Since 1998 and the first version of the IAS-USA recommendations, more than four thousand treatment-naïve HIV-infected patients started ART in the SHCS until the end of 2007, being prescribed one of more than two hundred different regimens. The majority of these participants received initial treatment according to IAS-USA recommendations in force at the time ART was started, as well as according to IAS-USA recommendations on antiretroviral drug resistance testing if primary antiretroviral resistance was shown 
. Throughout the whole study period, 5% of patients received regimens in violation with these recommendations. In a large cohort of HIV infected US veterans, it was found that between 1998 and 2004, no patient was treated with a regimen that violated protocols and that less than 3% of participants started a regimen with modest activity 
. The differences between studies comparing and evaluating ART guidelines might be explained by differences in HIV cohorts, but probably to a greater extent by variations in interpretation and use of international recommendations.
The baseline characteristics of the patients receiving violation combinations were of special interest, since it was suspected that these regimens might lead to a higher proportion of viral failures. In our study, these patients were more often female and highly educated. Even though it is unknown why these sub-populations were more likely to receive initial ART in violation of recommendations, physicians should be aware of these associations in order to avoid the prescription of these inferior regimens.. Highly educated patients may also have been more active in the negotiations regarding the choice of the initial treatment regimen with the physician, favouring sometimes regimens known to be of low virological efficacy. In their small study of self-reported initial treatment in a US-cohort of HIV infected women, Cocohoba et al. reported a significant association between the prescription of violation regimens in patients with a higher CD4 count and lower viral load at baseline 
. Similarly, we found that a CD4 cell count above 350 cell/µl was a predisposing factor for receiving such unfavorable regimens. Previous studies showed a high variability of ART prescription in relation to the year of treatment initiation, violation regimens being used more frequently in the early years of the combination ART era 
. In the SHCS, patients who started ART in the late 90's were significantly more likely to receive a violation regimen than those who started after 2000, possibly because of the physician's lack of experience with combination ART and international treatment recommendations. It also seems that the aim of suppressing viral load to levels below 50 copies/ml, was less prominent in the early years of combination ART, as shown by the significant proportion of dual ART regimens reported for the first period in this study.
In the SHCS, patients treated according to the IAS-USA recommendations between 1998 and 2007 were significantly more likely to achieve an undetectable viral load (<400 cp/mL) after one year, compared with those on a violation regimen. Importantly, patients on violation regimens were more likely to change their treatment to a different regimen during the first six months of ART. As a consequence, changes from a violation regimen to a recommended one might have had a positive impact on clinical outcomes in this sub-group of patients. This might have decreased the difference in virological outcome between patients on violation ART and those on recommended regimens. When the definition of an undetectable viral load was restricted to less than 50 copies/ml, the association between treatment group and virological outcome was not statistically significant. Even though this second definition is widely used in the clinical settings, it may not be appropriate in this context, as some patients might experience single episodes of low-level viremia, so-called blips, which often do not have any clinical consequences. Notably, IDU's and patients from Sub-Saharan Africa were less likely to have an undetectable viral load one year after treatment start compared to the other risk groups, even though they were not prescribed violation regimens more often. These associations have both been described in previous studies and might be explained by lower treatment adherence, as described in the SHCS by Glass et al. 
Another relevant finding of this study relates to the important role of the SHCS in the daily clinical management of HIV infected patients in Switzerland. Participants who started ART more than 3 months before being included in the SHCS were more often prescribed regimens in violation with the recommendations and were less likely to have an undetectable viral load after one year. Although this seems to support the management of HIV infected patients by physicians experienced in the field of HIV medicine, this finding could also be explained by differences in access to care or other socio-economic factors.Finally, immunological response to ART in patients on violation regimens showed a less favorable trend compared to CD4 recovery in patients on recommended initial ART, although the difference was not statistically significant in the multivariable model. As expected, younger patients and those with a low CD4 count at baseline had a better immunologic recovery than the others.
There are several limitations to this study. First, it has to be noted that our classification of the different initial ART regimens in the SHCS was based on expert judgement and not on pre-specified objective criteria. Second, detailed description of antiretroviral combinations is not available in every set of recommendations thus allowing for a wider range of treatments accepted in the different treatment categories depending on the year of release. Third, our statistical analyses rely on observational data, which leads to different types of bias. For example, data on patient history is only collected twice a year, and is therefore subject to recall bias. CD4 counts and viral load values were not always obtained exactly 12 months after ART initiation, the ones measured closest to this time period had to be used. Finally, the logistic regression models cannot be adjusted for every single existing confounder, which means that residual confounding has to be taken into account when interpreting the results. Finally, given the large amount of ART-related issues discussed in the IAS-USA treatment recommendations, we could not consider all determinants of ART prescription for our analyses. As a consequence, even though possible adverse events and pill count, for instance, should be considered when choosing the appropriate initial ART regimen, we decided to limit our analyses to the description of individual predictors for receiving violation regimens and the evaluation of the virological and immunological response to the different ART regimens.
In summary, our results show that in the SHCS, 5% of patients received initial regimens in violation with the IAS-USA recommendations. These patients were less likely to achieve viral load suppression after one year. Our results suggest that, in the context of constant increase in the number of therapeutic options and knowledge on specific drug-related side-effects and interactions, the release of updated treatment recommendations as well as the promotion of their use are important to guarantee the best possible care of HIV infected patients.