TOPICAL IMMUNE MODULATORS Imiquimod

5 Jun

Introduction

Imiquimod has  no  direct antiviral activity, but  it induces numerous cytokines in human peripheral mononuclear blood cells  (Fig.  3.27).  As an  immune response modifier, it stimu- lates interleukin-l (IL-1),  IL-6,  IL-8,  tumor necrosis factor (TNF), and  interferon-alpha. Imiquimod has  been  shown to be highly effective in  the  treatment of common and/or genital warts  caused by  the   human  papillomavirus. Imiquimod should be considered the  first line  of therapy for most  genital warts as  it has  a  high  rate of efficacy,  it is  easy  to  use,  and recurrence rates of genital warts are  low  (263).  It is  FDA approved for therapy of actinic keratoses and  superficial basal cell  carcinomas. Other conditions in  which successful use  of imiquimod has  been  reported include squamous cell  carci- noma in situ and  lentigo maligna (264).

Mechanism of Action

The regression of warts is strongly associated with a decrease in HPV DNA and  mRNA  expression of both  early and  late viral proteins. Tyring et  al.  (265)  indicates that the  clearance of genital warts and  the  reduction in  baseline wart area result from the induction of interferon-alpha, -beta, -gamma, and TNF- alpha (Fig.  3.28).  Imiquimod acts  as  an  immune response modifier by affecting the innate and  acquired immune response.

It stimulates natural-killer cell  activity, contributes to  the maturation of Langerhans cells,  and  augments the  effective- ness of T cells (266).

Clinical  Studies and  Reports of Imiquimod Usage

Most antiviral studies of imiquimod involve its usage with human papilloma virus infections (See Table 3.24) (264–272,275–282).

Treatment

Imiquimod is applied as  a cream (Table 3.25).  Most  patients tolerate  imiquimod, and  the  medication can  be  applied at home.  Imiquimod cream applied to the  skin  does not  enhance phototoxicity or UV-damage to cells  or DNA (274). Generally, imiquimod is  effective for  self-treatment of genital warts at home  with some  minor, local adverse effects. These inflamma- tory  reactions stop  when treatment  is  stopped temporarily. Localized skin   reactions can  often  be  controlled by  fewer applications per  week  or  by  leaving medication on  for  a shorter period of time. For  those patients who have recurring warts, a  second treatment  regimen with imiquimod is  often effective. Imiquimod is considered to be a cost-effective treat- ment for condylomata accuminata when compared with surgi- cal  excision, loop  electrosurgical excision, electrodessication, CO2 laser, podofilox,  and  pulsed-dye lasers. The  ease  of use  of imiquimod and  other factors, such  as  fewer  office visits and the low recurrence rate following imiquimod use, contribute to the  choice of this treatment modality (283).

Adverse Effects

The  main side  effects  of imiquimod are  at the  site  of applica- tion.  Skin reactions are  common and  treatment may  be tem- porarily discontinued for a few days. These reactions include:

Erythema. This  is the  most  common local skin  reaction

(270). Itching. Burning.

Pain. Usually mild pain in patients with daily  treatments over  time.

INTERFERON-ALPHA AND COMBINATIONS

Introduction

Interferon is an antiviral protein that may be formulated from purified, natural,  human interferon -alpha proteins or  pro- duced as  a glycoprotein using recombinant DNA techniques. One drawback to interferon has  been  its sustainable bioavail- ability and  short “time in residence” in the  body. The advent of pegylated interferon  (PEG-interferon)—a combination of equal amounts of polyethylene glycol and  interferon -alpha to form  a 40 kDa  branched structure—provided a longer-lasting interferon with fewer  injections required to administer a sus- tained virological response rate. By coadministering ribavirin with PEG-interferon alpha -2a, sustained virological responses of 56% are recorded. A comparison with PEG-interferon alone or standard alpha interferon -2b with ribavirin yields responses of

Table 3.25 Treatment with Imiquimod

Clearance of genital warts
Imiquimod cream (5%) applied to wart area without occlusion, 3 times per week prior to bedtime. After  6–10  hours, the  area should be washed with soap  and  water to remove the  medication. Continue for 16 weeks or until there is a complete clearance of warts.

30% and  45% respectively (284). These early reports have led to the  testing of other treatments being  combined with PEG- interferon for a variety of diseases. A histamine dehydrochlo- ride  is currently being  tested. Another study focuses  on a new molecule that is interferon-alpha fused to albumin. Therapies that provide longer-acting therapy and  improved side-effect profiles are  the  future.

Interferon-Alpha

Introduction

Interferon-alpha has  FDA approval for the treatment of hairy- cell  leukemia, Kaposi’s   sarcoma,  condyloma acuminata, chronic HBV  or  HCV  infection, and  melanoma (after local excision). Natural  and  recombinant interferon-alpha can  be used to  treat  condyloma acuminata  (285,286). The  most important application of interferon-alpha is as antiviral ther- apy  for  hepatitis B  and   C  as  there is  a  potentially fatal sequelae of these infections, such  as cirrhosis and  hepatocellu- lar  carcinoma. Interferon-alpha as  an  intralesional injection can  be used for refractory or recurring external condylomata acuminata. Interferon is also FDA-approved for treatment for AIDS-related Kaposi’s  sarcoma and  melanoma after excision (Fig.  3.29).  Interferon alpha-2b is effective in early control of HCV infection to prevent chronic HCV infection (287).

Mechanism of Action

Alpha interferons filter through the  glomeruli of the  kidneys, degrade to smaller proteins, and  enter the  circulatory system. Interferons bind to specific membrane receptors on a cell’s sur- face.  There is  high  species specificity for  binding to  these receptors. The  binding begins a cascade of events that induce protein synthesis and  a variety of cellular responses, includ- ing  the  inhibition of viral replication and  cell  proliferation. Macrophages stimulate phagocytosis, lymphocyte cytotoxicity is  boosted, and  human  leucocyte antigen  expression occurs when interferons are  introduced. It is not  clear which one or more  of these events enhance the  therapeutic effect  of inter- ferons (Fig. 3.30).

Clinical Studies and Reports that Support the Use of Interferon

Alpha

Interferon-alpha has  been  shown to have positive benefits as well as side  effects  (19,20,35–40,286–300) (Table 3.26).

Treatment

Use  of interferon-alpha for  therapy is  shown in  Table 3.27. When treating  molluscum contagiosum virus (MCV)  with interferon-alpha, those patients without systemic symptoms, and  with a relatively intact immune system and  limited lym- phadenopathy experience the  best  results. For  AIDS-related Kaposi’s  sarcoma, treatment should be continued until there is no further evidence of the  tumor unless adverse effects  pre- clude   further therapy. PEG-interferon has   recently been approved and  appears to  be  more  effective than  standard interferon therapy for HCV infection.

Adverse Effects

Injections. Intralesional injections are painful and time- consuming.

Systemic adverse effects  include:

Neutropenia.

Constitutional symptoms include:

Fatigue. Fever. Myalgias. Lethargy.

Headaches (influenza-like syndrome).

Central nervous system dysfunction, including de- pression.

Gastrointestinal disturbances.

Bone marrow suppression. Bone marrow suppression often  occurs  when this medication is  combined with other medications.

Possible autoimmune phenomena include:

Psoriasis. May worsen with treatment (295).

Asthma. May  be exacerbated with treatment  (294,295).

Special Considerations

Failure of other therapies. Interferon-alpha should be reserved for cases where other therapies have failed or for which no other effective therapy is available.

Combination therapy with cytodestructive or surgi- cal  treatment. Treatment of condyloma acuminatum with Interferon-alpha is most  effective when combined with additional cytodestructive/surgical treatments.

PEG-Interferon

Introduction

Pegylated interferon-alpha is  a  combination of interferon- alpha with polyethylene glycol  (PEG).  Polyethylene glycol  is commonly used in the  food and  cosmetic industries. Pegylating interferon enhances the pharmacological activity of the protein— better efficacy,  fewer  and  less  serious adverse events, and  bet- ter patient satisfaction. PEG-interferon combined with ribavi- rin   is  most   effective in  treating hepatitis C  (see  “PEG- Interferon and  Ribavirin”, page 214) (Fig. 3.31).

Mechanism of Action

To retard renal and  cellular clearance of interferon and  other protein molecules, a minimum mass of 40–60  kDa is required. Smaller molecules will continue to pass through the  glomeru- lus (301,302). Branched chains are  less  susceptible to proteol- ysis  than are  linear chains. The  polyethylene glycol  chains may  attach at a  single site  or  multiple sites, with multiple sites being  less  preferred. Native interferon has  a half-life of

2.1  hrs   with a  1.0  hr residence time. Two  linear 20  kDa pegylated interferon chains linked by lysine have a half-life of  23  hours and   a  residence time of 32  hours. Branched monopegylated chains (2 × 20 kDa) have a half-life of 15 hours and  a 20 hr plasma residence time. These peglyated chains are combined with others to improve absorption, distribution, and elimination characteristics of interferon alpha-2a. The  pri- mary differences between interferons and  pegylated interfer- ons  is  size.  Larger-sized (pegylated) interferons have better distribution and  absorption, and  less  elimination (Fig. 3.32).

Clinical  Findings and  Reports That Support the  Use of PEG-Interferon

While  pegylated interferon-alpha suppresses viral acitivity, other studies indicate that  coadministration of pegylated interferon-alpha with another antiviral or immunomodulator enhances the  performance of the  antiviral or  other therapy. More recent clinical studies are  focusing on dual or three-way therapy; these are  discussed later in this section.

Treatment

When treating chronic hepatitis C, the  results of the  first few weeks of therapy are  often  a  better predictor of long-term results than extensive “predictive” testing by genotyping, viral load  analyses, and  extent of cirrhosis damage. Antiviral ther- apy  is recommended for persons whose  alanine aminotrans- ferase levels   are   abnormal, and   who  have HCV  RNA  in serum and  evidence of cirrhosis (presence of fibriosis, inflam- mation, and  necrosis) (303). The primary measures of efficacy

Fig. 3.32      Comparison of interferon and pegylated interferon. Pegylated interferons are larger in structure and  are more difficult to remove from  the  kidneys. Therefore, unpegylated interferons experience renal clearance much faster.

are  a reduction in viral load  and  normalization of liver  func- tion.  Virus loads  should drop  below  the  detection limit for a validated PCR-RNA technique with a  normal blood  level  of the  liver  enzyme AGT.  Interferon alpha-2b is  administered frequently (usually 3 times a /week  for chronic hepatitis C or daily  for melanoma) because of rapid clearance via the  glom- erulus. By  pegylating interferon-alpha,  delayed clearance occurs  and  administration of pegylated interferon-alpha can often  be reduced to once a week  (304).

Adverse Effects

Pegylated interferon-alpha has  an  adverse event frequency profile similar to  that of standard  interferon alpha-2a. Side effects  usually decrease in severity as treatment continues.

Depression. Pyrexia. Rigors.

Nausea and vomiting. Impaired concentration. Alopecia.

Psychiatric  events. May   include  severe  depression, psychosis, and  personality disorders.

Special Considerations

Hepatitis C patients. Hepatitis C patients with cirrho- sis  of the  liver  often  have other issues pertaining to safety and  tolerability, such  as neutropenia and  throm- bocytopenia. Myalgia, arthralgia, and  injection-site in- flammation  are   commonly reported  by   chronic hepatitis C  patients. Other adverse events occur  as often  as  with standard interferon-alpha.

There may  be contraindications to taking pegylated inter- feron  in  patients with a history of heart disease, kidney dis- ease, seizures, or depression.

Ribavirin and Interferon-Alpha/PEG-Interferon Alpha

Introduction

Ribavirin is  approved to  treat  respiratory syncytial virus (RSV). It is also  approved for synergistic use  with interferon- alpha in the  treatment of chronic hepatitis C when interferon- alpha monotherapy has  failed (305–308). The  combination is well  tolerated, but  more  adverse effects  are  to  be  expected with the combined treatment. Hepatitis C is prevalent in HIV- positive persons and  treatment of HCV in this population can be challenging.

Mechanism of Action

The mechanisms of the  enhanced efficacy  of ribavirin therapy combined with interferon therapy are unknown. What is known,

however, is that the  two  combined with each  other are  more effective than either taken alone.

Clinical  Studies and  Reports to Support Ribavirin  and

Interferon Alpha  Usage

The  most  effective therapy for treating chronic hepatitis C is the  ribavirin–PEG-interferon-alpha  combination therapy (309–316) (Table 3.28).

Treatment

Interferon-alpha and  ribavirin is used to treat chronic hepati- tis C viral infection (Table 3.29).

Adverse Effects

Ribavirin can cause :

Hemolytic anemia. Usually compensated for by reduc- ing the  ribavirin dosage (317).

Interferon can cause:

Neutropenia.

Constitutional symptoms include:

Fatigue. Fever. Myalgias. Lethargy.

Headaches (influenza-like syndrome).

Central nervous system dysfunction, including depression.

Gastrointestinal disturbances.

Bone marrow suppression. Bone marrow suppression often  occurs  when interferon-alpha is  combined with other medications.

Possible autoimmune phenomena include: Psoriasis. May worsen with treatment. Asthma. May be exacerbated with treatment. Myasthenia gravis (318).

Special Considerations

Ribavirin is teratogenic. As a precaution against preg- nancy and  birth defects, female patients on  ribavirin must practice effective contraception during the  treat- ment period and  for 6 months thereafter.

PEG-interferon and ribavirin. Clinical studies have demonstrated that this combination therapy is currently the  most  effective treatment for hepatitis C infections.

Concomitant use of ribavirin and zidovudine. This usage combination should be avoided as  in vitro  stud- ies  indicate that ribavirin interferes with the  activity of zidovudine against HIV.

Triple therapy. Other combinations may  provide en- hanced therapy with fewer  side  effects, such  as  triple therapy of interferon-alpha, ribavirin, and  ursodeoxy- cholate to improve liver  chemistry (319). Other combi- nations will  surely follow.

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