Mortality in the HAART era was explored in a number of presentations to the Second International AIDS Society Conference on HIV Pathogenesis and Treatment in Paris yesterday.
Investigators from Canada, France and the Netherlands presented data which demonstrated that death in HIV-positive patients in the HAART era has fallen significantly since 1996. However, the studies found that the risk of dying was increased by a number of factors including the early emergence of resistance to antiretrovirals, hepatitis C virus coinfection, non-AIDS cancers, pre-treatment with suboptimal therapy, and lifestyle factors widespread in the population.
Early resistance to HAART and the risk of death
The impact of the emergence of resistance in the first twelve months of HAART on prognosis was examined by Canadian investigators involved in the HAART Observational Medical Evaluation and Research (HOMER) study, which involved 851 adult patients who started HAART between 1996 and 2000.
By the end of March 2002, 93 patients had died, representing a mortality rate of 10.9%. Resistance to anti-HIV drugs was observed in 155 (18.2%) patients during the first year of HAART. Resistance to all three licensed classes was seen in four (2.6%) of patients, to two classes in 42 (27.1%) and to one class in 109 (70.3%).
Resistance to 3TC was most frequently reported (93, 10.9% of patients), with 46 (5.4%) individuals also having resistance to another nucleoside analogue. Protease inhibitor resistance was present in 28 (3.3%) patients, and 59 (6.9%) individuals were resistant to non-nucleoside analogues.
After adjusting for other factors, multivariate analysis indicated that patients who developed resistance to NNRTIs in the first year of HAART had a hazard ratio of death of 2.73 (95% CI, 1.48 – 5.04, p=0.001) compared to those who did not.
The Canadian investigators concluded that although fewer than 7% of patients developed NNRTI resistance during the four years of analysis, it was predictive of death.
Hepatitis C and mortality
Since the advent of HAART several studies have indicated that mortality due to hepatitis C is increasing in HIV-positive patients. French investigators presented data from the MORTAVIC 2001 study which added to this evidence.
A cohort from 65 HIV treatment centres across France, involving 25,178 HIV-infected individuals contributed the data for the study. Investigators compared their findings to two early studies using the same cohort and methodology that were conducted pre-HAART, in 1995, and in the early HAART era in 1997.
In 2001, 265 (1.1%) deaths were recorded in the cohort. Of these 129 (48%) had an AIDS-defining illness as cause of death, 38 (14%) deaths were due to end-stage liver disease, and other causes accounted for the remaining 98 (37%) deaths.
End stage liver disease accounted for 28% of non-AIDS deaths, and 95% (36 of 38 individuals) of patients dying due to liver disease had chronic hepatitis C infection.
When the investigators compared their findings to those of earlier studies, they found that deaths from end stage liver disease were significantly more frequent than in 1997 (6.6%, P
Improved prognosis due to HAART explained the growing importance of liver disease to mortality in HIV-positive patients, particularly for those coinfected with hepatitis C. However, investigators also found that patients were significantly more likely to be heavy drinkers in 2001 (67.7%) than in 1995 or 1997(p
French AIDS deaths in 2000, the Mortalite study
A study involving 185 French HIV wards, treating over 64,000 patients in 2000 provided further information on AIDS-related deaths.
In 2000, 964 deaths in HIV-positive individuals were reported during data collection for the Mortalite study.
Information on the patients’ demographic background was obtained. Average age was 41 years, and 78% were men, 28% were injecting drug users and 27% were gay or bisexual. A third were classified as being socio-economically disadvantaged, 52% smoked and 33% had alcohol problems.
Immunological data and treatment histories were also obtained, revealing that average CD4 cell count was 94 cells/mm3 (range 19 – 260 cells/mm3, and that HAART had been used by 86% of patients before death.
Although AIDS was responsible for the deaths of 456 (47%) patients, there were other factors which significantly contributed to the number of deaths. These included a non-HIV, or non-hepatitis C or hepatitis B related cancer (103 patients, 11% of deaths). In addition, hepatitis C was recorded as the cause of death in 89 (9%) of patients, hepatitis B in 15 (2%), cardiovascular disease in 67 (7%), other infections in 57 (6%), suicide or overdose in 55 (6%), accident in 17 (2%), and anti-HIV treatment side-effects in 11 patients (1%). HIV was diagnosed within twelve months of death in 20% of cases.
Causes of death in the Netherlands
Causes other than AIDS were also revealed to be causing significant numbers of deaths in data presented by Dutch investigators involved in the ATHENA cohort study.
The ATHENA cohort involves over 3,000 patients who have been followed since starting treatment with HAART. Between 1996 and 2002, the deaths of 459 patients were recorded. These deaths were assessed by three independent doctors who assigned a probable cause of death using three categories, HIV, non-HIV, and unknown.
HIV-related mortality fell from 3.8 per 100 patients years of follow-up in 1996 to 0.5 per 100 patient years in 2000. However, the frequency of non-HIV-related deaths remained stable at 0.4 per 100 patient years in 1996 and 0.9 in 2002 (p
CD4 cell count was the most significant predictor of HIV-related death, with a hazard ratio of 0.61 (95% CI, 0.52 – 0.72), per log10 fall in CD4 cell count. However, age, suboptimal pre-treatment prior to HAART, interrupting HAART (taking HAART less than 67% of the time) and a previous AIDS-defining illness were also significantly associated with the risk of death (all p
The most significant factor associated with non-HIV related death was injecting drug use, with a hazard ratio of 4.8 (95% CI, 2.94 – 7.84).
The ATHENA investigators stressed the role of HAART in reducing mortality, but that non-HIV mortality was still substantially greater than that seen in the general population.
Hogg RS et al. The impact of the emergence of antiretroviral resistance in the first year on survival in subsequent years Antiretroviral Therapy 8 (suppl.1), abstract 86, 207, 2003.
Rosenthal E et al. Mortality due to hepatitis C-related liver disease in HIV-infected patients in France in 2001 (Mortavic 2001 study). Antiretroviral Therapy 8 (suppl.1), abstract 87, 207, 2003.
Lewden C et al. Causes of death in HIV-infected adults in the era of highly active antiretroviral therapy (HAART): the French survey Mortalite 2000. Antiretroviral Therapy 8 (suppl.1), abstract 88, 208, 2003.
van Sighem A et al. Mortality after starting highly active antiretroviral therapy. Antiretroviral Therapy 8 (suppl.1), abstract 89, 208, 2003.