The Origins of AIDS (27 page)

Meanwhile, at the receiving end of the plasma equation, technological advances contributed to the dissemination of the virus. Haemophiliacs have a genetic deficiency in a coagulation factor (usually, factor VIII) which, in the absence of treatment, leads to their early death, generally from bleeding inside the brain. Blood transfusions and, in the 1950s, administration of plasma were not very effective because they contained little of the missing coagulation factor. Starting in the mid-1960s, ‘cryoprecipitates’ were used: the freezing and thawing of plasma led to some concentration of factor VIII, which was recuperated after such cycles. One treatment required cryoprecipitates obtained from three to six donors. Unfortunately, the titre of factor VIII in cryoprecipitates varied substantially from lot to lot. Furthermore, they had to be stored at −40
^o
C and thawed slowly before being administered
.

These shortcomings were solved around 1972 with the marketing of factor VIII concentrates, in which the quantity of the coagulation factor was high and fixed, and the product conserved as a dry powder, a
revolution in the treatment of haemophilia. From the mid-1970s, concentrates were even used preventively and administered regularly (forty to sixty times per year) to some high-risk haemophiliacs. However, the production of factor VIII concentrates required the pooling of plasma obtained from between 2,000 and 25,000 donors, implying that the recipients would be potentially exposed during each treatment to any infectious agent present in the plasma of thousands of individuals. A given lot would be administered to dozens of recipients. Even if much diluted through this pooling process, HIV which had been present in a single donor would be found in many of the vials prepared: in
Scotland, eighteen of thirty-two haemophiliacs who had been exposed to a single HIV-infected batch developed HIV infection
.
^43
–
46

It is likely that some of the plasma sent to the US by
Hemo-Caribbean was used to produce
albumin and
immunoglobulins (products whose manufacturing processes inactivated HIV, in contrast with coagulation factors), and the
Port-au-Prince company was shut down before factor VIII concentrates became widely used. It could have been worse.
¹⁷

When Hemo-Caribbean was forced out of business, plasma traders used other sources, one of which was
Managua,
Nicaragua, where one centre was owned by the dictator Anastasio Somoza and a Cuban entrepreneur. For a few years, the
Compania Centroamericana de Plasmaferesis was the largest plasma collection centre in the world. With two dozen doctors and a few hundred employees, it could process plasma from up to 1,000 donors per day. Somoza ordered the 1978 killing of the editor of a local newspaper,
Pedro Joaquin Chamorro, also a prominent opponent of Somoza’s rule, who had dared to criticise this blood trade. At the latter’s funeral, a riotous crowd burned down the plasma centre and that was the beginning of the end for Somoza. Chamorro’s widow later became president of the country
.
^22
,
23

In the 1970s, about 20% of the plasma produced in the US came from the Third World. A considerable proportion of commercial plasma used in North America and Western Europe was bought and sold by brokers. The largest plasma brokers were a
Montreal company called Continental Pharma Cryosan, and Brandenberger AG in Zurich. During the heyday of the plasma trade in the early 1970s, plasma was bought in at least twenty-five developing countries to be exported to pharmaceutical companies in the industrialised world. Apart from those already mentioned, the list included
Belize,
Brazil,
Colombia,
Costa Rica, the
Dominican Republic,
El Salvador,
Guatemala,
Puerto Rico,
Taiwan,
Thailand and even
African countries such as
Lesotho. In Latin America, blood became known as
el oro rojo
, the red gold.
⁴⁷

A large and respected French company had another interesting idea: extracting plasma from placentas, which came from
France but were also imported from other countries. All of this slowed down after 1975 when the
WHO’s annual assembly of health ministers unanimously adopted a resolution condemning such practices and urging member states to enact legislation to protect blood donors and blood recipients. Plasma trafficking became illegal in some countries, and the traders who continued risked fines and/or jail terms. These did not deter everybody, given the anticipated hefty profits. For instance, plasma was exported from
South Africa to
Belgium,
Austria,
China and
India well into the 1980s and 1990s.
^47
–
49

Such wheeling and dealing necessarily meant that the ethical standards of non-profit corporations were not respected. Following investigations by the
Royal Canadian Mounted Police, Continental Pharma Cryosan pleaded guilty in 1980 to charges that it had mislabelled the source of some plasma that it traded. An internal draft memo written in 1977 by a Health Canada official had commented, concerning the same company: ‘It is evident we are dealing with more than technical violations, but rather a calculated and deliberate business designed to take advantage of legal loopholes providing possibly hazardous products on the world market.’ This was referring to the fact that Canadian regulations did not apply to blood products that were to be re-exported from the country.
The Krever Commission inquiry into Canada’s blood supply established that Continental Pharma Cryosan had bought plasma from American prisoners in 1983 and resold it to a number of clients, including
Connaught Laboratories in Toronto, the sole Canada-based plasma fractionator.
Such practices were discouraged by the US Food and Drug Administration (FDA) because prisoners were already thought to be at greater risk of being infected with the putative aetiological agent of AIDS.
In June 1983,
Health Management Associates, a company buying plasma from prisoners in Arkansas, informed Continental Pharma Cryosan that thirty-eight units of plasma had been obtained from four prisoners who had previously tested positive for HBV antigen and should have been excluded, even if their more recent test was negative.
^50
,
51

As a measure of the ongoing international circulation of plasma two years into the AIDS crisis, four of these thirty-eight units had been sold
by Continental Pharma Cryosan to Connaught, while the other thirty-four had been vended to companies in Switzerland, Spain,
Japan and
Italy. Continental Pharma Cryosan did not inform Connaught of the problem. Eventually Health Management Associates recalled the thirty-eight units and informed the FDA, which then informed Health Canada, which in turn informed Connaught. Up to that time, Connaught apparently did not know that it was processing plasma obtained from prisoners. Because the process required the pooling of a large number of donations, small quantities of plasma from the four HBV-infected donors was now present in 2,409 vials of coagulation factor
concentrates, only 417 of which could be retrieved. The others had already been administered
.

Then, a fifth Arkansas donor was found to have been HBV-positive in the past. This prisoner had sold plasma thirty-four times over ten months
. Only twenty-seven out of 1,968 vials that included plasma from this man could be recalled
. That was too much for the Canadian Red Cross, the national distributor of blood products, which cancelled its contract with Connaught. The Krever Commission also revealed that Connaught had earlier processed plasma from inmates in four
Louisiana prisons. There, prison plasma collection centres were exploited by Community Plasma Center Inc., which sold the plasma to Health Management Associates, which resold it to Continental Pharma Cryosan, which then resold it to Connaught between November 1982 and January 1983
.
⁵¹

A class action lawsuit initiated by
HCV-infected haemophiliacs against the Canadian Red Cross, Connaught Laboratories and Continental Pharma Cryosan was eventually settled as part of a larger arrangement that included several other parties, after the defendants collectively agreed to pay a multi-million dollar compensation to the plaintiffs, most of which had been raised by the Canadian Red Cross selling some of its assets
.

We will never know for sure how often and from what sources HIV entered this transcontinental network. However, the point is that, throughout the 1970s and the early 1980s, any virus present in plasma samples could have travelled thousands of miles in all directions within days or weeks of being collected, and ended up in the veins of many recipients
.

Here we will review how, from its central African crucible, HIV managed to disseminate throughout Africa, at the same time as it did so across the Atlantic. But first we need to review two epidemiological terms. As explained in
Chapter 1
, ‘
incidence’ is a measure of new cases of HIV that occur among previously uninfected subjects over a period of time. The same individuals have to be tested repeatedly: this is time-consuming, expensive and rarely used. ‘
Prevalence’ is the proportion of individuals who have HIV at some point in time, a snapshot that indicates the current distribution. As the median interval between HIV infection and death in Africa is about ten years, measures of HIV prevalence reflect an accumulation of individuals infected from as little as a few weeks ago to more than ten years earlier. Over time, prevalence in a population increases if the number of new infections since the previous survey was greater than the number of individuals who died from HIV or other causes. Prevalence decreases when the reverse occurs, i.e. the number of deaths is higher than the number of new infections
.

Information about the dynamics of HIV-1 in the 1960s–1970s can be inferred by analyses of archival samples, as well as by surveys carried out in the first few years after the identification of HIV-1. Among samples from the adult population, not a single case of HIV-1 was found in Gabon or among the
Congo-Brazzaville
pygmies. It is surprising, however, that two cases of
HIV-2 infection were found in 1967 in samples from Gabon, a country not endemic for this retrovirus, and one wonders what the results would be if these sera were tested with modern methods. No HIV-infected person was identified among 250 individuals at the
Yonda leprosarium of the DRC, whose blood had been stored since 1969.
The HIV-1 positive samples from that early period came from Kinshasa where 0.25% of women attending a well-baby clinic in 1970 were HIV-1-infected, and from the village of
Yambuku where prevalence was 0.8% in 1976.
By 1980, among a similar group of Kinshasa mothers, 3.0% were HIV-1-infected
.
^1
–
4

Thus in countries inhabited by the
P.t. troglodytes
source of HIV-1, prevalence probably remained minimal for most of the fifty years that followed
cross-species transmission around 1921, too low to be detected in more than a handful of retrospectively diagnosed cases but high enough for the virus to persist. This is not contradictory. In Western Europe and North America, HIV-1 prevalence in the general adult population has remained around 0.1–0.2% for the last twenty-five years, and it is the much more effective transmission within small subgroups (gay men,
injection drug users) which allows HIV-1 not to disappear. In central Africa between 1921 and 1970, HIV-1 prevalence was probably of the same order of magnitude for the overall adult populations but higher among the core groups of urban free women and their clients and among patients attending specific health institutions where iatrogenic transmission occurred. These sanctuaries allowed HIV-1 to persist, and eventually to disseminate when conditions were ripe.

In 1980–4, not a single case was found among adults from the
Sangha region of
Congo-Brazzaville or the
Campo area of Cameroon. At the same time, in
Lambaréné (the region of Gabon of Albert Schweitzer fame), three cases of HIV-1 infection were documented among 1,407 patients attending the hospital and one more among 1,313 adults living there. In 1984–5, in
Franceville and other rural regions of Gabon, only three out of 1,648 villagers were HIV-1 infected. We can be pretty sure that Gabon, despite its large population of
P.t. troglodytes
, is not the site where HIV-1 emerged: prevalence thirty years ago was too low, especially considering that sampling patients attending health institutions overestimated the true prevalence.
^3
–
5

In 1985–6, among samples of 300–500 individuals representative of the adult (fifteen to forty-four years) male and female population, HIV-1 prevalence remained minimal in rural Gabon,
Equatorial Guinea,
Yaoundé,
Douala and smaller cities of Cameroon (all around 0.3%) as well as in
Port-Gentil (0.5%).
However, prevalence was 1.4% in
Franceville, 1.8% in
Libreville, 4.4% in
Bangui and 4.6% in
Brazzaville. In the same cities, HIV-1 prevalence among pregnant women was either identical to the former measures (Brazzaville, Bangui, rural Gabon), a bit higher (Yaoundé: 1.3%) or a bit lower
(Libreville: 0.5%)
. This modest prevalence in Douala and Yaoundé suggests that these urban centres were
not involved in the early dissemination of the virus
. In
Kinshasa, among pregnant women, hospital employees and blood donors tested in 1984–5, prevalence varied between 5 and 8%, figures which were similar to those documented in Brazzaville, reflecting the strong links between the twin cities
.
^4
,
6

At the time, Kigali, the capital of Rwanda, had the highest HIV-1 prevalence in the world: between 15 and 20% among blood donors, factory employees and hospital workers, 50% among STD patients and 80% or more among prostitutes.
Bujumbura, the capital of Burundi, was not far behind, with 16% of pregnant women infected.
The gender imbalance that we described in Léopoldville as the main driver of prostitution also existed in Kigali. In 1972, out of the 60,000 inhabitants of this small town, 2,000 were free women selling sexual services: the city was basically a large brothel. By the early 1980s, the male/female ratio among adults aged twenty to thirty-nine years was 1.57 in Kigali, 1.50 in
Nairobi and 1.39 in Bujumbura compared to 0.98 in
Kinshasa. In Kigali, the excess of males was driven largely by local customs rather than by the former coloniser’s policies (which is why it persisted long after freedom from colonial rule). Traditionally in Rwanda, men marry at a much older age than women, and the age group corresponding to the unmarried cohort was also the one that moved to the capital in search of a better life. Since marriage or other types of romantic consortship were impossible, sex was purchased and the supply followed the demand
. Of the 10,000 inhabitants of Butare, the second largest city of Rwanda and the site of its national university, 293 were prostitutes, 80% of whom were already HIV-1-infected in 1983–4, as were 28% of men presenting with an STD
. The lack of male
circumcision further fuelled transmission
.
^4
,
7
–
11

Nobody kept ancient collections of sera which could have been tested to document when the virus arrived. However, in Rwanda, 85% of isolates belong to subtype A while, in Burundi, 81% belong to subtype C. This marginal diversity implies that the virus was certainly introduced in Kigali and Bujumbura a long time after Léopoldville
. The explosive epidemics in these two small adjacent countries resulted from the introduction from the Congo basin of two
different founder HIV-1 subtypes, with very successful subsequent dissemination locally. The dramatic prevalences reflected a high incidence in the previous years rather than a slow spread
.
^12
–
14

In the DRC, by 1986 the virus was widespread. For instance, among sex workers in small towns of the
Equateur province, prevalence varied
between 9%
and 13%. In the remote
Nioki hospital where I had worked, 2% of blood donors and 3% of trypanosomiasis patients were HIV-1-infected, and having travelled to Kinshasa was the strongest risk factor. In Kimpese, a Protestant mission 225 kilometres west of Kinshasa, 4% of pregnant women were HIV-1-infected, with considerable diversity and a predominance of subtype A, much like in the capital.
Such diversity with a predominance of subtype A was also noted in
Mbuji-Mayi, Kisangani and
Bwamanda while at the extreme south-east of the country, in
Lubumbashi near the
Zambian border, 1,400 kilometres from Kinshasa, subtype C accounted for 51% of isolates, suggesting a more recent introduction of the virus. Because of the decay of the roads, travel between Lubumbashi and Kinshasa had to be by plane, much more expensive than the river boat to Kisangani.
^15
–
19

Surveys of sex workers during the late 1980s revealed high prevalences in
Kinshasa (27–40%), Brazzaville (34%) and
Pointe-Noire (46%), an intermediate prevalence in
Bangui (12–21%), but much lower figures in
Douala (6.5%) and
Yaoundé (7.5%). As prostitutes represent a sentinel population in which HIV (along with other sexually transmitted pathogens) is amplified at the outset of an epidemic, these data suggest that the virus was introduced into this core group earlier in Kinshasa, Brazzaville and Pointe-Noire than in the major cities of Cameroon
.
Once more, Cameroon can be ruled out as the site of the early spread of the virus, even if ‘patient zero’ might very well have been Cameroonian
.
⁴

From its DRC bridgehead, the virus slowly managed to propagate into other regions of the continent. Using molecular methods, it was estimated that HIV-1 reached parts of East Africa in the 1970s, where subtype A was probably introduced from the Zairean city of Kisangani
. By the mid-1980s, the virus had infected 1–2% of pregnant women in
Nairobi and
Dar es Salaam, 8% in
Lusaka and 11% in
Kampala.
^4
,
20

Meanwhile, HIV-1 subtype C spread to southern Africa via
Lubumbashi in the
Katanga province of the DRC, through adjacent Zambia
.
In
Zimbabwe, HIV-1 group C was introduced in the early 1970s; after a short period of slow growth, the number of infected individuals expanded rapidly during 1979–81, coinciding with the return of tens of thousands of refugees and freedom fighters at the end of the liberation struggle. The best documentation of the emergence of HIV-1 comes from the Karonga district of northern
Malawi, where a large collection of blood samples had been collected for long-term studies of leprosy. Of about 1,000 adults bled in
1981, none was HIV-infected. The following year, 4 of 4,354 specimens (0.1%) were HIV-reactive. By 1988, 1.1% of adults were HIV-infected. Testing of these archived samples showed that initially (1982–4) HIV-1 subtypes A, C and D were introduced, with subsequent explosive growth of subtype C but only limited spread of the others, reinforcing the idea that subtype C might be more transmissible.
Later, history would repeat itself: the gender imbalance in the mining towns of South Africa led to rapid HIV transmission between prostitutes and miners, who brought it back, during their annual leaves, to their home areas in
South Africa,
Mozambique,
Lesotho and
Swaziland. This epidemic would eventually dwarf all others.
^20
–
23

At the other end of the continent, the economic metropolis of Abidjan was the hub around which HIV-1 disseminated in West Africa. Testing of stored samples did not show evidence of HIV-1 before 1980, while two persons were infected with
HIV-2 in 1966. The viruses then spread exponentially among sex workers, half of whom were infected by the
mid-1980s. Quickly, HIV-2 was superseded by HIV-1, whose sexual transmission is more effective, and the dominant HIV-1 strain came to be
CRF02_AG, which was rare in the DRC but relatively common in
Gabon and
Cameroon, implying a northward progression towards West Africa. Abidjan, a booming city that attracted
migrants, especially male agricultural workers from
Burkina and
Ghanaian female sex workers, was the only major city in West Africa with a gender imbalance
. Its male/female ratio among adults aged twenty to thirty-nine was 1.23 in 1983 (1.38 in 1955), compared to ratios close to 1.0 in urban Ghana
,
Senegal,
Mali and
Benin. Prostitution flourished, the best possible breeding ground for
HIV-1
.
^4
,
11
,
24

To summarise, during the 1970s and into the early 1980s, the virus disseminated silently but relentlessly throughout the African continent, at about the same time that it crossed the Atlantic to establish a foothold first in Haiti, and then in the US. At this stage, its subsequent transformation into a global epidemic became unavoidable.

As the number of infected persons had expanded considerably, there could now be multiple introductions of the virus into various other parts of the world, rather than single founder effects. The same methods that
allowed a reconstruction of the epidemic history in Africa, Haiti and the US were deployed to track down retrospectively what had occurred elsewhere. The history of the global and mainly post-1981 dissemination of HIV-1 could fill a whole book. I will present here just a brief overview of selected foci, as an illustration of the epidemiological genius of this retrovirus and of the power of currently available tools in evolutionary biology.

Starting in the early 1980s, HIV-1 group B was successfully re-exported from the US to Western Europe, through several channels. First, there were multiple introductions by European homosexuals who vacationed in
San Francisco or
New York (and a few in
Port-au-Prince), or the other way around by American gay men who had a good time in Europe. As an example, in the United Kingdom, between 1981 and 1987 there were at least six independent successful introductions of HIV-1 group B followed by exponential transmission within the gay community until the early 1990s, while several other introductions became epidemiological dead ends. Second, the exportation of unheated contaminated
plasma: HIV prevalence among
haemophiliacs of various European countries in the late 1980s paralleled the proportion of their
coagulation factors that had been imported from the US.
And third, through drug addicts, a small fraction of whom were rich enough to inject their heroin or cocaine on both sides of the Atlantic. Within these three Western European subpopulations, nearly all HIV-1 infections were initially caused by subtype B, which could only have originated from the US. The same country also re-exported HIV-1 to Canada, most of Latin America, Australia and even to the white gay community of South Africa
.
^25
–
29

Although some other subtypes were introduced at roughly the same time, it is only in the 1990s that non-B subtypes spread within Western Europe. These infections were initially documented among travellers and
migrants from endemic countries, especially sub-Saharan Africa. Eventually, in some European countries, non-B subtypes managed to get transmitted within the local population and became predominant. For instance in Greece, subtype A is now the most common subtype, having been imported from East Africa and re-exported to Albania.
^30
–
31

Meanwhile in
India, the country with currently the third highest number of HIV-infected individuals in the world (after South Africa and
Nigeria), HIV was first recognised in 1986, but certainly had been present for a few years. It spread swiftly, especially among the core
group of sex workers and their clients, but also among intravenous drug users. Subtype C represents around 95% of all Indian HIV-1 infections, and seems to have been introduced from South Africa, which is not surprising given the latter country’s large Indian population that must travel intermittently to its homeland
.
^32
–
36

Throughout south and south-east Asia, intravenous drug use played a major role in the dissemination of several subtypes of HIV-1 along heroin trafficking routes.
In Thailand, a variant of subtype B (Thai B or B’) and the
recombinant CRF01_AE were introduced simultaneously and recognised around 1985–7. The former, imported from North America or Europe, spread among IDUs while the latter, originating from Africa, disseminated via heterosexual transmission. Exponential spread among IDUs and female
prostitutes followed almost immediately, in 1988–9. Eventually CRF01_AE had much more success and became the predominant strain, even among IDUs, which allowed it to be re-exported quickly to Vietnam, while B’ reached Myanmar
.
^37
–
40

In
China, phylogenetic analyses showed that HIV-1 subtype B’ was introduced around 1985 or shortly thereafter through intravenous drug users, from the Golden Triangle region, the opium-producing area that covers the boundaries of Burma, Laos, Thailand and China. A few years later, around 1991, the same subtype reached the cohorts of paid plasma donors, among which it propagated exponentially, as described in
Chapter 12
.
^41
–
42

Beyond these main events, a large number of country-specific or risk group-specific importations of each and every subtype and recombinant have been documented across the six continents, from the remote regions of
Brazil to the former republics of the
Soviet Union. Never in human history has the global dissemination of a pathogen been studied so thoroughly. This bewildering diversification of the virus will make it even harder to develop an effective vaccine, or at least one that could be distributed globally.