Impact of acyclovir episodic therapy on genital ulcer healing and genital HIV1 RNA among men and wom

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Impact of acyclovir episodic therapy on genital
ulcer healing and genital HIV-1 RNA among men and
women in Malawi

• S. Phiri1, I. Hoffman2, H. Weiss3, WC. Miller2,
  F. Martinson4, N. Nyirenda4, D. Kamwendo4, S.
  Fiscus2, C. Chen5, L. van der Hoeven6, D.
  Chilongozi4, M. Cohen2, P. Mayaud3
• 1 Lighthouse, Malawi 2 UNC Chapel Hill, USA 3
  LSHTM, UK 4 UNC Project, Lilongwe, Malawi 5 CDC
  - Atlanta, USA 6RHU MOH, Malawi

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Genital ulcer disease (GUD) in Africa and
management

• Shift in GUD aetiologies in Africa.
• Haemophilus ducreyi (HD), Treponema pallidum (TP)
  , Klebisiella granulomatis (donovanosis),
  Chlamydia trachomatis
• Increasingly high proportion of Herpes simplex
  virus type-2 (HSV-2). (Htun, 2001 Hoyo, 2005)
• GUD Syndromic management in Malawi covers
  treatment for syphilis and chancroid, and not for
  genital herpes (HSV-2).
• WHO guidelines (2003) recommend inclusion of
  acyclovir if HSV-2 aetiological prevalence 30

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HSV-2 and HIV-1 Synergy
? Acquisition?
? Transmission?
HSV-2
HIV-1
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Genital Ulcer Disease in Malawi

• 45 of STI patients are HIV-positive
• 15-30 of STI patients have GUD
• GUD studies in 1994 and 2000
• T pallidum 30 ? 29
• H ducreyi 26 ? 26
• HSV-2 10 ? 35
• Observed reduced healing rates (estimated at 65
  on clinic records) in 2003

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Study objectives

• Primary
• To evaluate impact of adding acyclovir episodic
  treatment to SM of GUD on genital ulcer healing
• Secondary
• To evaluate impact of acyclovir on detection and
  quantity of lesional, genital and plasma HIV-1
  RNA among HIV-1/HSV-2 co-infected men and women.
• To describe the aetiological pattern of GUD in
  Lilongwe, Malawi

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Study methods 1

• Study Setting Lilongwe, Malawi
• Kamuzu Central Hospital STI clinic - provides
  care to 800 patients per month.
• Population Men and women presenting with GUD
• Design Randomized double-blind
  placebocontrolled trial.
• Follow-up Patients interviewed, examined and
  samples collected at days 0, 2 or 4, 7, 14 and
  28.
• Blood for serologies and HIV-1 RNA and CD4
• Ulcer swab for aetiology and lesional HIV-1 RNA
• Cervical swab for HIV-1 RNA
• Seminal plasma for HIV-1 RNA

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Study methods 2

• Laboratory methods
• GUD aetiology from lesional swabs by real-time
  PCR (HD, TP, HSV-2, C trachomatis L1-3 LGV)
• Serologies for HIV-1 (Determine and Uni-Gold),
  HSV-2 (HerpeSelect, Focus) and syphilis (RPR and
  TPPA)
• Plasma, genital secretion and lesional HIV-1
  RNA for HIV-1 sero done using Roche Amplicor
  and Nuclisens (400 copies/mL)
• Treatment
• All GUD patients were treated with benzathine
  penicillin 2.4MU i.m. STAT Ciprofloxacin 500mg
  orally STAT
• 2 tablets of 400mg acyclovir or matching placebo
  (2 tablets 800mg BID X 5 Days)

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Planned analysis

• Primary outcome Ulcer Healing
• Proportion of men and women with a healed ulcer
  at D14 (D7 and D28)
• Time to ulcer healing over time
• Secondary outcomes lesional, cervical, seminal
  and plasma HIV-1 RNA
• Proportion with HIV-1 RNA at D14 (D7 and D28)
• Mean quantity of HIV-1 RNA at D14 (D7 and D28)

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Results Flow chart of all men and women Enrolled
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Ulcer aetiology
Primary genital herpes, n67 (17)
Proportions will not add up to 100 due to mixed
aetiologies
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Baseline Characteristics
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Baseline Biological Results
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Ulcer Healing Proportion of participants with a
90 reduction in ulcer size
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Ulcer healing over time among all men and women
with GUD
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HIV-1 shedding among HIV / HSV-2 infected
patients at Day 14 (primary endpoint)
RR or coeff are adjusted for day 0 values,
except for seminal plasma no measurement taken
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HIV-1 RNA seminal shedding among HIV-1 positive
men with HSV-2 infection
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Conclusions

• Acyclovir had little impact on ulcer healing
• There was a reduction in frequency of lesional
  and seminal plasma HIV-1 RNA
• This suggests that herpes therapy may may reduce
  genital HIV transmission

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Acknowledgements

• KCH STI Clinic, Lilongwe
• Clinic Team
• UNC Malawi
• Francis Martinson, David Chilongozi, Debbie
  Kamwendo
• UNC Chapel Hill
• Irving Hoffman, William C Miller, Susan Fiscus,
  Myron Cohen
• LSHTM, London
• Philippe Mayaud, Helen Weiss

• RHU - MOH, Malawi
• Len van der Hoeven
• CDC, Atlanta
• Cheng-Yen Chen
• DSMB
• Simon Cousens (Chair, LSHTM), Late George Joaki
  (UNC Malawi), Peter Leone (UNC Chapel Hill)
• The Trial was funded by National AIDS Commission
  and UNC Fogarty (FIC)