In a small percentage of persons infected with human immunodeficiency virus type 1 (HIV-1), there is no progression of disease and CD4+ T-cell counts remain stable for many years. Studies of the histopathological, virologic, and immunologic characteristics of these persons may provide insight into the pathogenic mechanisms that lead to HIV disease and the protective mechanisms that prevent progression to overt disease.

We compared the immunological and clinical outcomes of lamivudine monotherapy and complete therapy interruption in the treatment of HIV-1-infected patients harbouring lamivudine-resistant virus. This 48-week, open-label pilot study randomly assigned HIV-infected patients receiving lamivudine-containing HAART and harbouring the M184V mutation to monotherapy with lamivudine 300 mg once daily (lamivudine group) or the discontinuation of all antiretroviral drugs (TI group). The primary endpoint was the occurrence of immunological or clinical failure; immunological failure was defined as the first report of a CD4 T-cell count less than 350 cells/μl, and clinical failure as the occurrence of a Centers for Disease Control and Prevention grade B or C event. The data were analysed on the basis of the intention-to-treat principle. By week 48, 20 of 29 patients in the TI group (69%; 95% CI 51–83%) and 12 of 29 in the lamivudine group (41%; 95% CI 26–59%) had discontinued the study because of immunological or clinical failure, which was significantly delayed in the lamivudine group (P = 0.018). Only patients in the TI group (6/29, 20.7%) experienced grade 3–4 clinical adverse events at least possibly related to HIV-1 (P = 0.02). The mean decline in CD4 cell percentage, viral rebound and recovery of HIV-1 replication capacity were significantly lower in the lamivudine group. The 24-week virological and immunological response after therapy resumption in patients who prematurely discontinued the study was similar in the two groups. In HIV-1-infected patients harbouring a lamivudine-resistant virus, lamivudine monotherapy may lead to a better immunological and clinical outcome than complete therapy interruption.

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Seventy to 40% of K‐RAS wild type colorectal tumors does not seem to benefit from treatment with antiepidermal growth factor receptor (anti‐EGFR) monoclonal antibodies. Recent data suggested that in presence of IGF‐1 system, altered activation colorectal cancer cells may escape anti‐EGFR mediated cell death. The interaction between IGF‐1 expression and K‐RAS mutational analysis was tested to verify the ability of IGF‐1 to identify a subgroup of patients more likely to benefit from EGFR‐targeted antibodies treatment. IGF‐1 expression and K‐RAS mutational status was assessed in advanced colorectal cancer patients receiving irinotecan/cetuximab. One hundred twelve patients were analyzed. IGF‐1 was negative in 30 patients (27%) and overexpressed in the remaining 82 cases (73%). In IGF‐1 negative and IGF‐1 positive tumors, we observed progressive disease in 9 (30%) and 55 (67%) patients, respectively (p = 0.001). Median progression‐free survival was 7.5 mo in patients showing IGF‐1 negative tumors and 3 mo for IGF‐1 expressing tumors (p = 0.002). Among K‐RAS wild type patients, IGF‐1 negative and positive tumors showed a partial response to cetuximab‐irinotecan in 13 (65%) and 11 (22%) cases, respectively (p = 0.002). Median progression‐free survival in IGF‐1 negative tumors was 10 mo and 3.2 mo in IGF‐1 positive colorectal cancers (p = 0.02). IGF‐1 proved to be a possible predictive factor for resistance to anti‐EGFR monoclonal antibodies in K‐RAS wild type colorectal cancer. Combined IGF‐1 and K‐RAS analysis may represent an effective strategy for a better selection of responding colorectal cancer patients.

The human immunodeficiency virus type 1 (HIV-1) fusion inhibitor enfuvirtide has recently been introduced into clinical practice and has exhibited efficient anti-HIV-1 activity in combination with other antiretroviral agents. In the present study, we addressed the effect of long-term treatment with enfuvirtide on the intrahost evolution of HIV-1. The genotype and phenotype patterns and the relative replication capacity (rRC) of enfuvirtide-resistant HIV-1 mutants were evaluated in samples from 11 subjects (7 virological nonresponders and 4 responders) who received the compound for more than 1 year in combination with different regimens. Selection of one or more mutations clustering in a sequence (amino acids 36 to 45) of the gp41 N-terminal heptad repeat was observed in samples from the seven virological nonresponders but not in those from responders. In two subjects who discontinued enfuvirtide, reversion of the resistant genotype was detected within 3 months. Recombinant clones bearing mutated gp41 sequences displayed reduced susceptibilities to enfuvirtide, with the 50% inhibitory concentrations (IC₅₀s) ranging from 0.6 to 12.8 μg/ml, whereas the IC₅₀ for isolates with baseline sequences was 0.013 ± 0.010 μg/ml. Interestingly, long-term monitoring of resistant variants provided evidence that ongoing adaptation to the drug is paralleled by phenotypic changes. A limited drop in the rRC in the absence of drug was observed for clones from four of the seven nonresponders bearing mutations associated with resistance. Overall, the data indicate that the different genotype patterns associated with a detectable degree of HIV-1 resistance to enfuvirtide generated during long-term treatments are characterized by a substantially low genetic barrier, possible ongoing adaptation with increased degrees of resistance, and limited influence on the viral rRC.