Approximately 39.5 million people worldwide are infected with human immunodeficiency virus (HIV).1 The standard of care for treatment of HIV infection centers around combination antiretroviral therapy (ART), involving the use of medications from at least two distinct therapeutic classes, to inhibit viral replication. This approach has been proven to slow the progression to acquired immunodeficiency syndrome (AIDS). There are four classes of antiretrovirals currently available, including the nucleoside reverse transcriptase inhibitors (NRTIs), nonnucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), and fusion inhibitors. Combination regimens include three or more antiretroviral agents. Therapy for HIV infection involves numerous adverse effects and the complication of resistance development. Once patients develop resistance to an agent in a particular class, they are likely to have cross-resistance to other agents in the class, which minimizes therapeutic options. This emphasizes the need for new approaches for the treatment of HIV, including agents with novel mechanisms of action.
This article will review several emerging antiretroviral therapies, focusing primarily on those in more advanced stages of clinical development. These include entry inhibitors, integrase inhibitors, and maturation inhibitors. The role of many of these agents will be as salvage treatment for patients with numerous HIV-resistant mutations to currently available agents, while others will be targeted as initial therapies for treatment-naïve patients.
Entry Inhibitors: CCR5 Antagonists
An exciting approach to treatment has involved the development of agents that inhibit the entry of HIV by preventing the binding of viral envelope proteins to receptors on host cells. These drugs differ from NRTIs, NNRTIs, and PIs in that they target a host cell receptor rather than affect enzymes utilized in viral replication.
In order to gain entry into its host CD4 cell, the envelope proteins of HIV bind to a main CD4 receptor as well as a key coreceptor (CCR5 or CXCR4)2 (FIGURE 1). The viral membrane fuses to the CD4 cell membrane with subsequent viral entry, resulting in infection of the host cell. Viruses that primarily use CCR5 as a coreceptor are known as R5 tropic and are present during both the acute seroconversion and asymptomatic phases of HIV infection.3,4 Viruses that use only CXCR4 as a coreceptor are known as X4 tropic. These may be more prevalent during later infection and result in more rapid progression of HIV infection, although CD4 counts are comparable to those of patients infected with R5 strains.3-6 Some variants of HIV utilize both the CCR5 and the CXCR4 coreceptors; these are known as dual tropic R5/X4 or mixed R5 and X4 viruses.3
There has been great interest in the development of treatments that antagonize these coreceptors, thereby preventing entry and subsequent infection of CD4 cells. Strategies that target the CCR5 receptor are in the most advanced stages of development. These include small- molecule CCR5 inhibitors as well as monoclonal antibodies to the CCR5 receptor.5,7 Table 1 provides a summary of those agents and their current clinical status.
Small-molecule CCR5 antagonists include aplaviroc, maraviroc, and vicriviroc. Trials of aplaviroc were halted in 2005 due to severe hepatotoxicity in several patients.5 As a result, safety assessments of the other two CCR5 antagonists have closely reviewed hepatic adverse effects, although neither has been consistently linked with hepatotoxicity.5 Although one clinical trial involving vicriviroc was halted in treatment-naïve patients due to virologic failure, data from a completed phase II trial in treatment-experienced patients indicated a significant decrease in viral load with vicriviroc as compared with placebo. 8,9 In this latter trial, there were four cases of lymphoma, the causality of which the authors indicated was uncertain.9 The agent with a large amount of promising data is maraviroc; these results are reviewed below.
Data from two major clinical trials assessing maraviroc in treatment-experienced patients was presented at the 14th Conference on Retroviruses and Opportunistic Infections in early 2007. 10,11 Together, these double-blind, placebo-controlled trials, known as MOTIVATE 110 and MOTIVATE 211, randomized a total of 1,076 patients worldwide to receive maraviroc twice daily, maraviroc once daily, or placebo in combination with an optimized background regimen of currently available ART. In both studies, maraviroc treatment resulted in significantly better viral suppression at week 24 as compared with placebo. Patients in both maraviroc groups also achieved significantly higher CD4 counts as compared to placebo (MOTIVATE 1 trial: CD4 increased by 107 to 111 cells/mL from baseline in maraviroc groups versus 52 cells/mL in placebo group, P<0.0001; MOTIVATE 2 trial: CD4 increased by 102 to 112 cells/mL in maraviroc groups versus 64 cells/mL in placebo group, P <0.001). Maraviroc was similar to placebo in terms of serious adverse effects, and none of the deaths in the studies were attributed to the study medication.
Following receipt of a fast-track designation from the FDA in July 2005, an expanded access program was developed by maraviroc's manufacturer the following year.12 In addition, the FDA Antiviral Drugs Advisory Committee unanimously recommended accelerated approval for maraviroc tablets for treatment of HIV in treatment-experienced patients in June 2007.13 The committee mandated a minimum of five years of follow-up of viral loads, CD4 counts, viral tropism, AIDS-defining illnesses, and mortality for patients who demonstrated virologic failure in the phase II/III studies presented in the new drug application.12 They also recommended that the package insert illustrate safety concerns with the CCR5 antagonist class, including hepatotoxicity. Ongoing studies are assessing the use of maraviroc in treatment-naïve patients.12 The drug received full FDA approval on August 6, 2007.14 Specific dosing information, drug interactions, adverse effects, and special considerations for maraviroc, located in the package insert, are listed in TABLE 2.15
Additional CCR5 antagonists in development include monoclonal antibodies that bind to the CCR5 receptor (TABLE 1). PRO 140 is an injectable agent that has been granted fast-track status by the FDA, with additional clinical trials planned in late 2007. 12,16 This agent is synergistic with small-molecule CCR5 antagonists; in addition, it demonstrates in vitro activity against HIV resistant to the small-molecule agents.6,16 CCR5mAb004 is another intravenous monoclonal antibody in early development.
Many potential issues are of concern with the CCR5 antagonist class. One is the possibility that these agents may select for X4 tropism, which has been correlated with disease progression.3 Another is the chance that altered CCR5 interactions permitting viral escape could occur through mutation of the virus, allowing use of an alternate coreceptor to gain entry into the CD4 cell.3,6 In addition, patients must be tested for coreceptor tropism prior to the use of these agents and periodically during treatment.3 In addition, concerns about hepatotoxicity, lymphomas, and increased susceptibility to other infections have plagued these agents.6 Ongoing and future clinical trials will assess these concerns to determine if they are clinically relevant.
Entry Inhibitors: CXCR4 Antagonists
These agents are in earlier stages of clinical development relative to CCR5 antagonists (TABLE 1). AMD070 is an orally bioavailable CXCR4 antagonist that is additive or synergistic with some currently available ART, including enfuvirtide.3 TNX-355 has been shown to significantly decrease viral load and increase CD4 counts in treatment-experienced patients.17
Integrase is a key enzyme involved in two distinct steps of the viral replication pathway: the processing of viral DNA strand ends and the catalyzing of the subsequent insertion of viral DNA directly into host cell chromosomes (FIGURE 1). These reactions are essential for viral replication. Inhibition of integrase activity can result in the inability of HIV to infect host cells. Because integrase inhibitors have a different mechanism of action than currently available agents, they represent a potential additional treatment option. Currently, two integrase inhibitors are under clinical development: raltegravir and elvitegravir.
Data from two raltegravir phase III trials were available in 2007.18,19 The BENCHMRK-1 and BENCHMRK-2 clinical studies were designed to evaluate the efficacy and safety of raltegravir in patients with demonstrated resistance to other classes of antiretroviral drug therapy.18,19 BENCHMRK-1 enrolled participants from Europe and Asia, and the patient population of BENCHMRK-2 was from North America and South America. Participants in both studies had a mean CD4 cell count of 152 cells/mL. Both studies are ongoing randomized, placebo-controlled evaluations of raltegravir 400 mg twice daily or placebo with optimized background ART. After 16 weeks, antiretroviral efficacy was demonstrated in both studies. In BENCHMRK-1, 61% of raltegravir-treated patients achieved a viral load of less than 50 copies/mL compared with 33% of those receiving placebo (P <0.001).18 CD4 count improved by 51 cells/mL in the raltegravir-treated patients compared to placebo (P <0.001).18 Findings of BENCHMRK-2 were similar, with a viral load of less than 50 copies/mL observed in 62% and 36% of raltegravir and placebo patients, respectively. 19 Compared to placebo, raltegravir-treated patients had a 46 cell/mL improvement in CD4 count (P <0.001). In both trials, adverse events were noted to be similar between groups. 18,19
The Antiviral Drug Advisory Committee of the FDA recommended approval of raltegravir for use in combination with other agents for treatment-experienced patients with HIV infection.20 Raltegravir was granted priority status by the FDA. In the briefing document supplied by Merck to the FDA, a dosing regimen of 400 mg twice daily, in combination with other unspecified agents, was recommended.21 Although raltegravir has a low potential for drug–drug interactions, a dosage increase may be recommended when it is coadministered with rifampin, phenytoin, or phenobarbital.21 Merck currently states that gender, age, organ function, race, or body weight does not impact raltegravir pharmacokinetics and that these factors will not alter drug dosing.21 The addition of raltegravir to other agents appears to be well tolerated. 21 At the time of this writing, the raltegravir specifics are only preliminary information, and readers are advised to consult the completed package insert when it becomes available.
Elvitegravir is currently in the phase II stage of clinical development.7 Pharmacokinetics and dose–response relationships have been studied in both treatment-naïve and experienced patients.22 Pharmacodynamic studies of elvitegravir have suggested a similar profile to PIs in that using "booster" doses of ritonavir can help maintain therapeutic plasma concentrations of elvitegravir. Coadministration with ritonavir 100 mg allows for once-daily elvitegravir dosing. In an ongoing dose-ranging study, the efficacy of elvitegravir 50 mg or 125 mg and ritonavir 100 mg daily added to standard therapy was compared to a boosted PI regimen.23 At 24 weeks, improvements were demonstrated in both viral load decline and CD4 count increases in patients receiving elvitegravir with ritonavir. It was noted that elvitegravir was well tolerated, and there was not a dose–response relationship with respect to adverse events.23 Elvitegravir should be administered with food due to the resulting improved bioavailability.22
Some ongoing concerns with the integrase inhibitor drug class include the possibility of unknown safety issues and the potential for development of resistance.24 Both agents appear to have very few adverse effects. Additional, smaller studies have listed headache, upset stomach, and increased liver function tests as adverse events. While the integrase enzyme is important for the viral life cycle, it does not appear to have an analogous role in host cell development. However, at concentrations 10- to 20-fold higher than therapeutic levels, integrase inhibitors may alter normal antibody production.24,25 The clinical consequences of higher drug concentrations have not been determined.
To be most effective in preventing resistance, integrase inhibitors should be taken in combination with other antiretroviral agents. Analysis of viral strains from participants who have failed raltegravir regimens has revealed several key mutation pathways. It is not clear if resistance to raltegravir leads to cross-resistance with elvitegravir. As with other antiretroviral drugs, selection of appropriate combination regimens with integrase inhibitors will be essential for preventing resistance. The importance of patient compliance with these regimens cannot be overemphasized.
Another step in the HIV viral life cycle involves the processes related to maturation of the virus. Several protein-processing events occur late in viral production, which are essential for the virus to maintain its ability to replicate (FIGURE 1). Experiments with maturation inhibitors have shown that they can inhibit viral infectivity and replication. This specific drug class is the intellectual property and a focus area of Panacos Pharmaceuticals; all of the following listed agents are undergoing clinical development through Panacos.26 Bevirimat (PA-457) is undergoing phase II clinical trials. In 2006, an Investigational New Drug Application was filed for a second-generation HIV maturation inhibitor (PA-1050040), with phase I trials anticipated to begin in 2007. Panacos is also evaluating a potential third-generation maturation inhibitor.
A phase IIa dose-ranging clinical study evaluated bevirimat in HIV-positive patients who had not previously received treatment.27 On day 11 of bevirimat therapy, there was a statistically significant viral load reduction in those patients receiving berivimat. A subsequent study demonstrated antiretroviral efficacy with bevirimat, but there was a lower-than-expected bioavailability of drug in some patients. Panacos is hoping to continue dose-escalation studies and improve the bevirimat formulation. The manufacturer is also investigating future agents that can potentially be effective in bevirimat-resistant HIV strains.
Although the increased availability of ART options has decreased morbidity and mortality among HIV-positive individuals in the past 10 years, management of HIV infection continues to be a challenge. Successful care entails the lifelong use of combination ART with optimal patient compliance to help prevent development of resistance and AIDS-related complications. Several emerging therapies are in the pipeline that target unique components of the viral life cycle and offer different mechanisms of action compared with existing alternatives. Trials have demonstrated improvements in viral load reduction and CD4 cell counts with the addition of either entry inhibitors, integrase inhibitors, or maturation inhibitors to standard ART. Future research will help further define the safety profile, resistance patterns, and ultimate place in therapy of these new drug therapies in the treatment of HIV infection.
The authors would like to acknowledge Karen L. Houle, MS, for her assistance in the development of Figure 1.
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