Swiss find no increase in transmitted resistance over past decade

Switzerland has seen no significant increase in the prevalence of transmitted drug resistance between 1996 and 2005, according to the results of a study published in the October 2007 issue of the journal, AIDS. The study’s authors say their findings suggest that effective antiretroviral therapy “by itself contributes to containment of the spread of primary HIV drug resistance in an optimal setting.”

Study background

Swiss investigators sought to assess the prevalence of transmitted resistance over time by analysing data from recently infected individuals who were broadly representative of recently diagnosed individuals in Switzerland between 1996 and 2005. Recent infection was defined as documented acute infection or an HIV-positive antibody test following an HIV-negative antibody test in the previous year.

A total of 925 individuals attending one of seven HIV outpatient clinics or private practices participating in the Swiss HIV Cohort Study were eligible for the study, although only 858 individuals had viral load samples over 1000 copies/ml within a year of the estimated date of seroconversion and before the initiation of antiretroviral therapy.

Of these 858, resistance data were available for 822 individuals. Most (71%) were infected with subtype B. Eighteen different non-B subtypes and circulating recombinant forms were identified, including CRF02 (7%), CRF11 (6%), subtype C (3%) and CRF01 (3%). Average CD4 cell count was 534 cells/mm³ and the average viral load was 5.0 log₁₀ copies/ml.

The majority of individuals acquired HIV via sex between men (42%); 32% acquired HIV via sex between men and women, and 20% via injection drug use. During the same period (1996-2005), 7221 individuals were diagnosed HIV-positive in Switzerland, the majority acquired HIV via sex between men and women (54%); 25% acquired HIV via sex between men and 15% acquired HIV via intravenous drug use.

Study results

The investigators found a prevalence of 7.7% for any transmitted drug resistance during the period 1996 to 2005. Most (5.5%) was nucleoside (NRTI) resistance; the majority (5%) with mutations conferring resistance to AZT (zidovudine, Retrovir) and d4T (stavudine, Zerit), although 1% had mutations conferring resistance to abacavir (Ziagen) and ddI (didanosine, Videx).

Another 1.9% of the samples harboured mutations that conferred resistance to both of the currently available non-nucleosides (NNRTIs), although 0.1% had cross-resistance to the investigational NNRTI etravirine (TMC-125).

Overall, 2.7% had some resistance to protease inhibitors (PIs), ranging between 0.1% with mutations conferring resistance to darunavir (TMC-114, Prezista) to 2.3% with mutations conferring resistance to indinavir (Crixivan). Prevalence of resistance to lopinavir (Kaletra), atazanavir (Reyataz), fosamprenavir (Telzir) and tipranavir (Aptivus) was found to be less than 1%.

The prevalence of dual or triple-class resistance was 2%. Among the 18 antiretrovirals analysed, the average number of drugs affected by transmitted resistance was 3.4 (range, 1-16). Resistance to the entire NRTI class was found to affect three individuals; two of these also had mutations that confererred resistance to NNRTIs. However, no individuals were found to have HIV that was resistant to all approved PIs.

In contrast to data from the United Kingdom, other European countries and Canada, the investigators found no significant changes in the prevalence of transmitted drug resistance over time. The only exception was an observed increase in the transmission of NNRTI-resistant strains from 0% in 2004 to 6.0% in 2005. This is similar to trends described in Spain and the UK.

In multivariate analysis, there was no difference in the prevalence of transmitted drug resistance according to gender, exposure category or ethnicity, but the prevalence of transmitted resistance was highest among individuals infected with subtype B virus. However, separate analyses of trends for B subtypes and non-B subtypes found that there had been no change in prevalence over time.

Analysis

In their discussion the investigators note that their findings of no temporal increase in the prevalence of transmitted HIV are in contrast with findings from other developed world studies during the same time period. They suggest that this “might be related to sampling biases [in other studies], for example a greater proportion of individuals with drug-resistant HIV-1 being tested in the later years owing to changes in resistance-testing policies.”

They point out that, "in contrast to many projections and modelling work, no significant increase of dual- or triple-drug resistance has occurred in Swiss HIV-infected individuals." Nevertheless they warn that the increase in the prevalence of NNRTI resistance “may potentially increase the risk of first-line virological failure” and recommend that all newly diagnosed individuals undergo resistance testing.

They also suggest that clinicians consider their data in the light of the fact that “first-line failure with NNRTI-based regimens leads to the emergence of drug resistance against more drug classes than with boosted PI based regimens.”

The investigators conclude by noting, “transmitted drug resistance in a well-defined, representative patient population in a country with large access to antiretroviral therapy has remained stable since 1996. ... This suggests that effective antiretroviral treatment by itself contributes to containment of the spread of primary HIV drug resistance in an optimal setting.”