IDUs acquire resistance at same rate as non-IDUs

A large Canadian study comparing rates of resistance in antiretroviral-naïve individuals with and without a history of injecting drug use (IDU) has concluded that there are no major significant differences between rates of resistance of the two groups during the first two-and-a-half years of highly active antiretroviral therapy (HAART). However, the IDU rate of non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance was slightly elevated, although this was of borderline significance. The study is published in the July 22^nd issue of the journal, AIDS.

In both resource-limited and wealthy countries worldwide, injecting drug users (IDUs) make up a significant and growing proportion of the HIV-infected population. Some studies have suggested that individuals with a history of IDU are disproportionately non-adherent to anti-HIV therapy compared with non-IDUs. Consequently, due to concerns over the emergence of resistance – with treatment repercussions that affect both the individual and the wider community if resistant HIV is transmitted - some HIV clinicians are being overly wary of prescribing HAART to IDUs.

Aware that these concerns are not based on quantitative evidence, researchers at the British Columbia Centre for Excellence, in Vancouver, Canada, analysed data from their HAART Observational Medical Evaluation and Research (HOMER) cohort, which includes more than 99% of all individuals receiving antiretrovirals in the province of British Columbia.

For the purposes of this study, analyses were restricted to HIV-infected men and women who were antiretroviral-naïve and first prescribed triple-drug HAART between August 1996 and September 1999 and were followed for either 30 months or until the end of March 2002. Data on IDU history was based on clinician reports on enrolment forms and from self-reports during the HOMER annual survey. Any positive report of IDU at any time during follow-up was considered to be indicative of a history of IDU. This approach did not separate current IDU with past IDU, however.

Based on previous studies of the cohort, it was assumed that cohort members did not harbour baseline resistance prior to initiating HAART. Although 1312 HOMER participants began antiretroviral therapy for the first time during the study period, 121 (9.2%) were excluded due to lack of available pre-therapy CD4 and viral load data.

Of the 1191 eligible participants, the majority were male (84.3%) and 335 (28%) had a history of IDU. Compared with non-IDUs, IDUs were more likely to be female (23% vs. 13%; p3; p=0.009).

The most common of the 26 initial HAART options (taken by 839, or 70.4% of the study population) included 3TC (lamivudine, Epivir), another nucleoside reverse transcriptase inhibitor (NRTI), and a protease inhibitor (PI). Around 75% of cohort members initiated PI-based HAART, compared with 25% NNRTI-based HAART, and there was no difference between non-IDUs and IDUs. No details are provided on individual drugs taken, or how often HAART components changed.

The researchers classified antiretroviral resistance into four categories:

• any PI resistance (30N, 46I/L, 48V, 50L/V, 54V/L/M, 82A/F/S/T, 84V, or 90M)
• any NNRTI resistance (100I, 103N, 106A/M, 108I, 181C/I, 188C/H/L, 190A/S, P225H, M230L, or 236L)
• 3TC resistance (184I/V; due the common appearance of this mutation and lack of NRTI cross-resistance)
• any other NRTI resistance (41L, 62V, 65R, 67N, 69D or insertion, 70R, 74V, 75I, 151M, 210W, 215F/Y, or 219E/Q)

One-in-four (298) cohort members had some evidence of resistance. A median of two resistance-associated genotypes were found per individual (range 0-13), and median time to at least one resistance mutation was eight months. Resistance to 3TC was the most common (204, 68.5%), followed by NNRTI (120, 40.3%), NRTI (98, 32.9%) and PI (68, 22.8%) resistance.

Using Kaplan-Meier analysis, there was no significant difference seen after 24 months of HAART between non-IDUs and IDUs in the cumulative rate of first PI (5.4% in non-IDUs vs. 5.6%, respectively; p=0.983) first NRTI (8.9% vs. 6.7%; p=0.387) or 3TC (17.2% vs. 20.3%; p=0.148) resistance.

However, the cumulative rate of first NNRTI resistance was found to be significant: 8.8% in non-IDUs vs. 12.6% in IDUs (p=0.013). Unadjusted Cox regression analysis again found that the only significant difference seen in the relative hazard (RH) between non-IDUs and IDUs was in the emergence of NNRTI resistance (RH=1.6; p=0.014).

After the researchers adjusted for NNRTI use in the initial HAART regimen, age, gender, viral load, baseline CD4 cell count, months on an NNRTI-containing regimen during follow-up, and adherence (above or below 95%), history of IDU became borderline independently associated with time to NNRTI resistance (RH=1.5; p=0.050).

In their discussion, the researchers argue that although this “marginal difference” demonstrates “a slightly elevated rate of NNRTI resistance among IDUs”, the crude 4% difference needs to put into context. “It is important to acknowledge that a difference exists, but that may be a case of statistical significance rather than clinical significance, particularly because adjusting for potential confounders appeared to diminish this difference rather than unmasking clinically relevant differences.”

The authors note that although the results of this study are of international significance, they may not be generalisable to settings where IDUs have greater barriers to accessing healthcare than in Canada, where universal free healthcare is available.

They conclude by saying that their findings “indicate that rates of resistance to all major classes of antiretrovirals between IDUs and non-IDUs are very similar during the first 30 months of therapy. These findings should allay fears among physicans that prescribing HAART to IDUs may result in elevated rates of antiretroviral resistance, and should be demonstrate that withholding HAART from IDUs, as a strategy to prevent elevated rates of resistance, is largely unsupported by quantative evidence.”