HAART patients at greater risk of severe side-effects than AIDS

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HIV-positive individuals who take HAART are more likely to experience a
serious or life-threatening treatment side-effect than develop an
AIDS-defining condition, according to a US study published in the
December 1st edition of the Journal of Acquired Immune Deficiency
Syndromes. The study investigators suggest that doctors should carefully
assess their patients' medical history and circumstances before
prescribing anti-HIV therapy so they can avoid the use of drugs that
could aggravate existing health conditions.
Investigators analysed the results from five US multi-centre HAART
trials that had a common system of reporting adverse events, AIDS events
and deaths between 1996 and 2001. Partial findings from the study were
presented at the Ninth Conference on Retroviruses and Opportunistic
Infections in 2002.

The investigators wished to establish the incidence and determinants of
serious or life-threatening treatment side-effects, AIDS-defining
illnesses and death.

Data were analysed from 2,947 patients who were followed for a median of
20.7 months, contributing 5,940 person-years of follow-up. At the time
of enrollment to the studies, 53% of individuals were antiretroviral
naïve, average age was a little over 39 years, 83% were male, 55% were
gay men, 16% had a history of injecting drug use, the median CD4 cell
count was 211 cells/mm3, and 40% had a previous AIDS diagnosis.

All the patients were prescribed anti-HIV therapy, and at the twelfth
month of follow-up 89% were receiving HAART (70% a protease inhibitor
and 19% a non-nucleoside-based regimen), 3% mono- or dual-nucleoside
analogue treatment, and 8% had stopped anti-HIV treatment on either a
permanent or temporary basis.

A severe or life threatening side-effect (grade 4 adverse-event) was experienced by 675 individuals (11.4 cases per 100 person years), 332 developed an AIDS-defining condition (5.6 cases per 100 person years), and 272 people died (4.6 cases per 100 person years).

The cumulative percentage of patients with a severe or life threatening
side-effect at month twelve was 15.6%, at month 24, 23.7% and at month
36, 30.8%. The corresponding percentages for AIDS events were 7.3%,
10.8%, 16.5%, and the percentages for deaths were 3/9%, 7.9% and 13.1%.

Liver-related side-effects were the most frequently reported adverse
events (148 patients, 2.6 per 100 person years).

When the investigators looked at the risk factors for the experience of
severe or life-threatening side-effects, they found that the risk was
lower in younger patients (hazard ratio [HR] 0.83 for every decade in
years, p=0.0001), and patients who had never taken anti-HIV drugs before
(HR=0.59, p=0.0001). The risks were increased for individuals with a
history of injecting drug use (HR=1.41, p=0.0006), lower baseline CD4
cell count (for every 100 cells/mm3, HR=1.06, p=0.04), and a prior
AIDS-defining illness (HR=1.22, p=0.03).

The investigators also found that women were at increased risk of
experiencing severe or life-threatening neutropenia (HR= 1.76, p=0.03),
whilst African Americans were at increased risk of neutropenia (HR=3.78,
p=0.0001), anaemia (HR=2.46, p=0.008), and kidney-related events
(HR=22.41, p=0.00250. People of Latino origin had an increased risk of
neutropenia (HR=2.75, p=0.01).
Of the 272 people who died, 159 experienced both a grade 4 adverse
reaction and an AIDS-defining illness.

Coinfection with hepatitis B (HR=5.97, p=0.0001) and hepatitis C
(HR=2.74, p=0.009) were significantly associated with the risk of
experiencing a severe liver-related side-effect.

The investigators note, "our principal finding is that the rate of grade
4 events is greater than the rate of AIDS events, and that the risk of
death associated with these grade 4 events was very high for many
events."

They believe that their study has two important implications. Firstly,
the procedure for collecting data of adverse events during clinical
trials needs to be improved. Secondly, doctors need to carefully assess
their patients for the existence of other medical problems, taking into
account social and economic status and drug and alcohol use. "For
example, patients at increased risk of cardiovascular events might
benefit from being placed on a protease inhibitor-sparing HAART regimen.
Similarly, patients with a history of severe depression may be better
off with an efavirenz-sparing HAART regimen."

Reference
Reisler RB et al. Grade 4 events are as important as AIDS events in the
era of HAART. JAIDS 34: 379 – 386, 2003.