Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT02439918 |
| Other study ID # |
12-054 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
N/A
|
| First received |
April 29, 2015 |
| Last updated |
May 6, 2015 |
| Start date |
June 2012 |
| Est. completion date |
August 2012 |
Study information
| Verified date |
April 2015 |
| Source |
Université de Sherbrooke |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
Canada: Health CanadaCanada: Ethics Review Committee |
| Study type |
Observational
|
Clinical Trial Summary
Kinshasa, Democratic Republic of Congo (DRC), is where human immunodeficiency virus type 1
(HIV-1) appears to have most diversified. The factors that lead to jumpstarting the HIV-1
epidemic remain unclear; mounting evidence suggests medical interventions may have
contributed. Hepatitis C virus (HCV) and human T-cell lymphotropic virus type 1 (HTLV-1) are
viruses compatible with long-term survival but with broadly similar modes of transmission as
HIV. The main objective was to assess the association of past intravenous treatment with HCV
and HTLV-1 seropositivity. The investigators hypothesized that medical interventions in the
mid-20th century may have facilitated the emergence of HIV-1 in central Africa.
To assess the association of injectable treatments with HCV and HTLV-1 infection and to
reconstruct past virus dynamics, the investigators conducted a cross-sectional study of 839
elderly long-term inhabitants of Kinshasa, with serological assays followed by amplification
and sequencing. Risk factors were assessed through logistic regression. Phylogenetic methods
were used to reconstruct the epidemic history of HCV.
Description:
1. Background
1.1 The emergence of HIV
The HIV/AIDS pandemic has so far caused about 29 million deaths, while 33 million
individuals currently live with HIV. Even if this will have no direct impact on the
future course of the epidemic, it is important to try to understand the factors that
allowed the successful emergence of HIV-1, first as a moral obligation towards the
victims, and then to draw lessons that could ultimately help mankind avoid facing
similar threats in the future.
There is now no doubt that the source of HIV-1 group M (the strain causing the
pandemic) is the Pan troglodytes troglodytes chimpanzee of central Africa. This primate
inhabits south Cameroon, Gabon, Equatorial Guinea, the Congo Republic, the south-west
of the Central African Republic (CAR), the Cabinda enclave and a small part of the
Democratic Republic of Congo (DRC) (the Mayombe area north of the river). It is thought
that the original cross-species transmission, from chimpanzee to man, occurred around
the beginning of the 20th century, probably through the manipulation of chimpanzee meat
by a hunter or a cook, so that the common ancestor of group M existed in humans around
1910-1920. It is extremely unlikely that this very first infected human lived in the
DRC, where populations of Pan troglodytes troglodytes were very small. The virus then
slowly disseminated along trading routes, eventually reaching Léopoldville and
Brazzaville no later than 1959.
It is in this large bi-national conurbation that the virus managed to flourish and
diversify, as supported by several findings:
1. The broadest genetic diversity of HIV-1 is found in Kinshasa and Brazzaville. All
HIV-1 subtypes and many recombinants have been found there. Indeed, the genetic
diversity of HIV-1 in Kinshasa in the mid-1980s, twenty-five years ago, was higher
than that currently found in any other part of the world.
2. The two most ancient isolates of HIV-1 have been located in Kinshasa, one from a
blood sample obtained in 1959 and the second from a lymph node biopsy obtained in
1960.
3. Testing of serum collections stored for years showed that among mothers bringing
their children to an under-five clinic in the Lemba district of Kinshasa, HIV
prevalence was 0.25% in 1970 and 3.0% in 1980.
4. HIV prevalence among the general adult population of Kinshasa and Brazzaville in
the mid-1980s was already between 5 and 8%, while it was far lower in Yaoundé,
Douala and Libreville, the other large cities of central Africa.
5. Several serologically proven cases of AIDS were diagnosed retrospectively among
Belgian nationals who were probably infected in the Congo in the 1960s.
The question that remains is to understand the factors that facilitated the emergence
of HIV-1 within this population in the middle of the 20th century (and not elsewhere).
For a long time, this has been attributed essentially to the urbanisation of central
Africa. The colonialists created cities in which adult men by far outnumbered women,
leading to the development of urban prostitution, so that eventually HIV-1 encountered
conditions that were propitious for its sexual spread, initially among prostitutes and
their clients, along the lines of what was later to be documented in Nairobi in the
1980s.
It is indeed very likely that prostitution ultimately played a substantial role in the
emergence of HIV-1 in Kinshasa/Brazzaville. However, for a long period of time,
prostitution in these two cities was rather of a "soft", low-risk, type: free women
(ndumbas) had 3-4 regular clients, to whom they provided not just sex but diversified
services (cooking, laundry, hair dressing, having a conversation) in exchange for
regular financial support rather than a fixed fee per intercourse. High-risk
prostitution, in which women could have sex with 3-4 different clients every day, up to
a thousand per year, appeared only circa 1960, around new venues called flamingos, bars
with rudimentary rooms nearby, in the context of the profound social and economic
changes prompted by the country's accession to independence.
For several years we have been investigating the possibility that some of the early
expansion of HIV occurred through well-intentioned medical interventions. For a long
time, because the early pharmaceutical products were poorly effective, drugs for the
treatment of tropical and other infectious diseases had to be administered
intravenously, through syringes and needles that were continuously re-utilised and
poorly sterilized, potentially allowing the transmission of blood-borne viruses. This
risk could not be appreciated at the time, initially because the existence of such
viruses was unknown, but also because acute infection with the Hepatitis C virus (HCV)
generally caused only a mild non-specific disease, while most adults had already been
infected with the Hepatitis B virus (HBV) during childhood, so that they were immune by
the time they received treatments against tropical diseases.
In Egypt, millions were infected with HCV during interventions for the control of
schistosomiasis, demonstrating that iatrogenic epidemics can indeed reach a massive
scale. In a community-based study of elderly individuals in Guinea-Bissau, we showed
that the HIV-2 epidemic might also have been largely iatrogenic, through the treatment
of African trypanosomiasis and the parenteral treatment of tuberculosis with
intramuscular streptomycin (augmented by transmission during ritual excision of the
clitoris in collective ceremonies), which contributed to the emergence of this other
simian-turned-human retrovirus 40 to 50 years ago. This latter study was possible
because HIV-2 increases mortality only 2 to 3-fold, in contrast with HIV-1 which
enhances mortality 10-fold.
We hypothesized that the same medical interventions, or others based on the mass
administration of parenteral drugs, may also have facilitated, at roughly the same
time, the emergence of HIV-1 in central Africa. Because of the high mortality
associated with HIV-1 infection, it is not possible to examine this hypothesis
directly. However, HCV and HTLV-1 (viruses compatible with a prolonged survival)
infections can be used as markers for the parenteral transmission of viruses, to
determine indirectly whether those interventions may have contributed to the emergence
of HIV-1.
We then conducted two epidemiological studies of elderly individuals (aged 55-60 years
or more) in central Africa. In Ebolowa, south Cameroon, where more than half of the
elderly are HCV-seropositive, HCV seropositivity was associated mainly with the
intravenous treatment of malaria with quinine, and also with traditional circumcision
of boys in group ceremonies. In the Nola region of southwest CAR, HCV seropositivity
was associated with the treatment of African trypanosomiasis before 1950, while HTLV-1
infection was associated with prophylactic injections of pentamidine (for the
prevention of trypanosomiasis, between 1947 and 1953) and with transfusions.
In this context, it would be relevant to try to assess whether parenteral transmission
might have played a role in the emergence of HIV-1 in Kinshasa half a century ago,
using the same two proxies, HCV and HTLV-1 infections.
1.2 Hepatitis C virus infection in central Africa
Africa is the continent with the highest HCV prevalence among its adult population. In
central Africa, 6% of adults are HCV-seropositive, compared to 2.4% in West Africa and
1.6% in eastern and southern Africa3. In many areas of central Africa, HCV prevalence
increases steeply with age, far beyond what could be expected from cumulative exposure
over time. Since there is only a modest heterosexual and vertical transmission of HCV,
it has generally been thought that most of this transmission occurred parenterally,
through injections, transfusions, immunizations and scarifications. It is now known
that the parenteral transmission of HCV is rather ineffective unless the needle had
first been inserted in the vein of a viremic individual. This was the mechanism that
drove the massive epidemic in Egypt, where a large number of individuals were infected
in the early 1960s during campaigns for the control of schistosomiasis through the
intravenous injections of antimonial drugs.
In sub-Saharan Africa, Cameroon is the country where the epidemiology of HCV has been
most thoroughly investigated. Several studies documented a high HCV prevalence, in
Yaoundé but also in many rural southern communities. A synthesis of these studies
demonstrated a cohort effect: in many areas, HCV prevalence was 40-50% amongst
individuals born before 1945, progressively decreasing to 15% for those born around
1960 and only 3-4% for those born after 1970. In several Cameroonian studies, HCV
prevalence peaked in cohorts corresponding to dates of birth around 1935. Furthermore,
molecular clock analyses revealed that the number of Cameroonians infected with HCV
started increasing exponentially around 1920 for genotype 4, and around 1940 for
genotypes 1 and 2. Since other modes of transmission are rather ineffective, this
implies a massive iatrogenic transmission of the virus in the last few decades of the
colonial era. As mentioned, in one of these high-prevalence communities, the
administration of intravenous antimalarials was the main risk factor for HCV infection.
It follows that if the HCV blood-borne virus was massively transmitted during medical
interventions in several areas inhabited by the Pan troglodytes troglodytes chimpanzee,
the same amplification might have occurred with SIVcpz which eventually became HIV-1.
In the DRC, HCV prevalence has been measured in only one study. Among Kinshasa sex
workers, HCV prevalence increased with age and reached 21% in those aged 41-55 years.
As the sexual transmission of HCV is rather ineffective, this prevalence must have
reflected to some extent the prevalence in the general adult population. Among pregnant
women aged 31-55 years, HCV prevalence was only 5.6% but one can presume that few of
them were aged more than 40 years.
2. Objectives
Our hypothesis is that the intravenous treatments of various infectious diseases with poorly
sterilized syringes and needles contributed to the transmission of HCV and HTLV-1 within the
city of Kinshasa in the middle of the 20th century, and that this could have as well
facilitated the early emergence of HIV-1.
The objectives of this study will be:
1. to determine whether HCV seropositivity (primary outcome) is associated with past
intravenous treatments against tropical and other diseases, especially during the
pre-1980 period.
2. to reconstruct the past dynamics of HCV in Kinshasa through molecular clock methods
based on the sequencing of local HCV isolates obtained from elderly individuals and
determine the period during which maximal transmission of this blood-borne virus
occurred.
3. to determine whether the same medical interventions were associated with the
transmission of HTLV-1 (secondary outcome).
4. to contribute to a better understanding of the epidemiology of HCV and HTLV-1
infections in the DRC.
