To test for confounding variables influencing treatment outcome, the groups with and without virologically effective therapy were evaluated in a multivariate analysis. After adjustment for the parameters age, sex, ethnic origin, disease stage of AIDS, CD4 cell count, and viral load, detection of primary drug resistance was not associated with treatment outcome. This could be shown for on-treatment analysis considering a detection limit of 50 copies/mL after 24 weeks [P = 0.97; odds ratio (OR) 0.98; 95% CI, 0.3-2.8] and 48 weeks (P = 0.25; OR 1.75; 95% CI, 0.3-2.9). Moreover, a similar result was found considering a detection limit of 400 copies/mL for the time points of 24 weeks (P = 0.88; OR 1.29; 95% CI, 0.1-3.5) and 48 weeks (P = 0.80; OR 1.70; 95% CI, 0.1-2.2).
The values of CD4 cell counts were as follows: mean ± SD at baseline were 185 ± 157 cells/mL in the subgroup with primary resistance and 175 ± 160 cells/mL in the subgroup without (P = 0.33). After 24 weeks, CD4 cell count was 376 ± 166 cells/mL in the group with resistance and 310 ± 193 cells/mL in the group without (P = 0.14). After 48 weeks, CD4 cell count was 450 ± 238 cells/mL in the group with resistance and 361 ± 199 cells/mL in the group without (P = 0.13).
The RESINA project is an ongoing prospective multicenter study on epidemiology of primary HIV drug resistance and treatment outcome in Nordrhein-Westfalen, Germany. Between 2001 and 2003, we studied 269 treatment-naive, chronically HIV-infected patients starting HAART who were followed for 48 weeks in an open cohort in 33 centers. We found a prevalence of primary HIV drug resistance of 11.2% in treatment-naive patients before initiation of first-line HAART. Most mutations were seen for NRTI. Only a small proportion of subjects had virus resistant against NNRTI, PI, or multiclass resistance. The most important finding of the study was comparable efficacy of first-line HAART in the group with resistance and the group with wild-type HIV.
The epidemiologic data are consistent with results from different European countries. For example, the prevalence of'resistance against NRTI in chronically infected patients is 8.6% in this study, 8.0% in France,21 7.8% in Italy,16 and 7.5% in several European countries.17 Differences in epidemiology may be because of varying distribution of transmission route, subtype, or other patients characteristics as well as study design. The latter can be demonstrated, for example, with the inclusion of the V118I mutation into mutation scores. Although classified as resistance-associated mutation,33 it was shown not to be associated with reduced treatment success in a retrospective study.36 We regarded this mutation as resistance of significance in our data set because of the classification of the International AIDS Society panel. Furthermore, the outcome of patients defined as having resistance would have been artificially improved by its omission from the list, so a conservative decision was made to include it.
Subgroups of participants that were overrepresented in the population carrying resistant strains were patients with shorter duration of HIV diagnosis, patients with subtype B, and whites. These seem to be at risk for acquiring primary drug resistance. Up to now, only the Combined Analysis of Resistance Transmission Over Time of Chronically and Acute Infected HIV Patients in Europe study reported on risk groups, with a prevalence of baseline resistance of 11.3% in subjects carrying HIV subtype B compared with 3.3% with non-B subtypes (P < 0.001),17 matching our results. Altogether, the presented epidemiologic data underscore the importance of further surveillance of primary drug resistance with better standardization of methods.
Reports about inferior treatment outcome in patients harboring primary drug resistance have been presented in a growing number of studies.7,8,24,27-30 The first major investigation on this phenomenon was a retrospective study that showed an increased time to viral suppression and a reduced time to virologic rebound in the group with resistance.8 Further studies found a higher rate of virologic failure in the participants with baseline resistance.27-30 In one study, resistant virus before treatment was seen in 34% to 38% of patients with viral failure, and multivariate analysis identified baseline resistance as predictive for viral rebound.27,37 Another investigation found a suppression of viral replication in 27% and 63%, respectively, of patients with resistance and 45% and 82%, respectively, in patients with wild-type virus with P values of 0.05 and 0.02, depending on the applied detection limit.29 Because of varying study settings, the discussed findings cannot be easily translated into our data set. However, they point to a similar direction, raising serious concerns that first-line HAART administered independent of results of resistance testing may lead to a less effective virologic outcome. As discussed earlier, primary drug resistance has to be analyzed separately in trials on HAART in treatment-naive patients according to Food and Drug Administration regulations. Consequently, first-line HAART should be guided by resistance testing. We present data on the outcome of this treatment strategy, which is the first prospective trial on efficacy on resistance-adapted first-line HAART that suggests similar virologic outcome in both arms.
The patients experienced substantial immunologic benefit from HAART. CD4 cell count rose from about 180 to more than 360 cells/μL after 48 weeks. The difference at baseline was small between the groups with and without resistance, but there was a more pronounced increase in the group with resistance compared with the group without that did not reach statistical significance. The different immunologic response may be because of the different distribution of baseline characteristics in the 2'groups, as shown in Table 1. Moreover, the knowledge that resistant virus was found may have resulted in a higher adherence level in the group with baseline resistance.
In summary, our study demonstrates similar virologic and immunologic efficacy of first-line HAART guided by genotypic resistance testing in patients harboring primary resistance as compared with patients with wild-type virus. This finding is in contrast with several trials reporting inferior efficacy of HAART in patients with primary'resistance who received a treatment combination independent of results of genotyping. Our findings contribute to the'growing body of literature on the value of genotypic resistance testing in HAART-naive patients before application of first-line'therapy.
Most HIV specialists of the largest state in Germany worked together for this prospective study. By covering a defined geographical region, selection bias is likely to be low in our investigation. The number of participants allows for an estimate of primary HIV drug resistance in chronically infected HIV-positive patients with a narrow confidence interval, which is an important parameter that has been requested by several scientists.25,26 One limitation of the trial is the open design of treatment evaluation, which may result in a bias of efficacy data because the patients were treated in clinical routine within a prospective cohort. As a consequence, a randomized controlled trial may help determine the true value of resistance-adapted first-line HAART. However, the documented negative impact of primary resistance on treatment outcome in retrospective studies raises ethical concerns about this approach. Moreover, the approximate prevalence of primary resistance of about 11% would require an enormous study population to prove equivalence of treatment strategies. Another limitation of this study is the heterogeneity of the population investigated. As shown in Table 2, the spectrum of mutations and administered HAART regimens was diverse; thus, it is difficult to compare with other trials. A more defined study population with specific genotypic results and treatment combinations would result in a reproducible data set. However, because of the prevalence of 11%, this limitation is difficult to deal with because a very large study population would again be required to produce a subgroup with similar characteristics. Another bias is the lack of data on therapeutic drug monitoring and adherence levels, which have been included into the protocol later. Finally, the'limitations of the method of genotypic resistance testing have'to be taken into account. Because only the predominant quasi-species can be evaluated with the applied method, minor variants may not have been detected. This finding was described recently38 and leads to the concern that the determined prevalence may be an underestimation. Despite these limitations, the prospective application of genotyping for combining HAART compounds is a new approach to improve first-line therapy. In doing this, our study tries to enhance the knowledge about the clinical relevance of primary resistance and may help define rational application of genotypic resistance testing. Further investigations on epidemiology and impact on therapy for primary HIV drug resistance are needed.
Primary HIV drug resistance is a problem of significant public health impact. Based on our observations, 3'conclusions should be drawn. First, the determined prevalence of primary resistance in this study region and in data from other countries makes continuing surveillance of this phenomenon necessary. Second, because of good efficacy of first-line HAART guided by resistance testing especially in the population with primary resistance, this method should also be considered in clinical routine. More data on this topic have to be collected. Third, to prevent transmission of resistant virus, all efforts should be made to enhance effectiveness of HAART regimens.
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The following were participants in the RESINA Study Team:
Arbter P, Krefeld; Becker-Boost I, Duisburg; Bifolchi-Schons S, Düsseldorf; Busch H, Christensen S, Münster; Carls H, Mauss M, Schmutz G, Düsseldorf; Gantke B, Düsseldorf; Fätkenheuer G, Köln; Ferdinand K, Köln; Hartmann P, Gippert, Quaing, Münster; Heese C, Münster; Herrmann S, Köln; Isernhagen K, Römer K, Köln; Kaiser R, Pfister H, Köln; Knechten H, Aachen; Kwirant F, Duisburg; Marder U, Düsseldorf; Mauruschat S, Wuppertal; Miasnikov V, Düsseldorf; Moers JD, Köln; Mutz A, Osnabrück; Oette M, Häussinger D, Düsseldorf; Reith M, Düsseldorf; Rieke A, Koblenz; Rockstroh JK, Bonn; Sandmann D, Wuppertal; Schäfer E, Bielefeld; Schmalöer D, Dortmund; Schoelzel S, Troisdorf; Scholten T, Hagen; Schumacher T, Mitrenga D, Köln; Schuster DK, Wuppertal; Stechel J, Köln; Theisen A, Wiesel W, Köln; Wichmann M, Köln.