
http://amedeo.com/lit.php?id=15890415
15. Herzmann C, Arasteh K, Murphy RL, et al. Safety, pharmacokinetics, and efficacy of
(+/-)-beta-2',3'-dideoxy-5-fluoro-3'-thiacytidine with efavirenz and stavudine in
antiretroviral-naive HIV-infected patients. Antimicrob Agents Chemother 2005, 49:2828-33.
http://amedeo.com/lit.php?id=15980356
16. Holdich T, Shiveley L, Sawyer J. Pharmacokinetics of single oral doses of apricitabine, a novel
deoxycytidine analogue reverse transcriptase inhibitor, in healthy volunteers. Clin Drug Investig
2006, 26:279-86. http://amedeo.com/lit.php?id=17163261
17. Hurwitz SJ, Otto MJ, Schinazi RF. Comparative pharmacokinetics of Racivir,
(+/-)-beta-2',3'-dideoxy-5-fluoro-3'-thiacytidine in rats, rabbits, dogs, monkeys and HIV-infected
humans. Antivir Chem Chemother 2005, 16:117-27. http://amedeo.com/lit.php?id=15889534
18. Katlama C, Ghosn J, Tubiana R, et al. MIV-310 reduces HIV viral load in patients failing
multiple antiretroviral therapy: results from a 4-week phase II study. AIDS 2004, 18:1299-304.
http://amedeo.com/lit.php?id=15362662
19. Kim EY, Vrang L, Oberg B, Merigan TC. Anti-HIV type 1 activity of 3'-fluoro-3'-deoxythymidine
for several different multidrug-resistant mutants. AIDS Res Hum Retroviruses 2001, 17:401-7.
http://amedeo.com/lit.php?id=11282008
20. Kravtchenko AV, Salamov GG, Serebrovskaya LV, et al. The first experience of HAART with
phosphazid + didanosine + nevirapine in HIV-infected patients in Russia. Abstract 3, 5th Int Conf
Drug Therapy 2000, Glasgow, Scotland.
21. Liang Y, Narayanasamy J, Schinazi RF, Chu CK. Phosphoramidate and phosphate prodrugs of
(-)-beta-d-(2R,4R)-dioxolane-thymine: Synthesis, anti-HIV activity and stability studies. Bioorg Med
Chem 2006, 14:2178-89. http://amedeo.com/lit.php?id=16314108
22. Locas C, Ching S, Damment S. Safety profile of SPD754 in cynomolgus monkeys treated for 52
weeks, Abstract 527, 11th CROI 2004, San Francisco.
http://www.retroconference.org/2004/cd/Abstract/527.htm
23. Machado J, Tsoukas C, Salomon H, et al. Antiviral activity and resistance profile of phosphazid
- a novel prodrug of AZT. Abstract 594, 6th CROI 1999, Chicago.
24. Murakami E, Ray AS, Schinazi RF, Anderson KS. Investigating the effects of stereochemistry on
incorporation and removal of 5-fluorocytidine analogs by mitochondrial DNA polymerase gamma:
comparison of D- and L-D4FC-TP. Antiviral Res 2004, 62:57-64. http://amedeo.com/lit.php?id=15026203
25. Murphy RL, Schürmann D, Kravec I, et al. Pharmacokinetics, safety and antiviral activity of the
nucleoside reverset following single doses in HIV-1 infected patients. Abstract 545, 2nd IAS 2003,
Paris.
26. Sitdykova YR, Serebrovskaya LV, Kravchenko AV. Immune reconstitution on treatment of
HIV-infected patients with phosphazid, didanosine and saquinavir/ritonavir once daily in russia.
Abstract 2.7/1. 9th EACS 2003, Warsaw, Poland.
27. Uckun FM, Pendergrass S, Venkatachalam TK, Qazi S, Richman D. Stampidine is a potent inhibitor
of zidovudine- and nucleoside analog reverse transcriptase inhibitor-resistant primary clinical HIV
type 1 isolates with thymidine analog mutations. Antimicrob Agents Chemother 2002, 46:3613-3616.
http://amedeo.com/lit.php?id=12384373
28. Uckun FM, Venkatachalam TK, Qazi S. Potency of stampidine against multi-nucleoside reverse
transcriptase inhibitor resistant human immunodeficiency viruses. Arzneimittelforschung 2006,
56:193-203. http://amedeo.com/lit.php?id=16570827
29. Zhang H, Öberg B, Harmenberg J, et al. Inhibition of multiple drug-resistant (MDR) HIV-1 by
3`-fluoro-2`,3``-dideoxyguanosine (FLG). Abstract H-182, 42nd ICAAC 2002, San Diego.
New NNRTIs
As with any other drug class, me-too-drugs are not needed here. Many have already been abandoned;
the road to approval is especially hard for NNRTIs. Since efavirenz in 1998, no NNRTI has made it
onto the market. In view of increasing resistance there is an urgent need for new NNRTIs - not only
for treatment-experienced patients but also for newly infected patients - almost 10 % of patients in
Europe with an acute HIV infection have viruses with at least one NNRTI resistance mutation (Wensing
2005). The most significant problem in development is the proof of action in Phase II/III studies.
The hurdle is the correct design: because the single substitution of a NNRTI into a failing regimen
is not ethically permissible, the remaining ART always has to be optimized - with options that are
often so effective that the effect of the new NNRTI cannot be determined. The latest example of this
dilemma was capravirine, which was curtailed in 2005, following a disastrous Phase II study (Pesano
2005).
Etravirine (TMC 125), from Tibotec, is the furthest developed. As a diarylpyrimidine (DAPY) analog
and a second-generation NNRTI, it works well against the wild-types, the resistant mutants, and, in
particular, against the classical NNRTI mutations such as K103N. The resistance barrier is higher
than that of other NNRTIs. By changing its confirmation, etravirine can bind flexibly to the reverse
transcriptase (Vingerhoets 2005). Mutations of the enzyme binding site therefore have less effect on
the binding and consequently on the potency (Das 2004).
In Phase I/II studies, etravirine lowered viral load by a considerable 2.0 logs in treatment-naïve
patients after one week (Gruzdev 2003), and still by 0.9 logs in the presence of NNRTI mutations
(Gazzard 2003, Sankatsing 2003). In C233, a Phase II trial on 199 patients with NNRTI- and
PI-mutations, who have previously been treated, the viral load was significantly less than with
placebo after 48 weeks (Cohen 2006). However, the overall effect decreased with increasing NNRTI
resistances: with one resistance, it was 1.38; with more than two, it was 0.54 logs. In vitro, Y181C
together with mutations on the codons 101, 179, 190, and 230, increase the resistance to etravirine
(Vingerhoets 2006).
A further Phase II study produced the first setback: in this trial on 116 patients with NNRTI
failure, etravirine was compared to a PI chosen by the investigator. The study was stopped
prematurely because etravirine was significantly inferior (Woodfall 2006). Tibotec argued that the
baseline resistances in this study, conducted in Thailand and South Africa, were more prolific than
expected. Etravirine, at a dose of 800 mg (2 x 200 mg tablets bid), is currently being investigated
together with the PI darunavir in Phase III studies (DUET). This study will show the true value of
the drug.
Etravirine has so far been well tolerated, although the typical problems of efavirenz and NNRTIs
(dizziness, rash) are to be expected. In the C233 trial, 20 % of patients developed a skin rash and
some had to stop etravirine. However, the rash is mild in most cases. There do not seem to be any
relevant interactions, with one exception: the level of etravirine sinks significantly when combined
with tipranavir (Kakuda 2006). An Expanded Access Program is being launched in February 2007.
Rilpivirine (TMC 278) first appeared in February 2005. Like etravirine, the substance is also a
DAPY-NNRTI (Janssen 2005). Rilpivirine is effective against most NNRTI-resistant viruses. In three
placebo-controlled dose-finding studies (up to 150 mg over 14 days) the substance was well tolerated
(de Bethune 2005). A Phase IIa study on therapy-na?ve patients receiving monotherapy for 7 days
produced an average decrease in the viral load of 1.2 logs. In addition, there was no dose-dependent
effect between 25 and 150 mg (Goebel 2005). A considerable advantage of rilpivirine is its very long
half-life of 40 hours. In combination with lopinavir, the level is significantly increased,
necessitating dose adjustment (Hoetelmans 2005).
In a randomized Phase IIb study, 368 therapy-naïve patients received 2 NRTIs at different doses (25,
75, 150 mg) or efavirenz (Pozniak 2007). Only the rilpirvirine doses were blinded, and not whether
rilpivirine or efavirenz were given: in addition, the NRTIs were chosen by the investigator. After
48 weeks, the effect with efavirenz was comparable, but with significantly less CNS side effects and
increases in lipids. Despite the rather unusual design of the trial, rilpivirine could be serious
competition for efavirenz (and etravirine) in the future. Phase III studies will continue with the
75 mg dose.
GW5634 is a benzophenone NNRTI, resulting from its predecessors GW8248 and GW8635, both of which had
poor oral bioavailability. GW5634 is the prodrug of GW8248, which has good efficacy in vitro against
NNRTI resistant viruses (Freeman 2003, Romines 2003, Hazen 2003). However, individual resistance
mutations have been detected (V106I, P236L, E138KL), indicating that GW5634 is not invincible. In
2005, the first in vivo data was published (Becker 2005). In 46 HIV patients with NNRTI mutations
the viral load sank by 1.2-1.6 logs after 7 days, a respectable result for a NNRTI.
BIRL 355 BS is a second generation NNRTI from Boehringer. It also seems to have a wide efficacy
against resistant viruses (Coulombe 2005). However, in the presence of the mutations Y188L and
Y181C/G190A the effect is limited (Wardrop 2005). Pharmacokinetic data show that boosting with
ritonavir is not necessary (Huang 2006). In Germany, a Phase IIa study is planned for 2007.
Calanolide A has been in development since 1997 by Sarawak MediChem Pharmaceuticals. This NNRTI with
its natural origin - it was extracted from plants that grow in the Malayan rainforest - seems to be
effective against the Y181C and K103N mutations (Quan 1999). Tolerability is good (Creagh 2001),
and in HIV-infected patients, the virus load was reduced by 0.8 logs after 14 days (Shereer 2000).
According to the firm, Phase II/III studies were planned for 2005 - but since then, nothing has been
heard. There is doubt that it will go any further.
The following NNRTIs are no longer being developed:
· Atevirdine from Upjohn, the company prioritized development of delavirdine (the right decision?)
· DPC 083 (BMS-561390) - May 2003 - poor PK/safety data
· DPC 961 - suicide thoughts in healthy volunteers; DPC 963
· Emivirine (MKC-442, Coactinone) - quite far developed by Triangle, but too weak
· GW420867X - GSK, classical me-too drug
· GW8248 - GSK, poor bioavailability
· HBY-097 - Hoechst-Bayer, unfavorable side effects
· Loviride - Janssen Pharmaceuticals, too weak in (at that time, relatively advanced) clinical
trials (CAESAR Study)
· MIV-150 - Medivir/Chiron, poor bioavailability, being developed further as a microbicide
· PNU142721 - Pharmacia & Upjohn, too similar to efavirenz (me-too)
· TMC120 (dapivirine) - Tibotec, poor oral bioavailability
· Capravirine (AG1549), probably too weak, Pfizer returned the rights to Shionogi in July 2005. The
future is uncertain.
References
1. Becker S, Lalezari J, Walworth C, et al. Antiviral activity and safety of GW695634, a novel next
generation NNRTI, in NNRTI-resistant HIV-1 infected patients. Abstract WePe6.2C03, 3rd IAS 2005, Rio
de Janeiro, Brazil.
2. Burnette M, Marr H, Owens B, Wheelan P, Moore K. Interspecies pharmacokinetics and scaling of
GW8248, a novel non-nucleoside HIV reverse transcriptase inhibitor, and its prodrug GW5634. Abstract
F-1837, 43rd ICAAC 2003, Chicago.
3. Cohen C, Steinhart CR, Ward DJ, 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.
TUPE0061, XVI IAC 2006, Toronto.
4. Coulombe R, Fink D, Landry S, et al. Crystallographic study with BILR 355 BS, a novel
non-nucleoside reverse transcriptase inhibitor (NNRTI) with a broad anti HIV-1 profile. Abstract
WePp0105, 3rd IAS 2005, Rio de Janeiro.
5. Creagh T, Ruckle JL, Tolbert DT, et al. Safety and pharmacokinetics of single doses of
(+)-calanolide a, a novel, naturally occurring nonnucleoside reverse transcriptase inhibitor, in
healthy, HIV-negative human subjects. Antimicrob Agents Chemother 2001, 45:1379-86. Originalartikel:
http://aac.asm.org/cgi/content/full/45/5/1379?view=full&pmid=11302799
6. Das K, Clark AD Jr, Lewi PJ, et al. Roles of conformational and positional adaptability in
structure-based design of TMC125-R165335 (etravirine) and related non-nucleoside reverse
transcriptase inhibitors that are highly potent and effective against wild-type and drug-resistant
HIV-1 variants. J Med Chem 2004, 47: 2550-60. http://amedeo.com/lit.php?id=15115397
7. de Béthune M-P, Andries K, Azijn H, et al. TMC278, a new potent NNRTI, with an increased barrier
to resistance and good pharmacokinetic profile. Abstract 556, 12th CROI 2005, Boston.
8. Freeman G, Romines K, Chanet J, et al. Novel benzophenone non-nucleoside reverse transcriptase
inhibitors with unique drug resistance profiles. Abstract 538, 2nd IAS 2003, Paris. Antiviral
Therapy 8: S328.
9. Fujiwara T, Sato A, el-Farrash M, et al. S-1153 inhibits replication of known drug-resistant
strains of HIV-1. Antimicrob Agents Chemother 1998, 42:1340-5. Original-Artikel
http://hiv.net/link.php?id=1995
10. Gazzard BG, Pozniak AL, Rosenbaum W, et al. An open-label assessment of TMC 125--a new,
next-generation NNRTI, for 7 days in HIV-1 infected individuals with NNRTI resistance. AIDS 2003,
17:F49-54. http://amedeo.com/lit.php?id=14685068
11. Gewurz BE, Jacobs M, Proper JA, Dahl TA, Fujiwara T, Dezube BJ. Capravirine, a nonnucleoside
reverse-transcriptase inhibitor in patients infected with HIV-1: a phase 1 study. J Infect Dis 2004,
190:1957-1961. http://hiv.net/link.php?id=15529260
12. Goebel F, Yakovlev A, Pozniak A, et al. TMC278: Potent anti-HIV activity in antiretroviral
therapy-naive patients. Abstract 160, 12th CROI 2005, Boston.
13. Grossman HA, Hicks C, Nadler J, et al. Efficacy and tolerability of TMC125 in HIV pts. with
NNRTI and PI resistance at 24 weeks: TMC125-c223. Abstract H-416c, 45th ICAAC 2005, Washington.
14. Gruzdev B, Rakhmanova A, Doubovskaya E, et al. A randomized, double-blind, placebo-controlled
trial of TMC125 as 7-day monotherapy in antiretroviral naive, HIV-1 infected subjects. AIDS 2003,
17: 2487-94. http://amedeo.com/lit.php?id=14600520
15. Hazen RJ, Harvey R, Ferris R, et al. Characterization of the anti-HIV-1 activity of GW8248 in
combination with other anti-retroviral drugs and in vitro selection for resistance. Abstract 445,
43rd ICAAC 2003, Chicago.
16. Hoetelmans R, van Heeswijk R, Kestens D, et al. Pharmacokinetic interaction between TMC278, an
investigational non-nucleoside reverse transcriptase inhibitor (NNRTI), and lopinavir/ritonavir
(LPV/r) in healthy volunteers. Abstract PE4.3/1, 10th EACS 2005, Dublin.
17. Huang F, Drda K, Scherer J, et al. Pharmacokinetics of BILR355 after multiple ascending doses
co-administered with ritonavir in healthy volunteers. Abstract 58B. 7th IWCPHT 2006, Lisbon,
Portugal.
18. Janssen PA, Lewi PJ, Arnold E, et al. In search of a novel anti-HIV drug: multidisciplinary
coordination in the discovery of 4-[[4-[[4-[(1E)-2-cyanoethenyl]-2,6-dimethylphenyl]amino]-2-
pyrimidinyl]amino]benzonitrile (R278474, rilpivirine). J Med Chem 2005, 48:1901-9.
http://amedeo.com/lit.php?id=15771434
19. Kakuda TN, Scholler-Gyure M, Woodfall B, et al. TMC125 in combination with other medications:
summary of drug-drug interaction studies. Abstract PL5.2, 8th ICDTHI 2006, Glasgow.
20. Pesano R, Piraino S, Hawley P, et al. 24-week safety, tolerability, and efficacy of capravirine
as add-on therapy to nelfinavir and 2 nucleoside reverse transcriptase inhibitors in patients
failing a NNRTI-based regimen. Abstract 555, 12th CROI 2005, Boston.
21. Pozniak A, Morales-Ramirez J, Mohapi L, et al. 48-week primary analysis of trial TMC278-C204:
TMC 278 demonstrates potent and sustained efficacy in ART naive patients. Abstract LB144 LB, 14th
CROI 2007, Los Angeles. Abstract: http://www.retroconference.org/2007/Abstracts/30659.htm
22. Quan Y, Motakis D, Buckheit R Jr,et al. Sensitivity and resistance to (+)-calanolide A of
wild-type and mutated forms of HIV-1 reverse transcriptase. Antiviral Therapy 1999, 4:203-9.
http://amedeo.com/lit.php?id=10723499
23. Romines K, St Clair M, Hazen R, et al. Antiviral characterization of GW8248, a novel
benzophenone non-nucleoside reverse transcriptase inhibitor. Abstract 535, 2nd IAS 2003, Paris.
24. Sankatsing SU, Weverling GJ, Peeters M, et al. TMC125 exerts similar initial antiviral potency
as a five-drug, triple class antiretroviral regimen. AIDS 2003, 17:2623-7.
http://amedeo.com/lit.php?id=14685056
25. Schaller LT, Burnetter T, Cowan J, et al. Prodrug strategies to deliver novel HIV-1
non-nucleoside reverse transcriptase inhibitors (NNRTIs) GW8248 and GW8635. Abstract 872, 43rd ICAAC
2003, Chicago.
26. Sherer R, Dutta B, Anderson R, et al. A phase 1B study of (+)-calanolide A in HIV-1-infected,
antiretroviral therapy-naive patients. Abstract 508, 7th CROI 2000, San Francisco.
27. 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, 79:12773-82.
http://amedeo.com/lit.php?id=16188980
28. Vingerhoets J, Peeters M, Corbett C, et al. Effect of baseline resistance on the virologic
response to a novel NNRTI, TMC125, in patients with extensive NNRTI and PI resistance: analysis of
Study TMC125-C223. Abstract 154, 13th CROI 2006, Denver.
29. Wardrop E, Tremblay S, L. Bourgon L, et al. In vitro selection of resistance and
characterization of HIV subtype sensitivity to the non-nucleoside reverse transcriptase inhibitor
BILR 355 BS. Abstract 1091, 45th ICAAC, Washington.
30. Wensing AM, van de Vijver DA, Angarano G, et al. Prevalence of drug-resistant HIV-1 variants in
untreated individuals in Europe: implications for clinical management. J Infect Dis 2005,
192:958-66. http://amedeo.com/lit.php?id=16107947
31. 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. Abstract PL5.6, 8th ICDTHI 2006,
Glasgow.
New protease inhibitors (PIs)
In view of the increasingly large competition within this group, the demands on new PIs have become
immense. Companies are losing interest in further research within this field and development in many
new PIs has been terminated.
PL-100 is a PI from the Canadian firm Ambrilla Biopharma, which now cooperates with Merck. The
substance is given as the pro-drug PPL-100 and is then metabolized to the active substance, which,
with a high genetic barrier, is supposedly active against PI-multiresistant viruses (Dandache 2006).
The PK data from healthy probands look good so far, and the long half-life of 30-37 hours makes this
an interesting agent. PL-100 may even be suitable for boosting other PIs (Wu 2006).
AG-001859 is an allophenylnorstatin-containing PI from Pfizer, being investigated in Phase I
studies. In vitro data shows that this substance has antiviral activity even in the presence of
multiple primary and secondary PI mutations (Hammond 2004).
SM-309515 is a new PI from Sumitomo Pharmaceuticals, which should be in Phase I studies. Earlier
versions failed due to the short half-life (Mimoto 2003). PK data in dogs seemed to be comparable to
atazanavir. The drug remained effective against mutations such as S37N, I47V, R57K, and I84V.
Conversely, sensitivity to all other PIs remained despite resistance against SM-309515. Ritonavir
boosting is now being tested in humans.
SPI-256 is a PI from Sequioa Pharmaceuticals. In vitro, the efficacy against PI-resistant viral
isolates is impressive (Gulnik 2006); in vivo data is not yet freely available. Studies should,
however have been started in 2006.
Out of sight, out of mind - development of the following PIs has been stopped:
· DPC 684 - cardiotoxic, apparently with a narrow therapeutic range
· DPC 681 - bought by BMS, which is not interested in further development
· GS 9005 (previously GS 4338) - from Gilead
· JE-2147 (AG1776, KNI-764) - from Pfizer, (nothing new since 1999)
· KNI-272 (Kynostatin), poor PK data
· Mozenavir (DMP-450) - development stopped by Gilead in 2002 as there were no advantages to other
PIs
· RO033-4649 - from Roche, probably too similar to saquinavir
· SC-52151 and SC-55389A - poor bioavailability
· TMC 126 - Tibotec is concentrating on TMC 114 - darunavir
· Brecanavir - from GSK - stopped end of 2006 due to poor PK data
References
1. Dandache S, Wainberg MA, Panchal C, Wu JJ. PL-100, a novel protease inhibitor with a high genetic
barrier. Abstract THAA0304, XVI IAC 2006, Toronto.
2. Gulnik S, Afonina E, Eissenstat M, Parkin N, Japour A, Erickson J. SPI-256, a highly potent HIV
protease inhibitor with broad activity against MDR strains. Abstract 501, 13th CROI 2006, Denver.
3. Hammond J, Jackson L, Graham J, et al. Antiviral activity and resistance profile of AG-001859, a
novel HIV-1 protease inhibitor with potent activity against protease inhibitor-resistant strains of
HIV. Antiviral Therapy 2004; 9:S17
4. Mimoto T, Nojima S, Terashima K, et al. SM-309515: a novel and promising HIV protease inhibitor
with favourable pharmacokinetics and resistance profiles. Abstract 873, 43rd ICAAC 2003, Chicago.
5. Wu JJ, Stranix B, Milot G, et al. PL-100, a next generation protease inhibitor against
drug-resistant HIV: in vitro and in vivo metabolism. Abstract H-253, 46th ICAAC 2006, San Francisco.
Entry inhibitors
There are three crucial steps for entry of HIV into the CD4 cell:
1. binding of HIV via the gp120 envelope protein to the CD4 receptor ("attachment" - target of
attachment inhibitors),
2. binding to co receptors (target of co-receptor antagonists) via conformational changes, and
finally
3. fusion of virus and cell (target of fusion inhibitors).
Figure 1: The three main steps of HIV entry into the cell (from: Moore JP, Doms RW. The entry of
entry inhibitors: a fusion of science and medicine. PNAS 2003, 100:10598-602, adapted with
permission).
Although very heterogeneous, attachment inhibitors, co-receptor antagonists and fusion inhibitors
are at present grouped together as entry inhibitors. It already seems clear that fascinating new
possibilities will open up with these drugs. On the other hand, a lot of the data does not go beyond
basic science at this stage, and many of the drugs discussed below may eventually disappear; some
have already done so.
Attachment inhibitors
The docking of the HIV glycoprotein gp120 on the CD4 receptor is the first step towards entry of HIV
into the cell. Theoretically, the docking (attachment) or interaction between gp120 and CD4 can be
inhibited through different mechanisms - so that the CD4 receptor as well as the binding site for
gp120 can be blocked. Both are currently being investigated. The attachment inhibitors are very
heterogeneous, so it is not possible to speak of a single drug class.
Since the beginning of the nineties, there have been a number of investigations into soluble CD4
molecules that prevent the attachment of HIV to the CD4 cell (Daar 1990, Schooley 1990). But, the
effect seen in vitro was not observed in vivo, probably due to the very short half-life of the
soluble CD4 (a few minutes). With the growing knowledge of the mechanism of HIV entry into the cell,
as well as following the success of T-20 as the first entry inhibitor, the development of attachment
inhibitors has been reinvigorated. However, most drugs are not far advanced in their development
yet, often have problematic PK data and are therefore still in the proof-of-concept stage.
TNX-355 (previously "Hu5A8") is a monoclonal antibody that binds directly to the CD4 receptor and
thereby prevents the entry of HIV. However, the mechanism of action has still not been completely
explained. In contrast to other attachment inhibitors, TNX-355 does not seem to prevent binding of
gp120 to CD4, but rather the conformational changes and thereby the binding of gp120 to CCR5 and
CXCR4. It is currently being developed by Tanox Biosystem (Houston, Texas). It can only be
administered intravenously. Following the initial early studies (Jacobsen 2004, Kuritzke 2004),
48-week data from a placebo-controlled Phase II trial are now available (Norris 2006). In this
study, extensively pretreated patients received TNX-355 as an infusion every two weeks for a year in
two different doses (10 or 15 mg/kg) or placebo in addition to an optimized ART regime. After 48
weeks, there was a long-lasting decrease in the viral load of approximately one log in both verum
arms of the study.
With respect to these data, TNX-355 is one of the most exciting new substances in HIV medicine.
There seems to be an inverse correlation between the sensitivity to TNX-355 and soluble CD4;
possibly TNX-355 resistant viruses are over sensitive for soluble CD4, which does not work alone
(see above) (Duensing 2006). It is still questionable whether the function of the CD4 cell is
affected. So far, no negative effects on the CD4 cells have been determined, and the TNX-355 binding
site on CD4 is allegedly located differently to the binding site on the natural CD4 ligand on the
HLA class II molecule. The CD4 cells should be able to perform their normal functions, even when
TNX-355 is occupying the HIV binding site. At least we hope this is the case.
BMS-488,043 is an early attachment inhibitor from BMS, which binds specifically and reversibly to
HIV gp120 and thereby prevents attachment to the CD4 cell. Unlike TNX-355, BMS-488043 does not bind
to the CD4 receptor. In early 2004, the first results in HIV-infected patients were published (Hanna
2004). On 800 mg and 1,800 mg, both twice daily, the viral load dropped after 7 days of monotherapy
by a median of 0.72 or 0.96 logs, respectively. In 15/24 patients, viral load was reduced by more
than one log. The substance was well tolerated in this study. However, pill burden is still high,
and the formulation requires further improvement. In addition, resistances may arise rapidly as the
gp120-binding site is one of the most variable positions of all. This type of attachment inhibitor
may be useful in the development of microbicides (Kadow 2006).
References
1. Daar ES, Li XL, Moudgil T, Ho DD. High concentrations of recombinant soluble CD4 are required to
neutralize primary human immunodeficiency virus type 1 isolates. Proc Natl Acad Sci U S A 1990,
87:6574-6578. http://amedeo.com/lit.php?id=2395859
2. Duensing T, Fung M, Lewis S, Weinheimer S. In vitro characterization of HIV isolated from
patients treated with the entry inhibitor TNX-355. Abstract 158 LB, 13th CROI 2006, Denver.
3. Hanna G, Lalezari L, Hellinger J, et al. Antiviral activity, safety, and tolerability of a novel,
oral small-molecule HIV-1 attachment inhibitor, BMS-488043, in HIV-1-infected subjects a novel, oral
small-molecule HIV-1 attachment inhibitor, BMS-488043, in HIV-1-infected subjects. Abstract 141,
11th CROI, 2004, San Francisco.
4. Jacobson JM, Kuritzkes DR, Godofsky E, et al. Phase 1b study of the anti-CD4 monoclonal antibody
TNX-355 in HIV-infected subjects: safety and antiretroviral activity of multiple doses. Abstract
536, 11th CROI 2004, San Francisco.
5. Kadow J, Wang HG, Lin PF. Small-molecule HIV-1 gp120 inhibitors to prevent HIV-1 entry: an
emerging opportunity for drug development. Curr Opin Investig Drugs 2006, 7:721-6.
http://amedeo.com/lit.php?id=16955683
6. Kuritzkes DR, Jacobson J, Powderly WG, et al. Antiretroviral activity of the anti-CD4 monoclonal
antibody TNX-355 in patients infected with HIV type 1. J Infect Dis 2004, 189:286-91.
http://amedeo.com/lit.php?id=14722894
7. Norris D, Morales J, Godofsky E, et al. TNX-355, in combination with optimized background
regimen, achieves statistically significant viral load reduction and CD4 cell count increase when
compared with OBR alone in phase 2 study at 48 weeks. Abstr. ThLB0218, XVI IAC 2006, Toronto
8. Schooley RT, Merigan TC, Gaut P, et al. Recombinant soluble CD4 therapy in patients with the
acquired immunodeficiency syndrome (AIDS) and AIDS-related complex. Ann Intern Med. 1990,
112:247-253. http://amedeo.com/lit.php?id=2297203
9. Trkola A, Ketas T, Kewalramani VN, et al. Neutralization sensitivity of human immunodeficiency
virus type 1 primary isolates to antibodies and CD4-based reagents is independent of coreceptor
usage. J Virol 1998, 72:1876-85. http://amedeo.com/lit.php?id=9499039
Co-receptor antagonists
In addition to CD4 receptors, HIV also requires so-called co-receptors to enter the target cell. The
two most important ones, CXCR4 and CCR5, were discovered in the middle of the 1990s. These
receptors, of which there are probably more than 200, are named after the natural chemokines that
usually bind to them. Their nomenclature is derived from the amino acid sequence. For CCR5 receptors
these are the "CC-chemokine" MIP and RANTES, for CXCR4-receptors it is the "CXC-chemokine" SDF-1.
HIV-variants use either the CCR5- or the CXCR4-receptors for entry into the target cell. According
to their receptor tropism, HIV variants are termed R5 if they use CCR5 as a co-receptor, whereas
viruses with a preference for CXCR4 are termed X4-viruses. R5 viruses are viruses that predominantly
infect macrophages (previously: "M-trope" viruses); X4 viruses mainly infect T cells (previously:
"T-trope" viruses). "Dual-trope" viruses can use both receptors, and in addition, there are still
mixed populations of R5- and X4 viruses. In most patients, R5 viruses are found in the early stages
of infection; the more virulent X4 viruses, which are probably able to infect a wider spectrum of
cell types, first occur in the later stages. The change in the tropism is frequently a consequence
of illness progression (Connor 1997, Scarkatti 1997). It is still not clear why this happens after
several years of infection, although the tropism shift only needs a few small mutations. It is
possible that R5 viruses are less flexible overall with regard to the cell type, but are therefore
not recognized so well by the immune system. X4 viruses are more flexible because of their low
glycosylation, but are also more immunogenic. They are neutralized better by the immune system and
it is likely that they only become apparent when there is a significant immune deficiency.
In large cohorts, approximately 80 % of all viruses showed CCR5 tropism, i.e., were R5 viruses. The
receptor tropism correlated with the stage of the infection. The higher the CD4 cell count and the
lower the viral load, the more R5 viruses tended to be present (Moyle 2005, Brumme 2005). In
contrast, X4 viruses are almost exclusively found in advanced stages of the disease. When the CD4
count is above 500 CD4 cells/µl, they are only found in 6 %; and in more than 50 % of patients at
less than 25 CD4 cells/µl (Brumme 2005). They also seem to be more frequent in treatment-experienced
patients (Demarest 2004). In addition, X4 viruses almost always occur in X4/R5-mixed populations;
pure X4 virus populations are very rare.
CCR5- and CXCR4-antagonists can be distinguished according to their specificity. They block the
respective co-receptor in a similar way to the natural chemokine, which they partially resemble
chemically. The development of CCR5 antagonists (some of which have "-viroc" at the end of their
names) is more advanced than for CXCR4 antagonists. This is mainly because the blockade of CCR5, at
least theoretically, has less clinical consequences. Individuals with a congenital CCR5 receptor
defect are healthy. With CXCR4, it is not so certain. A congenital, harmless defect in humans is not
known, and in trials on animals, CXCR4 blockade had far-reaching consequences.
In the development of CCR5 antagonists, a few setbacks have had to be overcome. As usual: the more
one learns about a drug class, the more questions arise. The most important are:
Are CCR5 antagonists hepatotoxic? In October 2005, the development of the CCR5 antagonist aplaviroc
was stopped after a few cases of severe hepatotoxicity were reported (Steel 2005). Since then, all
CCR5 antagonists have been under close observation. So far, no negative data has been received on
vicriviroc, but, at the end of 2005, Pfizer reported one case of hepatic failure with subsequent
liver transplant in a patient on maraviroc. However, the patient, who was from Thailand, had also
received hepatotoxic isoniazid. Interim result: there is currently no evidence to suggest that all
CCR5 antagonists are hepatotoxic, but vigilance is required.
Which patients would CCR5 antagonists be suitable for? In the first instance, it is only for those
with R5-tropic viruses, that is the viruses that use the CCR5 co-receptor. Although past studies
demonstrated that the proportion of X4-tropic viruses is around 20 % overall (Brumme 2005, Moyle
2005), it seems that particularly patients with advanced HIV infection and extensive prior therapy
would consequently hardly benefit. In ACTG 5211, a Phase IIb study on vicriviroc in 368 pretreated
patients, only 48 % had R5-tropic viruses, 48 % had X4/R5 combinations, and 4 % pure X4-tropic
viruses (Wilkin 2006). This means that CCR5 antagonists are not suitable as a salvage strategy in
many patients.
Will the expected X4 shift cause any harm? It is known that X4 viruses are associated with rapid CD4
cell decline and disease progression (Connor 2997, Scarkatti 1997). On CCR5 antagonists, a shift to
X4 viruses can be expected due to the selection pressure, and this has also been observed in a few
patients in some studies. Although phylogenetic studies have demonstrated that X4-tropic viruses
emerging under treatment with CCR5 antagonists are probably selected from pre-existing pools and do
not develop as a result of a switch in receptor usage (Westby 2006), the consequences of the X4
selection for the patient remain uncertain. One important study was recently published, in which
patients with X4/R5 mixed populations received maraviroc. After 24 weeks, the CD4 cells were
increased in contrast to placebo (Mayer 2006) - progression of HIV under CCR5 antagonists seems to
be rather unlikely at the moment, at least in the mid-term.
What are the other consequences of CCR5 antagonists? Patients with congenital co-receptor defects
are healthy. Nevertheless, it is feared that blockade of these receptors could have negative
consequences. Moreover, the action of coupling to the receptor could possibly induce an autoimmune
reaction. So far, neither problem has been observed in monkey models (Peters 2005). In an analysis
of completed Phase I-II studies with maraviroc, no negative effects on the immune function were
detected (Ayoub 2007). In contrast, the reports of tumors (especially malignant lymphoma) in one
study with vicriviroc were somewhat unsettling (Gulick 2006). There is no explanation for this at
the moment, given that HIV patients with a congenital defect in the CCR5 co-receptor rarely develop
lymphoma (Rabkin 1999). So far, these results have not been seen in other studies.
Does the tropism have to be tested in each patient prior to therapy? An important problem is how to
test for viral tropism. Although the administration of a CCR5 antagonist does not seem to have any
negative effects even in mixed X4/R5 populations (see above), a test is necessary before treatment
on the grounds of costs alone, in order to individually assess whether the use of a CCR5 antagonist
is appropriatet. Only a few laboratories can perform the tropism test as it is very complicated and
requires living cells. Therefore, an attempt is being made to determine HIV tropism genetically, and
thereby develop simpler and faster test methods. Research so far has concentrated on the V3 loop of
the envelope protein gp120, because HIV binds with this region on the co-receptor (Jensen 2003, Briz
2006). However, the tropism does not seem to be determined through the sequence of the V3 loop alone
- viruses with identical V3 loops can be distinguished from each other by their tropism (Huang
2006). In other words: it will take some time before a simple tropism test is ready. It has also not
been clarified who is supposed to pay for the tropism test before the start of therapy with CCR5
antagonists. Health insurances will not jump to reimburse the costs, and therefore it will probably
be the responsibility of the manufacturers of the CCR5 antagonists to start with.
What is known about resistances? Because the co-receptor antagonists all bind similarly to the
receptor, there is a theoretical risk of classical predominant cross resistance. There are no data
available from in vivo studies,although this has been debated in several in vitro studies (Westby
2006, Mosley 2006). There is also a possible a synergy between individual agents, as indicated in
one recent study (Murga 2006). A combination of CCR5 antagonists seems to be at least theoretically
possible. The mechanisms of the development of resistances have not yet been completely explained,
and resistance testing is still problematic (Pugach 2006). However, it seems that resistance does
not necessarily imply a shift in tropism from R5 to X4. Viruses can be resistant to CCR5
antagonists, but still have R5 tropism.
Maraviroc (UK 427,857, Celsentri™, Selzentry™) from Pfizer is currently the most promising CCR5
antagonist. In a double blind randomized study, in which 63 patients with R5-trope viruses received
different doses of maraviroc, the median drop in virus load was 1.6 logs after 10-15 days on
maraviroc 2 x 100 mg/day (Fätkenheuer 2005).
Three large Phase II/III trials on R5 viruses are currently running on therapy-naïve patients (1,026
studies) as well as on pre-treated patients with class 3 resistance (MOTIVATE-1 and -2). In the
Maraviroc arms of the MOTIVATE trials, the virus load was one log less than on placebo after 24
weeks (each with optimized concomitant antiretroviral therapy). In the Maraviroc arms with twice
daily dosing, 45% of the patients achieved a viral load of less than 50 copies/ml versus 23% on
placebo (Nelson 2007, Lalezari 2007). Of the patients who had no active substance in the background
therapy (genotypical resistance testing), 41% reached a viral load of less than 400 copies/ml versus
6% on placebo (FDA Briefing Document Maraviroc).
What is the anti-viral effect on non-R5 viruses? In a double blind, randomized, Phase II pilot study
on 113 pre-treated patients with X4-trope viruses, as expected, there was no visible significant
difference in the reduction of viral load. Indeed, surprisingly, the CD4-cell count increased
markedly (Mayer 2006).
In the 1026 studies, the 917 therapy-naïve patients who received treatment with AZT + 3TC, were also
given efavirenz, Maraviroc 300 mg twice daily, or Maraviroc 300 mg once daily. However, at the
beginning of 2006, the once-daily arm of Maraviroc was prematurely terminated - performance was
worse in comparison to the control arm with efavirenz. The Maraviroc arm with twice daily dosing is
still running unchanged, and the results of the trial are expected in the middle of 2007.
The first resistance data have also been made available recently: mutations on the codons A316T and
I323V in the V3-loop of the envelope protein together cause resistance to Maraviroc (Mosley 2006).
Caution has to be taken with interactions when prescribing. Maraviroc itself does not seem to affect
the level of other medications, but it is influenced as a CYP3A4 substrate by protease inhibitors
(except tipranavir/r) and efavirenz. The dose of Maraviroc should be halved when given together with
a protease inhibitor, tipranavir excluded, and doubled when given together with efavirenz if no
additional PI is used concomitantly (Abel 2005, Abel 2006).
So far, the tolerability in the above studies has been outstanding: comparable to placebo. The only
specific side effect is obviously an orthostatic hypotonia, which is however rare with the usual
doses.
Maraviroc is therefore an interesting substance for patients with resistant R5-viruses, and it may
also help to save HAART toxicity. The data on therapy-naïve patients are excitedly awaited. The
Expanded-Access-Program for more than 30 countries started in May 2007 and the license is expected
this year.
Vicriviroc (SCH-D, or 417690) is a CCR5 antagonist from Schering-Plough with oral bioavailability.
Its binding affinity for the CCR5 co-receptor is greater than that of its predecessor SCH-C
(Stritzki 2005). Vicriviroc is already in Phase II studies. In the Phase I studies, the highest dose
of 50 mg daily induced an average drop in the viral load of 1.62 logs (Schürmann 2004). The
substance has been well tolerated. Arrhythmias (QT elongation), such as those on SCH-C, were not
observed (Sansone 2005).
Data from a Phase II study on therapy-naïve patients has shed doubt on the long-term effects of
vicriviroc (Greaves 2006). Vicriviroc was compared in various doses to efavirenz (all 91 patients
also received AZT and 3TC), but after an average observation period of 32 weeks, the trial was
prematurely ended, because therapy failure occurred more frequently in vicriviroc patients (> 50
copies/ml in 57 % on 25 mg, 45 % on 50 mg, 22 % on 75 mg) than in efavirenz patients.
The observation that the rate of therapy failure at the higher doses was relatively low, provides
hope that the problem with vicriviroc is dose dependent. The ACTG 5211 trial on
treatment-experienced patients seems to support this hypothesis (Gulick 2006). After 24 weeks, on 5,
10 and 15 mg vicriviroc - boosted each time with 100 mg ritonavir - there was a significant drop in
the viral load of at least one log in comparison to placebo. Of course, in the light of these data,
it would appear that vicriviroc needs to be boosted with ritonavir. However, it was worrying that 4
out of 118 patients developed a malignant lymphoma - an unusual proportion, even in this advanced
patient group. Since then, no new cases have arisen, so that vicriviroc development is progressing
forward.
TAK-652 is a CCR5 antagonist from the Japanese company Takeda. It has good oral bioavailability
(Baba 2005) and shows synergistic effects with T-20 in vitro (Tremblay 2005). Laboratory data also
show that for complete resistance there have to be several mutations in the V3 region (and in the
env gene) at the same time. The tropism does not appear to change with the mutations (Baba 2006).
INCB9471 is also an orally available CCR5 antagonist from Incyte. Phase I trials on healthy subjects
were started in 2006. The data from these are not yet available, and the first studies on HIV
patients were planned for the end of 2006.
Pro-140 is a CCR5 antagonist from Progenics, which acts as a monoclonal antibody (Trkola 2001). It
is therefore not a chemokine derivative like maraviroc or vicriviroc, and appears to even have a
synergistic reaction with these agents (Murga 2006). Pro-140 has to be infused. In animal studies
(SCID mouse model), single doses of the drug achieved significant and dose-dependent reductions in
viral load without evidence of rebound under treatment (Franti 2002). The normal function of CCR5
receptors is apparently not disturbed, at least not at the doses that are required for inhibition of
HIV replication (Gardner 2003). In summer 2005, the first clinical data were published - 20 healthy
volunteers tolerated the single intravenous dose well, and dose-dependent concentrations were
measured (Olson 2005). The long-lasting effect of pro-140 was surprising. The CCR5 receptors were
blocked for more than 60 days in some cases. Despite good tolerability, the firm decided to observe
the probands for longer than was planned (Olson 2006). In December 2006, one study on 39 HIV
patients with single intravenous doses of 0.5, 2.0 or 5.0 mg/kg was completed - the results are
expected soon.
CCR5mAb004 from Human Genome Sciences is also a monoclonal antibody, which is currently in Phase I
studies. The resistance barrier was very high in vitro, (Giguel 2006).
Aprepitant (Emend™) is a neurokine-1 receptor antagonist, which is licensed as an anti-emetic for
highly emetic chemotherapy. The substance clearly has an effect on R5-trope viruses via the
down-regulation of CCR5 receptors. The initial laboratory data have shown relatively impressive,
dose-related effects on HIV replication (Wang 2006).
AMD 11070 is a CXCR4 receptor antagonist from AnorMED. In two pilot studies (Moyle 2007, Saag 2007),
the efficacy in HIV-infected patients with dual trope viruses was proven. After 10 days of
monotherapy, the viral load dropped by at least one log in 4/9 or 3/6 patients respectively.
However, the latest reports are that development of AMD 11070 has been prematurely stopped due to
hepatotoxicity. Binding to the X4 receptor is localized somewhat differently to the predecessor
agent AMD 3100, which gives us a bit of hope that there is still some room in the development for
newer, more potent and hopefully less toxic CXCR4 antagonists (Wong 2007) - with AMD 11070, the
start has at least been made.
KRH-3955 and KRH-3140 are two new CXCR4 antagonists that have been shown to be effective at least in
mice (Tanaka 2006).
References
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maraviroc. Abstract 76, 7th IWCPHT 2005, Quebec.
2. Abel S, Taylor-Worth R, Ridgway C, Weissgerber G, Kraft M. Effect of boosted tipranavir on the
pharmacokinetics of maraviroc (UK427,857) in healthy volunteers. Abstract 77, 7th IWCPHT 2006,
Lissabon, Portugal.
3. Ayoub A, van der Ryst E, Turner K, McHale M. A review of the markers of immune function during
the maraviroc phase 1 and 2a studies. Abstract 509, 14th CROI 2007, Los Angeles. Abstract:
http://www.retroconference.org/2007/Abstracts/29741.htm
4. Baba M, Miyake H, Wang X, Okamotoand M, Takashima K. Isolation and Characterization of human
immunodeficiency virus type 1 resistant to the small-molecule CCR5 antagonist TAK-652. Antimicrob
Agents Chemother. 2006 Nov 20. http://amedeo.com/lit.php?id=17116673
5. Baba M, Takashima K, Miyake H, et al. TAK-652 inhibits CCR5-mediated human immunodeficiency virus
type 1 infection in vitro and has favorable pharmacokinetics in humans. Antimicrob Agents Chemother
2005, 49:4584-91. http://amedeo.com/lit.php?id=16251299
6. Briz V, Poveda E, Soriano V. HIV entry inhibitors: mechanisms of action and resistance pathways.
J Antimicrob Chemother 2006, 57:619-627. http://amedeo.com/lit.php?id=16464888
7. Brumme ZL, Goodrich J, Mayer HB, et al. Molecular and clinical epidemiology of CXCR4-using HIV-1
in a large population of antiretroviral-naive individuals. J Infect Dis 2005, 192:466-74.
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8. Connor RI, Sheridan KE, Ceradini D, Choe S, Landau NR. Change in coreceptor use coreceptor use
correlates with disease progression in HIV-1--infected individuals. J Exp Med 1997, 185:621-8.
http://amedeo.com/lit.php?id=9034141
9. Demarest J, Bonny T, Vavro C, et al. HIV-1 co-receptor tropism in treatment naive and experienced
subjects. Abstract H-1136, 44th ICAAC 2004, Washington.
10. Fatkenheuer G, Pozniak AL, Johnson MA, et al. Efficacy of short-term monotherapy with maraviroc,
a new CCR5 antagonist, in patients infected with HIV-1. Nat Med 2005, 11:1170-2.
http://amedeo.com/lit.php?id=16205738
11. Franti M, O'Neill T, Maddon P, et al. PRO 542 (CD4-IgG2) has a profound impact on HIV-1
replication in the Hu-PBL-SCID mouse model. Abstract 401, 9th CROI 2002, Seattle, USA.
12. Gardner J, Cohen M, Rosenfield SI, Nagashima KA, Maddon PJ, Olson WC. Immunotoxicology of PRO
140: a humanized anti-CCR5 monoclonal antibody for HIV-1 therapy. Abstract 876, Abstract 444, 43rd
ICAAC 2003, Chicago.
13. Giguel F, Beebe L, Migone TS, Kuritzkes D. The anti-CCR5 mAb004 inhibits hiv-1 replication
synergistically in combination with other antiretroviral agents but does not select for resistance
during in vitro passage. Abstract 505, 13th CROI 2006, Denver.
14. Greaves W, Landovitz R, Fatkenheuer G, et al. Late virologic breakthrough in treatment naive
patients on a regimen of combivir + vicriviroc. Abstract 161LB, 13th CROI 2006, Denver.
15. Gulick R, Su Z, Flexner C, et al. ACTG 5211: phase 2 study of the safety and efficacy of
vicriviroc in HIV-infected treatment-experienced subjects. Abstract ThLB0217, XVI IAC 2006, Toronto.
16. Huang W, Toma J, Fransen S, et al. Modulation of HIV-1 co-receptor tropism and susceptibility to
co-receptor inhibitors by regions outside of the V3 Loop: Effect of gp41 amino acid substitutions.
Abstract H-245, 46th ICAAC 2006, San Francisco.
17. Jensen MA, van't Wout AB. Predicting HIV-1 coreceptor usage with sequence analysis. AIDS Rev
2003, 5:104-112. http://amedeo.com/lit.php?id=12876899
18. Lalezari J, Godrich J, DeJesus E, et al. Efficacy and safety of maraviroc plus optimized
background therapy in viremic, ART-experienced patients infected with CCR5-tropic HIV-1: 24-week
results of a phase 2b/3 study in the US and Canada. Abstract 104LB, 14th CROI 2007, Los Angeles.
Abstract: http://www.retroconference.org/2007/Abstracts/30635.htm
19. Mayer H, van der Ryst E, Saag M, et al. Safety and efficacy of maraviroc, a novel CCR5
antagonist, when used in combination with optimized background therapy for the treatment of
antiretroviral-experienced subjects infected with dual/mixed-tropic HIV-1: 24-week results of a
phase 2b exploratory trial. Abstract ThLB0215, XVI IAC 2006, Toronto.
20. Mosley M, Smith-Burchnell C, Mori J, et al. Resistance to the CCR5 antagonist maraviroc is
characterised by dose-response curves that display a reduction in maximal inhibition. Abstract 598,
13th CROI 2006, Denver.
21. Moyle GJ, Wildfire A, Mandalia S, et al. Epidemiology and predictive factors for chemokine
receptor use in HIV-1 infection. J Infect Dis 2005, 191:866-72.
http://amedeo.com/lit.php?id=15717260
22. Moyle G, DeJesus E, Boffito M, et al. CXCR4 antagonism: proof of activity with AMD 11070.
Abstract 511, 14th CROI 2007, Los Angeles. Abstract:
http://www.retroconference.org/2007/Abstracts/29173.htm
23. Murga JD, Franti M, Pevear DC, Maddon PJ, Olson WC. Potent antiviral synergy between monoclonal
antibody and small-molecule CCR5 inhibitors of human immunodeficiency virus type 1. Antimicrob
Agents Chemother 2006, 50:3289-96. http://amedeo.com/lit.php?id=17005807
24. Nelson M, Fätkenheuer G, Konourina I, et al. Efficacy and safety of maraviroc plus optimized
background therapy in viremic, ART-experienced patients infected with CCR5-tropic HIV-1 in Europe,
Australia and North America: 24 week results. Abstract 104aLB, 14th CROI 2007, Los Angeles.
Abstract: http://www.retroconference.org/2007/Abstracts/30636.htm
25. Olson W, Doshan H, Zhan C et al. First-in-humans trial of PRO 140, a humanized CCR5 monoclonal
antibody for HIV-1 therapy. Abstract WePe6.2C04, 3rd IAS 2005, Rio de Janeiro.
26. Olson WC, Doshan H, Zhan C. Prolonged coating of CCR5 lymphocytes by PRO 140, a humanized CCR5
monoclonal antibody for HIV-1 therapy. Abstract 515, 13th CROI 2006, Denver.
27. Peters C, Kawabata T, Syntin P, et al. Assessment of immunotoxic potential of maraviroc in
cynomolgus monkeys. Abstract 1100, 45th ICAAC 2005, Washington.
28. Pugach P, Marozsan AJ, Ketas TJ, et al. HIV-1 clones resistant to a small molecule CCR5
inhibitor use the inhibitor-bound form of CCR5 for entry. Virology 2006 Dec 11, Epub ahead of print.
http://amedeo.com/lit.php?id=17166540
29. Rabkin CS, Yang Q, Goedert JJ, et al. Chemokine and chemokine receptor gene variants and risk of
non-Hodgkin's lymphoma in human immunodeficiency virus-1-infected individuals. Blood 1999,
93:1838-42. http://amedeo.com/lit.php?id=10068655
30. Saag M, Rosenkranz S, Becker S, et al. Proof of concept aof ARV activity of AMD 11070 (an orally
administered CXCR4 entry inhibitor): results of the first dosing cohort A studied in ACTG protocol
A5210). Abstract 512, 14th CROI 2007, Los Angeles. Abstract:
http://www.retroconference.org/2007/Abstracts/30166.htm
31. Sansone A, Kraan M, Long MJ, et al. QTc interval analysis of SCH 417690, a novel CCR5 inhibitor.
Abstract 1095, 45th ICAAC, Washington.
32. Scarlatti G, Tresoldi E, Bjorndal A, et al. In vivo evolution of HIV-1 co-receptor usage and
sensitivity to chemokine-mediated suppression. Nat Med 1997, 3:1259-65.
http://amedeo.com/lit.php?id=9359702
33. Steel HM. Special presentation on aplaviroc-related hepatotoxicity. 10th EACS 2005, Dublin.
34. Strizki JM, Tremblay C, Xu S, et al. Discovery and characterization of vicriviroc (SCH 417690),
a CCR5 antagonist with potent activity against human immunodeficiency virus type 1. Antimicrob
Agents Chemother 2005, 49:4911-9. http://amedeo.com/lit.php?id=16304152
35. Tanaka Y, Okuma K, Tanaka R, et al. Development of novel orally bioavailable CXCR4 antagonist,
KRH-3955 and KRH-3140: binding specificity, pharmacokinetics and anti-HIV activity in vivo and in
vitro. Abstract 49 LB, 13th CROI 2006, Denver.
36. Tremblay CL, Giguel F, Chou TC, et al. TAK-652, a novel small molecule inhibitor of CCR5 has
favorable anti-HIV interactions with other antiretrovirals in vitro. Abstract 542, 12th CROI 2005,
Boston.
37. Trkola A, Ketas TJ, Nagashima KA, et al. Potent, broad-spectrum inhibition of HIV type 1 by the
CCR5 monoclonal antibody PRO 140. J Virol 2001, 75:579-88. Original-Artikel:
http://jvi.asm.org/cgi/content/full/75/2/579?view=full&pmid=11134270
38. van Rij RP, Visser JA, Naarding M, et al. In vivo evolution of X4 HIV-1 variants in the natural
course of infection coincides with reduced sensitivity to CXCR4 antagonists. Abstract 395, 9th CROI
2002, Seattle, USA.
39. Wang X, Douglas S, Lai JP, et al. Neurokinin-1 receptor antagonist inhibits drug-resistant HIV-1
infection of monocyte-derived macrophages in vitro. Abstract 511, 13th CROI 2006, Denver.
40. Westby M, Lewis M, Whitcomb J, et al. Emergence of CXCR4-using human immunodeficiency virus type
1 (HIV-1) variants in a minority of HIV-1-infected patients following treatment with the CCR5
antagonist maraviroc is from a pretreatment CXCR4-using virus reservoir. J Virol 2006, 80:4909-20.
http://amedeo.com/lit.php?id=16641282
41. Westby M, Smith-Burchnell C, Mori J, et al. Reduced maximal inhibition in phenotypic
susceptibility assays indicates that viral strains resistant to the CCR5 antagonist maraviroc
utilize inhibitor-bound receptor for entry. J Virol 2006 Dec 20, Epub ahead of print.
http://amedeo.com/lit.php?id=17182681
42. Wilkin T, Su Z, Kuritzkes D, et al. Co-receptor tropism in patients screening for ACTG 5211, a
phase 2 study of vicriviroc, a CCR5 Inhibitor. Abstract 655, 13th CROI 2006, Denver.
43. Wong R, Bodard V, Metz M, et al. Understanding the interactions between CXCR4 and AMD 11070, a
first-in-class small-molecule antagonist of the HIV coreceptor. Abstract 495, 14th CROI 2007, Los
Angeles. Abstract: http://www.retroconference.org/2007/Abstracts/29751.htm
Fusion inhibitors
(For T-20, see above)
Although the fusion inhibitor (FI) T-20 was the first entry inhibitor, there has still been little
development in this field. The usually necessary subcutaneous injections are unappealing for
patients and clinicians - expectations in the HAART era are high. It still needs to be demonstrated
whether "small molecule" FIs, a new group of fusion inhibitors with oral bioavailability, are
effective (Jiang 2004 + 2005).
T-649 is a T-1249 analog that binds to the HR2-region of gp41, like T-20. However, the binding site
overlaps only partially with that of T-20 (Derdeyn 2001). Mechanisms for T-649 resistance have also
been discovered (Heil 2002), and since the end of T-1249, the future of T-649 is in doubt.
FP-21399 is being developed by Lexigen (previously Fuji ImmunoPharmaceutical). A single dose shows
good tolerability, with the most frequent side effects being discoloration of the skin. The initial
viral load data were not convincing - only 2 out of 13 HIV patients had a decrease in viral load of
at least 1 log after 4 weeks (Dezube 2000). Since then, not much has been heard and further
development is in doubt.
TRI-999 and TRI-1144 are two new second generation FIs, that were developed by Trimers in
cooperation with Roche (Delmedico 2006). According to studies on monkeys, the potency and
pharmacokinetics of these peptides are much improved in comparison to T-20. Although administration
is still by injection, it may be possible to limit this to once a week. The data from human
investigations are not yet available, but TRI-1144 will probably continue.
Sifurvitide is a new FI, which is being developed in China. In monkeys it has demonstrated a long
half-life in contrast to T-20, but oral administration is not possible (Dai 2005). Phase I trials
are allegedly being carried out on humans.
Out of sight, out of mind: terminated entry inhibitors:
· AMD 3100 (CXCR4A), AnorMed, cardiotoxicity
· SCH-C/Ancriviroc (CCR5A), Schering-Plough, arrhythmias
· TAK-779, TAK-220 (CCR5A), Takeda, replaced with TAK-652
· Aplaviroc/GW873140/AK602 (CCR5A), GSK, hepatotoxicity
· BMS 806 (attachment inhibitor), poor pharmacokinetics
· Pro-542 (attachment inhibitor), Progenics, concentrated on Pro-140
· T-1249 (fusion inhibitor) Roche/Trimeris, little prospect of success
References
1. Dai SJ, Dou GF, Qiang XH, et al. Pharmacokinetics of sifuvirtide, a novel anti-HIV-1 peptide, in
monkeys and its inhibitory concentration in vitro. Acta Pharmacol Sin 2005, 26:1274-80.
http://amedeo.com/lit.php?id=16174446
2. Delmedico M, Bray B, Cammack N, et al. Next generation HIV peptide fusion inhibitor candidates
achieve potent, durable suppression of virus replication in vitro and improved pharmacokinetic
properties. Abstract 48, 13th CROI 2006, Denver.
3. Derdeyn C, Decker J, Sfakiands J, et al. Sensitivity of HIV-1 to fusion inhibitors is modulated
by coreceptor specificity and involves distinct regions of gp41. Abstract 75, 1st IAS 2001, Buenos
Aires, Argentina.
4. Dezube BJ, Dahl TA, Wong TK, et al. A fusion inhibitor (FP-21399) for the treatment of HIV
infection: a phase I study. J Infect Dis 2000, 182: 607-10. http://amedeo.com/lit.php?id=10915097
5. Heil M, Decker J, Sfakianos J, et al. Analysis of patient-derived HIV-1 isolates suggests a novel
mechanism for decreased sensitivity to inhibition by T-20 and T-649. Abstract 392, 9th CROI 2002,
Seattle.
6. Jiang S, Lu H, Liu S, Zhao Q, He Y, Debnath AK. N-substituted pyrrole derivatives as novel human
immunodeficiency virus type 1 entry inhibitors that interfere with the gp41 six-helix bundle
formation and block virus fusion. Antimicrob Agents Chemother 2004, 48:4349-59.
http://amedeo.com/lit.php?id=15504864
7. Jiang S, Lu H, Liu S, et al. Small molecule HIV entry inhibitors targeting gp41. Abstract
TuOa0201. 3rd IAS 2005, Rio de Janeiro.
Integrase inhibitors
General
The development of integrase inhibitors have been relatively slow. Suitable investigation methods to
test the integrase inhibition effect were lacking, and some identified substrates were too toxic.
The development first started to gather speed around 2000. At that time, the principle of strand
transfer inhibition was discovered (Hazuda 2000). Since 2005, clinical studies have proceeded
rapidly, and lately, following the first data from raltegravir (MK-0518, see below), integrase
inhibitors became the promising new drug class in HIV medicine.
Integrase, along with reverse transcriptase and protease, is one of the three key enzymes in the
HIV-1 replication cycle. This enzyme, which consists of 288 amino acids and is coded by the HIV pol
gene, is involved in the integration of viral DNA into the host genome, and is essential for the
proliferation of HIV (Nair 2002). This fact makes it an interesting starting point for antiviral
drugs. A further, at least theoretical advantage: integrase is probably not present in human cells.
The integration of viral DNA takes place in at least four steps, all of which can be theoretically
inhibited by different integrase inhibitors. Analogous to the entry inhibitors, one may be able to
distinguish different active groups (Reviews: Pommier 2005, Lataillade 2006).
The steps are as follows:
1. Binding of the integrase inhibitor in the cytoplasm to the viral DNA: thus forming a relatively
stable pre-integration complex ? this step can be prevented by pyranodipyridimine as an
integrase-DNA-binding inhibitor.
2. 3¢-processing: in an initial catalytic step, the integrase excises a dinucleotide from either end
of the viral DNA to produce 3¢-hydroxyl ends within the pre-integration protein complex ? this can
be inhibited by processing inhibitors include styrylquinolone or di-ketoacids.
3. Strand transfer: after the changed pre-integration complex has been transferred into the nucleus
of the cell through the nuclear pores, the integrase binds to the host DNA. In this way, it mediates
the docking and the irreversible binding of the hydroxyl ends of viral DNA to the phosphodiesterases
bridges of the host DNA ? this step is inhibited by the two integrase inhibitors that are currently
the furthest developed, raltegravir and elvitegravir, so-called strand transfer inhibitors (STIs).
4. Gap repair: the combination of viral DNA and host DNA is an intermediate product with gaps, which
are repaired by host-cell repair enzymes. Integrase is probably not needed for this ? but the repair
can be inhibited by methylxanthine, for example.
As with all new classes of drugs, there are still a lot of unanswered questions about integrase
inhibitors. For example, the tolerability over a few weeks is known to be good, but nothing is known
about long-term toxicity. This also applies to the development of resistances: according to initial
laboratory data, a cross-resistance that overlaps classes through single mutations seems to be
possible. The following briefly describes some of the drugs in more detail.
Individual substances
Raltegravir (MK-0518, Isentress™) is an integrase inhibitor (or more exactly a strand-transfer
inhibitor, STI) from MSD, and currently the most exciting new drug of all in the treatment of HIV.
Raltegravir is a naphtyridinecarboxamide with a wide efficacy against R5- and X4 -tropic viruses.
Even HIV-2 is suppressed. On monotherapy, the viral load dropped by 1.7-2.2 logs after 10 days
(Markowitz 2006). The data from a Phase II study are still impressive (Grinzstein 2006): 116
patients with a long pre-treatment (median 10 years, in which approximately 30 % had no more active
substances in resistance testing) received 200-600 mg raltegravir bid or placebo. After 8 weeks,
63-67 % of the patients had attained a viral load of less than 50 copies/ml, in contrast to 8 % in
the placebo group - a truly exceptional result for such an intensively pre-treated patient group.
This was confirmed by BNCHMRK-1 and -2, two large Phase III trials, in which 699 patients with
three-class resistance received either 2 x 400 mg raltegravir daily or placebo in addition to an
optimal therapy (Cooper 2007, Steigbigl 2007). After 16 weeks, 79 % (versus 43 %) reached a viral
load below 400 copies/ml. Even in those patients in whom genotypic testing failed to identify a
single active drug, the rate was an impressive 57 % (versus 10 %). Tolerability in these studies was
excellent and comparable to the placebo arm. Similarly encouraging were the results of the
double-blind, randomized Phase II study on 197 therapy-naïve patients. With a backbone of TDF+FTC,
they received either efavirenz or different doses of raltegravir (Markowitz 2006). The proportion of
patients under 50 copies/ml increased in the raltegravir arms more quickly than in the efavirenz
arm, and was equally high in both arms after 24 weeks. The tolerability of raltegravir was very good
here, too. CNS disturbances or dyslipidemia were seen less frequently than on efavirenz (Teppler
2006).
Data on the development of resistances is still limited, but there appears to be two genetic
resistance strains, either through the mutation N155H or Q148K/R/H, which are located in the
catalytic nucleus of the integrase (Cooper 2007). Plasma levels are significantly elevated by
atazanavir (Mistry 2006), but reduced by tipranavir.
The expanded-access program was announced at the beginning of 2007.
Elvitegravir (GS 9137, earlier JTK-303) is an integrase inhibitor produced by Gilead, and is
biochemically similar to the quinolone antibiotics (Sato 2006). Like raltegravir, elvitegravir also
inhibits strand transfer. Single doses had oral bioavailability, were safe and well tolerated
(Kawaguchi 2006), and in vitro, a synergy existed with other medicines (Matsuzaki 2006). In a study
on 40 HIV-infected patients (therapy-na?ve and pre-treated), the viral load sank by approximately 2
logs after 10 days of monotherapy (DeJesus 2006). Significant disadvantages seem to be that
elvitegravir has to be boosted with 100 mg of ritonavir (Kearney 2006), but then single daily dosing
is possible. The preliminary data from a Phase II study, in which 278 patients were either given
three boosted doses (20, 50 and 125 mg) of elvitegravir or a new boosted PI, showed a good response
(Zolopa 2007). Although the 20 mg arm had to be stopped early due to a high failure rate, more
patients in the higher-dosed arms had a viral load under 50 copies/ml (approximately 40 versus 30 %)
after 16 weeks. Before the data is rapidly compared with the raltegravir data, be warned that this
study was constructed differently - the comparison was with an active PI and not with placebo. As
with raltegravir, the tolerability was very good.
Even with elvitegravir, resistance mutations can be selected through in-vitro passages and there
also seem to be two resistance pathways over T66I or E92Q (Jones 2007). Above all, E29Q seems to be
responsible for higher resistance (36 times). The resistances of elvitegravir and raltegravir
overlap partially, and cross-resistances that overlap classes might also be possible (Kodama 2006,
Jones 2007). Hopefully clinical data will refute these suspicions.
GSK-364735 is an integrase inhibitor from GSK, which has been developed together with Shionogi. In a
Phase I study, on 79 healthy probands, between 50 and 400 mg/day was well tolerated (Reddy 2007).
Phase II studies are underway.
References
1. Cooper D, Gatell J, Rockstroh J, et al. Results of BENCHMRK-1, a phase III study evaluating the
efficacy and safety of MK-0518, a novel HIV-1 integrase inhibitor, in patients with triple-class
resistant virus. Abstract 105aLB, 14th CROI 2007, Los Angeles. Abstract:
http://www.retroconference.org/2007/Abstracts/30687.htm
2. DeJesus E, Berger D, Markowitz M, et al. Antiviral activity, pharmacokinetics, and dose response
of the HIV-1 integrase inhibitor GS-9137 (JTK-303) in treatment-naive and treatment-experienced
patients. J AIDS 2006, 43:1-5. http://amedeo.com/lit.php?id=16936557
3. Grinsztejn B, Nguyen BY, Katlama C, et al. Potent antiretroviral effect of MK-0518, a novel HIV-1
integrase inhibitor, in patients with triple-class resistant virus. Abstract 159LB, 13th CROI 2006,
Denver.
4. Hazuda DJ, Felock P, Witmer M, et al. Inhibitors of strand transfer that prevent integration and
inhibit HIV-1 replication in cells. Science 2000, 287:646-50. http://amedeo.com/lit.php?id=10649997
5. Jones G, Ledford RM, yu F, et al. In vitro resistance profile of HIV-1 mutants selected by the
HIV-1 integrase inhibitor, GS-9137 (JTK-303). Abstract 627, 14th CROI 2007, Los Angeles. Abstract:
http://www.retroconference.org/2007/Abstracts/29251.htm
6. Kawaguchi I, Ishikawa T, Ishibashi M, Irie S, Kakee A. Safety and pharmacokinetics of single oral
dose of JTK-303/GS 9137, a novel HIV integrase inhibitor, in HIV healthy volunteers. Abstract 580,
13th CROI 2006, Denver.
7. Kearney B, Mathias A, Zhong L, et al. Pharmacokinetics/pharmacodynamics of GS-9137 an HIV
integrase inhibitor in treatment-naive and experienced patients. Abstract 73, 7th Int Workshop Clin
Pharm HIV Therapy 2006, Lisbon, Portugal.
8. Kodama E, Shimura K, Sakagami Y, et al. In vitro antiviral activity and resistance profile of a
novel HIV integrase inhibitor JTK-303/GS-9137. Abstract H-254, 46th ICAAC 2006, San Francisco.
9. Lataillade M, Kozal MJ. The hunt for HIV-1 integrase inhibitors. AIDS Patient Care STDS 2006,
20:489-501. http://amedeo.com/lit.php?id=16839248
10. Markowitz M, Morales-Ramirez JO, Nguyen BY, et al. Antiretroviral activity, pharmacokinetics,
and tolerability of MK-0518, a novel inhibitor of HIV-1 integrase, dosed as monotherapy for 10 days
in treatment-naive HIV-1-infected individuals. J AIDS 2006, 43:509-515.
http://amedeo.com/lit.php?id=17133211
11. Markowitz M, Nguyen B-Y, Gotuzzo F, et al. Potent antiretroviral effect of MK-0518, a novel
HIV-1 integrase inhibitor, as part of combination ART in treatment-naive HIV-1 infected patients.
Abstract THLB0214, XVI IAC 2006, Toronto.
12. Matsuzaki Y, Watanabe W, Yamataka K, et al. JTK-303/GS 9137, a novel small-molecule inhibitor of
HIV-1 integrase: anti-HIV activity profile and pharmacokinetics in animals. Abstract 508, 13th CROI
2006, Denver.
13. Mistry C, Wenning A, Merschman S, et al. Atazanavir and ritonavir increase plasma levels of
MK-0518. Abstract P291, 8th ICDTHI 2006, Glasgow.
14. Nair V. HIV integrase as a target for antiviral chemotherapy. Rev Med Virol 2002, 12:179-93.
http://amedeo.com/lit.php?id=11987143
15. Pommier Y, Johnson AA, Marchand C. Integrase inhibitors to treat HIV/AIDS. Nat Rev Drug Discov
2005, 4:236-48. http://amedeo.com/lit.php?id=15729361
16. Reddy S, Min S, Borland J, et al. A double-blind, parallel, randomized, placebo-controlled,
single and repeat dose-escalation study to investigate the safety, tolerability, and
pharmacokinetics of the HIV integrase inhibitor GSK364735 in healthy subjects. Abstract 562, 14th
CROI 2007, Los Angeles. Abstract: http://www.retroconference.org/2007/Abstracts/28885.htm
17. Sato M, Motomura T, Aramaki H, et al. Novel HIV-1 integrase inhibitors derived from quinolone
antibiotics. J Med Chem 2006, 49:1506-8. http://amedeo.com/lit.php?id=16509568
18. Steigbigel R, Kumar R, Eron J, et al. Results of BENCHMRK-2, a phase III study evaluating the
efficacy and safety of MK-0518, a novel HIV-1 integrase inhibitor, in patients with triple-class
resistant virus. Abstract 105bLB, 14th CROI 2007, Los Angeles. Abstract:
http://www.retroconference.org/2007/Abstracts/30688.htm
19. Teppler H, Azrolan N, Chen J, et al. Differential effect of MK-0518 and efavirenz on serum
lipids and lipoproteins in antiretroviral therapy (ART)-naive patients. Abstract H-256a. 46th ICAAC
2006, San Francisco.
20. Zolopa A, Mullen M, Berger D, et al. The HIV integrase inhibitor GS9137 demonstrates potent ARV
activity in treatment-experienced patients. Abstract 143 LB, 14th CROI 2007, Los Angeles. Abstract:
http://www.retroconference.org/2007/Abstracts/30571.htm
Maturation inhibitors
Maturation inhibitors inhibit HIV replication in a late phase of the reproduction cycle, i.e., by
the budding of new virions.
Bevirimat (PA-457) is a derivative of betulinic acid, which is isolated as triterpene carbonic acid
from birch bark. Bevirimat (manufacturer: Panacos) inhibits replication in a very late phase of the
reproduction cycle, i.e. the budding or maturation of new virions (Li 2003). Bevirimat inhibits the
transition of the capsid precursor (p25) into the mature capsid protein (p24), to produce
non-infectious viruses. Because of its novel method of action, bevirimat is also effective against
resistant viruses. Following the publication of the first results of a small study on HIV patients
at the start of 2005 (Martin 2005), the data of a Phase IIa placebo-controlled trial were published
in autumn 2005, in which patients received an oral once-daily monotherapy of PA-457 for 10 days
(Beatty 2005). In the highest dosage group (200 mg) a reduction in viral load of 1.03 logs was
reached; in the 100 mg group it was just 0.48 logs. However, some patients had no significant
reduction in the viral load. Fortunately, the drug has a long half-life, and a once daily dose will
definitely be possible (Smith 2006). Bevirimat has so far been well tolerated. Resistance has not
yet been observed in humans, although in the laboratory, resistance mutations in the capsid and in
the gag regions can be selected. Because these were point mutations, a low resistance barrier is
suspected. Resistant mutants are therefore less capable of reproducing than the wild-type viruses
(Adamson 2006). Bevirimat also works synergistically with other antiviral drugs (Kilgore 2006).
UK-201844 is a maturation inhibitor from Pfizer. It was discovered after the screening of more than
one million drugs (Blair 2006). The method of action seems to lie in the interaction with gp160
processing, which leads to the production of non-infectious virus.
Maturation inhibitors are, without a doubt, an interesting class of new drugs. Whether a prototype,
such as bevirimat, will make it as far as the clinic, is still unclear Phase IIb/Phase III studies
are awaited.
References
1. Adamson C, Salzwedel K, Castillo A, et al. Viral resistance to PA-457, a novel inhibitor of HIV-1
maturation. Abst. 156, 13th CROI 2006, Denver.
2. Beatty G, Jacobson J, Lalezari J, et al. Safety and Antiviral Activity of PA-457, the
First-In-Class Maturation Inhibitor, in a 10-Day Monotherapy Study in HIV-1 Infected Patients.
Abstract Abstract H-416D, 45th ICAAC 2005, Washington.
3. Blair W, Cao J, Jackson L, et al. Execution of a high throughput HIV-1 replication screen and the
identification of a novel small molecule inhibitor that targets HIV-1 envelop maturation. Abstract
50LB, 13th CROI 2006, Denver.
4. Kilgore N, Reddick M, Zuiderhof M, et al. The first-in-class maturation inhibitor, PA-457, is a
potent inhibitor of HIV-1 drug-resistant isolates and acts synergistically with approved HIV drugs
in vitro. Abstract 509, 13th CROI 2006, Denver.
5. Li F, Goila-Gaur R, Salzwedel K, et al. PA-457: a potent HIV inhibitor that disrupts core
condensation by targeting a late step in Gag processing. Proc Natl Acad Sci U S A 2003,
100:13555-60. http://amedeo.com/lit.php?id=14573704
6. Martin D, and others. The safety, tolerability, and pharmacokinetics of multiple oral doses of
PA-457, the first-in-class HIV maturation inhibitor, in healthy volunteers. Abstract 551. 12th CROI
2005, Boston.
7. Martin D, Jacobson J, Schurmann D, et al. PA-457, the first-in-class maturation inhibitor,
exhibits antiviral activity following a single oral dose in HIV-1-infected patients. Abstract 159,
12th CROI 2005, Boston.
8. Smith P, Forrest A, Beatty G, et al. Pharmacokinetics/pharmacodynamics of PA-457 in a 10-day
multiple dose monotherapy trial in HIV-infected patients. Abstract 52, 13th CROI 2006, Denver.
Immunotherapy
In addition to conventional ART, immunomodulatory treatment strategies have been investigated
(Reviews: Mitsuyasu 2002, Sereti 2001). All of these therapies still lack proof of clinical benefit.
Some approaches are nevertheless addressed briefly below.
Interleukin-2 (IL-2, Aldesleukin, Proleukin™) is a cytokine that is produced by activated T cells
and which induces proliferation and cytokine production in T-, B- and NK cells (Review: Anaya 2005).
It is licensed in Europe for the treatment of metastatic renal cell carcinoma. At the beginning of
the 90s, IL-2 was already used intravenously in HIV-infected patients (Wood 1993), but it is now
administered subcutaneously.
The most important effect is the increase in CD4 and CD8 cells (Kovacs 1996). Memory cells initially
increase, followed by na?ve T cells (Chun 1999, Carcelain 2003). The CD4 nadir is predictive for the
CD4 cell increase (Markowitz 2003). The increasing CD4 cells under IL-2 probably have the same
qualities as "normal" CD4 cells (Valdez 2003). The source of the CD4 cell increases is also a
subject of some discussion. Some authors suspect that the increase is more due to peripheral
expansion than to increased thymus output (Lu 2003), others have assigned greater importance to the
thymus (Carcelain 2003). Newer studies suggest that the effect of IL-2 is above all based on a
reduced T-cell turnover or cell death (Kovacz 2005, Sereti 2005, Vento 2006).
Table 3.1: Larger, randomized IL-2 studies on HIV-infected patients.
Study n Patients
(CD4 median at baseline) Doses of
Interleukin-2 (MIU) Main results
(In each case with versus without IL-2)
ANRS 079
Levy 2001 118 PI-naïve
(CD4 200-550) 2 x 5
for 5 days
10 cycles Median CD4 increase (865 versus 240 after 74 weeks)
No difference in VL
ACTG 328
Mitsuyasu 2001 174 HAART
(CD4 264) 1 x 7.5
for 5 days
every 8 weeks Median CD4 increase (614 versus 396 after 84 weeks)
CPCRA 059
Abrams 2002 511 HAART
(> 300 CD4) 2 x 1.5-7.5
for 5 days
every 8 weeks CD4 increase in the IL-2 arms higher by 251 at month 12, no difference in viral load
Lalezari 2002 115 HAART
(< 300 CD4) 1 x 1.2
daily for 6 months No difference in CD4, but in NK and naïve CD4
ANRS 082
Katlama 2002 72 HAART
(< 200 CD4) 2 x 4.5
for 5 days
every 6 weeks Median CD4 increase (51 versus 11 after 24 weeks)
Davey 2000 82 HAART
(CD4 2-500) 2 x 7.5
for 5 days
every 6 weeks Median CD4 increase (384 versus 64 after 52 weeks)
VL -0.28 vs 0.09 log (p=0.03)
ACTG 248
Vogler 2004 115 ART
(CD4 3-700) 1 x 1.0
daily No significant difference
VL = viral load, MIU = Million International Units
The duration of treatment interruption cannot be lengthened if IL-2 is given beforehand (Henry
2006).
It is still not clear whether the increase in CD4 cells on IL-2 has a clinical benefit. In order to
answer this question, two large randomized studies, funded for years, were designed, ESPRIT and
SILCAAT. In view of the low number of clinical events neither of these studies will provide
definitive answers.
ESPRIT (http://www.espritstudy.org) is a study in which around 4,000 patients with more than 300 CD4
cells/µl are being treated in addition to HAART with IL-2 or placebo (Emery 2002). After three
cycles, 64 % of patients in the IL-2 arm had an increase in CD4 cells of at least 200/µl (Weiss
2003).
SILCAAT has a similar concept, but enrolled patients with 50-299 CD4 cells/µl. Patients receive a
total of 6 cycles of IL-2 subcutaneously over 5 days every 8 weeks. After enrolment of 1,957
patients, the study was stopped in 2002, as it was simply too expensive for the manufacturer.
However, SILCAAT is now continuing again. In the first analyses (Levy 2003), 449 patients, had a
median CD4 cell increase of 123/µl after one year. This gain was greater with better CD4 cells at
baseline. It seems to indicate that even IL-2 has limited effects for reconstituting the immune
system once it has been destroyed.
Summary: despite SILCAAT and ESPRIT, IL-2 therapy must be viewed skeptically at the moment. In our
view, there are only a few patients who should potentially be considered for therapy with IL-2.
These are patients with no immunological response, whose CD4 cell counts remain low despite good
viral suppression over longer periods of time (Crespo 2006). It is still not clear whether in these
patients, who only rarely develop AIDS, it is simply a question of laboratory cosmetics.
Interleukin-12 stimulates T lymphocytes and NK cells to generate a Th1-type immune response. In a
randomized Phase I study with 100 ng/kg 2 x/week, the drug was well tolerated but had no effect on
lymphocyte subpopulations, antigen-specific immune response or viral load (Jacobson 2002). Further
development is therefore uncertain. The same would appear to be true for interleukin-10 (Angel 2000)
or interleukin-15 (Ahmad 2005). In the age of HAART, such experimental therapies have to meet
ever-increasing standards.
Interleukin-7 seems to be more promising. This cytokine plays a fundamental role in T-cell
homeostasis and influences amongst other things the formation and maturation of CD4 cells. In two
pilot studies, 6 and 16 HIV patients received different doses injected subcutaneously (Levy 2007,
Sereti 2007). In both trials, good CD4 increases were observed together with good tolerability. The
IL-2-type side effects were not observed. If these results can be confirmed in large studies,
interleukin-7 could become an option for those patients in whom immune reconstitution remains low
despite good viral suppression
Other Immunotherapies than interleukins (listed alphabetically)
Other immunotherapies
The prototype of a therapeutic vaccination already suffered disaster years ago: Remune™, a vaccine
developed by a team headed by the late Jonas Salk, is comprised of an envelope-depleted (gp120)
virus which, although indeed immunogenic, does not seem to provide any clinical benefit. One trial
was interrupted prematurely in May 1999. More than 2,500 patients had taken part for a mean of 89
weeks in this multinational study, which was designed to evaluate the addition of Remune™ to HAART.
As well as the lack of clinical benefit advantages with respect to CD4 cell count or viral load were
not shown (Kahn 2000).
Cyclosporin A (Sandimmune™) - Immune activation may lead to increased HIV replication, and an
attractive treatment hypothesis has been to suppress the immune system in an attempt to slow down
viral replication. Cyclosporin, which is normally used for prophylaxis of organ transplantation
rejection, could be such an inactivator of the immune system (Rizzardi 2002). However, in clinical
studies, cyclosporin A is disappointing: it has no effect on CD4/CD8 cells, nor on expression of
activation markers (Calabrese 2002, Lederman 2006). Cyclosporin A therefore has no future in the
therapy of chronically infected HIV patients. Whether cyclosporin A might improve treatment of acute
HIV infection needs to be clarified in further studies.
G-CSF and GM-CSF are used in HIV patients for a variety of reasons. The cytokine G-CSF (granulocyte
colony stimulating factor) is available as filgastrim (Neupogen™), pegfilgastrim (Neulasta™) and
lenogastrim (Granocyte™). GM-CSF (granolocyte macrophage stimulating factor) is available as
sargramostim (Prokine™) or molgramostin (Leucomax™). G-CSF is licensed for treatment of prolonged
neutropenia in patients with advanced HIV infection to reduce the risk of bacterial infections.
Treatment with G-CSF can be particularly useful in patients on chemotherapy or myelosuppressive
drugs such as gancyclovir or AZT. G-CSF significantly reduces bacterial infections in neutropenic
HIV patients. In a randomized study on 258 neutropenic HIV patients with CD4 cell levels below
200/µl, the rate of severe neutropenia after 24 weeks was 2 versus 22 % in the control group
(Kuritzkes 1998). The incidence of bacterial infections was reduced by 31 %, and the number of
inpatient days was reduced by 45 %. There was no effect on viral load. In patients with CMV
retinitis, G-CSF was also shown to have significant survival benefit (Davidson 2002).
GM-CSF achieved a slight decrease in viral load in three double-blind, randomized studies (Angel
2000, Skowron 1999, Brites 2000); however, in one study in patients with uncontrolled infection
there was a slight increase (Jacobsen 2003). GM-CSF seems to prevent significant loss of CD4 cells
during longer treatment interruptions (Fagard 2003). However, in view of the costs and side effects
outside clinical studies such approaches cannot be recommended
Hydroxyurea (HU, Litalirä) is an old chemotherapeutic agent, which is still used today in chronic
myeloproliferative illnesses. It inhibits DNA synthesis via ribonucleotide reductase and leads to an
intracellular deficiency in deoxynucleoside triphosphate.
As early as 1994, the synergistic effects with ddI on HIV replication were shown (Lori 1994). In
1998, a placebo controlled Swiss study on 144 patients showed that after 12 weeks on HU, 54 % versus
28 % in the placebo arm reached a viral load below 200 copies/ml (Rutschmann 1998). HU really became
fashionable with the case of the "Berlin patient" - the patient that took HU in addition to
indinavir+ddI in the acute phase and later had no measurable viremia, even without HAART (Lisziewiez
1999). Was this due to hydroxyurea? Smaller studies seemed to confirm this (Hellinger 2000, Lori
1999, Rodriguez 2000), and many doctors started to prescribe HU, even to children. Some dreamed of a
cheap alternative to ddI for Africa. But, the hopes rapidly disappeared. Above all, the combination
with ddI+d4T proved to be problematic - the incidence of polyneuropathy increased to almost 30/100
patient years (Moore 2000). In ACTG 5025, in which HU was tested as a "stabilizer" of virologically
sufficient therapy, three patients died of pancreatitis (Havlir 2001). The risk of pancreatitis
seems to increase 4-fold on HU (Moore 2001). At least 3 controlled studies showed no positive
effects, just toxicity (Blackenberg 2004, Stebbing 2004, Swindells 2005). It had no effect in
randomized studies of primary infection - the Berlin patient could not be "reproduced" (Zala 2002).
Interferons have an antiretroviral effect (Mildvan 1996) of 0.5-1 logs on 3 mill IU daily (Haas
2000, Hatzakis 2001). Because interferons have to be injected subcutaneously and have side effects
which are not insignificant, they are not being pursued further in HIV medicine. It is not clear
whether the pegylation of interferons will change anything.
Corticosteroids have been and continue to be discussed. However, this treatment has so far not stood
the test of controlled studies. In a placebo-controlled study with 0.5 mg prednisone/kg over 8
weeks, there were no effects on CD4 cells or viral load (McComsey 2001). In ACTG 349, 24 patients
were treated with 40 mg prednisone daily or not in a double-blind randomized design (Wallis 2003).
After 8 weeks, there was a trend towards higher levels of CD4 cells in the prednisone arm (> 40 %, p
= 0.08), but there were no effects on activation markers or apoptosis. Two patients on prednisone
developed necrosis of the femoral head. This study should advise caution before the use of steroids
for "immunological" reasons is considered.
Murabutide is a synthetic muramyldipeptide with a variety of effects on the immune system. It can
raise unspecific resistance to infection, induce anti-inflammatory cytokines and growth factors, and
strengthen the anti-viral effects of cytokines such as IL-2 or interferon. In HIV patients in
France, it is mainly used as an immune modulator, although with, at most, moderate effects (Bahr
2003).
Mycophenol (Cellcept™) - is an inhibitor of inosine monophosphate (IMP) dehydrogenase and is
normally used for prophylaxis of acute transplant rejection as well as for some autoimmune diseases.
Through the inhibition of lymphocyte proliferation and the subsequent reduction of target cells, the
replication of HIV should be inhibited. Initial reports seem to demonstrate an effect on viral load
at least in some patients (Margolis 2002, Press 2002). Whether this will be confirmed by randomized
trials seems uncertain (Sankatsing 2004, Margolis 2006).
THC, Cannabinoids have no effect. A prospective randomized study, in which patients could either
smoke marijuana or receive TCH tablets (dronabinol, Marinol™) or placebo in addition to HAART,
showed no effects on lymphocyte subpopulations or lymphocyte function after three weeks (Bredt
2002). THC, which is metabolized via the cytochrome P450 system, however, had no detrimental effects
on viral load or plasma levels of protease inhibitors (Abrams 2003).
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