By Michael Carter

Thanks to improving anti-HIV treatment, people with HIV, in the first five years after diagnosis with HIV, now have mortality rates similar to those seen in the general population, according to a large European study published in the July 2nd edition of the Journal of the American Medical Associations.

However, although the investigators also found a dramatic overall reduction in the risk of death for people with HIV since effective anti-HIV treatment became available in 1996, they still found that longer-term infection with HIV was still associated with an increased risk of death.

Many studies have recorded significant and sustained falls in rates of serious illness and death in HIV-positive patients in countries like the UK since effective anti-HIV treatment became available. But soon after such treatment was first introduced, a Swiss study suggested that even patients doing well on antiretroviral therapy still had an increased risk of death compared to HIV-negative individuals of a similar age.

However, earlier studies examining the impact of treatment on mortality were limited because they lacked information on the duration of HIV infection in their populations. Furthermore, anti-HIV treatment and care has improved significantly in recent years, and anti-HIV drugs are now considerably more potent, less toxic and easier to take than the first generation of effective anti-HIV medicines.

Investigators from the European CASCADE cohort collaboration, therefore, looked at rates of death amongst HIV-positive patients enrolled in 23 cohort studies and compared these to those seen in the general age-matched population. All the patients enrolled in the CASCADE cohorts had a date of infection with HIV that was accurate to within 18 months. Data were also available on the use of antiretroviral therapy.

A total of 16,534 HIV-positive individuals were included in the investigators’ analysis. These patients were infected with HIV between 1980 and 2006, the median year of infection being 1994. The majority of patients were infected with HIV via sex with another man (57%), with 24% of infections attributed to heterosexual sex and 18% to injecting drug use. The median duration of follow-up was a little over six years.

In all, 2571 individuals died by the end of 2006. This compared to an estimated mortality of 235 for age-matched HIV-negative individuals.

But the rate of excess mortality amongst patients with HIV declined significantly during the period under observation. Before effective anti-HIV treatment became available in 1996, patients with HIV had an excess mortality rate of 41 per 1000 patient years. This decreased in every subsequent year and was just 6 per 1000 patient years by the period, 2004 – 06. Indeed, in this most recent period, patients with HIV had an increased hazard of death compared to HIV-negative individuals of just 0.09 (95% CI, 0.07 – 0.11).

Factors associated with an increased risk of death were older age (p < 0.001) and infection with HIV via injecting drug use (p < 0.001). Women appeared to have a lower risk of death than men (p = 0.001). But in subsequent multivariate analysis, only injecting drug use remained associated with a significantly increased risk of death (p < 0.001).

When the investigators took a closer look at mortality amongst patients infected with HIV through sex, they found that mortality rates for these individuals decreased towards background levels seen amongst their HIV-negative peers between 1996 and 2006. Indeed, by 2004 – 06, there was no evidence of any excess mortality amongst patients with HIV in any age group during the first five years following infection with HIV.

But in the longer-term, some excess mortality was still evident, being 4.8% amongst 15 – 24 year olds in the first ten years after infection with HIV and 4.3% in those aged 45 and above.

Rates of excess mortality were, however, higher amongst injecting drug users, being 5% greater than rate seen in the general population in the first five years after diagnosis with HIV, increasing to 6.2% by year ten.

The investigators then looked at uptake of antiretroviral therapy. They found that the amount of time patients spent on anti-HIV treatment increased from 17% in 1996-97 to 73% by 2004 – 06. Approximately equal numbers of patients were taking antiretroviral regimens based on NNRTIs (40%) and protease inhibitors (42%) by 2006. Of the patients taking a protease inhibitor, 79% were taking a ritonavir-boosted protease inhibitor by 2006.

“We found that the gap in mortality rates between HIV-infected individuals in our study and the general population narrowed in every calendar period from 1996 onwards”, write the investigators. By 2004 – 06, excess mortality amongst people with HIV was “94% lower than pre-1996 levels.” Accompanying this decreased risk of death was increased uptake of antiretroviral therapy and increased use of more potent and effective regimens – those based on an NNRTI or boosted protease inhibitor.

The investigators note that many of the patients in their study had been infected with HIV for a considerable time. They therefore believe that the excess mortality rate seen ten years after diagnosis “may be pessimistic in terms of the long-term outlook for more recently infected individuals.”

Despite this optimism the investigators caution: “it is likely that even with current standards of HIV management, some long-term excess mortality would remain because problems of toxicity, resistance, and therapy adherence are likely to increase with time receiving highly active antiretroviral therapy.”


Reference
Bhaskaran K et al. Changes in the risk of death after HIV seroconversion compared with mortality in the general population. Journal of the American Medical Association, 300: 51 – 59, 2008.