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10/14/2009
1
Herpes virus co-factors in HIV
infection
Dr Jane Deayton
Barts and the London Queen Mary
School of Medicine
Introduction
• Herpes viruses very common and often co-
exist with HIV
• Establish life-long latent infection
• Cause disease in immunocompetent host
• Specific herpes-related disease with HIV
• Interactions with HIV at cellular level
10/14/2009
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Herpes viruses
• Herpes Simplex Virus 1
• Herpes Simplex Virus 2
• Varicella Zoster Virus
• Epstein Barr Virus
• Cytomegalovirus
• Human Herpes Virus 6
• Human Herpes Virus 7
• Human Herpes Virus 8 (KSHV)
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HIV
Immune Deficiency
Herpes Reactivation
VIRAEMIA
HIV
Immune deficiency
Herpes Reactivation
End-Organ Disease
+
+
After Griffiths J Clin Virol 2006:35;498-93
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HSV-2
HSV-2 and risk of HIV acquisition
and transmission
• Multiple studies
• Consistent finding across populations
• 2-3 x increased risk HIV acquisition
• 2 x increased risk HIV transmission
• Prevalent and incident HSV-2 increases risk of
HIV acquisition
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Freeman 2006 AIDS;20:73-84
Possible mechanisms
• Break in epithelium
• Recruitment of CD4+ cells to ulcer
• HSV-2 up-regulates HIV replication in vitro
• High levels HIV in HSV-2 ulcers
• Increased HIV levels in plasma and genital
secretions with clinical and sub-clinical HSV-2
reactivations
• HSV-2 marker of high risk sexual behaviour
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Studies of HSV suppression
Aciclovir 400mg bd v Placebo
HIV - / HSV-2 +
• 2 cohorts women and MSM (n=3172 + 821)
• No difference in HIV acquisition rates
• Cohort women (n=125)
• Reduced shedding HSV AOR 0.24
• No effect on HIV AOR 1.08
Celum 2008 Lancet;371:2109-19, Watson-Jones 2008 NEJM;358:1560-71
Persistence of HIV-1 receptor
positive cells after HSV-2
• Skin biopsies
• Persistent CD4+ cell infiltration even after
healing (median 8 x increase)
• Aciclovir 20/52 no effect
• Increased susceptibility to ex vivo HIV-1
infection
• Suggests need to control inflammation rather
than HSV-2 replicationZhu 2009 NatMed;15:886-93
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HSV and risk of HIV disease
progression
• Faster progression in HSV-2 infected HIV+
patients
• HSV-2 associated with reduced HIV-specific T-
cell responses and immune activation
• Aciclovir conferred additional benefit in
patients on AZT monotherapy
• 20 – 40% reduced risk of death with
suppressive ACV
Stein 1996 JID;173:504-7, Ionnadis 1998 JID;178:39-59
• Guanosine nucleoside analogue
• ACV-TP is chain terminating substrate for HIV
Reverse Transcriptase
• Aciclovir directly inhibits HIV infection in
single-cell assay
• Direct anti-HIV effect in co-infected cells
• V75I mutation emerged under selective
pressure of ACV
Effect of Aciclovir on HIV
replication
Lisco 135LB, Vanpouille 567, McMahon 566 CROI 2009
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CMV
CMV and risk of disease and death
• CMV implicated as co-factor since early in HIV epidemic
• Studies in HIV-infected haemophiliacs showed that CMV seropositivity at HIV seroconversion was associated with increased risk of AIDS
• Increased risk of AIDS not associated with CD4 count
• Follow-up study at 13 years showed increased risk death associated with CMV positivity 1.82
Webster 1989 Lancet;2:63-6, Webster 1992;ClinExpImm:6-9, Sabin 1993 BJH;83:330-3
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Effect of CMV and HIV loads on mortality
Pre-HAART era
Spector 1999 J Virol;73:7027
0 10 20 30 40 50 60
2
3
4
5
6
Log
CM
V l
oa
d (
cop
ies/
ml)
Time (weeks)
Change in CMV Load Following HAART
Deayton 1999 AIDS; 13:1203-6
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CMV viraemia and risk of death
HAART-era
Study n Risk of death p
Deayton, 2004 374 4.14 0.005
Wohl, 2005 190 4.92 0.038
Jabs, 2005 1583 1.90 0.002
Deayton 2004 Lancet;363:2116-21, Wohl 2005 JAIDS;38:538-44, Jabs 2005 Ophthtal;112:771-9
CMV viraemia and risk of death
HAART-era
• CMV viraemia associated with increased risk
of death
• Strongest predictor of death is recent CMV
viraemia
• Independent of
– CD4 count
– HIV load
– Anti-retroviral treatment
– Demographics
Deayton 2004 Lancet;363:2116-21
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Possible mechanisms
• CMV activates latent pro-viral HIV
• CMV expands tropic range of HIV
• CMV directly pathogenic even in absence of end-organ CMV disease– Linked to hypertension and atherosclerosis
• CMV reactivation reflects impaired CD4 function even with apparently good CD4 responses
• CMV viraemia may be a surrogate marker for immune function after HAART
Pre-emptive therapy for CMV in
patients on HAART• CD4<100, n=338
• 68 (20%) CMV viraemia on PCR
• Randomised to Valganciclovir or Placebo
– Low rate CMV disease (n=10)
– High rate death (n=15)
• 14% placebo group CMV disease at 12/12
• Sensitivity CMV PCR
• Effect of HAART on CMV viraemiaWohl 2009 HIV Clin Trials;10:143-50
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• Herpes viruses and HIV inextricably linked
• Large body of data showing that HSV-2
– Increases risk HIV acquisition
– Increases risk HIV transmission
– Increases HIV load in plasma and genital
secretions
– Increases rate of HIV disease progression
• BUT negative or conflicting results in trials of
anti-HSV therapy on acquisition and
transmission of HIV
Summary
• Anti-HSV therapy reduces HIV load and
increases survival
• Ongoing work to look at this as part of HIV
prevention strategies
• Role of Aciclovir in treating HIV needs further
evaluation
Summary
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Summary
• CMV remains important in era of HAART
• End-organ CMV disease uncommon but
viraemia still occurs and may be
underestimated
• HAART results in reduction of HIV and CMV
loads
–May partially explain efficacy of HAART
• CMV strongly associated with disease and
death
– Independent marker of poor prognosis
Summary
• Be aware of CMV especially if CD4<100
• Patients with CMV viraemia may benefit from
anti-CMV therapy as well as HAART
– Reduce risk of CMV disease
– Reduce risk of death
• Further work required
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