MAJOR ARTICLE
Iatrogenic Transmission of Human T Cell Lymphotropic Virus Type 1 and Hepatitis C Virus through Parenteral Treatment and Chemoprophylaxis of Sleeping Sickness in Colonial Equatorial Africa Jacques Pe´pin,1 Annie-Claude Labbe´,2 Fleurie Mamadou-Yaya,3 Pascal Mbe´lesso,4 Sylvestre Mbadingaı¨,3 Sylvie Deslandes,1 Marie-Claude Locas,2 and Eric Frost1 1
Department of Microbiology and Infectious Diseases, Universite´ de Sherbrooke, Sherbrooke, and 2Department of Microbiology and Immunology, Universite´ de Montre´al, Montreal, Quebec, Canada; 3Ministry of Public Health and 4Faculty of Health Sciences, University of Bangui, Bangui, Central African Republic
(See the article by Pe´pin et al, on pages XXX–XXX, and the editorial commentary by Strickland, on pages XXX–XXX.)
Background. The simultaneous emergence of human immunodeficiency virus (HIV)–1 group M and HIV-2 into human populations, circa 1921–1940, is attributed to urbanization and changes in sexual behavior. We hypothesized that the initial dissemination of HIV-1, before sexual transmission predominated, was facilitated by the administration, via reusable syringes and needles, of parenteral drugs against tropical diseases. As proxies for highly lethal HIV-1, we investigated risk factors for hepatitis C virus (HCV) and human T cell lymphotropic virus 1 (HTLV-1) infections, blood-borne viruses compatible with prolonged survival, in an area known in 1936–1950 as the most virulent focus of African trypanosomiasis. Methods. Cross-sectional survey of individuals 55 years and older in Mbimou land and Nola, Central African Republic. Dried blood spots were used for HCV and HTLV-1 serologic testing and nucleic acid detection. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were measured by logistic regression. Results. The only risk factor for HCV genotype 4 infection was treatment of trypanosomiasis before 1951 (OR, 3.13; 95% CI, 1.38–7.09). HTLV-1 infection was associated with having received ⭓2 injections of pentamidine for trypanosomiasis chemoprophylaxis (adjusted OR, 2.03; 95% CI, 1.01–4.06) and with transfusions (adjusted OR, 2.82; 95% CI, 1.04–7.67). From historical data, we predicted that 59% of Mbimous 65 years and older would report treatment for trypanosomiasis before 1951; only 11% did so. Conclusions. Treatment of trypanosomiasis before 1951 may have caused iatrogenic HCV transmission. Population-wide half-yearly intramuscular pentamidine for trypanosomiasis chemoprophylaxis in 1947–1953 may have caused iatrogenic HTLV-1 transmission. These and other interventions against tropical diseases could have iatrogenically transmitted SIVcpz, jump-starting the HIV-1 epidemic. The excess mortality among patients with trypanosomiasis treated before 1951 supports this hypothesis. The most recent common ancestors of human immunodeficiency virus (HIV)–1 group M and HIV-2 were dated in ∼1921 and ∼1940, respectively [1, 2]. Their simultaneous emergence into human populations, a few thousand kilometers apart, is attributed to the urbani-
Received 8 February 2010; accepted 3 May 2010; electronically published 24 August 2010. Reprints or correspondence: Dr Jacques Pe´pin, CHUS, 3001, 12e`me Avenue Nord, Sherbrooke, Que´bec, J1H 5N4 Canada (
[email protected]). Clinical Infectious Diseases 2010; 51(7):000–000 2010 by the Infectious Diseases Society of America. All rights reserved. 1058-4838/2010/5107-00XX$15.00 DOI: 10.1086/656232
zation of Africa: rare infections acquired while hunting or cutting primate meat resulted in epidemiologic dead ends, until large-scale displacement of men for public works or commercial enterprises led to transactional sex within cities, multiplying the opportunities for sexual transmission. However, transmission of hepatitis C virus (HCV) during parenteral treatment of schistosomiasis in Egypt showed that iatrogenic epidemics can be massive [3]. Did similar mechanisms facilitate the emergence of HIV-1 and HIV-2? HIV-2 infection is compatible with a prolonged survival; among elderly individuals in Guinea-Bissau, HIV2 was associated with 3 routes of parenteral transmission: HCV and HTLV-1 in Equatorial Africa • CID 2010:51 (1 October) • 000
treatment of sleeping sickness (African trypanosomiasis), treatment of tuberculosis with intramuscular streptomycin, and ritual clitoridectomy [4, 5]. HIV-1 originated from the Pan troglodytes troglodytes chimpanzee and emerged somewhere within this ape’s habitat, in Equatorial Africa west of the Oubangui and Congo rivers (Figure 1) [6, 7]. Although excision is uncommon there, trypanosomiasis was epidemic in the early 20th century, and streptomycin was introduced for the treatment of tuberculosis in the 1950s [8]. Because almost all untreated HIV-1–infected individuals die within 15 years, we opted to study the role of tropical disease control programs in the iatrogenic transmission of 2 blood-borne viruses compatible with survival, human T cell lymphotropic virus (HTLV)–1 and HCV, as proxies for putative iatrogenic transmission of HIV-1. We conducted a survey in the Nola-Bilolo area, Central African Republic, the most virulent focus of trypanosomiasis in Equatorial Africa during the colonial era and the only one where high incidences persisted until the 1940s [9, 10]. It is located 160 km north of sites in Cameroon (Figure 1), where 25%–32% of chimpanzees are infected with SIVcpz, and within kilometers of a site where a seropositive chimpanzee was identified [7]. METHODS Historical review. The study was approved by ethics committees of the Central African Republic Ministry of Health and
the Centre Hospitalier Universitaire de Sherbrooke in Canada. Historical data on the epidemiology of trypanosomiasis in the Nola-Bilolo focus were reviewed [9–18]. Annual incidence was measured as the total number of new cases and as Indice de Contamination Nouvelle (ICN), a measure of risk (new cases in a year divided by number of individuals never diagnosed as having the disease) [19]. Using ICN measures, we developed a model to calculate the proportion of individuals in each birth cohort treated for trypanosomiasis before 1951. We summed each birth cohort’s risk for trypanosomiasis during each calendar year and assumed that (1) before 1936, the first year for which ICN was available, 20% of individuals aged ⭓6 years had had trypanosomiasis; (2) risk during the first 6 years of life was one-fifth that of older children and adults; and (3) 25% of patients with trypanosomiasis died of the disease or its treatment [13–18, 20]. Field survey. In October-November 2006, participants were recruited by house visits in (1) 31 villages west of Nola up to Bige´ne´ (8 km from the Cameroonian border) known as pays Mbimou (Mbimou land), the area with the highest incidence of trypanosomiasis in the 1936–1950 period; and (2) Nola town and 3 villages along the Kadei river, grouped in forthcoming analyses (Figure 1). Inclusion criteria were age of ⭓55 years and willingness to consent. Exclusion criteria were dementia or inability to communicate. A questionnaire gath-
Figure 1. Map of Equatorial Africa showing the location of the Nola-Bilolo focus of African trypanosomiasis, the distribution of the Pan troglydytes troglodytes reservoir of SIVcpz and human immunodeficiency virus 1, the collection sites where SIVcpz-infected chimpanzees have been found (letters within circles) [7] and the river networks. 000 • CID 2010:51 (1 October) • Pe´pin et al
negative. HIV serologic testing used Detect-HIV (Adaltis), followed by Genie II HIV-1/HIV-2 (Bio-Rad) and INNO-LIA HIV I/II Score (Innogenetics). Two participants had insufficient samples and only HCV could be tested. Sample size estimate and data analysis. We estimated that the prevalence of HCV or HTLV-1 infection would be 6% in unexposed individuals and 12% among those treated for trypanosomiasis and that the latter would include one-third of participants. Aiming for 80% power, we needed to recruit 840 individuals. Data were analyzed with Stata statistical software, version 10.0 (Stata). Proportions were compared with the x2 or Fisher exact test. Adjusted odds ratios (ORs) and their 95% confidence intervals (CIs) were calculated by logistic regression. Models were built sequentially, starting with the variable most strongly associated with the outcome. Models were compared using likelihood ratio tests, keeping variables significant at the P ⭐ .05 level.
ered sociodemographic characteristics, dates of migration, scarifications, circumcision, excision, and medical history. For participants unaware of their age, an estimate was made from historical events widely known locally. Vaccination scars were recorded. Capillary blood was deposited on filter papers and stored at 4C for 1–2 months before testing. Questionnaires and samples were identified only by a number. Laboratory assays. Samples were screened for HCV antibodies using Detect-HCV, version 3 (Adaltis). Reactive samples were further tested with the Ortho HCV 3.0 enzyme-linked immunosorbent assay (ELISA; Ortho) and Monolisa Anti-HCV Plus Version 2 (Bio-Rad): dually nonreactive samples were considered HCV negative, samples reactive with all 3 ELISAs were considered HCV positive, whereas samples with discordant results were tested by INNO-LIA HCV Score (Innogenetics), whose result was definitive unless only indeterminate bands were present, in which case polymerase chain reaction (PCR) was performed. HCV genotyping relied on amplification of a 380–base pair fragment of the NS5B gene [21]. Samples were screened for HTLV-1 antibodies using DETECT-HTLV (Adaltis). Reactive samples were further tested with Ortho HTLV-I/HTLV-II Ab-Capture ELISA (Ortho) and INNO-LIA HTLV I/II Score (Innogenetics). INNO-LIA reactive (HTLV-1 and HTLV untypable) samples were considered HTLV-1 positive; those showing only bands against HTLV-2 were considered HTLV-1 negative. Samples reactive by Ortho and nonreactive by INNO-LIA, as well as those indeterminate by INNO-LIA, were tested by PCR targeting the Tax gene [22]; PCR-positive samples were considered positive and the others
RESULTS Characteristics according to ethnic groups. Table 1 compares characteristics of Mbimous to all other ethnic groups. Of 154 Mbimous living in Nola for whom we had detailed data on migration, only 54 (35%) were born in Nola; others had migrated from Mbimou land later in life, and their exposure to trypanosomiasis was similar to those who remained in their villages. Mbimous were older and more likely to be female, reflecting immigration into Nola of younger males from elsewhere. Mbimous were more likely to be widowed (data not
Table 1. Characteristics of Participants, According to Ethnic Group Ethnic group Mbimous (n p 529)
Characteristic Age, median years (interquartile range)
64 (59–74)
All others (n p 376) 61 (57–69)
P !.001
Male sex
195 (37)
207 (55)
!.001
Current residence in Mbimou land Pentamidine injections for prophylaxis of trypanosomiasis
364 (69)
30 (8)
!.001
171 (32) 110 (21)
237 (63) 20 (5)
!.001
248 (47)
118 (31)
Never Treated up to 1950
450 (85) 38 (7)
365 (97) 5 (1)
Treated after 1950
41 (8)
6 (2)
53 (10) 55 (10) 478 (90)
12 (3) 23 (6) 362 (96)
95/195 (49) 63/195 (32)
131/204 (64) 110/207 (53)
Never Once or number unknown Twice or more Past treatment for trypanosomiasis
Ever treated for yaws Ever treated for schistosomiasis Vaccination scars present Men reporting past urethral discharge Men reporting past genital ulcer
!.001 !.001
.03 .001 .003 !.001
NOTE. Data are no. (%) of patients, unless otherwise indicated.
HCV and HTLV-1 in Equatorial Africa • CID 2010:51 (1 October) • 000
Table 2. Risk Factors for Infection with Hepatitis C Virus (HCV) Genotype 4 or with Human T Cell Lymphotropic Virus (HTLV)–1 a
HTLV-1
HCV genotype 4
Risk factor
Proportion (%) of HCV genotype 4–positive participants
Age, years 55–64
30/485 (6.2)
1.00
32/496 (6.5)
1.00
65–74 ⭓75
21/225 (9.3) 14/158 (8.9)
1.56 (0.87–2.79) 1.47 (0.76–2.86)
20/233 (8.6) 15/167 (9.0)
1.36 (0.76–2.44) 1.43 (0.75–2.71)
Never
27/396 (6.8)
1.00
31/407 (7.6)
1.00
Once or number unknown Twice or more
28/386 (7.3) 9/92 (9.8)
1.07 (0.62–1.85) 1.48 (0.67–3.27)
22/401 (5.5) 14/94 (14.9)
0.70 (0.40–1.24) 2.12 (1.08–4.17)b
55/787 (7.0)
1.00
59/813 (7.3)
OR (95% CI)
Proportion (%) of HTLV-1–positive participants
OR (95% CI)
Pentamidine injections for prophylaxis of trypanosomiasis
Past treatment for trypanosomiasis Never Treated up to 1950 Treated after 1950 Transfusion Never Ever Vaccination scar, left arm Absent Present Vaccination scar, right arm Absent Present
8/42 (19.0) 2/46 (4.3)
3.13 (1.38–7.09)b 0.60 (0.14–2.56)
1.00
6/43 (14.0) 2/47 (4.3)
2.07 (0.84–5.11) 0.57 (0.13–2.40)
61/641 (7.3) 4/31 (12.9)
1.00 1.89 (0.64–5.59)
61/868 (7.0) 5/32 (15.6)
1.00 2.45 (0.91–6.59)
7/66 (10.6) 58/809 (7.2)
1.00 0.65 (0.28–1.49)
2/70 (2.9) 65/833 (7.8)
1.00 2.88 (0.69–12.01)
61/840 (7.3) 4/33 (12.1)
1.00 1.76 (0.60–5.17)
66/867 (7.6) 1/34 (2.9)
1.00 0.37 (0.05–2.73)
NOTE. CI, confidence interval; OR, odds ratio. a b
Excluding 7 patients infected with HCV genotype 1, 6 infected with genotype 2, and 17 HCV seropositive but from whom the virus could not be amplified. P ! .05.
shown); to have been treated for trypanosomiasis, schistosomiasis, or yaws; and to have received pentamidine chemoprophylaxis. No interethnic difference was seen for parenteral treatment of tuberculosis (10 participants), of leprosy (5 participants), or for transfusions (32 participants). Mbimou men were less likely to report past sexually transmitted infections. Almost all men were circumcised. Only 2 Mbimou women (1%) and 14 (8%) of other ethnicities had been excised. Risk factors for HCV infection. The prevalence of HCV antibodies was 10.5% (95 of 905 participants). Sixty-five participants were infected with genotype 4, 7 with genotype 1, and 6 with genotype 2, whereas in 17 the virus could not be amplified. Genotype 4 so predominated that it would have been impossible to identify risk factors for other genotypes, and our main analyses were restricted to correlates of genotype 4 infection, excluding those infected with genotypes 1 and 2 or of unknown genotype. The only parenteral exposure associated with HCV genotype 4 was treatment of trypanosomiasis before 1951 (Table 2). Genotype 4 infection was not associated with treatments against yaws, schistosomiasis, tuberculosis, or leprosy or with sex, ethnicity, marital or educational status, or 000 • CID 2010:51 (1 October) • Pe´pin et al
presence of scarifications (data not shown). None of the sexspecific factors (for men, circumcision, having paid for sex, past genital ulcer, and past urethral discharge; for women, excision, having “sold” sex, past genital ulcer, and past vaginal discharge) was associated with HCV genotype 4 (data not shown). No risk factor became significant after adjustment for treatment of trypanosomiasis before 1951. Risk factors for HTLV-1 infection. Of 903 participants, 67 (7.4%) were considered HTLV-1 infected; 9 patients with only bands against HTLV-2 were considered HTLV-1 negative. Table 2 displays risk factors for HTLV-1 infection, more common among participants who had received ⭓2 pentamidine injections for trypanosomiasis chemoprophylaxis. HTLV-1 infection tended to be more common among those treated for trypanosomiasis before 1951 and transfusion recipients. HTLV-1 infection was not associated with past treatment against yaws, schistosomiasis, tuberculosis, or leprosy or with sex, ethnicity, marital status or educational status, presence of scarifications, or any of the sex-specific factors (data not shown). In multivariate analysis, HTLV-1 infection was independently associated with having received ⭓2 injections of prophylactic
Figure 2. Number of new cases and risk (Indice de Contamination Nouvelle [ICN]) of human African trypanosomiasis (HAT) in Mbimou land, 1936– 1950. This measure of annual risk corresponds to the proportion of the population who developed trypanosomiasis each year among those never diagnosed previously as having HAT.
pentamidine (adjusted OR, 2.03; 95% CI, 1.01–4.06) and with having received a transfusion (adjusted OR, 2.82; 95% CI, 1.04– 7.67). None of 8 women married to a HTLV-1–infected man was herself HTLV-1 infected. In a secondary analysis that excluded the 31 participants found on Innolia to be HTLV positive but nontypable, having received ⭓2 pentamidine injections for prophylaxis of trypanosomiasis was even more strongly associated with HTLV-1 infection (adjusted OR, 3.92; 95% CI, 1.64–9.38), but transfusion no longer was. HIV infection. Only 12 participants (1.3%) were HIV infected (the oldest was aged 72 years), whereas 7 (0.8%) remained indeterminate. Given this low prevalence, no risk factor could be elicited. Predicted and observed prevalence of past trypanosomiasis. Detailed data being available for Mbimou land, historical analyses focused on Mbimous. High incidence of trypanosomiasis persisted until the late 1940s (Figure 2) [9––18]. Risk (ICN) was a staggering 45% in 1936, decreased to 7% in 1942, increased to 18%–20% in 1943–1944, and decreased again, reaching !1% in 1949. The epidemic was eventually controlled through authoritarian measures to implement case-finding surveys every other month and half-yearly intramuscular prophylactic pentamidine to the whole population [9, 10]. Demographic impacts were noteworthy: the population decreased from 8679 inhabitants in
1934 to 3389 in 1951 because of death from trypanosomiasis or its treatment, low fertility, and emigration of individuals scared by the epidemic [9–11,23]. Using ICN measures of risk and previously mentioned assumptions, we calculated the predicted cumulative prevalence of past trypanosomiasis for each birth cohort to be compared to its observed prevalence among Mbimous surveyed in 2006, 56 years after the disease was brought under control. Table 3 stratifies participants according to their age in 2006. Among those aged ⭓65 years, in each stratum the proportion who reported a diagnosis of trypanosomiasis before 1951 was much lower than predicted. This was true both for those living in Mbimou land and in Nola (data not shown). Overall, for individuals ⭓65 years, we predicted that 59.3% would report a diagnosis of trypanosomiasis before 1951; only 11.1% did so. The accuracy of our model could be verified against the 1948 census; the model predicted that 37.0% of Mbimous then had a history of trypanosomiasis, whereas according to the contemporary medical report 39.1% (1690 of 4324) reported such a history [18]. DISCUSSION Our study attempted to indirectly delineate whether parenteral transmission played a role in the emergence of HIV-1 in EquaHCV and HTLV-1 in Equatorial Africa • CID 2010:51 (1 October) • 000
Table 3. Prevalence of Past Trypanosomiasis Diagnosed before 1951 among Mbimous Persons Predicted from Historical Data and Observed during the Survey Observed prevalence of trypanosomiasis diagnosed before 1951, % (proportion)b
Age in 2006, years
Predicted prevalence of trypanosomiasis a diagnosed before 1951, %
0–3 4–8
56–59 60–64
0.4 6.9
2.6 (3/114) 4.5 (5/111)
9–13 14–18
65–69 70–74
32.5 68.3
5.3 (4/76) 4.8 (3/63)
19–23 ⭓24
75–79 ⭓80
88.4 90.4
11.1 (7/63) 25.0 (15/60)
Age in 1950, years
a b
Among those expected to have survived up to 2006, based on historical data. Among those surveyed in 2006.
torial Africa several decades ago. As proxies for parenteral transmission of HIV-1, we used 2 other blood-borne viruses, HCV and HTLV-1, both compatible with a prolonged survival and more prevalent in Equatorial Africa than elsewhere, for reasons hitherto unclear. The efficacy of parenteral transmission of HCV is only twice that of HIV-1; that of HTLV-1 is unknown [24]. We selected as the study site the only area where extremely high incidence of trypanosomiasis persisted well into the 1940s, so that some patients could still be alive. When Europeans colonized the heartland of Equatorial Africa, population displacements provoked epidemics of trypanosomiasis. In 1917–1919, of 89,743 individuals screened in Oubangui-Chari (now Central African Republic), 5347 were diagnosed as having trypanosomiasis and treated (mostly with subcutaneous drugs) using only 6 syringes [20]. In an area east of Yaounde´ (Cameroon), of 194,889 inhabitants, 42% had trypanosomiasis diagnosed and were treated in 1920–1928 with subcutaneous and/or intravenous injections [19]. French colonial physicians belonged to the military: decisions about therapeutic regimens were transmitted down the chain of command. From 1928 onward, trypanosomiasis patients in Afrique E´quatoriale Franc¸aise were to receive 12 weekly injections of subcutaneous or intravenous orsanine or, if cerebrospinal fluid was altered, 12 weekly injections of intravenous tryparsamide, to be repeated annually for 3 years [25]. In the Nola district, treatment was centralized in the Bilolo hypnoserie, where 600 patients could be treated at any one time [9, 18]. This focus was known for a high frequency of resistance to arsenicals. Until melarsoprol was introduced (1953), many patients received combination therapies [9, 10, 18]. Transmission of blood-borne viruses might have been compounded by the use, for relapsing cases, of he´te´rohe´mothe´rapie, the intramuscular administration of whole blood (10 mL) from convalescent patients; in 1945, 1097 such injections were administered [13–17]. Pentamidine was used as chemoprophylaxis of sleeping sickness from 1946 until the late 1950s. Hoping to eradicate the disease, intramuscular injections were given to all inhabitants 000 • CID 2010:51 (1 October) • Pe´pin et al
of endemic foci (except pregnant women and infants), every 6 months, for several years. Approximately 3.7 million injections were given in the Belgian Congo, 2.8 million in Afrique E´quatoriale Franc¸aise and 835,000 in Cameroon [8]. In Mbimou land, pentamidinization started in 1947 and continued until 1953: some received up to a dozen injections [9, 10, 12]. It was abandoned when countries became independent and resources were allocated to more pressing needs. The injections were exquisitely painful, and outbreaks of gas gangrene, including one near Nola, made the practice unpopular. Pentamidine was available in bottles of 25 g, enough for 100 injections. A contemporary description gives a flavor of the potential for transmission of blood-borne pathogens: “principles of mass production and time and motion study should be invoked to ensure the maximum speed and efficiency in getting through, say, 250 injections in a morning. The man actually giving the injection should merely have to turn half around in order to hand over his used syringe and take a freshly charged one. As he turns back again, a freshly iodined buttock, and the appropriate dose, should present themselves before him” [26, p 723– 724]. HTLV-1 seems to have been transmitted during prophylactic injections of pentamidine. HTLV-1 subtype B predominates in Equatorial Africa, sharing 198% homology with the P. troglodytes simian T cell lymphotropic virus–1 [27]. HTLV-1 infects CD4 cells and is an interesting proxy for HIV-1. Equatorial Africa has high HTLV-1 prevalences, with a north-south gradient: 0%–2% in Chad, northern Central African Republic, and Cameroon to 5%–10% in forested areas of Gabon, Equatorial Guinea, and southern Cameroon [28]. Age gradients suggest a cohort effect [28, 29]. Apart from breast-feeding, modes of transmission remain unclear. Among Kinshasa prostitutes, HTLV-1 infection was not more prevalent than in other women [30]. Patients with sickle cell anemia and leprosy have a high prevalence, suggesting iatrogenic transmission. In the Mbandaka leprosarium (Figure 1), 37% of patients were HTLV-1 infected in 1969; throughout 22 years, the mortality ratio as-
sociated with HTLV-1 was only 1.4 [31]. Consequently, we could link HTLV-1 infections documented in 2006 to at least 1 exposure that occurred ⭓53 years earlier. After Egypt, Equatorial Africa has the highest HCV prevalence in the world [32]. Our data suggest that HCV genotype 4 may have been transmitted during trypanosomiasis treatment in the 1930s and 1940s. Molecular clock analyses, based on our samples, revealed exponential spread from 1935 through 1965 [21]. Occasions for HCV transmission may have varied among areas, depending on the local epidemiology of tropical diseases. In Cameroon, where the HCV prevalence among elderly individuals is ⭓50%, intravenous antimalarial agents have been incriminated [33]. The main limitation is that our findings (HCV transmission during treatment of trypanosomiasis and HTLV-1 transmission during its chemoprophylaxis) are based on small numbers of participants. This was expected given the extremely long interval (150 years) between exposures and measurement of outcomes. During this half-century, many residents of Mbimou land or Nola died for all kinds of reasons, biasing downward our measures of association. Furthermore, if within this cohort HIV-1 was iatrogenically transmitted, these individuals would have long disappeared. Thus, we measured only a fraction of the transmission of blood-borne pathogens that may have occurred during the treatment and chemoprophylaxis of trypanosomiasis. For some exposures, recall biases are likely given this long interval. However, the distribution of diseases outlined in Table 1 is congruent with contemporary medical reports [13–17]. Among Mbimous, there was a substantial difference between predicted and observed prevalence of past trypanosomiasis. Trypanosomiasis was an important event in one’s life, even as a child: it seems hardly possible that a recall bias could have been of such a magnitude. Measures of risk could have been overestimated if the denominator was underestimated, but medical censuses were considered more reliable than the administrative ones. Differential migration of cases outside the study area seems unlikely. This finding may thus reflect excess mortality among individuals treated for trypanosomiasis in the 1930s and 1940s, far beyond what could be attributed to the disease or its treatment. Our model assumed that 25% of patients died of trypanosomiasis or its treatment; this was certainly not an underestimate [18]. Hepatitis B would be an unlikely culprit: this virus is universal in Central African Republic and most infections resolve. The excess mortality associated with HCV is modest in nonaddicts, and HTLV-1– associated mortality is marginal [31, 34]. By elimination, it is plausible that SIVcpz was introduced into these cohorts and amplified exponentially by parenteral transmission among patients, causing their premature mortality a decade or so later. Serial passage of SIVcpz between trypanosomiasis patients or
pentamidine recipients could have generated a pool of infected individuals large enough for the virus to disseminate sexually along trading routes, the tributaries of the Congo river, reaching Kinshasa/Brazzaville not later than 1959–1960 [1]. This may have occurred in other trypanosomiasis foci in southern Cameroon or Afrique E´quatoriale Franc¸aise, where, even if less remarkable than in Nola, incidence was high enough to prompt pentamidinization [12]. Other therapeutic regimens may have facilitated dissemination of the virus in specific locations: intravenous antimalarials, arsenicals against syphilis or yaws, streptomycin against tuberculosis, and parenteral treatments of leprosy [8]. In conclusion, our data suggest that iatrogenic transmission of HCV genotype 4 and HTLV-1 occurred during mass interventions for the control of sleeping sickness in the first half of the 20th century. These interventions, and perhaps others for the control of tropical diseases, might have jump-started the HIV-1 epidemic in regions of Equatorial Africa endemic for SIVcpz,, from a handful to a few hundred infected individuals, a threshold beyond which sexual transmission could prosper, facilitated by urbanization and ensuing changes in behavior. Unfortunately, the mortality associated with HIV-1 infection precludes epidemiologic testing of this hypothesis. Acknowledgments Christian Audet designed the figures. We are grateful to Me´lissa Beaudet, Nathalie Bastien, and Danielle Dumulong for performing some of the serologic tests; Dieudonne´ Guezza, Jean-Charles Kounda Boungbi, Samuel Mongai, and Andre´ Sandoka for data collection; Aline Pueyo, Institut de Me´decine Tropicale du Service de Sante´ des Arme´es, Marseilles, for providing access to some documents; and all study participants for their kind collaboration. Financial support. Associated Medical Services/Canadian Institutes for Health Research and Fonds de Recherche en Sante´ du Que´bec. Potential conflicts of interest. All authors: no conflicts.
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