by Pepin
Within Cameroun, there was little regional variation in the incidence rates of syphilis, but dramatic variations in the incidence of yaws, sometimes measured at over 200 per 1,000 inhabitants per year in the southern regions (where almost the whole population would be treated, mostly with injectable drugs, over just a few years) compared to less than 1 per 1,000 in the north. Coincidentally, the regions hyperendemic for yaws corresponded to the habitat of P.t. troglodytes.
Several therapeutic regimens with three to fifteen injections of metallic drugs were used: (i) arsenicals: IV novarsenobenzol, IV fontarsol, IM acetylarsan, IM sulpharsenol or oral stovarsol (children only); (ii) IM bismuth salts; or (iii) IV or IM mercury salts. Combination therapies made it possible to shorten the duration of treatment. Overall, patients received fewer injections than planned as some did not return when their skin lesions improved (in contrast with trypanosomiasis for which patients felt the need to receive all intended injections to improve their chances of survival).37–40
Data on consumption of antitreponemal drugs were more exhaustive for Cameroun, where the use of parenteral arsenicals increased dramatically, up to 688,750 vials in 1952 (Figure 12), in parallel with a rising incidence and better funding after the war. Overall, 51% of parenteral arsenicals used against yaws were administered IV. For bismuth salts, Figure 12 shows the numbers of vials. However, most of the bismuth came as bulk powder, which was then diluted locally with water. For 1952–4, it can be calculated that some 500,000 additional injections of bismuth were made each year. In AEF-3, use of parenteral arsenicals doubled to 394,189 vials in 1949; there is little information about bismuth. Mercury salts, cheaper but much more toxic, were abandoned in 1951.
When penicillin became available, older drugs were not abandoned immediately because the supply of the revolutionary drug was limited (and one can imagine that African colonies were not at the top of the list). In 1957, of 91,032 syphilis cases in Cameroun, 6% were treated with IM penicillin alone; others received metallic drugs alone (72%) or in combination with penicillin (23%). For yaws (105,513 cases) corresponding proportions were 43%, 46% and 11%.
It is remarkable that such a high incidence of yaws persisted despite millions of injections of metallic drugs, decreasing only after the introduction of penicillin, which was more effective, less toxic and easier to administer. The development of a depot form of penicillin, slowly absorbed from the muscle, made it possible to treat with a single IM injection the patients, their asymptomatic family contacts and, in some communities, all children. This eventually interrupted the chain of transmission but the disease was never eradicated. When incidence of yaws dropped to a low level, control programmes were discontinued, as this intervention now seemed far too costly compared to its limited health impacts.
New cases of yaws and syphilis and consumption of antitreponemal drugs in Cameroun Français and AEF-3.
Adapted from Pepin.10
From segregation to cure
Leprosy is a disease of skin and nerves caused by Mycobacterium leprae, a bacterium which reproduces extremely slowly (one division every twelve days, instead of every half-hour for many other bacteria), hence its sluggish progression. Apart from the all too evident disfiguring lesions of the face (and elsewhere), known since biblical times, leprosy alters sensory perception, which in turn leads to auto-amputation of the extremities. For a long time, many leprosy patients did not receive any pharmacological treatment and were segregated into leprosaria, euphemistically called ‘agricultural colonies’ in French Africa.
Figure 13 summarises the numbers of leprosy patients who did receive treatment. They were far fewer than cases of yaws or syphilis, but would ultimately receive the highest number of injections. Treatments were administered over several years, so these figures are a combination of new incident cases and prevalent cases diagnosed in the previous years. In Cameroun, from the late 1930s, a serious therapeutic effort was made. In AEF-3, which had fewer human and financial resources, the policy was not to bother with leprosy until modern therapeutic agents were introduced in the early 1950s. The extraordinary number of patients then treated included the cases that had been accumulating for decades because the disease was not lethal.
Initially, extracts of chaulmoogra, an Indian medicinal plant, were the main agents, given mostly IM (two to three times a week for the first year, then weekly for several years) but also orally, rectally, IV or directly in the lesions. Chaulmoogra was provided as bulk oil locally diluted or as vials. From the early 1930s to the late 1940s, following enthusiastic reports by a renowned Saigon dermatologist, many lepers in Cameroun received IV methylene blue (a dye, resulting in greenish urine) concomitantly with IM chaulmoogra. The intended regimen of thirty to sixty IV injections over one year was often stopped prematurely due to adverse effects. Another medicinal product, aqueous Caloncoba, was given IV as an adjuvant to chaulmoogra. In 1939, 20% of Cameroonian lepers received chaulmoogra monotherapy, 24% Caloncoba monotherapy, 13% methylene blue monotherapy while others received various combinations of these. This wide variety of regimens indicated that none had a clear-cut beneficial effect. Caloncoba and methylene blue progressively lost favour.38–39
A new class of antimicrobial drugs, the sulphones, was introduced in the 1950s and proved dramatically superior. At last there was an effective treatment. Non-compliant patients received a depot sulphone solution, administered fortnightly by visiting nurses to patients queuing by the side of the road, while those thought to be more reliable were given an oral sulphone which they took every day at home. By 1957, all Cameroonian lepers received sulphones, 80% orally and 20% IM. In AEF-3, the proportion treated with IM sulphones varied from 15% in Oubangui-Chari to 60% in Moyen-Congo. These treatments were continued for a few years in patients with less severe leprosy and longer in cases of lepromatous leprosy where the bacterial load in infected tissues is higher.41
Quinimax
The other extremely common tropical disease for which injectable drugs were used on a large scale was malaria. Malaria can be caused by five different species of the Plasmodium parasites. Plasmodium falciparum is the most important by far, the one that kills. It causes fever with other non-specific symptoms such as muscle aches. In the severe form, the parasites destroy a large number of red blood cells (necessitating a transfusion), or lead to the occlusion of small blood vessels within the brain (the patient becomes comatose). In highly endemic areas of Africa, children develop some immunity against the parasite so that the severe forms are rarely seen above five years of age.
Cases of leprosy under treatment, and new cases of tuberculosis diagnosed in Cameroun Français and AEF-3.
Adapted from Pepin.10
This disease received little attention in the annual reports of the colonial health systems because it was not a specific target of disease control interventions. Malaria was so common that its control was seen as being beyond the reach of even the most enthusiastic health planners. Counting cases was pointless in countries where half of the children carried a small number of malaria parasites in their blood year round. Furthermore, malaria was fatal almost exclusively among children, and the authorities were interested mainly in short-term investments in the health of adults who paid taxes, produced cash crops and could be conscripted into the colonial army.
Thus the treatment of malaria was left to the discretion of each hospital and health centre, and no statistics were tabulated. It is hard to estimate the proportion of cases treated parenterally, but various preparations of quinine were available. In francophone Africa, for a long time the most popular product was called Quinimax. Parenteral quinine was generally administered IV rather than IM because the latter route caused abscesses or even gangrene at the injection site. Quinine tablets were available, and the injectable forms were given mostly to patients when a rapid effect was deemed necessary (cerebral malaria, severe anaemia), or to those presenting with nausea or vomiting who would not tolerate oral administration. Injections became very popular among t
he Africans, who thought this route had to be more powerful than any oral medication, so that in practice the indications for the parenteral treatment of malaria were broader than those mentioned in the textbooks. Another antimalarial drug, quinacrine, could also be administered SC, IM or IV. Its use increased during WWII, when allied countries were cut off from their Asian sources of quinine. Chloroquine, which first appeared after the war, was almost always given orally.37–39
And the rest
In the 1930s and 1940s, only 1,000 cases of schistosomiasis were reported annually in Cameroun, and around 2,000 in AEF-3. Most patients were left untreated as the adverse effects of IM antimonials or IV emetine seemed worse than the symptoms of the infection. Clearly, the control of schistosomiasis did not play in central Africa the same role as in Egypt in the dissemination of blood-borne viruses.42
No parenteral drug was used against filariasis, another group of tropical diseases. Most cases corresponded to Loa loa or Mansonella perstans found incidentally creeping in the blood during examinations for malaria or trypanosomiasis. These infections brought about little symptoms and were left untreated. River blindness was uncommon in central Africa, in contrast with its disastrous impact in West Africa. The only short-lived attempt for its mass treatment with IV suramin took place in the Mayo Kebbi district of Tchad, which is outside our region of interest. This strategy was quickly abandoned because of the severe adverse effects induced by the destruction of the parasite.
Tuberculosis was remarkably uncommon until 1950, with fewer than 500 cases annually in Cameroun and less than 1,000 in AEF-3 (Figure 13). No treatment was offered and there was no attempt to segregate patients in sanatoria. Later, incidence increased dramatically, coinciding with the introduction of chemotherapy. Most patients received IM streptomycin daily for the first month, then two to three times per week for eighteen to twenty-four months, along with oral drugs. In Cameroun, annual streptomycin consumption increased from 100 (1949) to 511,941 grams (1959). The huge rise in incidence is troubling, and one wonders whether this may to some extent have reflected the early emergence of HIV-1, which substantially enhances the risk of developing tuberculosis. However, the introduction of effective treatments may have increased the number of patients seeking a diagnosis, the supply of diagnostic tests or the aggressiveness of case-finding activities, as will be reviewed in the next chapter for the Belgian Congo.43
Vaccines administered on a large scale were those against smallpox (since the early 1920s) and yellow fever (mid-1940s). The latter was a ‘scratch vaccine’ administered ID, simultaneously with the former. The policy was to re-immunise everyone every four to six years. Year-to-year variations (Figure 14) depended on vaccine availability, perceived threats and opportunities for immunisation by mobile teams. Other vaccines of unproven efficacy were given selectively and are unlikely to have played a part in the spread of blood-borne viruses.44
An accident of history
Spain owned a tiny colony in central Africa, Guinea Espanola (now Guinea Ecuatorial), which is also inhabited by the P.t. troglodytes. It consisted of a continental part, Rio Muni, squeezed between Gabon and Cameroun, and the Atlantic islands of Fernando Poo (now Bioko) and Annabon (the islands were part of a deal between Spain and Portugal, exchanged for the Sacramento colony in South America in the late eighteenth century). Reports of the health system suggest that the epidemiological situation of this small population was similar to that of Gabon and Cameroun, as were the health interventions. During the 1940s and 1950s, incidence rates of yaws varied between 37 and 50 per 1,000, syphilis between 3 and 4 per 1,000, and trypanosomiasis between 0.3 and 2.1 per 1,000. Pentamidinisation was used in some areas. It is thus possible that blood-borne viruses were transmitted in Guinea Espanola as well.45–48
From tropical diseases to blood-borne viruses
So the opportunities for the parenteral transmission of viruses throughout central Africa were numerous. Now we will try to understand how more than 40% of the elderly population of southern Cameroon got infected with HCV, as a model for the putative parenteral transmission of HIV-1. Given that HCV is transmitted more efficiently through IV rather than other types of injections, for any given patient the highest risk must have been for sleeping sickness cases treated with IV tryparsamide (around thirty-six injections) or leprosy patients given IV methylene blue or Caloncoba plus IM chaulmoogra over a period of years, followed by patients who received just a few IV injections, for instance to treat malaria, then those who received the biannual pentamidine IM injections and finally, at the other end of the spectrum, individuals given only intradermal immunisations every five years.49
Figure 14 Number of individuals vaccinated against smallpox and yellow fever in Cameroun Français and AEF-3.
Adapted from Pepin.10
Indeed, in Africa, Brazil and Asia, leprosy patients treated in the distant past are more likely than others to be infected not just with HCV but also with HBV and the HTLV-1 retrovirus. However, the proportion of Cameroonians ever treated for trypanosomiasis or leprosy was lower than the 40–50% who became HCV-infected in some areas, implying that other interventions must have played a role as well.50–54
In Cameroon, populations with a high HCV prevalence live in Yaoundé or communities in the southern rain forest (Figure 9 and Map 5). I initially believed that the HCV epidemic could have been driven by campaigns against yaws, for several reasons. First, the sheer numbers: from the mid-1930s till the late 1950s, in some regions, the whole population developed yaws within a few years and received antitreponemal drugs. Second, the age distribution: yaws was more common among children who had the opportunity to survive until the mid-1990s when HCV surveys were carried out. Third, the rise in incidence of yaws in Cameroun after 1935 corresponds chronologically to what can be inferred to be the period of highest HCV transmission. Fourth, the geographic distribution of HCV coincides with that of yaws, whose incidence was much higher in coastal and forested regions than in northern savannahs.10
The same north–south gradient in yaws incidence was observed in the AEF, now mirrored by a higher HCV prevalence in southern areas. In these countries, HCV prevalence is three to six times lower in Pygmies than Bantus, perhaps reflecting less intensive uptake of medical interventions among the former. There is also a north–south gradient in HTLV-1 prevalence, suggesting that this retrovirus may have been transmitted iatrogenically during the same interventions.7,55–58
But there was another common tropical disease with a marked north–south gradient in incidence: malaria. While malaria occurs throughout tropical Africa, its distribution is heterogeneous, in line with that of its vector, the female anopheline mosquito. The risk of malaria is quantified by the number of infective mosquito bites sustained each year by each person. In tropical Africa, the median number of infective bites is 77 per year, but in the rural and rainy areas of central Africa this number is generally ≥≥200. The record belongs to a village of Equatorial Guinea, where humans sustain 1,030 infective bites per year, three per day! In large cities such as Kinshasa and Brazzaville, the risk is lower (3–30 bites) because there is less stagnant water where the vectors can breed and many more humans in relation to the population of mosquitoes. But one just has to drive fifteen kilometres to the semi-rural areas around Kinshasa and the risk goes up to 620 bites per year.59–61
In the southern and forested areas of Cameroon, there is up to 4,000 mm of rain each year, compared to only 800 mm in the extreme north. The number of infective bites varies accordingly, with high values in the south-west of the country, and low values in the arid north. The risk of developing malaria, and of eventually needing to receive IV quinine, varies along the same patterns. Thus malaria also correlated nicely with HCV distribution: a marked north–south gradient, a high incidence so that a large proportion of the population would receive parenteral antimalarial drugs at least once, the correct age distribution (more severe in children) and the correct time frame (the frequency of its parenteral treatment p
resumably increased in parallel with the development of fixed health services, from the 1930s onward).
To determine which interventions had really driven HCV transmission in southern Cameroon, we conducted a survey in the city of Ebolowa, among individuals aged sixty years or more, 56% of whom were HCV-infected, the highest prevalence in the world, while 74% had antitreponemal antibodies, indicating prior yaws or syphilis. We found no evidence that HCV had been transmitted during yaws treatment; many cases occurred during childhood and those treated parenterally received IM rather than IV injections.62
However, 80% of the interviewees had experienced at least once in their lifetime an episode of illness for which IV injections were administered, and in about two-thirds of the cases this was for the treatment of malaria. HCV infection was associated with such treatments against malaria and, in the men’s case, with having been circumcised traditionally (during collective ceremonies, using knives or broken bottles). Because of its high frequency, the IV treatment of malaria had been the main driver of the transmission of HCV.62
We conducted a similar study of elderly individuals in a rural area of south-west Central African Republic (in and around Nola) which used to be, in the 1930s and 1940s, the most virulent focus of African trypanosomiasis. HCV prevalence was much lower than in Cameroun but we found that having been treated for trypanosomiasis in the 1930s and 1940s was associated with HCV, while having received injections of pentamidine for the prevention of trypanosomiasis (between 1946 and 1953) was associated with infection with the HTLV-1 retrovirus. The latter, although much less studied as a blood-borne agent, is an interesting proxy for HIV-1, because it also originated from Pan troglodytes and infects CD4 lymphocytes (without causing AIDS). We also documented an extraordinary excess mortality amongst individuals who had been treated for sleeping sickness in the 1930s and 1940s. After excluding all other causes, we concluded that this excess mortality was probably caused by the iatrogenic transmission of HIV-1.63