A surprise finding in two recent studies suggests people of African origin are better able to fight CD4 decline, writes Gus Cairns.
All other things being equal, people of African background – which includes both Africans living in Europe and African-Americans in the USA - progress more slowly to AIDS than people of other racial backgrounds.
This finding, from two studies presented at the recent Conference on Retroviruses and Opportunistic Infections in Montreal, may seem contrary to experience. But the findings are robust: in both Europe and the USA people of African descent with HIV had slower CD4 declines and progressed more slowly to AIDS compared with people of European descent, and the figures were highly statistically significant. If they subsequently had higher mortality, this was to do with unequal access to good treatment; but the studies showed that they started with an advantage when it came to fighting CD4 declines.
The figures would need to be confirmed by other surveys, and causation is not clear. But the European researchers suggest that it might be down to having an immune system already primed to deal with more diseases than Europeans. As in the ‘hygiene hypothesis’ explaining why allergic conditions such as asthma have increased in rich countries, Europeans may be paradoxically too disease-free to cope well when HIV comes along.
The US study found a specific and unexpected association with hepatitis B infection: people who had caught hepatitis B and had resolved it were more likely to develop AIDS slowly. The US researchers suggest that genes that are known to be associated with slow HIV progression may help people fight off hepatitis B once infected. Hepatitis B infection, like HIV, is more common in Africans and African-Americans than in Europeans.
In the European study,1 the CD4 decline in patients of African and European descent in the Swiss HIV Cohort2 were compared. For the current study 463 European and 123 African patients were chosen and matched by age. Unusually for a cohort study, the majority were women. The African patients had, on average, been infected for a shorter time (seven versus eleven years) and had a lower CD4 count at the time of cohort recruitment - 494 in Africans and 577 in Europeans.
The Africans were observed for four years before they started HIV therapy and the Europeans five years. During that time the Africans averaged half the HIV viral load (5300 versus 10,250 in Europeans). They also had nearly half the rate of CD4 decline of the Europeans: the average annual CD4 decline was 28.2 cells/mm3 in Africans and 52.5 cells/mm3 in Europeans. These differences were highly statistically significant: there was less than a one-in-a-thousand chance that the findings were a random effect.
The researchers analysed results according to HIV subtype, because in some other studies viral subtype has been associated with faster progression. The subtypes analysed were A (most common in East Africa), B (predominant in Europe and North America), C (mainly from southern Africa) and AG (west Africa). The average viral load was at least 10,000 in every subtype analysed in Europeans and below 10,000 in every subtype in Africans, and Africans had slower CD4 declines in every subtype except type A.
The researchers, calling their findings “remarkable”, surmise that one reason for slower progression in Africans might be “evolutionary adaptation to higher overall levels of antigenic exposure in Africa”. In other words, Africans may be more likely to have genes that developed in response to other tropical infections, and which confer a degree of resistance to HIV.
The US study3 presented tended to support this theory by finding that African-Americans had slower HIV progression than other ethnicities and also tended to have specific genes associated with slower progression. It also uncovered an unexpected and very strong association with hepatitis B infection.
The Multicenter AIDS Cohort Study (MACS)4 studied 234 people not taking HIV treatment, comparing 55 ‘long-term non-progressors’ (LTNPs) with 179 ‘expected progressors’ (EPs). The definition used for LTNPs was that none of these people had progressed to an AIDS-defining illness 15 years after infection, while EPs had all progressed to AIDS by their twelfth year of infection. The LTNPs were observed for as long as 22 years after infection, by which time just two people had developed AIDS. In the EPs the shortest time to an AIDS diagnosis was three years and the median time about 6.5 years.
A number of factors were associated with being an LTNP. The first was age at infection: 60% of LTNPs were aged 25 to 35 at infection compared with 45% of EPs; in contrast 13% of EPs were over 45 at infection compared with 2% of LTNPs (just one person).
The second was African ethnicity. Nearly a quarter (22%) of LTNPs were African-American compared with just 4% of EPs. This was highly statistically significant.
This was a striking enough finding, but more striking was the association with hepatitis B. Nearly three-quarters (73%) of LTNPs, versus 42% of EPs, had had hepatitis B and had ‘resolved’ it, i.e. had cleared the virus and developed protective antibodies to it. In contrast, 22% of LTNPs and 56% of EPs had either never been infected with hepatitis B or had been vaccinated against it. The same associations were not seen with hepatitis C nor with HHV-8, the virus that causes Kaposi’s sarcoma.
The researchers also found three specific immune-system genes to be associated with slow progression and note that they “have also been associated with recovery from hepatitis B infection”, though why slow progression should be associated with higher rates of hepatitis B infection in the first place is unclear. It could be because white people are more likely to have the hepatitis B vaccine, or because the same genes that confer resistance to HIV progression might also confer vulnerability to hepatitis B.
Either way, these two surveys produce results contrary to what many people might have expected. If Africans were given equal access to optimal HIV therapy and good-quality healthcare, they might well do better than Europeans.
1. Müller V et al. African Ethnicity Is Associated with Slower Disease Progression in the Swiss HIV Cohort Study. 16th Conference on Retroviruses and Opportunistic Infections, Montreal (CROI), abstract 1025, 2009.
3. Phair J et al. Slow Progression of HIV-1 Infection in the Multicenter AIDS Cohort Study. CROI abstract 1027, 2009.