The strongest predictor of how quickly a person will progress to AIDS is the speed with which they reach their viral ‘set point’ after acute infection according to a US study published in the May 15th edition of the Journal of Infectious Diseases (now available online). It also finds that having at least seven HIV-related symptoms during the first four months or so of infection is predictive of slower progression to AIDS.
The viral ‘set point’ is the level of viral load in the period between primary infection, when there is no immune control of HIV and viral loads are characteristically in the millions, and late stage infection, when the viral load increases and CD4 counts fall rapidly.
This tends to be a ‘steady state’ in individuals because it represents a delicate balance between the body mounting a sufficiently strong immune response to control HIV and mounting one so strong that there are more activated T-cells in which the virus can replicate.
Viral load ‘set points’ in individuals range from undetectable to several hundred thousand, and it has been theorised that the size of the set-point viral load is correlated with the speed of progression to Aids; that is, the higher the set-point figure, the shorter the time that set point can be maintained.
However researchers from the Institute of Human Virology in Baltimore, USA and from Port of Spain in Trinidad have found that the speed with which the person reaches the set point is an even stronger predictor of progression.
Twenty-two individuals identified in primary HIV infection from the Trinidad Seroconverter Cohort were studied and followed for seven years. During this time 45% developed AIDS, using the US Centers for Disease Control definition (i.e. a CD4 count under 200 cells/mm3 and/or AIDS-defining symptoms). Antiretrovirals became available during the study period but as they were not given to subjects with CD4 counts over 200 cells/mm3, this did not confound the study results.
The patients’ eventual ‘set point’ predicted how quickly they would develop Aids. All individuals with a set-point viral load over the median figure of 25,000 copies/ml had progressed to AIDS within 4.5 years of infection. In contrast, half the patients who had viral loads under 25,000 copies/ml, or a quarter of the total, had still not progressed to AIDS after seven years.
But the rate of viral load decline from the acute infection peak was even more strongly predictive of progression to AIDS. The median viral load decline following acute infection declined fourfold (0.63 log) every month, meaning that the median set-point viral load of 25,000 copies/ml would be achieved three to four months after acute infection.
All eleven patients who had a slower viral load decline than this had progressed to AIDS within five years of infection. In contrast, only one-quarter of the patients whose viral load decline was faster had progressed to AIDS by the end of the seven-year study.
In univariate analysis, fast initial clearance of HIV and a set-point that was maintained for more than 20 months were both associated with a tenfold lower likelihood of progressing to AIDS, while having a set-point viral load of over 25,000 copies/ml was associated with 6.4 times the likelihood of progression.
In multivariate analysis, a high rate of initial clearance of HIV was consistently associated with a tenfold lower likelihood of progression, regardless of the set-point viral load or CD4 count of subjects. In contrast, a low viral set-point was not a statistically significant predictor of progression to AIDS in the absence of fast clearance after acute infection.
The strongest immune correlate of fast viral clearance after infection was the total CD4 count during that initial clearance, suggesting that a robust immune response to HIV is crucial in suppressing the initial burst of HIV replication. However, a strong anti-HIV CD8 response during chronic infection predicted faster progression.
It is probably for this reason that patients with faster clearance rates of HIV after acute infection were more likely to complain of ‘viral’ symptoms such as fever, fatigue, headache, muscle aches and night sweats during acute infection. In contrast, other studies have shown that people who complain of these symptoms during chronic infection are faster progressors.
The researchers comment that “a down modulation of CD8 activation during steady state may involve different immune effector mechanisms such as the Th2 response.” This means that whereas generalised immune activation is ‘good’ during acute infection, it is better to have high circulating levels of cytokines, such as IL-2, that actually dampen down the immune response during chronic infection and ensure that fewer T-cells get activated.
The researchers also found that in this Caribbean cohort, the overall average time from infection to AIDS was shorter than that reported from European and US cohorts, despite a similar average viral load. This generally shorter time, which has also been observed recently in Thailand, may reflect generally lower CD4 counts or poorer immune responses in patients from developing countries.
Further information on this website
Exposure and primary infection - research summary
Treatment during primary infection - research summary
Reference
Blattner W et al. Rapid clearance of virus after acute HIV-1 infection: correlates of risk of AIDS. Journal of Infectious Diseases 189 (May 15, online advance publication).