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 coexist with HIV Establish life-long latent infection Cause disease in immunocompetent host Specific herpes-related disease with HIV Interactions with HIV at cellular level 1
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) 2
HIV Immune Deficiency Herpes Reactivation VIRAEMIA HIV + Immune deficiency + Herpes Reactivation End-Organ Disease After Griffiths J Clin Virol 2006:35;498-93 3
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 4
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 5
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 replication Zhu 2009 NatMed;15:886-93 6
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 Effect of Aciclovir on HIV replication 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 Lisco 135LB, Vanpouille 567, McMahon 566 CROI 2009 7
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 8
Effect of CMV and HIV loads on mortality Pre-HAART era Spector 1999 J Virol;73:7027 Change in CMV Load Following HAART 6 5 Log CMV load (copies/ml) 4 3 2 0 10 20 30 40 50 60 Time (weeks) Deayton 1999 AIDS; 13:1203-6 9
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 10
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 viraemia Wohl 2009 HIV Clin Trials;10:143-50 11
Summary 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 12
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 13