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New Drug Targets for HIV and Hepatitis C Virus Coinfection
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Clinical Infectious Diseases July 1 2005
Ellen M. Tedaldi
Comprehensive HIV Program, Temple University School of Medicine, Philadelphia, Pennsylvania
ABSTRACT
Current interferon (IFN)-based therapies for hepatitis C in patients coinfected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) may be limited by incomplete virological response, lack of adherence, and poor tolerability.
Newer therapies for hepatitis C will target viral replication (e.g., HCV serine protease inhibitors, helicase inhibitors, RNA interference, or an HCV polymerase inhibitor). Other treatments will focus on viral translation (e.g., antisense molecules). Additions to IFN therapy that can modulate the immune response (e.g., thymosin, isatorbine, or injectable histamine) may improve tolerability of treatment. There need to be targets that minimize the inflammatory response by the liver (e.g., IFN-y).
There are some therapeutic vaccines in early development.
Drugs to replace or enhance ribavirin are being studied with IFN-based treatments.
Strategic treatment trials that address sequencing of HCV and HIV therapy with current and future therapeutic agents and combination therapy need to be undertaken.
INTRODUCTION
The treatment of hepatitis C in patients coinfected with HIV continues to be a therapeutic challenge. The recent publication of 3 clinical trials of pegylated IFN and ribavirin in patients coinfected with HIV and hepatitis C virus (HCV) underscores the limitations of current strategies: incomplete virological response, especially among those infected with HCV genotype 1, intolerance to anti-HCV medications, and nonadherence to visits [1-3]. Even with the more favorable HCV genotypes 2 and 3, the sustained virological responses (SVR) with pegylated IFN and ribavirin were attenuated, compared with responses in patients infected with HCV alone [4-6].
In addition, IFN-based regimens appear to be less effective in African Americans and in patients with higher HCV loads [4-7]. Treatment outcomes for patients coinfected with HIV and HCV are affected by nonvirological and nonpharmacological issues, such as psychiatric comorbidity, active alcohol or substance use, and advanced HIV disease [8, 9]. Despite this discouraging overview of the current formulary, there are several areas of investigation with potential applicability in the treatment for hepatitis C.
IFN AND RIBAVIRIN THERAPIES: CONTINUED
Combination therapy with IFN, most likely pegylated IFN-a and ribavirin, will continue to form the basis for anti-HCV therapy for the next few years. The medications work synergistically in an incompletely defined manner to enhance cellular defenses that affect viral replication, modulate specific anti-HCV immune responses, and decrease the inflammatory and fibrotic response of the liver.
Various alternative formulations of IFN are being investigated for improved rates of SVR and better side effect profiles. Omega IFN, a genetically engineered type 1 IFN that is active in vitro against DNA, RNA, and retroviruses, was used in a study of patients with chronic hepatitis C due to HCV genotype 1. About one-third of patients showed normalization of alanine aminotransferase levels and clearance of HCV RNA within the first month of treatment [10]. There are plans to develop an implantable drug delivery system, as well as an oral prodrug, which will eliminate the need for injections.
IFN-a fused to albumin (Albuferon; Human Genome Sciences) can prolong the half-life of IFN and may permit dosing every 2 weeks. A phase 1/2 study for treatment-experienced patients is ongoing.
IFN-y has been studied in the HCV replicon model and may have antiviral effects that are antifibrotic. Preliminary research is investigating the sequential use of IFN-a and IFN-y to treat patients who do not experience a response to standard therapy.
Ribavirin has several antiviral effects. It directly inhibits HCV NS5B polymerase, thereby disrupting HCV RNA strand synthesis and viral replication. It inhibits inosine 5′-monophosphate dehydrogenase (IMPDH), an enzyme involved in guanine nucleotide synthesis. It causes mutagenic activity by its incorporation into the synthesis of the negative-sense HCV RNA strand with mispaired bases, resulting in error catastrophe of the complementary strand of genomic RNA. Finally, it acts as an immunomodulator by stimulating the Th1 immune response.
Viramidine is a ribavirin prodrug that is converted in the liver by adenosine deaminase to active ribavirin. The reported lower incidence of hemolysis may related to the diminished uptake by erythrocytes [11]. A current phase 2 trial is comparing viramidine with ribavirin in combination with pegylated IFN.
Levovirin is an L-isomer of ribavirin with immunomodulatory properties that may be greater than those of ribavirin, but clinical trials are not proceeding at this time [12].
IMPDH inhibitors, such as merimepodib (VX-497) and mycophenylate (CellCept; Roche Pharmaceuticals), are under investigation as anti-HCV therapies in conjunction with IFN-a. These drugs have an antiviral effect by depleting intracellular stores of guanine nucleotides that then inhibit viral replication. They may also enhance the mutagenic effects of ribavirin. Mycophenylate is used as part of the standard posttransplantation therapy for immunosuppressive effects by inhibiting cell replication through depletion of guanosine triphosphate. The compounds are part of phase 2 studies with pegylated IFN in patients who do not respond to standard therapies.
IMMUNOMODULATORS
Included here are compounds such as histamine dihydrochloride, thymosin-a1, and cytokines such as IL-2, IL-10, and IL-12. These last 3 immunomodulatory cytokines have been disappointing in clinical studies for several reasons, including systemic side effects to which patients are intolerant, inconsistent effect on HCV RNA levels, and high rates of virological relapse [13-15].
Histamine dihydrochloride (Ceplene; Maxim Pharmaceuticals) has both antioxidant effects and immunomodulatory activity. It is now being studied in a phase 3 multicenter trial with pegylated IFN-a2b and ribavirin.
Thymosin-a1 (thymalfasin; Zadaxin; SciClone Pharmaceuticals) is a peptide synthesized from the human thymus gland that has antiviral effects of enhancing Th1 responses through up-regulating expression of major histocompatibility complex class 1 molecules in virus-infected cells. It is administered subcutaneously twice a week. A few studies in the United States and Europe are looking at the addition of thymosin to pegylated IFN-a2a and ribavirin in treating patients with and without cirrhosis who have not experienced a response to prior treatment with IFN.
Isatoribine (ANA245, Anadys245) is thought to stimulate immune responses and raise levels of IFN-a and TNF-a by reacting with a receptor on WBCs called Toll-like receptor. The parenteral form is being evaluated in phase 1 trials. An oral prodrug of isatoribine is still in phase 1 preclinical development.
INHIBITORS OF HCV REPLICATION
Drugs that target the specific enzymes involved in replication of HCV are still early in development. The understanding of the genomic structure of HCV and the capacity to design agents that might result in an improved virological response are still emerging. As with therapies for HIV, the use of these compounds will probably be more effective in a combined approach with or without the current IFN-plus-ribavirin strategies. Also, the capacity to evaluate these drugs clinically has been hampered by the lack of an easily used animal model. The HCV replicon system enables compounds to be evaluated but cannot incorporate all of the clinical parameters needed for drug development (e.g., resistance of the virus). Agents are being developed that target viral enzymes (e.g., serine protease, RNA-dependent RNA polymerase, and helicase), viral envelope proteins (e.g., a glucosidase inhibitors, entry inhibitors, monoclonal antibodies, and immunoglobulin), viral RNA (e.g., ribozymes and antisense oligonucleotides), and cellular proteins (e.g., prenylation inhibitors) and that interfere with RNA (small interfering RNA). (note from Jules Levin: the two most advanced HCV drugs in development are NM283, a polymerase inhibitor, in phase 2 with phase 3 in planning stage, and the Vertex protease inhibitor, for which the first study results in patients were presented at the DDW conference in May 2005. Both of these drugs show potent suppression of HCV replication and are moving ahead in development, at this time.)
HCV is an enveloped positive-sense RNA virus that has 10 structural (e.g., core, E1, E2, and p7) and nonstructural (e.g., NS2/NS3 metalloprotease, NS3 helicase, NS4A and NS3 serine protease, and NS5A and NS5B polymerase) proteins. The nonstructural proteins encode the enzymes that are specific for HCV replication. Translation occurs after the formation of a binary complex between the 40S ribosomal subunit and the HCV internal ribosome entry site within the 5′-untranslated region of the HCV genome [16].
Similar to the HIV protease inhibitor class, the HCV protease inhibitor compounds prevent cleavage of the HCV virion. The oral NS3 serine protease inhibitor, BILN 2061, has been the most widely discussed. Although the data in a phase 1 study showed a >l log10 decrease in HCV RNA levels in patients with infection due to HCV genotype 1, there was a quick rebound after 1 week. In addition, there have been concerns about cardiac toxicity in primates receiving the drug for more prolonged periods [17, 18].
Other drug targets against the NS5B RNA-dependent RNA polymerase and the NS3 helicase/NTPase would affect HCV RNA strand synthesis. Recently, several phase 1 clinical studies with RNA-dependent RNA polymerase compounds have begun [19].
Despite the approval of the first viral entry inhibitor compound for HIV, enfuvirtide (Fuzeon; Roche Pharmaceuticals), there are no agents in the immediate clinical arena for inhibition of HCV entry. The targeting of envelope proteins through monoclonal antibodies, thereby attempting to neutralize HCV, is another area of investigation. Research with monoclonal antibodies, however, is focused on the transplant recipient and the high recurrence of hepatitis C after surgery.
Drugs that target viral RNA, such an antisense oligonucleotides, function by forming an RNA-RNA antisense or RNA-DNA antisense hybrid that inhibits RNA translation or RNA replication. ISIS 14803 has been evaluated in phase 1 and 2 trials. The compound administered intravenously 3 times weekly did demonstrate a >1 log10 decrease in HCV RNA levels for approximately one-third of participants, but this was offset by frequent elevations in hepatic transaminase levels. The parenteral route will also limit the usefulness of this compound [20].
Ribozymes are enzymes composed of RNA rather than proteins that can bind to and catalyze the cleavage of specific mRNA sequences. This effectively interferes with protein synthesis. Theoretically, more than one binding site could be targeted or other genetic material introduced. Toxicity concerns have limited further development of these concepts [20].
An interesting area of research in both HIV and HCV is RNA interference, which involves small interfering RNA that bind to complementary areas of mRNA and effectively "silence" that gene product [21]. The potential therapeutic application that could prevent the expression of certain HCV proteins may be limited by the specificity of the target mRNA for other cellular genes.
Another approach to interfering with replication of HCV is the disruption or alteration of cellular proteins. Prenylation inhibitors that effect site-specific lipid modification of cellular proteins through posttranslational mechanisms have been described [22]. Many proteins involved in various signal transduction processes use this prenylation process. The statin compounds are inhibitors of prenylation and may provide an indirect possibility for interfering with HCV replication.
ANTIFIBROTIC AND MAINTENANCE THERAPIES
Although clearance of HCV is incomplete for many patients enrolled in therapeutic trials with IFN plus ribavirin, there appears to be histological improvement, even for those who do not experience a response to treatment [23]. Clinical trials are under way now that will evaluate the strategy of maintenance pegylated IFN therapy for patients with fibrosis and nonresponse to therapy [24, 25].
VACCINES
The development of vaccines for hepatitis C is stymied by the limitations of current knowledge of immunologic mechanisms and by the lack of availability of animal models for evaluating potential products. HCV results in chronic infection in most persons, but the immune correlates for clearing infection in the 15% of patients who do control HCV are still unclear. Preventive vaccines that could protect against the establishment of HCV infection require a better understanding of the required immune responses that would enhance appropriate humoral and cellular responses. The need to provide vaccination for the various genotypes and quasi species is complicating these efforts. A therapeutic vaccine could enhance suppression of HCV and thus prevent the complications of chronic infection.
A number of studies have provided intriguing observations about the development of hepatitis C vaccination. These include the observations that previous HCV infection might provide some protective immunity against the duration of viremia following reinfection or against other strains of HCV [26, 27]. In summary, significant basic science and clinical design issues will encumber vaccine development for the near future.
SUMMARY
Although the future of therapy for HCV is challenged by the limitations of available antiviral therapies, there are prospects for novel targets against viral replication. The emerging understanding of the viral genome and immune dynamics may enable the development of effective therapeutic vaccines. Research will need to include HIV-coinfected patients earlier in the process of evaluating therapeutic agents and treatment strategies. The coordination of the anti-HCV and anti-HIV research programs will be important for populations with coinfection. With reports of hepatic morbidities associated with antiretroviral therapy for HIV in coinfected patients, there is urgency to advancing the research agenda for treatment for HIV and HCV.
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