French researchers have found consistently higher rates of serious illness and death that were neither AIDS-defining nor attributable to side effects of HAART, in patients on antiretroviral therapy with CD4 cell counts below 100 cells/mm3, viral loads above 10,000 copies/ml, and with hepatitis C (HCV) co-infection. These results, drawn from the Aproco-Copilote cohort, were presented at the 47th Interscience Conference on Antimicrobial Agents and Chemotherapy in Chicago this week.
Since effective anti-HIV therapy became available, illnesses that are neither AIDS-defining, nor the side-effects of antiretroviral drugs have become a major source of serious ill health and death in HIV-positive individuals. However, little published data have explored the risk factors for non-AIDS non-HAART-related clinical illness.
French investigators wished to determine the incidence and risk factors for serious illness or death, that neither constituted an AIDS-defining illness nor was attributable to the side-effects of anti-HIV therapy, in the era since potent HIV treatment became available.
They therefore analysed data collected from 1231 patients enrolled in the APROCO/COPILOTE multicentre observational cohorts who initiated protease inhibitor-based antiretroviral therapy between 1997 and 1999. (From 1281 patients originally enrolled from the cohort, 1231 with at least one follow-up visit were analysed.) The median age was 36 years, and 77% of the cohort was male.
At baseline, the median CD4 count was 279 cells/mm3 and the median viral load was 4.5 log10 copies/ml; 34% smoked, 23% had hepatitis C, 5% had hepatitis B; the median length of HIV infection was only four years, and 45% were antiretroviral-naïve.
A validation committee analysed each report of serious illness or death, and multivariate analysis was used to see if these non-AIDS-, non-HAART-related events could be significantly related to CD4 cell count or HIV viral load.
Clinical events were considered "severe" if they required hospitalisation or an extension of hospitalisation, or led to a life-threatening (grade 3 or 4) condition or death.
Events were excluded if they were AIDS-defining, asymptomatic, or deemed solely related to HAART (lipodystrophy, drug hypersensitivity, drug-related organ toxicities, anaemia or lactic acidosis).
Patients were followed for a median of 88 months (just over seven years) for a total of 7664 person-years. Out of the total cohort of 1231 patients, a total of 713 non-AIDS-, non-HAART-related serious illnesses or deaths were recorded in 385 patients. Incidence of such events was 10.5 per 100 person-years of follow up; incidence of AIDS-defining events was 2.7 per 100 person-years.
The most frequent non-AIDS-, non-HAART-related events were infections (23%) – mainly bacterial airway infections (13%), cancer-related events (10%) – mostly solid tumours (8%), cardiovascular illness (10%), psychiatric (9%) – mostly depression (7%), and neurological events (6%) including neuropathy (2%).
These events were more frequent in people aged over 60 (hazard ratio [HR], 2.1; 95% CI: 1.3 – 3.2, p=.001), coinfection with hepatitis C virus (HR, 1.8; 95% CI: 1.4 – 2.2, p<.001 a="" below="" cd4="" cell="" cells="" count="">3 (HR, 2.5; 95% CI: 1.8 – 3.6, p<.001 above="" and="" ci:="" copies="" load="" p="" viral="">
Infections represented 42% of the events occurring in patients with a CD4 cell count below 100 cells/mm3 and 42% of events occurring in patients with a viral load above 10,000 copies/ml.
“Non-AIDS, non-antiretroviral-related severe clinical events, especially bacterial infections, may be favoured by persistent immunosuppression and virological replication”, concluded the investigators.
The SMART treatment interruption study found that non-AIDS-defining illnesses occurred more frequently in patients with lower CD4 cell counts, and the occurrence of such events in patients with CD4 cell counts between 200 – 350 cells/mm3 is one of the reasons why some doctors are advocating the earlier initiation of anti-HIV therapy.
The poster presenters concurred, noting that "the control of HIV replication may protect against the occurrence of non-AIDS-events, notably bacterial infections in HAART-treated patients. These results give further arguments against interruptions of antiretroviral treatment."
Ferry T et al. Incidence and risk factors for the occurrence of non-AIDS defining non-HAART-related severe clinical events in HIV-infected adults in long-term follow-up, Aproco – Copilote Cohort (ANRS CO8). 47th Interscience Conference on Antimicrobial Agents and Chemotherapy, abstract H-1722, Chicago, 2007.