Syphilis and HIV
Graham P Taylor
The ‘discovery’ of the New World On August 3, 1492, Columbus set sail from Palos, Spain, with three small ships, the Santa Maria, the Pinta, and the Nina. On October 12, the expedition reached land, probably the Bahamas. Later that month, Columbus sighted Cuba, which he thought was China, and in December Hispaniola, which Columbus thought might be Japan. The local population, the Teino, were friendly – so Columbus captured and manacled some of them. The explorer returned to Spain with gold, spices, "Indian" captives and possibly something else in March 1493
1494
King Charles VIII France raises a 25000 strong army to invade the Kingdom of Naples (October 1494). The army includes 8000 Swiss Mercenaries Notorious for massacres of each city taken en route to Naples Naples falls February 1495 Italians get annoyed and rise against the French and form the League of Venice (includes several Italian States, Spain and England) The French leave Naples 20 May 1495 to defend the countryside Battle is joined at Fornova – both sides sustain heavy casualties and officially both sides won. The Italians a tactical victory the French a strategic victory
Syphilis in 15th Century Europe Following the first reports among the troops who fought at Naples syphilis spread rapidly across Europe by the end of 15th century.
Gottlieb MS et al, Pneumocystis carinii pneumonia and mucosal candidiasis in previously healthy homosexual men: evidence of a new acquired cellular immunodeficiency NEJM 1981;305:1425-1431
MMWR Morb Mortal Wkly Rep. 1981 Jul 3;30(25):305-8. Kaposi's sarcoma and Pneumocystis pneumonia among homosexual men--New York City and California. Centers for Disease Control (CDC).
Rapid increase in reports
593 cases reported 1 June 1981 – 15 Sept 1982 Incidence of AIDS roughly doubled from 1979 4 risk groups were identified accounting for • 75% • 13% • 6% • 0.3%
Homosexual or Bisexual Men Injecting Drug Users Haitians Haemophilia A
Morb Mort Wkly Rep 1982;31:507-8
What led to the spread of HIV? – contemporary perspective 1986: Follow-up investigation has indicated that many of the AIDS patients who could not originally be placed in a high-risk category were from countries where heterosexual transmission may account for many AIDS cases, had histories of gonorrhoea or syphilis, or had sexual contact with a female prostitute. MMWR Morb Mortal Wkly Rep. 1986 Jan 17;35(2):17-21 1987: Case-control study in San Francisco, Prior syphilis OR 2.5 (p 0.04) Moss AR et al Am J Epidemiol. 1987 Jun;125(6):1035-47 1990: 4863 patients attending two inner-city sexually transmitted disease clinics was conducted in 1988. Syphilis serology+ 24.3% HIV + v Syphilis –ve 3.5% HIV+. OR for HIV if T pallidum seropositive 6.8 ♀ 8.7♂ Quinn TC et al Arch Intern Med. 1990 Jun;150(6):1297-302
Risk Factors and Population Attributable Fraction of HIV transmission Rakai. Uganda RCT of STI management to reduce transmission of HIV HIV transmission risks associated with STD symptoms in HIV-positive partners of 167 HIV discordant couples HIV incidence was determined in 8089 HIV-negative subjects over 10 457 person years. Population attributable fraction of HIV transmission for GUD (in the incident case) was 8.8% (CI 3.7-13.8) Only 8.2% of reported GUD was caused by treatable syphilis or chancroid Gray RH et al AIDS. 1999 Oct 22;13(15):2113-23.
AIDS & Africa (1983) Ann Soc Belg Med Trop. 1983 Mar;63(1):73-4. [Acquired immune deficiency syndrome in 3 patients from Zaire] Taelman H, Dasnoy J, Van Marck E, Eyckmans L. Lancet. 1983 Mar 19;1(8325):642. Acquired immune deficiency syndrome in Black Africans. Clumeck N, Mascart-Lemone F, de Maubeuge J, Brenez D, Marcelis L.
Lancet. 1983 Apr 23;1(8330):925. AIDS in a Danish surgeon (Zaire, 1976) Bygbjerg IC.
AIDS & Africa (1959) Earliest isolate of HIV is from Kinshasa, 1959 A second isolate also from Kinshasa , 1960
An African HIV-1 sequence from 1959 and implications for the origin of the epidemic. Tuofu Zhu, Bette T. Korber, Andre J. Nahmias, Edward Hooper, Paul M. Sharp & David D. Ho Nature. 1998 Feb 5;391(6667):594-7
Molecular analysis estimates the time to most recent common ancestor as 1921 (possibly 1908)
M Worobey et al. Nature 455, 661-664 (2008) doi:10.1038/nature07390
Non-human primate retroviral infections may not be very infectious within humans Non-human primate retroviruses have been infecting humans for 1000‟s years: HTLV-2 ~ 60,000 - 400,000 years HTLV-1 ~ 3,000 – 50,000 years SIV cpz ~ 100 years (HIV-1 group M) SIVsmm ~ 60 year (HIV2) Without always establishing human infection: SFV PTLV3 PTLV4
What permissive factors pervaded DRC in the Early 20th Century that resulted in the establishment of HIV-1? Urbanisation – consequent upon colonisation
The origin and growth of the major settlements near the epicentre of the HIV-1 group M epidemic.
Kinshasa population grew 3 fold between 1919 and 1929 to 47,000
M Worobey et al. Nature 455, 661-664 (2008) doi:10.1038/nature07390
What permissive factors pervaded DRC in the Early 20th Century that resulted in the establishment of HIV-1? Urbanisation – Social disruption: 1928 Kinshasa males outnumbered females 4:1 Of 6000 females living in one part of the city: 1724 married 1600 “illegitimate relationship” 2676 “live mainly on prostitution”
STI epidemics – Annual incidence Kinshasa 1925: Syphilis ~ 8% (urbanisation = syphilization) Chancroid ~ 1% LGV ~0.5% (Male circumcision rates ~ 80%) De Sousa et al Plos One 2010;5:4, e9936
Modelling the origin of HIV De Sousa et al Modelled 4 conditions: pre-colonial village, Kinshasa 1919, 1929 and 1958 The variables in the scenarios were: Numbers of women, men, married couples, „femmes libresâ€&#x; % males circumcised GUD frequency in CSW, femmes libre, other women and men
De Sousa et al Plos One 2010;5:4, e9936
Scenario-independent parameters for the simulations behavioural:
Number of non-spousal partners per year Single women 1.5 Married women 0.2 Single men 3 Duration of short links 52 weeks (♀) 26 weeks (♂) Number of sex acts per week: Stable 2 Short link 0.24 CSW visits per man py 2 Sex acts per CSW py 600 Probabilities of short link formation and establishment
De Sousa et al Plos One 2010;5:4, e9936
Scenario-independent parameters for the simulations microbiological: Duration of acute HIV infection 12 weeks Transmission multiplier for acute infection 10 Duration of GUD 10 weeks Per sex act HIV transmission probabilities: ♀♂ and ♂♀ 0.001 ♀♂ (not circumcised) 0.0025 ♂♀ (GUD) 0.07 ♂ (GUD) ♀ 0.04 ♀ (GUD) ♂ (Circumcised) 0.04 ♀ (GUD) ♂ (not circumcised) 0.43 ♀♂ (GUD) 0.023 ♀♂ and ♂♀ (all GUD) 0.43
De Sousa et al Plos One 2010;5:4, e9936
Kinshasa 1919 and GUD are the major players
De Sousa et al Plos One 2010;5:4, e9936
Effect of HIV on early syphilis
HIV +ve
HIV -ve
p
Duration of GUD
11 days
10 days
0.2
Multiple lesions
87%
62%
0.02
Deep ulcers
64
43
0.08
Larger
504mm2
109 mm2
0.06
Primary syphilis diagnosed
36%
19%
<0.01
Presence of ulcers in Secondary Syphilis
13%
2%
<0.01
Rompalo AM et al; Sex Transm Dis. 2001 Aug;28(8):448-54
Assay to quantify T . Pallidum
Tipple C et al STI 2011 Oct;87(6):479-85.
Demographics and Diagnoses of 99 subjects
Tipple C et al STI2011 Oct;87(6):479-85.
More treponemes in HIV co-infection Ulcers: Overall 1832 copies/strip (251-14244) HIV-1 +ve - 2115 (757-14244), HIV-1 -ve - 648 (251-2742). Secondary ulcers: 251 copies/strip Blood (extracted immediately): Secondary = 575 copies/mL Primary = 148 copies/mL Modal RPRs were 1:128 and 1:16
Two things everyone knows about syphilis
Itâ&#x20AC;&#x;s gone away
Itâ&#x20AC;&#x;s easily treated
36 million prevalent cases in 2005
Rapid increase in prevalence of mutations British Columbia1 2000-3 2% 2004 44%
San Francisco2 99-02 4% 2003 37% 2004 56%
1Morshed 2Mitchell
and Jones. CMAJ 2006; 174:349 et al. Clin Infect Dis 2006; 42:337-45
Global picture of macrolide resistance Czech Rep2. 2005-8 37% Seattle1: 2001-3 13%
Dublin1 2002 88% Shanghai4 2007-8 100%
Baltimore1 1998-2000 11%
1Lukehart
et al. New Eng J Med 2004;351:154-8 2Matejkova. J Med Microbiol 2009;58:832-6
Madagascar3 2000-7 0%
3Martin
4Martin
et al. Sex Trans Dis 2010;37:544-8 et al. Clin infect Dis 2009;49:515-21
Results: resistance mutation analysis Wild-type 6 (33.3%)
2006-8 18 patients
26 patients in total
2011 8 patients Tipple C et al STI 2011 Oct;87(6):486-8
A2058G mutants 11(61.1%)
HIV negative: 2 HIV positive: 4 HIV negative: 5 HIV positive: 6
A2059G mutants 1 (5.6%)
HIV positive
Wild-type 2 (25%)
HIV positive: 2
A2058G mutants 6 (75%)
HIV positive: 3 HIV negative: 3
Whatâ&#x20AC;&#x2122;s happening locally?
Bacterial STI from all STD clinics end of 2012
Infectious Syphilis NGU-Male
Late Syphilis Gonorrhoea & PGC
No. of cases
250 200 150
100 50
0 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 2008
2009
Source: QSTDR/SIMU/NSACP/28/5/2013
2010
2011
2012
Source: Quarterly Return from all STD clinics
Molecular typing of T pallidum in Colombo Samples from 24 patients Patient Demographics and Sample types Stage of Disease
14 Primary and 10 Secondary
Samples
24 Ulcer Swabs
Gender
24 (100%) male
Sexuality
11 (46%) MSM; 12 (50%) heterosexual; 1 (4%) not applicable (neonate)
HIV-1 status
24 (100%) negative
Colombo: resistance mutation analysis
100 % Wild type
100 % HIV uninfected
Summary Syphilis epidemic in Europe at end of 15th century – rapid spread SIV (probably) poorly infectious in humans – multiple zoonosis without establishing infection in human Conditions in central Africa (Chimpazee belt) early 20th century permissive to establish HIV-1 Social change, distorted population growth, multiple partners – epidemic of GUD (mostly syphilis) and passage of SIV – HIV in humans. HSV now commonest cause of GUD. HIV distorts syphilis (mutually more infectious) Macrolide resistance common (but not yet in Sri Lanka)
Acknowledgments
London C Tipple M Hanna M McClure D Goldmeier
Colombo
D Mallikarachchi K Buddhakorala G Weerasinghe O de Alwis Staff and Patients Jefferiss Wing Central STD Clinic