Interactions between Genital Herpes and HIV Infection: the South African Experience

1
Interactions between Genital Herpes and HIV
Infection the South African Experience

• Ron Ballard PhD
• Department of Clinical Microbiology and
  Infectious Diseases, University of the
  Witwatersrand, Johannesburg, South Africa

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HIV-HSV interactions

• HSV and HIV have a complex relationship
• HSV-2 is a risk factor for HIV acquisition and
  transmission
• Controlling HSV shedding/GUD with antivirals may
  impact on HIV acquisition, transmission and
  progression

3
Interactions between conventional STIs and HIV
Impaired immunity
Altered frequency, natural history and
susceptibility
HIV
STI
Increased transmission Increased progression to
clinical disease
High-risk sexual behaviour
4
Determinants of the HIV/AIDS epidemic in
developing countries
Impoverishment
Social Factors (Majority of Population)
HIV/AIDS
High Risk Sexual Behaviour
Including Poor education Rapid
urbanization Migratory labour Social
instability
High Prevalence of Conventional STIs
5
Aetiology of genital ulcer disease Lesotho
(19931994)
Single Infections PCR Results Chancroid 41
(41) Syphilis 16 (16) Genital Herpes 17
(17) Lymphogranuloma venereum (LGV) 3
(3) Mixed Infections Chancroid Syphilis 5
(5) Chancroid HSV 6 (6) Chancroid
LGV 3 (3) Chancroid Syphilis HSV 1
(1) HSV LGV 1 (1) HSV Syphilis 1
(1) Unsolved Cases 6 (6) HIV 35 (35)
6
Relative prevalence of STD syndromes in a mining
community, South Africa (19921999)
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Q What is the influence of HIV infection
on genital herpes?
A The relative frequency of genital herpes
compared with other causes of genital ulceration
8
Prevalence of HIV infection in migrant mine
workers with GUD
9
Prevalence of chancroid by year of study
10
Prevalence of genital herpes by year of study
11
Attributable risk of HIV for increase in
prevalence of genital herpes (19861998)
12
Association between incident GUD and HIV
infection
HIV Serology RR Infection n Pos ()
Neg () (95 CI) P-value Syphilis 128a
33 (25.8) 95 (74.2) 0.41 lt0.001
(0.280.59) Chancroid 336b 159 (47.3) 177
(52.7) 1.10 NS (0.941.29) Herpe
s 230b 137 (59.57) 93 (40.43) 1.74 lt0.001
(1.402.17)
a Multiplex-PCR positive patients b Culture or
multiplex-PCR positive patients
RR relative risk CI confidence intervals
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Q What is the influence of HIV infection on
genital herpes?
AThe influence on clinical presentation of
genital herpes
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Genital herpes presentation in an HIV negative
patient
15
Severe atypical herpetic lesions in an HIV
Patient (1)
16
Severe atypical herpetic lesions in an HIV
patient (2)
17
Severe atypical herpetic lesions in an HIV
patient (3)
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Q What is the influence of genital herpes on HIV
infection?
A Influence on HIV shedding in co-infected
patients with active genital lesions
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Influence of reproductive tract infections and
their treatment on vaginal and lesional shedding
of HIV
Ballard RC, Htun Ye, Bredell H, Puren A, Dangor
Y, Radebe F, Tshabalala V, Martin D STD
Reference Centre, Dept. of Clinical Microbiology
and Infectious Diseases, University of
Witwatersrand and South African Institute for
Medical Research and National Institute for
Virology, Johannesburg, South Africa
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A Genital ulcerations
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Study population
70 HIV-positive patients with genital ulcerations
at the East Driefontein STD clinic,
Carletonville, South Africa
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Study design
Initial visit Recruitment of HIV men (70)
Clinical assessment Laboratory
investigations (STD, HIV, CD4) Syndromic
management of GUD Return visits (Day 7, Day 14,
Day 21) Clinical assessment Laboratory
investigations (STD, HIV)
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Laboratory investigations (a)
Molecular tests Culture
Treponema pallidum Haemophilus ducreyi
Haemophilus ducreyi Herpes simplex virus
Herpes simplex virus Chlamydia trachomatis
Chlamydia trachomatis
Serology
RPR/FTA-Abs
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CD4 count (Flow cytometry)Plasma HIV viral
load (RT-PCR)Lesional shedding of HIV (RT-PCR)
Laboratory investigations (b)
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Sample collection for HIV testing
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2.4 Mu benzathine penicillin Gpluserythromycin
or ciprofloxacin(treatment for
chancroid)plusValaciclovir 500 mg twice daily
for 5 days(At first return visit if clinically
indicated)
Syndromic management of GUD
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Aetiology of genital ulcerations at initial visit
Single infections Haemophilus ducreyi
41 (59) Treponema
pallidum
0 Lymphogranuloma venereum
3 (4) Herpes simplex virus
14 (20) Mixed
infections H. ducreyi HSV
6 (9) H. ducreyi
T. pallidum HSV 1
(1) T. pallidum HSV
2 (3) H. ducreyi T.
pallidum 1
(1) Unknown aetiology
2 (3)
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Distribution of CD4 counts among HIV men with
GUD
43
37
10
CD4 Count/ml
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Association of lesional HIV shedding with plasma
HIV viral load at initial visit
Mann-Whitney test, P0.001 X2 test, plt0.001,
Odds ration 99 (95 CI 10948)
30
Comparison of HIV plasma viral load, HIV shedding
and immune status at initial visit by ulcer
aetiology
Mann-Whitney U test a vs b (P 0.03), a vs c
(P 0.008)
Mann-Whitney U test - 1 vs 2 (p0.03), 1 vs 3
(p0.008)
31
Influence of syndromic treatment of genital
ulcerations on rates of lesional HIV shedding by
ulcer aetiology
without antiviral therapy
32
Effect of antibiotics or valaciclovir treatment
on HIV shedding in cases of proven genital herpes
All patients ceased shedding by Day 21
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B Vaginal Discharges
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Study Population
57 consecutive HIV-positive women complaining of
vaginal discharge attending an STD clinic at
Esselen Street, Johannesburg
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Syndromic management of vaginal discharge

• Ciprofloxacin 500 mg p.o. stat
• plus
• Doxycycline 100 mg b.d. for 7 days
• plus
• Metronidazole 400 mg b.d. for 7 days
• plus
• Clotrimazole 200 mg vaginal tablet stat
• plus
• Valaciclovir 500 mg b.d. for 5 days
• (If clinically indicated)

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Association of vaginal HIV shedding with plasma
HIV viral load at initial visit
Mann-Whitney test, P 0.001 X2 test, P
0.001 Odds ratio 7.6 (2.127.5)
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Influence of treatment of infections on HIV
vaginal shedding
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Effect of valaciclovir treatment on HIV
shedding in cases of herpes cervicitis
UD Undetectable (lt400 copies/ml)
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Conclusions 1

• Lesional and vaginal shedding of HIV is related
  to HIV plasma viral load.
• Fewer patients with HIV plasma viral loads lt10
  000 copies/ml shed HIV than those with gt10 000
  copies/ml.
• Significantly higher HIV plasma viral loads were
  detected in those patients with genital herpes.
• Successful syndromic treatment of genital tract
  infections results in a decrease in HIV viral
  shedding.

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Conclusions 2

• Treatment failure and delayed ulcer healing noted
  due to concomitant HSV infection, resulting in
  prolonged HIV shedding.
• Specific antiherpes therapy significant reduced
  HIV shedding in those patients with proven
  genital herpes.
• Syndromic management of GUD should include
  management of genital herpes to reduce shedding
  and thus spread of HIV.
• In women, asymptomatic herpes cervicitis may be a
  significant factor in HIV shedding.

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Q What is the influence of genital herpes on
HIV infection?
A Influence on potential acquisition of HIV in
HSV-2 seropositive teenagers
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Association between STIs and HIV among teenagers

• South African, community-based study
• Approximately 600 teenagers sampled
• Questionnaires
• Blood and urine specimens collected

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Association between STIs and HIV among teenagers
in a South African community laboratory methods
Blood Syphilis serology RPR test FTA-ABS
test HIV serology ELISA Herpes
serology HSV-1 HSV-2 First-catch
urine Chlamydia trachomatis (CT-LCR) Neisseria
gonorrhoeae (GC-LCR)

MRL Elisa
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STI prevalence rates among teenagers in a South
African community by gender
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Association Between STIs and HIV Among Teenage
Girls in a South African Community
Fishers Exact Test
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Summary (1)

• HIV infection influences the clinical
  presentation of genital herpes, causing
  reactivation and more severe disease
• Genital herpes has become more common in the HIV
  era
• Genital herpes, as with other STIs, is associated
  with increased HIV shedding from the genital
  tract
• HIV shedding is not reduced with antibiotic
  therapy (unlike other STIs), but can be reduced
  with herpes-specific antiviral therapy

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Summary (2)

• 5. Genital herpes is associated with an increase
  in HIV plasma viral load (unlike chancroid) which
  is independent of CD4 counts
• 6. Among teenagers, HSV-2 seropositivity is more
  common and probably precedes HIV seropositivity
• 7. HSV-2 has a greater association with HIV
  seropositivity than syphilis, gonorrhoea or
  chlamydial infections, indicating that it may be
  a major co-factor in HIV acquisition

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Questions

• Can addition of specific anti-herpes antiviral
  therapy to syndromic management protocols
  significantly reduce transmission of HIV?
• Can suppressive anti-herpes therapy protect HSV-2
  seropositive / HIV seronegative patients against
  acquisition of HIV?
• Would an effective herpes vaccine have a role to
  play in protection against HIV?