Africans and African Americans progress to AIDS more slowly: strong association with hepatitis B

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Two posters, one from Europe and one from the USA, presented at the recent Conference on Retroviruses and Opportunistic Infections (CROI) in Montreal, found that people of African descent with HIV have slower CD4 declines and progress more slowly to AIDS compared with people of European descent.

The European researchers suggest that immune-response priming due to exposure to other pathogens might be the reason why Africans progress more slowly, while the USA study found a strong association with hepatitis B infection; people who had caught hepatitis B and had either resolved it or had the chronic disease were more likely to be long-term non-progressors. They suggest that genes that are known to be associated with slow HIV progression may also make people more vulnerable to hepatitis B infection.

In the European study, the CD4 decline in patients of African and European descent in the Swiss HIV Cohort were compared. This ongoing study has recruited about 15,000 people with HIV since 1988 and currently contains about 7000 patients.

Glossary

long-term non-progressor

An HIV-infected person who remains free of AIDS symptoms (such as immune system decline or opportunistic diseases) for an unusually long period of time in the absence of treatment. These individuals typically have strong CD8+ T-cell responses, minimal lymph node damage and a relatively low viral load. About 10% of HIV-positive people seem to be long-term non-progressors. Most, but not all, are elite (or HIV) controllers. 

subtype

In HIV, different strains which can be grouped according to their genes. HIV-1 is classified into three ‘groups,’ M, N, and O. Most HIV-1 is in group M which is further divided into subtypes, A, B, C and D etc. Subtype B is most common in Europe and North America, whilst A, C and D are most important worldwide.

gene

A unit of heredity, that determines a specific feature of the shape of a living organism. This genetic element is a sequence of DNA (or RNA, for viruses), located in a very specific place (locus) of a chromosome.

pathogen

Any micro-organism which can cause disease. There are four main types: bacteria, fungi, protozoa, viruses. Parasitic worms are sometimes described as pathogens.

AIDS defining condition

Any HIV-related illness included in the list of diagnostic criteria for AIDS, which in the presence of HIV infection result in an AIDS diagnosis. They include opportunistic infections and cancers that are life-threatening in a person with HIV.

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 – with three-quarters of African patients and nearly 60% of European patients female.

The African participants had been infected, on average, for a shorter time (seven versus eleven years) and had had a shorter time off antiretrovirals, during which CD4 counts were measured (average four versus five years). Average CD4 count at the time of cohort recruitment was 494 in Africans and 577 in Europeans.

The Africans had a twofold lower average viral load or ‘setpoint’ during the observation period (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/in Africans was 28.2 cells/mm3 in Africans and 52.5 cells/mm3 in Europeans.

The researchers analysed results according to HIV subtype, because in some other studies viral subtype has been associated with faster progression (although there were not enough patients with subtype D, which has been associated most often with fast progression). The subtypes analysed were A (most common in East Africa), B (predominant in Europe), 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 under 10,000 in every subtype in Africans. The highest annual CD4 decline per subtype was in subtype C in Europeans (80 cells/mm3) and subtype A in Africans (50 cells/mm3), while the lowest were subtype A in Europeans (45 cells/mm3) and subtype B in Africans (20 cells/mm3).

There was a relationship observed between setpoint viral load in Europeans and CD4 decline, but not in Africans. Every tenfold (1 log) increase in setpoint viral load in Europeans was associated with 42 more CD4 cells/mm3 lost per year, but viral load appeared to have no relationship with CD4 decline in Africans.

The researchers call their findings “remarkable” and hypothesise that one reason for slower progression in Africans might “reflect evolutionary adaptation to higher overall levels of antigenic exposure in Africa”. In other words, Africans may be more likely to have genes that became predominant in response to other tropical infections and confer a degree of resistance to HIV.

The other study 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 a remarkable and very strong association with hepatitis B infection.

The Multicenter AIDS Cohort Study (MACS) is the oldest HIV cohort study in the world; since 1984 it has recruited over 7000, originally HIV-negative, gay men and observed average time to HIV infection and the subsequent course of disease.

For this study it compared 55 long-term non-progressors (LTNPs) with 179 “expected progressors” (EPs). The definition used for LTNPs was that none of them 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 as long as 22 years after infection, by which time two people had developed AIDS. In the EPs, the shortest time to AIDS 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 (p=<0.001).

This was a striking enough finding, but what was also unexpected 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 had 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. In addition, 5% of LTNPs had chronic hepatitis B infection versus 1% of EPs – but the numbers here were too small to be significant. The same associations were not seen with hepatitis C infection or 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, none of them unexpected. These were the B57* HLA gene, also associated with abacavir hypersensitivity (30% of LTNPs versus 6% of EPs), one copy of the CCR5Δ32 delete gene (37% of LTNPs versus 13% of EPs) and another chemokine-receptor gene called RANTES-403A.

The researchers note that these genes “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. Vaccination could be a confounder (as indicating white ethnicity), or the same genes that confer resistance to HIV progression might also confer vulnerability to hepatitis B.

References

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, poster abstract 1025, 2009.

Phair J et al. Slow progression of HIV-1 infection in the Multicenter AIDS Cohort Study. 16th Conference on Retroviruses and Opportunistic Infections, Montreal, poster abstract 1027, 2009.