The second main source of evidence concerning the possible link between HIV and increased risk of serious non-AIDS disease or death comes from studies considering the association between CD4 count (and HIV RNA level) and risk of serious non-AIDS events. This involves comparing HIV infected people when they are in different states of immunodefiency so there is not such a clear problem with confounding than when comparing with HIV-uninfected groups, although as in any comparison not protected by randomization the possibility of residual bias is always present.
shows data from the DAD study of around 33,000 people with HIV followed in 10 cohorts and data from the large CASCADE collaboration of seroconverter cohorts, restricted to ART-naïve patients (51
). On the left is the rate of death from causes other than AIDS, according to the most recent CD4 count at the time. There is a strong tendency for the rate of death from non-AIDS causes to be higher at lower CD4 count. Importantly, this trend seems to continue all the way through the CD4 count range, so it is not just the case that those with low CD4 count have raised risk of death from causes other than AIDS, those with counts of 350–500 even appear to be at increased risk compared with those with counts above 500. These trends are essentially unaffected by adjustment for other factors. On the right are the corresponding rates for all-cause mortality. At higher CD4 counts the rate of non-AIDS death is almost as high as those for all cause death, emphasising that in people in this higher CD4 count range, serious morbidity and mortality is dominated by non-AIDS conditions. These trends are highly consistent across the two studies. This trend in risk of non-AIDS death with CD4 count was also found in New York cases with a previous AIDS diagnosis, based on minimum CD4 count (52
). Also, in collaborative analysis the rate of death in ART-naïve patients referred to above, Lodwick et al confirmed this trend for mortality (53
Figure 2 Rate of non-AIDS and all cause death according to most recent CD4 count in D:A:D and CASCADE (derived from refs 50, 56 and unpublished data).
The association between the CD4 count and incidence of serious but non-fatal non-AIDS events has also been considered in some studies, including the Strategies for Management of Antiretroviral Therapy (SMART) trial (54
). The primary aim of SMART was to compare incidence of opportunistic disease (similar, but not identical, definition to AIDS) and death between use of either continuous ART or intermittent ART (Stop or defer ART when CD4 count > 350, restart or start ART when CD4 count < 250) (SMART) among 5472 patients with a CD4 count > 350 at enrolment. The intermittent arm was stopped in Jan 2006, and the protocol modified so that ART experienced patients recommended to restart ART, when there was found to be a raised rate of this primary endpoint but patient follow-up continued for another 18 months. Throughout the entire trial the incidence of serious non-AIDS diseases (non-AIDS cancer, CVD events, liver cirrhosis, renal failure, non-AIDS death) was assessed, as it was hypothesized that less use of ART would reduce the risk of contracting these diseases which were viewed as “complications” to ART. For serious non-AIDS events as a whole there were 346 events, compared with 164 AIDS events, emphasising the fact that risk of these types of events is higher than risk of AIDS events for patients in a relatively high CD4 count range (55
). Considering both arms together, there was an overall hazard ratio for risk of 0.94 per 100 cell higher CD4 count (95% CI 0.90 – 0.98) after adjustment for age, gender, prior AIDS, hepatitis B or C infection and smoking status (SMART, unpublished data). Further, data from the Flexible Initial Retrovirus Suppressive Therapies (FIRST) trial that compared virological, immunological and clinical outcomes for patients randomly allocated to three different antiretroviral treatment strategies for initial ART were used to assess the association between latest CD4 count and risk of serious non-AIDS diseases (with a similar definition to SMART); the hazard ratio was 0.82 (0.72 – 0.93) after adjustment for age, gender, race, prior AIDS and hepatitis B or C infection (56
These associations between CD4 count and risk of non-AIDS diseases seem consistent across different types of events (57
). Evidence of an association with CD4 count has been reported for liver death (51
), non-AIDS malignancy (60
), and kidney disease (34
). The one exception is perhaps CVD where there is has not been strong evidence for a link with the CD4 count when considering risk of myocardial infarction that includes non-fatal as well as fatal cases (63
), and in one study considering CVD mortality a suggestion of a stronger association with HIV RNA level than with CD4 count (57
). shows adjusted relative hazards for the effect of CD4 cell count on risk of these four conditions for four studies, SMART, DAD, CASCADE and FIRST, generally illustrating the consistency of these effects. For cardiovascular disease, there is a suggestion of a stronger effect when considering fatal CVD.
Figure 3 Adjusted hazard ratios (per 100 cell/mm3 higher CD4 count; with 95% confidence intervals) for the association between latest CD4 count and risk of various serious non-AIDS diseases, or deaths from these diseases. (derived from refs 50, 55, 56 and unpublished (more ...)
Two further recent studies looking at the association between the CD4 count and non-fatal as well as fatal non-AIDS have come from France. The Aquitaine cohort looked at all hospitalisations in HIV-infected people in that study between 2000 and 2004 (64
). There was the same trend in CD4 count with the percent hospitalised present for non-AIDS cancers and digestive events, again not much so for CVD events. Further, the distribution of the burden of morbidity according to cause was found to be heavily weighted towards non-AIDS-related events, with less than 1% of hospitalizations in those with CD4 count above 500 were ascribed to AIDS. This association with latest CD4 count was also found in APROCO COPILOTE (65
It is also worth considering whether there is an effect of latest HIV RNA as well as of latest CD4 count. If we are thinking about whether ART can have a benefit in terms of risk of these diseases then the reduction in viral load induced by ART could be an additional benefit on top of that gained from the resulting rise in CD4 count. In most studies HIV RNA is high either in those who are ART naïve, ART-experienced but off ART, or virologically failing so there is confounding between HIV RNA level and the factors that lead people to be in these situations. This complicates interpretation of the association. In the SMART trial however - this was not the case because patients were randomly allocated to be on ART or not. The adjusted (including for the most recent CD4 count) hazard ratio for serious non-AIDS events according to the most recent HIV RNA level – above or below 400 copies/mL – was 0.70 (95% 0.56 – 0.88) (). Considering separate conditions, this was strongest for renal, CVD and deaths due to other causes, but there is no such trend when looking at non-AIDS cancer. When additionally adjusted for latest HIV RNA level the hazard ratio for the latest CD4 count became 0.96 (0.92 – 1.01). Of note, impairment of immune function exists for both HIV and the above mentioned transplant patients, whereas HIV-RNA obviously only affects HIV patients; hence, the CD4 gradient data does suggest that immunodeficiency per se increases risk of these diseases, but that HIV-RNA additionally may also contribute.
HIV RNA and risk of serious non-AIDS events: SMART. Adjusted hazard ratio for latest value < 400 vs. > 400 copies/mL. Adjusted for age, gender, prior AIDS, hep B/C, smoking, latest CD4 count. (SMART unpublished data)