New HIV Protease Inhibitors for Drug-Resistant Viruses
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SPECIAL REPORT New HIV protease inhibitors for drug-resistant viruses Stefano Rusconi† & Several second-generation protease inhibitors have been developed over the last few Ottavia Viganò years. These compounds have been used in preregistrative clinical trials or are currently in †Author for correspondence various Phases (I, II or III) of their progress towards use in HIV-1-infected patients. All drugs Cattedra di Malattie Infettive e Tropicali, in this category have been designed in order to reach high plasma levels and possibly Dipartimento di Scienze overcome the issue of cross-resistance among the compounds belonging to this class. Cliniche "Luigi Sacco", Taking into account the rapid occurrence of protease inhibitor cross-resistance, clinicians Università degli Studi, via G.B. Grassi 74, who are treating patients living with HIV/AIDS will need new active protease inhibitors in 20157 Milano, Italy the near future. These newly developed compounds will be the subject of our review. Tel.: +39 023 904 3350 Fax: +39-025 031 9758 [email protected] An overview of antiretroviral therapy in order to guide treatment decisions for HIV-1- An impressive acceleration has been observed infected patients [28,29]. Taking all these issues regarding drug discovery activity towards the into consideration, the management of anti-HIV-1 agents over the last decade. Nucleo- HIV/AIDS infection has become much more side and non-nucleoside inhibitors of reverse complicated than before, and discrepancies transcriptase (RT) have demonstrated high anti- between treated and untreated populations have viral activity both in vitro and in vivo [1–3]. How- become wider and wider. ever, RT inhibitors have shown only transient efficacy when administered as single or dual Medical needs therapy because of the emergence of resistant The pandemic phenomenon determined by viral variants [4–7]. On the basis of the evidence HIV/AIDS spread in such a rapid fashion as to that viral protease is essential to the life cycle of cause a disaster in terms of global health – the HIV-1, and after the development of first-gener- tragic burden was especially apparant in low- ation HIV-1 protease inhibitors (PIs) [8–12], the resourced countries [30]. According to the 2004 introduction of PIs into combination-therapy United Nations (UN) AIDS data, at the end of regimens has resulted in a marked improvement 2004 39.4 million people were living with in clinical outcomes [13–16]. HIV/AIDS, 3.1 million died and 4.9 million Combination regimens aim to suppress viral were newly infected during 2004. Among those replication in infected individuals for as long as who had been infected in 2004, 95% were from possible. Nevertheless, residual viral activity often poor countries and of these, approximately 70% persists during therapy and this condition repre- live in sub-Saharan Africa [101]. sents an ideal requisite for the emergence of Drug availability through highly active anti- drug-resistant viral variants with low suscep- retroviral therapy (HAART) – a combination of tibility to all classes of HIV-1-inhibitory at least three drugs with or without a fusion compounds [17–19] . This indicates that the selec- inhibitor – has dramatically changed the history tion of resistant viral mutants is driven by drug of the infection as well as the related morbility pressure [20,21], and may also be sustained by a and mortality [31,32]. HIV/AIDS has become, at reduced adherence to antiretroviral regimens and least in developed countries, a manageable dis- suboptimal levels of anti-HIV compounds in ease, also allowing for novel approaches such as Keywords: clinical efficacy, bodily fluids. Within the PI class of compounds, structured treatment interruptions (STIs). drug-resistance, HIV-1, novel HIV-1 variants resistant to one compound have There is absolute need for novel antiretroviral compounds, protease shown different degrees of cross-resistance to agents. Of course, improvement of adherence inhibitors, response other PIs currently available [22–27]. In this con- and appropriate selection of first-line regimens text, combination therapy against HIV-1 requires are crucial factors determining the future not only the monitoring of CD4+ lymphocytes development of resistance to antiretrovirals. It is and viral load, but also the introduction of geno- evident from the HIV/AIDS pandemic that Future Drugs Ltd typic resistance tests and drug-sensitivity assays improvements in current agents are needed, in 10.1586/14750708.3.1.79 © 2006 Future Drugs Ltd ISSN 1475-0708 Therapy (2006) 3(1), 79-88 79 SPECIAL REPORT – Rusconi & Viganò terms of greater antiretroviral potency, activity monotherapy [22] . Together with the progressive towards drug-resistant viruses, fewer adverse accumulation of mutations selected by IDV events and availability of reaching tissue and cel- monotherapy, these patients harbored viruses lular reservoirs. An increasing number of patients that also became resistant to other PIs such as are failing multiple PI-including regimens, which saquinavir (SQV) and amprenavir (APV) [22]. would imply the failure of all three classes of anti- The follow-up of this study demonstrated that HIV drugs in many circumstances. These the extent of IDV resistance and cross-resistance patients need new therapeutic options, either to other PIs depended upon the single amino new uses of regimens with existing drugs, new acid substitutions, their number and the combi- agents with unique resistance profiles or different nation in which they appeared [23]. Ritonavir mechanisms of suppressing the virus. (RTV) has also been described as potentially inducing a large extent of unique or cross-resist- Activity of protease inhibitors ance within the PI class [36]. Resistance to PIs The HIV protease is responsible for cleavage of occurs as a result of amino acid substitutions the gag and gag–pol precursor polyproteins to inside the substrate-binding domain of the pro- the structural and functional proteins, granting tease or at distant sites, so-called compensatory the maturation and infectivity of progeny mutations [22,37,38]. These amino acid changes viruses. HIV PIs exert their activity during the reduce affinity between the PI and the late stages of viral replication, thus interfering protease [39], such as in the V82A mutation [40]. with the formation of functionally active virions. The complex picture of emergence of cross- Given this indubitable activity, new regimens, resistance to PIs was reported in several studies including PIs, present new challenges, such as an performed both in vitro [41,42] and amelioration of patient compliance (through a in vivo [26,38,43]. Additional data are becoming simple and practical schedule), an attempt to available on PI-related resistance following overcome adverse events, such as the occurrence sequential treatment with several compounds of lipodystrophy, and an introduction of more within this class of drugs. Winters and colleagues bioavailable compounds. This would likely have recently reported that an initial treatment include novel dual PI-boosted regimens and with SQV may cause a full development of cross- provide a more efficient method of attaining resistance to IDV and nelfinavir (NFV) in sustained viral suppression in naive or chroni- patients that will receive such regimens as part of cally treated HIV-1-infected individuals. Several an active anti-HIV-1 combination therapy [24]. pharmaceutical companies have developed, or Dulioust and colleagues have observed that pre- are in the process of developing, an increasing vious therapy with SQV followed by IDV number of second-generation PIs, either with or allowed for a viral evolution that maintained the without a flexible structure and peptidomimetic, initial selection of drug resistance and adapted over the last few years. These novel compounds the viral population to IDV pressure [25]. These will be reviewed herein. results suggest that HIV-1 quasispecies would likely be able to adapt to the presently available Resistance to protease inhibitors drugs, which target the same enzyme. Taking In 1988, the protease enzyme of HIV-1 was crys- into account the rapid occurrence of PI cross- tallized and its 3D structure determined [33], resistance, clinicians treating HIV-1-infected allowing for the rapid development of PIs. Ini- patients will need improved, active PIs in the tially, it was hypothesized that HIV-1 protease, near future. unlike RT, would be unable to accommodate mutations, thus leading to drug resistance had Compounds obviously been unproven. PIs have significantly Tipranavir changed the prognosis of HIV-1 infection. How- Tipranavir (TPV) (Figure 1) is a nonpeptidomi- ever, their use is associated with the appearance metic inihibitor of the HIV protease [44] and of a large pattern of single mutations in the pro- demonstrates little cross-resistance with the tease gene inhibitors which favors the develop- other PIs. Previous papers demonstrated the effi- ment of multidrug resistance (MDR) to other cacy of TPV against a wide spectrum of drug compounds within the same class of drugs [34,35]. resistant isolates [45]. TPV demonstrated elevated Condra and colleagues gave the first virologic dose-response properties against a variety of iso- demonstration of cross-resistance to PIs in lates derived from HIV-1-infected subjects with patients subjected to indinavir (IDV) multidrug resistance to other PIs [46]. After these 80 Therapy (2006) 3(1) New HIV protease inhibitors for drug-resistant viruses – SPECIAL REPORT Figure 1. Tipranavir. 50 copies/ml than in the comparator group. At 24 weeks, 34% of patients in the TPV/RTV group and 16% of patients in the comparator group achieved a viral load of less than 400 copies/ml, and 23 versus 9% achieved less OH than 50 copies/ml. Patients treated with H TPV/RTV presented higher CD4 values than N those treated with a RTV-boosted comparator SO2 PI. The median change from baseline in the CD4+ cell count at week 24 was +34 cells/µl in O O N patients receiving TPV/RTV (n = 582) versus +4 cells/µl in the comparator group (n = 577).