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Review Novel Compounds for the Treatment of HIV Type-1 Infection

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Review Novel Compounds for the Treatment of HIV Type-1 Infection Antiviral Chemistry & Chemotherapy 19:189–200 Review Novel compounds for the treatment of HIV type-1 infection Hans-Jürgen Stellbrink1,2* 1Infektionsmedizinisches Centrum Hamburg, Hamburg, Germany 2ICH Study Center, Hamburg, Germany *Corresponding author: E-mail: [email protected] Despite the recent licensure of several new antiretroviral inhibitors) and elvitegravir (integrase inhibitor). The compounds, there is still a need to develop additional potential of other compounds with new modes of action agents. Problems with antiviral activity, tolerability, is less clear. Currently, maturation inhibitors appear ease of administration, extent of cross-resistance and promising but for other drugs, obstacles to continued pharmacokinetic as well as pharmacodynamic interac- development, such as the need of parenteral application tions still represent important obstacles to life-long (that is, monoclonal antibodies) or toxicity (for example, control of HIV type-1 replication by highly active anti- immune modulating agents and pegylated interferon), retroviral therapy. Several compounds stem from the are already apparent. For even more compounds in the same classes as currently available drugs: apricitab- preclinical development phase, an assessment of their ine and elvucitabine (nucleoside reverse transcriptase possible clinical role is still premature. This review pro- inhibitors), rilpivirine (non-nucleoside reverse tran- vides an overview and a summary of the current status scriptase inhibitor), vicriviroc and INCB009471 (CCR5 of drug development in the field. Introduction Antiretroviral drug combination therapy has been very >20 licensed antiretroviral drugs. Pharmacodynamic successful in reducing morbidity and mortality of HIV interactions, such as the antagonism between zidovu- type-1 (HIV-1) infection [1,2]. Most of the clinical dine and stavudine, high rates of toxicity with didano- benefits have been achieved with combinations of two sine plus stavudine or increased risk of virological fail- nucleoside/nucleotide reverse transcriptase inhibitors ure with didanosine plus tenofovir (reviewed in [3]), as (NRTIs) with either a protease inhibitor (PI) or a non- well as numerous pharmacokinetic interactions actually nucleoside reverse transcriptase inhibitor (NNRTI). limit the number of combination options substantially. The therapeutic development has been greatly acceler- Although infrequent in primary treatment, virologi- ated in comparison with other fields of medicine by the cal failure and development of resistance or class-wide use of validated surrogate parameters in clinical trials cross-resistance remain important issues. Side effects, (plasma viral load and CD4+ T-cell count), which forms however, represent the most important reasons for dis- the basis on which drugs are licensed rapidly. Further- continuing drugs in clinical routine [4,5]. Therefore, more, the principles of combination therapy have been the development of new drugs should aim to reduce incorporated into development strategies, with the con- toxicity, improving the ease of administration without sequence that even novel compounds are tested early as reducing the antiviral effect. part of a combination rather than as individual drugs. Novel galenic preparations of currently licensed The strategic goal of therapy has shifted from short- compounds are not within the scope of this review. term protection from imminent risks to normalization They include a 625 mg preparation of nelfinavir with of life expectancy; however, toxicity, adherence and a 30% higher oral bioavailability, extended-release the development and transmission of resistance remain stavudine, extended-release nevirapine and ritonavir important obstacles to reaching this goal. Moreover, tablets (melt-extrusion preparation circumventing the the actual number of combination options is much requirement for refrigeration). These preparations, more limited than anticipated, given that there are however, despite increasing the ease of administration, ©2009 International Medical Press 1359-6535 (print) 2040-2066 (online) 189 Stellbrink.indd 189 22/5/09 09:31:58 H-J Stellbrink are unlikely to overcome the treatment-limiting only caused by the positive and negative b-enantiomer toxicities of the parent compounds. of emtricitabine in this setting. The beneficial long-term clinical experience with Unlike other NRTIs, KP-1461 is reported to utilize NRTIs, NNRTIs and PIs stimulates the development of error induction in reverse transcriptase as a mechanism novel compounds from within these groups, which are of action. A Phase IIa study was recently halted, appar- less cross-resistant, easier to administer and have a differ- ently because of a lack of antiviral effect [12]. ent toxicity profile. However, in order to overcome limi- Because zidovudine is licensed but problematic as tations resulting from extended resistance, novel com- a result of its side effects of lipodystrophy and anae- pounds with new modes of action have to be developed mia, fozivudine tidoxil as its prodrug has little chance with the ultimate goal of normalizing life expectancy. for further development. Phosphazid, another zidovu- dine prodrug, is licensed in Russia, but for the reasons Methods mentioned above is unlikely to reach other markets. Similarly, because the parent compound of fosalvudine, This review summarizes novel compounds under devel- alovudine (MIV-310), was discontinued because of its opment for the treatment of HIV-1 infection. They were limited effect on multidrug-resistant virus, fosalvudine classified as Category 1, which included compounds that is unlikely to be developed further. In December 2006, were in Phase II or III or had passed Phase II successfully, Medivir outlicensed alovudine to Presidio Pharmaceuti- Category 2, which included compounds that were either cals, so that the fate of the compound remains unclear. in or had passed Phase I, and Category 3, which included Recently, new clinical trial results were presented drugs that had not yet been investigated in human trials regarding amdoxovir. It demonstrated marked antiviral (preclinical). As pharmaceutical companies often do not activity in combination with zidovudine in a very small announce the discontinuation of development of a com- trial [13]. A small but significant decrease in viral load pound, only those compounds were included for which (0.37 log10 units) was observed in patients with virus published manuscripts, conference abstracts, or internet strains carrying a median of six NRTI mutations (range or press reports after 1 January 2006 indicated contin- 1–8) [14,15]. Lens opacities, observed in monkeys, ued development. Only publicly accessible information were initially reported from a pilot trial [16], but did was evaluated. In Category 3, only lead compounds were not appear to be an issue in larger studies [14,15,17]. included. The most promising drugs, primarily from Cat- egories 1 and 2, are discussed below. Non-nucleoside reverse transcriptase inhibitors New galenic preparations of currently available drugs are not within the scope of this review and are therefore Tibotec has developed rilpivirine (TMC278) as a first-line not included. NNRTI with similar activity to efavirenz and, most likely, The data were acquired by searching scientific data- less neuropsychiatric toxicity and less blood lipid increase bases (Entrez PubMed), conference abstracts, company [18–20]. The drug is active in vitro against variants car- homepages and public patent registries. This review sum- rying key NNRTI resistance mutations and appears to marizes the status in the field as of November 2008. require more mutational steps for a marked reduction of sensitivity than efavirenz or nevirapine. According to cur- Nucleoside reverse transcriptase inhibitors rent trial results, the compound has a high potential for and related compounds first-line therapy. It might be especially helpful in the set- ting of transmitted NNRTI resistance mutations. In view Apricitabine and elvucitabine have demonstrated anti- of the widespread use of antigastritic medication, how- viral activity in clinical trials [6–8], with apricitabine ever, its pH-dependent absorption [21] might represent a also being active against NRTI-resistant strains in a pilot problem for future routine clinical use. trial [7]. Both are the most promising compounds within UK-453061 by Pfizer is activein vivo [22] and contin- this class; however, as both are cytidine analogues, they ues to be investigated, whereas the fate of GW695634 cannot be combined with lamivudine or emtricitabine. by GlaxoSmithKline is unclear. The same applies Moreover, elvucitabine has exhibited myelosuppression to BILR 355 BS, which requires ritonavir boosting, [9] and is being tested at lower doses now, which casts almost automatically restricting it to a small segment a doubt on its tolerability. Despite induction of cross- of the market. Table 1 shows details of the reverse tran- resistance to lamivudine because of the M184I muta- scriptase inhibitors currently under development. tion [10], it shows activity against virus strains carrying the M184V lamivudine/emtricitabine resistance muta- Protease inhibitors tion [9]. The antiviral activity of racivir in a pilot trial in patients with lamivudine- resistant virus was limited PPL-100 (MK8122), a prodrug of PL-100, is currently but significant [11]. It is currently unclear if the effect is investigated in humans in a cooperation of Merck and 190 ©2009 International
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