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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

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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