A total of 2357 resistance tests on samples from antiretroviral therapy naive patients between February 1996 and May 2003 were available for analysis. One hundred and seventy two (7%) samples were from patients known to have been recently infected at the time of testing. Overall, 116 (4.9%, 95% confidence interval 4.1% to 5.9%) samples showed medium level resistance and 219 (9.3%, 8.1% to 10.5%) showed high level resistance to one or more drugs. When these categories were combined, reduced drug susceptibility was identified in 335 (14.2%, 12.8% to 15.7%) samples. All further analyses are based on this inclusive definition of resistance unless stated otherwise.
Patterns of resistance
In total, 233 (9.9%, 8.7% to 11.2%), 106 (4.5%, 3.7% to 5.4%), and 108 (4.6%, 3.8% to 5.5%) samples harboured mutations that cause resistance to nucleoside or nucleotide reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, and protease inhibitors, respectively. Most samples (n = 257; 10.9%, 9.7% to 12.2%) were resistant to one drug class only (mostly nucleoside or nucleotide reverse transcriptase inhibitors); 44 (1.9%, 1.4% to 2.5%) showed evidence of resistance to two classes and 34 (1.4%, 1.0% to 2.0%) showed evidence of resistance to three classes.
shows the most commonly observed mutations as highlighted by the Stanford HIVdb algorithm among the 335 resistant samples. Mutations at codon 215 in the reverse transcriptase gene including the reversion mutations T215C/D/E/S, were most commonly observed; these changes were often associated with M41L. We did not observe K65R, I74V, or Y115F, associated with abacavir, didanosine, and tenofovir resistance. No mutations were detected associated with resistance to multinucleoside or nucleotide reverse transcriptase inhibitors, such as Q151M or insertions at codon 69. The most common non-nucleoside reverse transcriptase inhibitor mutation was K103N, which noticeably reduces the activity of all drugs within this class. Mutational patterns in protease were more complex, with a high frequency of several natural polymorphisms, which do not by themselves confer significant resistance.
Most common mutations (frequency ≥10) in samples showing resistance to HIV drugs in United Kingdom
Among individual nucleoside or nucleotide reverse transcriptase inhibitors drugs the prevalence of reduced drug susceptibility ranged widely from 2.5% (lamivudine) to 7.6% (zidovudine) (). The low level of resistance to lamivudine despite its widespread use provides indirect evidence that the lamivudine resistant virus is relatively “unfit.” Due to strong cross resistance, we observed virtually identical figures for the non-nucleoside reverse transcriptase inhibitors delavirdine (4.1%), efavirenz (4.2%), and nevirapine (4.3%). Resistance was generally least common among individual protease inhibitors, ranging from 2.1% (lopinavir) to 4.3% (nelfinavir).
Prevalence of resistance to individual drugs
shows the most commonly prescribed first line antiretroviral therapy regimens in the six participating centres in the UK Collaborative HIV Cohort Study over the same period (February 1996 to May 2003) covered by our analysis. Overall, around 9% of first line regimens may have had reduced efficacy as a consequence of primary resistance (6% under the stricter definition of high level resistance). Estimates depended on regimen and were comparatively high for the most popular regimens—zidovudine-lamivudine plus either efavirenz or nevirapine (11% to 12%).
Prevalence of primary resistance to drugs for HIV comprising most common first line regimens used in UK collaborative HIV cohort study
The prevalence of primary drug resistance has increased noticeably, although patterns are specific to drug class and partly depend on whether medium level resistance is included (). The proportionate increase in resistance to nucleoside or nucleotide reverse transcriptase inhibitors was much smaller than for the non-nucleoside reverse transcriptase inhibitors or protease inhibitors, with some evidence of a levelling off in prevalence. In contrast, the rate of increase of resistance to non-nucleoside reverse transcriptase inhibitors has been approximately linear and has become as common as resistance to nucleoside or nucleoside reverse transcriptase inhibitors. The pattern for resistance to protease inhibitors was less clear: if medium level resistance is included, trends paralleled those of resistance to non-nucleoside reverse transcriptase inhibitors, whereas there was no indication of a recent increase if analysis was for high level resistance. In the most recent period for which data are available (2002-3), the prevalence of resistance to any antiretroviral drug, nucleoside or nucleotide reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, and protease inhibitors was 19.2% (95% confidence interval 15.7% to 23.2%), 12.4% (9.5% to 15.9%), 8.1% (5.8% to 11.1%), and 6.6% (4.4% to 9.3%), respectively. Finally, we found primary resistance to at least one drug among an estimated 13% of first line regimens started in 2002-3 in the UK collaborative HIV cohort study (9% for high level resistance only).
Prevalence of medium or high level drug resistance and high level drug resistance by calendar time. Values are number of samples tested at each time point
Demographic and clinical factors
shows the prevalence of drug resistance according to selected demographic factors. Some of the crude comparisons are misleading because of confounding by calendar year and centre, and more reliable inference is through the odds ratios adjusted for these two factors. Mode of infection was not a strong risk factor apart from an apparently lower risk among injecting drug users. Associations with ethnicity and subtype of HIV, which are closely inter-related, were marginally significant. The rate of resistance was higher, although not substantially, in white patients and in those infected with subtype B virus. Patients younger than 30 experienced the highest level of resistance (odds ratio 1.32, 95% confidence interval 1.02 to 1.72), although there was no clear trend across older age groups. The strongest determinant of primary resistance was acute infection: 22% of patients in this category had mutations conferring resistance compared with 14% of patients with an unknown duration of infection. In contrast, we found no apparent effect of CD4 count, a marker of the duration of infection, both overall and in a subanalysis excluding recently infected patients (data not shown).
Effect of demographic and clinical factors on prevalence of primary resistance to HIV drugs in United Kingdom