Changing Causes of Death and Disease Among HIV Positive People in the HAART Era

As a consequence of HAART, there has been a significant and sustained decrease in HIV-associated deaths in the U.S. and Europe since 1996. However, between 1966 and the present, new morbidities have emerged in individuals treated with effective antiretroviral therapy.
Although the rate of HIV-related death remains low in developed countries, there is increasing concern about osteopenia (bone loss), coinfection with hepatitis B virus (HBV) or hepatitis C virus (HCV), cardiovascular disease, and other conditions among people with HIV.
As described in the September 2006 Journal of Acquired Immune Deficiency Syndromes, researchers conducted a prospective, multicenter, observational analysis to evaluate the most significant trends in morbidity and mortality among HAART-treated patients enrolled in the HIV Outpatient Study (HOPS). The researchers analyzed rates of death, opportunistic disease, and non-AIDS-defining illnesses determined to be primary or secondary causes of death among HOPS patients treated since 1996.
Results
" Among 6945 HIV positive patients followed for a median of 39.2 months, the death rate fell from 7.0 deaths per 100 person-years (PY) in 1996 to 1.3 deaths per 100 PY in 2004 (P = 0.008 for trend).
" Deaths that included AIDS-related causes decreased from 3.79 per 100 PY in 1996 to 0.32 per 100 PY in 2004 (P = 0.008).
" Proportional increases also occurred in deaths involving liver disease, bacteremia/sepsis, gastrointestinal disease, non-AIDS malignancies, and renal disease (P = <0.001, 0.017, 0.006, <0.001, and 0.037, respectively.)
" Liver disease was the only reported cause of death for which absolute rates increased over time -- albeit not significantly -- from 0.09 per 100 PY in 1996 to 0.16 per 100 PY in 2004 (P = 0.10).
" The percentage of deaths due exclusively to non-AIDS-defining illnesses rose from 13.1% in 1996 to 42.5% in 2004 (P < 0.001 for trend).
" In 2004, the most frequent non-AIDS-defining causes of death were cardiovascular, hepatic, and pulmonary disease, and non-AIDS-defining malignancies.
" Mean CD4 cell counts closest to death (n = 486 deaths) increased from 59 cells/mm3 in 1996 to 287 cells/mm3 in 2004 (P < 0.001 for trend).
" Patients dying due to non-AIDS-defining causes were more likely to be HAART experienced and initiated HAART at higher CD4 cell counts than those who died with AIDS-defining conditions.
Conclusion
In conclusion, the authors wrote, "Although overall death rates remained low through 2004, the proportion of deaths attributable to non-AIDS diseases increased and prominently included hepatic, cardiovascular, and pulmonary diseases, as well as non-AIDS malignancies."
"Longer time spent receiving HAART and higher CD4 cell counts at HAART initiation were associated with death from non-AIDS causes," they added, noting that the CD4 cell count at the time of death increased over time.
Discussion
In their discussion, the authors noted that their study revealed several major findings. While overall death rates remained stable through the ninth year of widespread HAART use in the HOPS cohort, the proportion of deaths with at least one non-AIDS-defining cause increased progressively over time, accounting for more than half of all deaths by the end of 2004.
As a group, compared with persons dying from AIDS-related conditions, persons with exclusively non-AIDS-defining causes of death tended to start antiretroviral therapy at higher CD4 cell counts, were more HAART experienced, and were more likely to have received HAART near the time of death. In addition, mean CD4 cell counts near the time of death, as well as the age at death, both increased significantly over time.
The researchers said that long-term HIV suppression, CD4 cell count stability or improvement, and clinical benefits due to antiretroviral therapy increasingly allowed HOPS participants to avoid AIDS-defining illnesses and delay death, even if they had a history of prior AIDS-defining illness. As a result, they explained, "more prolonged survival allowed chronic underlying comorbid conditions or risks for such conditions to become more clinically relevant," particularly liver disease (especially chronic coinfection with HBV or HCV), hypertension, diabetes, cardiovascular disease, pulmonary disease, and non-AIDS-defining malignancies.
Further, they suggested, "HIV treatments themselves may have resulted in conditions that contributed to an increased likelihood of certain deaths." In particular, the wrote, "The study data can be interpreted to imply that the increased proportion of non-AIDS-related causes of death can be attributed to longer antiretroviral therapy (e.g., PI use and myocardial infarctions as seen in this cohort)."
Recent reports from this and other cohorts, they continued, "demonstrate mortality benefits of initiating antiretroviral therapy earlier in the course of HIV infection (i.e., at higher CD4 cell counts) and the survival benefits of maintaining continuous HAART even when higher CD4 cell counts have been achieved" - although recent studies have provided conflicting data about structured treatment interruptions.
"[W]hile appreciating the shift in the spectrum of illnesses contributing to death among those living longer in the HAART era," the authors concluded, "it is important to emphasize that any contributions of antiretroviral therapy to the risk for non-AIDS-defining illnesses are clearly outweighed by the benefits consequent to HAART's use in reducing overall mortality and AIDS-related morbidity. These benefits are dramatic, durable, and unequivocal."
The authors also emphasized the importance of clinicians being aware that "other underlying, nontraditionally HIV-related conditions are ever more likely to figure prominently in the risk for death and disease," and that such conditions should therefore be aggressively screened, monitored, and treated.
Furthermore, they noted, "Although HIV-infected persons are clearly living longer as a consequence of effective HAART, they may be dying earlier than those in the general population, albeit not from traditionally HIV-associated conditions. These observations underscore the need for improved vigilance on the part of clinicians in maintaining proactive and preventive medical care and routine screening for all HIV-infected persons receiving HAART."
09/08/06

Reference

F J Palella, R Baker, A C Moorman, and others. Mortality in the Highly Active Antiretroviral Therapy Era: Changing Causes of Death and Disease in the HIV Outpatient Study. Journal of Acquired Immune Deficiency Syndromes 43(1): 27-34. September 2006.