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Introduction: Our aims were to investigate the adherence to national guidelines of initial antiretroviral therapy (ART) in the Spanish multicenter CoRIS cohort during the years 2010-2015, to identify the reasons for the prescription of nonrecommended treatments, and to explore the role of institutional constraints to guideline compliance. Methods: ART regimens were classified as recommended, alternative or nonrecommended according to the guidelines. Physicians were asked the reasons for prescribing nonrecommended regimens. Factors associated with the prescription of non recommended regimens were assessed using multivariable logistic regression. Results: During the study period, 586 (10.7%) of 5479 patients who started ART were given a regimen not recommended in the guidelines. The most frequent reasons for prescribing nonrecommended regimens were: enrolment in clinical trials (43.3%), comorbidities and/or interactions (10.2%), pregnancy (8.7%), and cost (7.7%). Among 37 participating centers, 16 (43%), treating 3561 patients, reported limitations related with the cost of ART, and 20 (54%), treating 1365 patients, reported restrictions for prescribing at least one recommended antiretroviral. In multivariable analysis, a higher risk of receiving nonrecommended regimens was associated with male gender, HIV acquisition by heterosexual transmission, low viral loads, initiation of treatment during the years 2011 to 2015, and initiation of treatment in a center with restricted access to at least one antiretroviral drug. Conclusions: Compliance to clinical guidelines was high. A high proportion of centres reported cost limitations for ART or restricted access to at least one recommended antiretroviral drug, with a significant impact on the choice of initial regimens. (C) 2019 Elsevier Espafia, S.L.U. and Sociedad Espaliola de Enfermedades Infecciosas y Microbiologia Clinica. All rights reserved.

Background. Tenofovir is a potent inhibitor of human telomerase. The clinical relevance of this inhibition is unknown. Methods. NEAT001/ANRS143 is a randomized trial that showed noninferiority over 96 weeks of ritonavir-boosted darunavir plus raltegravir versus tenofovir disoproxil fumarate/emtricitabine in 805 antiretroviral antiretrovrial-naive HIV-infected adults. We compared changes in whole-blood telomere length measured with quantitative polymerase chain reaction in 201 randomly selected participants (104 raltegravir and 97 tenofovir disoproxil fumarate/emtricitabine). We performed multivariable estimative and predictive linear regression. Results. At week 96, participants receiving tenofovir disoproxil fumarate/emtricitabine had a statistically significant higher gain in telomere length than participants receiving raltegravir. Difference in mean telomere length change between groups (tenofovir disoproxil fumarate/emtricitabine minus raltegravir) from baseline to week 96 adjusted by baseline telomere length was 0.031 (P = .009). This difference was not significantly confounded by age, gender, known duration of HIV infection, CD4 (baseline/nadir), CD8 cells, CD4/CD8 ratio, HIV viral load (baseline/week 96), tobacco and alcohol consumption, statins, or hepatitis C. Conclusion. Antiretroviral-naive HIV-infected adults receiving ritonavir-boosted darunavir and tenofovir disoproxil fumarate/emtricitabine had a significant higher gain in blood telomere length than those receiving ritonavir-boosted darunavir and raltegravir, suggesting a better initial recovery from HIV-associated immunosenescence.

In a recent report, Balestrieri et al. (1) asserted that the effect of lamivudine (3TC) against human T-cell leukemia virus type 1 (HTLV-1) at therapeutic concentrations is seen mainly on cell proliferation, with little or no direct antiviral effect. These findings are supported by biochemical studies that have shown a high level of 3TC resistance by the reverse transcriptase (RT) of HTLV-1 (3). We and others have examined the efficacy of 3TC in HTLV-1-infected patients with HTLV-1-associated myelopathy-tropical spastic paraparesis (6, 8). In most of these patients, we saw a reduction in HTLV-1 proviral DNA load following several weeks of therapy. However, in almost all cases this decline in HTLV-1 viremia was transient and most patients regained baseline HTLV-1 load titers after a while. Despite experiencing virological failure, only silent mutations and few amino acid changes in the HTLV-1 RT could be recognized after extensive analyses, which hardly could explain high levels of 3TC resistance. Furthermore, none of the HTLV-1-positive patients examined so far have developed genetic changes during therapy with 3TC in the conserved LPQG (Q151 M) or YMDD (M184V) motifs, which are associated with resistance to this drug in other lentiviruses (7). Taken together, these data suggest that HTLV-1 RT presents primary resistance to 3TC, and codons other than 151 or 184 could be implicated. In human immunodeficiency virus type 1 (HIV-1), a novel set of mutations in the RT, E44D and V118I, has been reported to produce 3TC resistance in the absence of the M184V mutation (5). In order to examine the possible role of these mutations in HTLV-1, we compared the amino acid sequence of the pol gene of HTLV-1 (GenBank {"type":"entrez-nucleotide","attrs":{"text":"D13784","term_id":"221866","term_text":"D13784"}}D13784) and subtype B HIV-1 (HXB2; GenBank {"type":"entrez-nucleotide","attrs":{"text":"K03455","term_id":"1906382","term_text":"K03455"}}K03455). Alignment was performed with the CLUSTAL X program. Whereas the aspartic acid at residue 44 was not found in the HTLV-1 RT, 118I was recognized as the consensus amino acid in HTLV-1. In vitro studies of HIV-1 have shown that an isoleucine at position 118 decreases the rate of 3TC incorporation, and this reduction does not depend on the presence of classical AZT mutations (M. Girouard, K. Diallo, B. Marchand, S. McCormick, M. A. Wainberg, and M. Gotte, XI Int. HIV Drug Resist. Workshop, Seville, Spain, abstr. 26, 2002). Resistance to 3TC develops when less of the drug monophosphate gets incorporated into the nascent cDNA due to steric conformation changes in the RT. In contrast, resistance to AZT and many other nucleoside analogs develops mainly as result of pyrophosphorolysis, by which there is an increased excision and removal of the incorporated chain terminator nucleotides (2). The V118I mutation produces an alteration of the structure-dependent binding in the HIV-1 RT which translates into lower affinity for 3TC. Although HIV-1 and HTLV-1 share only ∼20% of amino acid sequence identity, their RT enzymes are quite similar. In fact, RTs from almost all lentiviruses share similar tertiary structures in palm and finger domains, in spite of high divergence in their amino acid residues (4). Taking into account all these considerations, the presence of an isoleucine at codon 118 could be in part responsible for a natural 3TC resistance by HTLV-1. Biochemical and site-direct mutagenesis studies should be conducted to confirm our hypothesis. In the meantime, for the benefit of patients with HTLV-1-associated myelopathy-tropical spastic paraparesis, antiretroviral therapy should no longer include 3TC.