To Get your CMEs

1
To Get your CMEs

• After viewing this eLearning Seminar, please go
  to our website, www.stdptc.uc.edu
• Sign in, look for the title of this seminar
• Follow directions to register
• Complete the evaluation
• Print out your CEU certificate!

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Coinfection HIV/HSV 2

• Dalia El Bejjani, M.D
• June 4, 2008

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HSV-2
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HSV facts

• Main cause of genital ulcers worldwide
  prevalence 10-60
• Most genital herpes is HSV-2 HSV-1 now accounts
  of 50 new cases in developed countries
• Lifelong infection with intermittent
  clinical/subclinical viral reactivation and
  shedding from mucosal surfaces

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HSV-2 facts

• Women are more susceptible to HSV-2 infection
  than men
• Same risk factors as other STIs
• Only 10-25 of individuals with HSV-2 Ab are
  aware that they are infected
• ( consistent across studies)
• W/o antiviral Rx, median recurrence rate after
  1st episode of HSV-2 infection is 4 recurrences
  /year

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HSV-2

• Disease activity and viral shedding highest
  within 6-12 months after HSV infection
• Immunosuppressed hosts have a higher frequency of
  reactivation, longer duration and increased
  severity of flares

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HIV/HSV-2

• 60-70 of HIV patients in the USA are coinfected
  with HSV-2 (up to 95 in Africa)
• HSV-2 increases risks of sexual acquisition of
  HIV by 3-fold
• Mucosal disruption by lesions provides a ready
  portal of entry for HIV
• Even subclinical HSV-2 reactivation ? activated
  CD4 cells infiltrate mucosa ? ready targets for
  HIV attachment and infection

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Virus-specific CD8 T cell responses are critical
to host control of HIV after infection
Sheth P et al. JID 2008 197 1394-1401
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Sheth P et al. JID 2008 197
1394-1401
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Conclusions

• HIV/HSV-2 coinfection associated with
• Narrower and weaker HIV-specific proliferative T
  cell responses
• Increased systemic T cell immune activation, as
  measured by CD38 expression
• These differences seen during chronic HSV-2
  infection, in the absence of clinically apparent
  HSV-2 reactivation
• HIV disease progression determined by several
  factors among which
• Plasma HIV viral load set point
• Degree of systemic immune activation

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Treatment guidelines
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Mode of action of nucleoside analogues

• Acyclovir, first effective anti-HSV drug
• Valacyclovir is an aminoacyl prodrug of acyclovir
  ? converted to acyclovir by host acetylases in
  the intestinal wall and the liver. 2-3 times
  greater bioavailability
• Acyclovir ? enters HSV infected cells ?
  phosphorylated by HSV thymidine kinase (TK) and
  cellular TK ? acyclovir tri-P
• Acyclovir tri-P is active metabolite ? inhibits
  HSV replication by selective inhibition of viral
  DNA polymerase and by termination of growing
  viral DNA strands

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JID 20071961500-8
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Consider Resistance

• lt 1 of strains in immunocompetent
• Up to 5 in HIV coinfected
• Consider alternative Rx (foscarnet) in refractory
  lesions and send for resistance testing

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Fig. 3 - Herpes genitalis. Giant lesion and
ulcers frequently are due to thymidine
kinase-resistant strains of HSV-2, in patients
who were previously treated with acyclovir.
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Mechanisms of HSV resistance to nucleoside
analogues

• 3 distinct classes of acyclovir-resistant TK
  mutants
• TK-negative ( TK N) mutants lack TK activity
• TK-partial (TKP) mutants have reduced levels of
  TK activity
• TK-altered ( TKA) substrate specificity
  phosphorylate thymidine but not acyclovir
• 95 of acyclovir-resistant HSV are TK deficient
  TKD TKN TKP
• Cross resistance with other drugs, such as
  famciclovir

Levin M et al. CID 2004 39 S 248-57
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In case of resistance to nucleoside analogues

• Use drugs with different mechanism of action
• Cidofovir and foscarnet act directly on HSV DNA
  polymerase ( instead of thymidine kinase)

Levin M et al. CID 2004 39 S 248-57
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Hypertrophic HSV in HIV infected patient
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CID 2007 44 e96-99
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JID 2006 194 42-52
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TAKE HOME POINTS
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The road ahead
HSV-2 vaccine
? Earlier HAART for HIV/HSV-2 coinfected
? HSV-2 suppressive Rx for coinfected patients
not on HAART
? TESTING ALL HIV PATIENTS FOR HSV-2 Ab
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Questions?

• Cincinnati HIV/STD Prevention Training Center
  Website
• http//www.stdptc.uc.edu
• Consultation Line 1-800-459-2820
• Email std.traincenter_at_cincinnati-oh.gov

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To Get your CMEs

• After viewing this eLearning Seminar, please go
  to our website, www.stdptc.uc.edu
• Sign in, look for the title of this seminar
• Follow directions to register
• Complete the evaluation
• Print out your CEU certificate!

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THANK YOU
Dalia El Bejjani, M.D Metrohealth Medical
Center Faculty, Division of Infectious
Disease Instructor, Case Western Reserve
University