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Human T cell lymphotropic virus type 2 (HTLV-2) infection is endemic in the American Indian population and Pygmy tribes in Africa. Nevertheless, HTLV-2 infection has been predominantly detected in U.S. and European injecting drug users (IDU). Noteworthy is that the HTLV-2a subtype is the main circulating variant in North America and Eastern Europe whereas the HTLV-2b subtype is mainly found in Western Europe, particularly in Italy and Spain where coinfection with HIV-1 is frequent. Twelve Spanish subjects infected with HTLV-2 were recruited for the study. All of them were IDUs coinfected with HIV-1. Molecular epidemiology was done by sequencing the LTR, env, and tax regions and by generating phylogenetic trees. The present study showed that all the sequences belonged to the HTLV-2b subtype and were closely related to other Spanish and Portuguese reported sequences, clearly differentiated from those belonging to the HTLV-2a subtype from Eastern Europe. Therefore, infection with HTLV-2b remains prevalent in Spain based on previous studies.

The objective of this study was to evaluate the activity of efavirenz after the failure of a nevirapine-containing regimen. This prospective study included 47 patients with plasma HIV loads >1000 copies/ml, and who had received nevirapine for at least 16 weeks, included in an efavirenz-based salvage regimen. The main outcome measure was virological response, defined as an HIV RNA level decrease of at least 1 log(10) copies/ml after 24 weeks, according to genotypic and phenotypic resistance to efavirenz. Phenotypic resistance was defined as a >10-fold increase in the IC(50). The median CD4(+) cell count was 236 x 10(6)/liter and the median HIV RNA level was 4.5 log(10) copies/ml. Mutations known to decrease susceptibility to nonnucleoside reverse transcriptase inhibitors were observed in 79% of patients, predominantly at residues 181 (49%), 103 (40%), and 106 (19%), but phenotypic resistance to efavirenz was seen in 62% of cases. All the strains with the K103N mutation showed high-level resistance to efavirenz, in contrast with 20% of those carrying exclusively the Y181C mutation. By week 24, 38% of patients had responded and 19% had achieved an undetectable HIV load. Virological failure was observed in patients with phenotypic resistance to efavirenz (67 vs. 11%; relative risk [RR], 4; 95% confidence interval [CI], 1.07-14.89; p = 0.04), or in presence of the K103N mutation (52 vs. 17%; RR, 1.77; 95% CI, 1.12-2.79; p = 0.02), and these results remained unchanged after adjusting for HIV load, or by resistance to the accompanying drugs in the salvage regimen. A previous longer period of nevirapine therapy was significantly associated with the emergence of efavirenz resistance (288 vs. 170 days, p < 0.01). We conclude that genotypic and/or phenotypic resistance assays permit the sequential use of nonnucleoside reverse transcriptase inhibitors in the clinical setting. Our data suggest that an early change after nevirapine failure could avoid the emergence of efavirenz resistance.

Cross-resistance to nelfinavir (NFV) is observed in patients failing protease inhibitor (PI)-containing therapies. We performed a study with 111 patients who started an NFV-based salvage regimen after failing PI-based therapy to evaluate genotypic changes and to identify factors associated with resistance to NFV. Genotypic and phenotypic resistance data at entry (111 and 51 samples) and after NFV failure (74 and 31 samples) were available. Median CD4(+) cell count was 208 x 10(6)/liter, HIV RNA level was 4.6 log(10) copies/ml, and median number of mutations in the protease was 9. At baseline, 51 and 14% of viral isolates showed high or intermediate phenotypic resistance to NFV. Phenotypic data correlated with virological outcome, reaching undetectability at the third month in 40, 14, and 0% of those patients with susceptible, intermediate, or resistant viral isolates, respectively. Phenotypic resistance to NFV was associated with the presence of the L90M mutation: 46% for resistant vs. 6% in susceptible strains. The number of mutations in the protease correlated with the fold-increase in the IC(50)-NFV. The D30N mutation was detected in only 1 of 74 patients who failed. In a logistic regression analysis, the number of mutations in the protease was associated with NFV cross-resistance (RR, 2.09 per each additional mutation; 95% CI 1.23-3.55; p < 0.01). In conclusion, phenotypic cross-resistance to NFV for PI-experienced patients can be predicted by the number of mutations in the protease. The L90M mutation is significantly associated with the subsequent failure of NFV-containing regimens. The presence of the D30N mutation was rare and not useful in identifying NFV-resistant isolates.

The high rate of protease inhibitor treatment failure in clinical cohorts makes it necessary to define novel salvage therapies. In a prospective study of 31 HIV-infected patients included in a salvage regimen with stavudine, nevirapine, nelfinavir, and saquinavir, viral load decreased a median of 1.65 log(10) and 1.95 log(10) after 6 and 12 months of treatment, respectively, and 35 and 56% of patients had an HIV RNA level below 50 copies/ml at the same time points. At baseline, the mean number of mutations in the protease gene was 10 (2-19), and the V82A and L90M mutations were present in 54 and 21% of patients. The presence of the V82A mutation did not affect significantly the rate of response (36 vs. 38%), whereas the L90M mutation was associated with treatment failure (0 vs. 43%). Plasma trough levels of nelfinavir (NFV) and saquinavir (SQV), in a twice daily dosing regimen, were above the protein-corrected IC(95) in most patients despite the addition of an enzymatic inducer such as nevirapine, and peak levels were 2- and 5-fold increased with respect to standard doses. However, pharmacokinetics of saquinavir-hard gel capsule (SQV-hgc) did not improve significantly in the three times daily dosing regimen. In conclusion, the combination of stavudine, nevirapine, nelfinavir, and saquinavir increased plasma drug levels and produced an adequate virological response in patients who had failed indinavir or ritonavir therapy. This degree of response is not significantly decreased in the presence of genotypic mutations associated with indinavir/ritonavir (IDV/RTV) resistance.