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Antiviral Drugs in the Treatment of Aids: What Is in the Pipeline ?

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Antiviral Drugs in the Treatment of Aids: What Is in the Pipeline ? October 15, 2007 EU RO PE AN JOUR NAL OF MED I CAL RE SEARCH 483 Eur J Med Res (2007) 12: 483-495 © I. Holzapfel Publishers 2007 ANTIVIRAL DRUGS IN THE TREATMENT OF AIDS: WHAT IS IN THE PIPELINE ? Hans-Jürgen Stellbrink Infektionsmedizinisches Centrum Hamburg ICH, Hamburg, Germany Abstract even targeting immune responses have to be devel- Drug development in the field of HIV treatment is oped. Continued drug development serves the ulti- rapid. New nucleoside analogues (NRTI), non-nucleo- mate goal of normalization of life expectancy. side analogue reverse transcriptase inhibitors (NNR- TI), and protease inhibitors (PI) are currently being in- METHODS vestigated in human trials. Furthermore, inhibitors of HIV attachment, fusion and integrase with novel Drug development in the field of HIV infection is modes of action are being developed, which offer new highly competitive, and a company’s decision to pur- perspectives for the goal of a normalization of life-ex- sue or discontinue the development of a drug is dri- pectancy in HIV-infected individuals. The most ad- ven by economic rather than scientific considerations. vanced compounds likely to become licensed soon in- Of all candidate compounds, only a few reach the lev- clude the NNRTIs rilpivirine and etravirine, the inte- el of trials in humans, and some exhibit lack of effica- grase inhibitors raltegravir and elvitegravir, and mar- cy or toxicity problems at this stage. Some compounds aviroc and vicriviroc, novel inhibitors of the CCR5 also have no obvious advantage over currently avail- chemokine receptor, which functions as the major able ones, so that their development is discontinued. coreceptor for HIV-1. Confidentiality of drug development within phar- maceutical companies and frequent renaming make it INTRODUCTION very difficult to trace the compounds and summarize the current state. Furthermore, the discontinuation of Highly active antiretroviral therapy (HAART) has development is not always announced in the public. markedly reduced the mortality of HIV-1 infected pa- Therefore, for the purpose of this review the com- tients [1; 2]. Combinations of two nucleoside reverse pounds were categorized as transcriptase inhibitors (NRTI) and either a protease inhibitor (PI) or a non-nucleosidic inhibitor of re- Category 1: Compounds that are in phase II or have verse transcriptase (NNRTI) have set the standard for passed phase II successfully HAART. The continuation of therapy for decades Category 2: Compounds that are either in or have with the aim of normalizing life expectancy, however, passed phase I is hampered by issues of toxicity, adherence, and the Category 3: Drugs that have not yet been investigated development and transmission of resistance. Despite in human trials (“preclinical”), but for which published the high number of licensed compounds, consider- manuscripts, conference abstracts, or internet or press able cross-resistance within the drug classes and phar- reports after January 2005 indicate the continuation of macodynamic as well as pharmacokinetic interactions drug development. Only publicly accessible informa- limit the number of combination options. HAART tion was evaluated. In the list of Category 3 com- modifications in previously untreated subjects are pri- pounds, no drug classes but only individual lead com- marily required due to toxicity and aherence [3], but pounds were included. virological failure remains an issue. Therefore, new drugs have to be developed for reduced toxicity, im- Drugs like amdoxovir and brecanavir are listed sep- proved ease of administration, and a more robust an- arately, because their development was discontinued tiviral effect. during studies in humans. NRTIs, NNRTIs, and PIs have the advantage of The data was acquired by searching scientific data- long-term clinical experience with the drugs and a bases (EntrezPubMed proven prognostic benefit. Therefore, the develop- http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed, ment of novel compounds from within existing drug conference abstracts, company homepages, and public classes is promising. They should exhibit toxicity pro- patent registries. files different from the available drugs, be easy to ad- Category 1 and 2 compounds are regarded as candi- minister and have activity against resistant variants. dates for further development, category 3 drugs are Furthermore, in order to improve virological response not discussed below. following resistance development, novel classes ex- This review summarizes the status in the field as of ploiting new targets in the viral replication cycle or August 2007. 484 EUROPEAN JOURNAL OF MEDICAL RESEARCH October 15, 2007 THE MOST PROMISING NEW ANTIVIRALS eration of Merck and Ambrilia Biopharma) [13; 14]. A unique feature of this compound is its potential to 1. NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS boost the levels of other drugs similar to ritonavir, AND RELATED COMPOUNDS which could make it attractive, provided it is not more toxic than ritonavir. A hallmark feature for new NRTIs should be high ac- tivity against NRTI-resistant variants, especially those 4. INTEGRASE INHIBITORS carrying the M184V mutation. Apricitabine and elvucitabine have demonstrated antiviral activity in After investigation into the details of the different clinical trials [4-6]. For apricitabine, activity against steps of viral integration over several years, the princi- NRTI-resistant strains was already confirmed in a pilot ple of strand transfer inhibition has now led to the de- trial [5]. That remains to be shown for elvucitabine. velopment of highly active antivirals. The Merck com- Both are the most promising compounds within this pound raltegravir has exhibited excellent antiviral ac- class. The antiviral activity of racivir in a pilot trial in tivity in both salvage therapy and treatment-naïve sub- subjects with lamivudine-resistant virus was limited jects [15-17]. Its independence from ritonavir boosting but significant [7]. Its similarity to emtricitabine, how- makes it attractive for all lines of therapy, although it ever, could jeopardize its further development. has to be administered twice daily. In contrast, elvite- Unlike other NRTI, KP-1461 utilizes error induc- gravir by Gilead requires ritonavir boosting but in turn tion in the reverse transcriptase as a mechanism of ac- can be dosed once daily. It is active in treatment-expe- tion. A phase IIa study has just begun and will soon rienced patients [18] and appears very promising, too. reveal the potential of this approach. Raltegravir is somewhat ahead in terms of clinical trial Since zidovudine is licensed and problematic due to results and will most likely be licensed earlier than its side effect of lipodystrophy, fozivudine-tidoxil as elvitegravir. Unfortunately, cross-resistance between its prodrug has little chance for further development. these two compounds is likely. Similarly, since the parent compound of fosalvudine, alovudine (MIV-310) was discontinued due to the lim- 5. CHEMOKINE RECEPTOR BLOCKERS ited effect on multi-drug resistant virus, fosalvudine is unlikely to succeed. However, in December 2006, Drugs that block the binding of HIV-1 to either the Medivir outlicensed alovudine to Presidio Pharmaceu- CCR5 or the CXCR4 receptor have theoretical advan- ticals, so that the fate of the compound remains un- tages over those mentioned above: 1. they aim at a cel- clear. lular target that does not underly mutational changes in the individual host and 2. they act extracellularly, 2. NON-NUCLEOSIDE REVERSE TRANSCRIPTASE making them independent from cellular uptake, activa- INHIBITORS (NNRTI) tion and efflux mechanisms. CCR5 receptor blockers are focussed on in other reviews in this issue of the Tibotec has developed rilpivirine as a first-line NNRTI journal. In contrast to CCR5, however, there is no bio- with similar activity to efavirenz, probably less neu- logical analogy to CXCR4 blockade. This raises con- ropsychiatric toxicity and less blood lipid elevation [8- cerns regarding side effects. The development of 10]. The drug is active in vitro against variants carrying CXCR4 blockers has indeed been hampered by unex- key NNRTI resistance mutations and requires more pected toxicities such as the dose-dependent leukocy- mutational steps for a marked reduction of sensitivity tosis induced by AMD070. This compound is now than efavirenz or nevirapine. According to current trial also being investigated as a haematological agent. It results, the compound has a high potential for first- therefore appears questionable if CXCR4 blockers will line therapy. It might be very helpful in the setting of be developed until licensure. increasing rates of transmitted NNRTI resistance mu- tations. 6. ATTACHMENT AND FUSION INHIBITORS Another Tibotec drug, etravirine, is also active against NNRTI-resistant strains and has the potential The humanized monoclonal antibody TNX-355 direct- to add significant activity to salvage regimens, as ed against the CD4 molecule developed by Tanox is demonstrated by the DUET-1 and -2 trial results in the most advanced attachment inhibitor. It has shown subjects with treatment failure and resistance [11; 12]. a clear antiviral effect [19; 20]. Due to its parenteral Unless unexpected toxicity issues appear in the trials, mode of application, however, it is unlikely to become both drugs are currently the most promising candi- attractive for any line of therapy before salvage. The dates for licensure. UK-453,061 by Pfizer continues to availability of other novel compounds
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