Substantial, but imperfect adherence a major risk factor for resistance amongst patients starting HAART

Individuals starting HAART for the first time with a high viral load, low CD4 cell count, and substantial, but imperfect levels of adherence are significantly more likely to develop resistance to antiretrovirals during the first 30 months of treatment, according to a Canadian study published in the February 1^st edition of The Journal of Infectious Diseases.

Cohort studies examining the factors associated with the development of resistance have largely been confined to patients with previous experience of antiretroviral treatment, with comparatively little data available for individuals who are naïve to HAART. Accordingly, investigators from the HAART Observational Medical Evaluation and Research (HOMER) cohort in British Columbia, Canada, conducted a retrospective longitudinal study to characterise the incidence and determinants of resistance in patients taking anti-HIV drugs for the first time.

Study design

All HIV-positive adults starting antiretroviral therapy between 1996 and 1999 were included in the investigators’ analysis, providing a total of 1191 patients. Follow-up was provided for 30 months after the initiation of HAART.

Viral load was measured at baseline, after one month of treatment, and then at three monthly intervals. Drug-resistance genotyping was performed on all blood samples with a viral load above 1000 copies/ml, and resistance tests were also performed on 732 baseline samples. Although it was assumed that blood samples with a viral load below 1000 copies/ml had no resistance mutations, 41 such samples did have genotypic resistance results available.

Drug resistance was divided into four categories: 3TC resistance; any other NRTI resistance; NNRTI resistance; and, protease inhibitor resistance.

Adherence was measured by studying patients’ prescription refill data. Additional information was provided by studying plasma concentrations of NNRTIs and protease inhibitors after the first month and the first three months of HAART.

Consistent with treatment practice at the time, the majority of patients started treatment with a protease inhibitor (74%), the remaining 26% of individuals starting therapy with an NNRTI-containing regimen.

Results

At baseline, individuals had a median CD4 cell count of 280 cells/mm³, and a median viral load of 120,000 copies/ml. The median age was 37 years and 84% of the cohort were men.

Drug resistance mutations were detected during the 30 months of follow-up in 298 patients (25%). The most commonly observed mutations were those conferring resistance to 3TC (204 patients, 69%), followed by NNRTI resistance (120 individuals, 40%), NRTI resistance (98 patients, 33%), and protease inhibitor resistance (68 individuals, 23%). Amongst patients who developed a resistance mutation, the median time after the initiation of HAART to resistance emerging was a little over eight months. In multivariate analysis a high baseline viral load (p

Investigators then looked at the prevalence and risk factors for multi-class resistance mutations. The most common multi-class resistance combination was 3TC and NNRTI resistance (32 individuals, 24% of patients with multiclass resistance). The risk factors for multi-class resistance were broadly similar to those for any resistance, except that injecting drug use ceased to be significant, and that patients treated with an NNRTI were almost twice as likely to have multi-class resistance (hazard ratio 1.84, p = 0.001).

The relationship between adherence and resistance was then examined by the investigators. In total, 56% of patients obtained 95% or more of their prescription refills. Compared to patients who obtained 0 – 20% of their refills, individuals who obtained 80 – 90% of their prescriptions had a significantly increased risk of resistance (p

Further analysis was performed including the patients who obtained 95% or more of their prescription refills, but had low plasma concentrations of drugs. Low drug concentrations were found to be significantly related to resistance (p

Analysis of baseline blood samples found that 53 patients (7%) had resistance mutations before they started taking HAART. Even when the investigators excluded these individuals from their analysis they found that the risk factors for resistance remained virtually unchanged: higher baseline viral load (p

“This study represents one of the first population-based evaluations of predictors of drug resistance in individuals initiating HAART”, conclude the investigators. “High baseline viral load, low CD4 cell counts, and substantial but imperfect levels of adherence were the strongest predictors of detection of antiretroviral resistance. These results underscore the need for measures to help HIV-1 infected individuals successfully integrate complex antiretroviral regimens into their daily routine.”