AF Capetti, S Di Giambenedetto, A Latini, G Sterrantino, I De Benedetto, MV Cossu and A Gori Ospedale Luigi Sacco-Polo Universitario, Milano, Lombardia, Italy, 2° Divisione di Malattie Infettive, Universit~ A Cattolica del Sacro Cuore, Roma, Italy, Unit of Infectious Dermatology, San Gallicano Hospital, Rome, Italy, Infectious Diseases Unit, Careggi University Hospital, Florence, Italy and Azienda Ospedaliera San Gerardo, Monza, Lombardia, Italy

7-11 November 2010, Tenth International Congress on Drug Therapy in HIV Infection, Glasgow, UK 15-30% of HAART-treated HIV-1-positive patients (pts) lack CD4+ increase despite full HIV viremia suppression. The increased risk for INR to progress till AIDS led us to investigate maraviroc (MVC) as a tool to intensify HAART in terms of immunological recovery. Randomised, multicentre, proof-of-concept study enrolling 100 pts divided into 2 arms (1:1), A:HAART+MVC, B:HAART. Inclusion criteria were: CD4 count ≥200 cells/µL and/or a recovery of CD4 cells <25% compared to the HAART initiation and with a stable virologic suppression after 1 year of HAART. Ultrasensitive HIV-RNA was quantified via Amplicor HIV-1 Monitor Kit v1.5. Naive CD45RA+, memory CD45RA-, activated HLA-DR+CD38+, proliferating Ki67+, CD4+, CD8+ T-cells were measured by flow cytometry. T-test was used for intra and inter-group comparisons. 100 pts have been randomized 64 pts reached week(w) 12: 37 in A and 27 in B arms. At baseline (BL), CD4/CD8 and immune-phenotype were comparable in arm A and B. At w12 no significant changes in mean CD4 recovery (+41.9 vs +24.5/µL; p=.241) and a statistically significant change in mean CD8+ count (+164.2 vs -27.3/µL; p=.004) were observed between pts in arm A and B. At BL and w12 an immunological study was carried out in 24 pts (13:arm A, 11:arm B): at w12, while B pts experienced a contraction of naïve CD4 (81 to 67%; p=.02) and CD8 (81 to 77%; p=.04) with a parallel rise in memory CD4 (16 to 30%; p=.02) and CD8 (13 to 17%; p=.06), no significant loss of naive CD4 (70 to 57%; p=.18) and CD8 (69 to 66%; p=.42) was displayed by A pts with a tendency to higher gain in memory CD4 (24 to 40%; p=.06) and CD8 (11 to 25%; p=.008). By w12, a similar reduction in activated HLA-DR+CD38+ CD8 and CD4 was shown in B (p=.05) and A pts (p=.03 and p=.02 for CD8 and CD4). A trend to Ki67+CD8 reduction was shown in A (p=.06) and not in B pts (p=.45). HIV-RNA quantification evidenced a trend to higher median values (BL vs w12) in B pts: 2 vs 5 cp/mL (p=.37). MVC does not seem to increase CD4 amount at significant level compared to arm B. Treatment with MVC is associated with a significant CD8+ gain, a preservation of phenotypically naïve CD4+ and parallel rise of memory pool, suggesting a role of MVC in reducing peripheral antigen-driven T-cell death, possibly preserving new T-cell production. MVC is able to further reduce T-cell activation and proliferation, suggesting a possible influence in better controlling the pro-inflammatory status. We acknowledge the participation of all investigators of the HSL/MVC01/2008 Study Group (NCT00884858).

7‐11 November 2010, Tenth International Congress on Drug Therapy in HIV Infection, Glasgow, UK

The impact of drug resistance mutations on viral fitness is one of the main issues being investigated in HIV therapy. Some, such as M184V, seem to reduce the replicative capacity of HIV [1], whereas others, such as thymidine analogue-related mutations, seem to potentiate virulence [2], and persist in the blood for years after the removal of selective pressure [3]. We report a case of an HIV-infected patient whose prevalent viral population continued to carry the K103N mutation for more than 7 years after a 2-year treatment with zidovudine and lamivudine plus loviride despite subsequent changes in therapy with the absolute exclusion of non-nucleoside reverse transcriptase inhibitors (NNRTI). M.N., a 50-year-old woman, a drug addict from 1976 to 1994, was diagnosed with HIV infection in 1984 and AIDS in 1994. On 30 May 1995, she was enrolled in the AVANTI-1 trial and randomly assigned to zidovudine and lamuvidune plus loviride (α-APA, an NNRTI that was not subsequently developed for insufficient potency in vivo). At the end of the trial the patient showed sustained benefit and passed to the Italian Expanded Access Program for loviride, LOV-INT-13. In February 1997, her viral load having risen to 28 000 copies/ml and CD4 cells fallen to 280 cells/mm3, the patient switched to stavudine and lamuvidine plus nelfinavir, with an immediate virological response (< 500 copies/ml, Chiron branched DNA (Chiron Corp., Emeryville, CA, USA), at week 4). After 2 years of such therapy the patient's adherence worsened, and she had a new virological rebound to 18 000 copies/ml and then to 42 000 copies/ml (May 1999). She switched to stavudine plus didanosine and ritonavir 100 mg twice a day plus indinavir 800 mg twice a day, and responded very well (< 80 copies/ml, nucleic acid sequence-based amplification, at week 4). We did not trust to recycle NNRTIs according to what has been reported in the literature. In May 2000, the patient experienced xeroderma with erysipelas of the feet, which relapsed after appropriate therapy. Highly active antiretroviral therapy was discontinued despite full viral suppression, and a resistance test by TruGene was performed after one week, on a viral load of 62 000 copies/ml. The patient was switched to stavudine plus lamivudine and ritonavir 100 mg twice a day plus saquinavir hgc 1000 mg twice a day, once again with full viral suppression (< 50 copies/ml, branched DNA), but after 3 years she started to take the therapy incorrectly, being tired of it, showing a low-level rebound of the virus (below 1000 copies/ml). Attempts with atazanavir and kaletra resulted in a failure to re-establish the drugs because of a full-blown psychological crisis. On 18 February 2004, her viraemia had reached 14 454 copies/ml, and a new genotype was performed using the same method. The genotypic results are shown in Table 1.Table 1: Resistance mutations from patient M.N.The persistence of NNRTI resistance mutations after treatment discontinuation was first described by Miller et al. [4] in 24 patients treated with loviride, and followed by various studies [5]. Various attempts to prevent the vertical transmission of HIV in developing countries showed how easy it is to obtain NNRTI resistance mutations, including the K103N mutation [6]. We felt that the persistence of this mutation for 7 years after the discontinuation of an NNRTI and despite subsequent NNRTI-sparing treatment lines might suggest a greater fitness of this strain and might deserve a report. As commercial NNRTI came into clinical use 6–7 years ago, we will check the status of the other patients who failed on these drugs at least 3 years ago.