Injection drug use, low baseline CD4 counts continue to predict poorer HAART response after six years

A large multi-cohort analysis has investigated factors affecting long-term response to potent antiretroviral therapy. Four to six years after starting anti-HIV treatment, higher rates of AIDS and mortality were seen in injection drug users and in those who had had AIDS-defining events or CD4 cell counts less than 25 cells/mm3 before starting therapy. The study, conducted by the Antiretroviral Therapy Cohort Collaboration, was published in the December 15th issue of the Journal of Acquired Immune Deficiency Syndromes.

Previous studies have found that rates of AIDS-related illness and death are higher in people who begin antiretroviral therapy with lower CD4 cell counts. Poorer response has also been found in injection drug users (IDUs) compared to other patients. However, most studies to date have looked at response over relatively short time periods. In this study, the Antiretroviral Therapy Cohort Collaboration (an international alliance of investigators from sixteen cohort studies of people with HIV – see analysed data from 20,379 HIV-positive adults who had been on anti-HIV drugs for up to six years.

Participating cohorts were included if they had enrolled at least 100 treatment-naïve patients, 16 years of age or older, who had begun treatment with a combination of at least three antiretroviral agents. People with baseline viral loads less than 1000 copies/ml were excluded as possibly not treatment-naïve. This yielded a total of 20,379 patients from twelve European and North American cohorts. (A prognostic model based on this same data set was recently published – see the aidsmap report here)

Baseline characteristics were as follows: median age, 36; median CD4 cell count 224 cells/mm3; median month of therapy initiation, February 1999. Before treatment initiation, 2737 patients (23%) had already had a diagnosis of AIDS; 3231 (16%) were presumed infected due to IDU.

Of the initial regimens, 66% were NRTI/PI, 24% NRTI/NNRTI, 7% NRTI only, 2% triple-class; and 2% other (NRTI-sparing, or including T-20). The majority of participants (88%) began on a three-drug regimen.

Over a total of 61,798 person-years of follow-up, 1844 participants developed at least one AIDS-defining event, and 1005 died. AIDS-defining events and deaths were analysed by: baseline CD4 cell count (<25, 25 to 49, 50 to 99, 100 to 199, 200 to 349, and >350 cells/mm3), baseline viral load (<100,000 or ≥100,000 copies/ml), presumed mode of transmission (IDU or other), and AIDS diagnosis before baseline (yes or no). Consistent with previous studies, lower baseline CD4 cell counts were consistently the strongest predictor of poorer outcomes. The effect was strongest for the lowest baseline counts, and tended to decline with length of time on therapy for all strata of CD4 count. Beginning therapy at a baseline CD4 cell count between 200 and 349 continued to show a benefit until the four-year mark. Compared to those beginning at >350 cells/mm3 (the comparator group), the hazard ratio for progression to AIDS at one to two years on therapy was 1.5 (95% confidence interval [CI]: 1.0 to 2.3), 1.4 at two to three years (95% CI: 1.0 to 2.1), and 1.0 at four to six years (95% CI: 0.6 to 2.0). For each time period, hazard ratios were progressively higher for each lower CD4 stratum. For baseline CD4 counts <25 cells/ mm3, the hazard ratio for developing AIDS was 3.7 at one to two years (95% CI: 2.2 to 6.1), 2.4 at two to four years (95% CI: 1.5 to 3.8), and 2.3 at four to six years (95% CI: 1.0 to 2.3). At four to six years, the hazard ratio for mortality was 2.5 (95% CI: 1.2 to 5.5) for baseline CD4 counts <25 cells/ mm3. For people presumed infected through IDU, at four to six years on HAART, the hazard ratio for AIDS was 1.6 (95% CI: 0.8 to 3.0) and the hazard ratio for mortality was higher at 3.5 (95% CI: 2.2 to 5.5). Note that cause of death was not analysed and was not necessarily directly due to HIV; mortalities due to hepatitis-related liver disease, overdose, trauma and other causes were not excluded. Mortality rates were still lower than would be expected in the absence of anti-HIV therapy. Diagnosis of AIDS before the initiation of anti-HIV treatment also continued to predict AIDS-defining events at four to six years, with a hazard ratio of 2.3 (95% CI: 1.2 to 4.4); the predictive value for mortality ceased to be significant. HIV viral load (greater than, or less than, 100,000 copies/ml) was not a significant predictor of progression or death at any time point. The study was limited by declining numbers of patients in follow-up after longer periods on antiretroviral treatment. At the end of the fourth year of anti-HIV therapy, 6838 participants were still being followed (23% of the original cohort); only 791 (4%) were followed for more than six years. As most original patients were still being followed up at the time of analysis, the researchers "do not believe that informative censoring is likely to be an important source of bias." However, results may have been confounded by socioeconomic and other factors which caused people to begin treatment late in the course of HIV progression. Larger hazard ratios for mortality than for development of AIDS were seen in several groups, which may be evidence of such confounding. Also, race and ethnicity were not included in the analysis due to lack of sufficient data. The researchers concluded that "rates of AIDS and death were persistently higher in patients infected [through injection drug use]", and that "although the prognostic value of baseline CD4 count and a prior AIDS diagnosis declined with time, patients who were severely immunodeficient when they started therapy experienced higher rates of AIDS and death up to 6 years later." They believe these results may "strengthen the case for screening for HIV, because delaying treatment… has long-term disadvantages." Reference Antiretroviral Therapy Cohort Collaboration. Importance of baseline prognostic factors with increasing time since initiation of highly active antiretroviral therapy: collaborative analysis of cohorts of HIV-1–infected patients. J Acquir Immune Defic Syndr 46 (5):607-615, 2007. Source: Wednesday, January 2, 2008

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