Alessandra Tartaglia

Co-receptor switch during HAART is independent of virological success.

The influence of antiretroviral therapy on co‐receptor tropism remains controversial. To verify if co‐receptor tropism shift was affected by HAART, the evolution of proviral DNA V3 genotype after 12 months of a new antiretroviral regimen was compared between responder and non‐responder patients. Baseline blood samples were collected from 36 patients infected with HIV‐1 subtype‐B (18 naïve and 18 experienced) for virus isolation and env V3 genotyping from plasma HIV‐1 RNA and PBMC DNA. DNA V3 genotyping was repeated after 12 months from initiating HAART. WebPSSM was used for categorizing V3 sequences into X4 or R5; for analysis purposes, dual/mixed viruses were considered as X4. From the 10 (28%) patients changing their proviral DNA V3 genotype during therapy, six shifted from R5‐to‐X4 and four from X4‐to‐R5. The lack of reaching virological suppression was not associated with an X4‐to‐R5 (P = 0.25) or R5‐to‐X4 (P = 0.14) shift; time‐to‐viral suppression and CD4 increase were similar in both groups. No association was found between tropism shift and patient baseline characteristics including age, sex, CDC stage, CD4 count, viral load, exposure and length of previous HAART, enfuvirtide use in the new regimen, number of reverse transcriptase and protease resistance‐associated mutations. Conversely, CD4 nadir was correlated to emergence of X4 virus in proviral DNA (mean 27.2 ± 30.6 in R5‐to‐X4 shifting patients vs. 161.6 ± 150.6 in non‐shifting patients, P = 0.02). The occurrence of a tropism shift in both directions was independent of HAART use, irrespective of its efficacy. The CD4 count nadir was the only baseline characteristic able to predict an R5‐to‐X4 viral shift. J. Med. Virol. 81:2036–2044, 2009.

Early and Sustained Virological Response in Non-Responders with Chronic Hepatitis C

AbstractObjectives: The purpose of this randomized open-label study was to assess the efficacy of treatment with pegylated interferon-α-2a versus pegylated interferon-α-2b, both plus ribavirin, in inducing early and sustained virological response (EVR and SVR) in chronic hepatitis C non-responders. Patients and methods: A total of 108 patients with chronic hepatitis C who were non-responders to previous combined therapy (standard interferon-α plus ribavirin for ≥3 months) were enrolled and equally randomized into two groups in this intention-to-treat analysis. The patients exhibited similar baseline features. One group received subcutaneous pegylated interferon-α-2a 180 μg once weekly, while the other was treated with subcutaneous pegylated interferon-α-2b 1.5 μg/ kg once weekly. Ribavirin 15 mg/kg/day was included in both protocols. Treatment duration for EVR was 12 weeks. Patients who demonstrated non-detectable hepatitis C virus (HCV) RNA or a ≥2 log10 reduction in viral load at week 12 continued therapy up to 48 weeks, with assessments every 3 months during a follow-up of 24 weeks. Results: All patients in both groups completed the EVR study, then seven patients receiving pegylated interferon-α-2a and seven patients receiving pegylated interferon-α2b discontinued treatment as a result of severe adverse effects. After 12 weeks of treatment, viral load reduction was >2 log10 with both pegylated interferon-α-2a (−2.53) and pegylated interferon-α-2b (−2.48) with no significant difference. At the end of week 48, HCV RNA was undetectable in 14 of 54 patients (25.9%) receiving pegylated interferon-α-2a and in 15 of 54 patients (27.7%) receiving pegylated interferon-α-2b. When terminating follow-up, an SVR was observed in 11 of 54 patients (20.4%) who received pegylated interferon-α-2a and 10 of 54 patients (18.4%) receiving pegylated interferon-α-2b. The incidence and severity of adverse events was similar in both groups. Conclusions: Our results seem to show that in chronic hepatitis C patients who are non-responsive to previous therapy, EVR to the two pegylated interferons did not significantly differ with a similar therapeutic efficacy defined as SVR.

Safety and effectiveness of a 12-week course of sofosbuvir and simeprevir ± ribavirin in HCV-infected patients with or without HIV infection: a multicentre observational study

The combination of sofosbuvir and simeprevir ± ribavirin (SOF + SMV ± RBV) for hepatitis C virus (HCV) treatment has been associated with high rates of sustained virological response (SVR). Few data are available regarding this regimen in HIV/HCV co-infected patients. This study evaluated the effectiveness and safety of a 12-week course of SOF + SMV ± RBV in a cohort of HCV monoinfected and HIV/HCV co-infected individuals. HCV-infected patients, with or without HIV infection, receiving a 12-week course of SOF + SMV ± RBV in four Italian centres from February to October 2015, were included in this retrospective observational study. Clinical and biochemical data were retrieved for all patients. A total of 88 individuals were evaluated: 29 (33.0%) HIV/HCV co-infected and 59 (67.0%) monoinfected. Most patients were males with HCV genotype 1b (62.5%) and 1a (25%) infection. RBV was used in 41 HCV monoinfected and 6 HIV/HCV co-infected patients. Cirrhosis was found in 67 patients (76.1%). The most common adverse events (AEs) were rash and/or pruritus (23.9%), fatigue (13.6%) and anaemia (9.1%). Serious AEs occurred in three patients (3.4%). No treatment discontinuations were observed. RBV use was associated with multiple AEs (P = 0.02). An overall SVR12 of 93.2% was achieved; 96.6% in HCV monoinfected and 86.2% in HIV/HCV co-infected individuals, without significance both in univariate (P = 0.09) and multivariate analyses (P = 0.12). A baseline platelet count ≥90 000/mm3 was associated with higher rates of SVR (P = 0.005). A 12-week course of SOF + SMV ± RBV was associated with good safety and high SVR12 rate both in HCV monoinfected and HIV-HCV co-infected individuals.

Both a protective and a deleterious role for the L76V mutation.

The L76V mutation, unknown in clinical isolates before 2001, has been described as associated with lopinavir resistance (LPV/r) (2, 6, 7), appearing to confer high levels of resistance to LPV and amprenavir; subsequently, it has also been included among darunavir resistance (DRV/r)-associated mutations (3). Lambert-Niclot et al. (5) suggested that the virological failure of a DRV/r-based regimen was due to the selection of mutations which, although increasing the level of DRV/r, did not affect tipranavir (TPV) susceptibility; moreover, L76V was found to be protective for the development of additional DRV-associated mutations. L76V has also been reported to increase TPV susceptibility (8, 9); nevertheless, the real clinical implication of this mutation in response to TPV-containing regimens is still unknown. We studied 176 human immunodeficiency virus type 1 (HIV-1)-infected multiexperienced patients previously exposed to a median of four protease inhibitors, who were administered a TPV resistance-based regimen. The impact on the TPV virological responses of both mutations included in the TPV mutation score (1, 4) and other protease mutations detected in >10% of the study population was evaluated. Virological success was defined as achieving a plasma viral load (pVL) of 1 log after 12 and 24 weeks of a TPV-based regimen. While no association between L76V and the virological outcome was observed using the pVL level of <50 cp/ml as the primary end point (unpublished data), when considering a pVL decrease of at least 1 log cp/ml, L76V correlated with virological response at week 12 (0.19 odds ratio [OR]; 0.04 to 0.86 95% confidence interval [CI]; P = 0.031) with univariate analysis. In the multivariate analysis, in which a stepwise estimation model with a backward procedure was used to select the set of mutations most strongly associated with virological response, three mutations (E34Q, I72VTL, and Q92K) were correlated with treatment failure, while L76V was still associated with virological success (0.04 OR, 0.01 to 0.31 95% CI, and P of 0.002 at week 12 and 0.18 OR, 0.036 to 0.088 95% CI, and P of 0.034 at week 24). Mutation I50LV, also associated with TPV hypersusceptibility, was detected in 7% of the patients and therefore was not included in the analysis. Furthermore, the CD4 nadir, the number of previous protease inhibitors, and CDC stage C classification were also significantly (P < 0.05) associated with virological failure. Therefore, the L76V mutation seemed to have a beneficial impact on virological response to TPV in our population with both analyses, thus extending the results of previous studies supporting the ability of L76V to resensitize HIV isolates to atazanavir and saquinavir (6). The molecular basis for this ambivalent behavior (which renders L76V either deleterious or protective) might depend on the particular location of residue 76 within the HIV protease. Because of its position in a secondary protein shell, residue 76 is directly in contact with the residues of the S2 pocket; while LPV, DRV, amprenavir, and indinavir develop a strong and penetrating hydrophobic binding within this pocket, atazanavir, saquinavir, and TPV do not deeply penetrate the shell, leading to no change or increased susceptibility (7). Our data strengthen the observations of Lambert-Niclot et al. (5), suggesting the noninvalidation of TPV susceptibility by DRV-associated mutations; in our experience, virological response to TPV benefited from the presence of L76V. In this respect, we agree with Lambert-Niclot et al., who stated that TPV may remain active after DRV use and that its presence could be useful to construct an optimal salvage regimen in multiexperienced patients.

Prolonged lamivudine treatment in patients with chronic active anti-HBe-positive hepatitis.

The efficacy of lamivudine (LAM) at 100 mg/d for 1 year in normalizing serum ALT levels and suppressing HBV DNA has been demonstrated in many studies. However, frequent relapses make long-term results modest. In the present study, we evaluated the efficacy of LAM administered for 3 years in patients with chronic active anti-HBe–positive hepatitis. Thirty-four patients with chronic active anti-HBe–positive hepatitis were treated with LAM (100 mg) once daily for 3 years. Before treatment, all patients demonstrated serum ALT levels >2 times normal levels for >6 months and HBV DNA positivity >5 pg/mL as determined by the sandwich hybridization test for nucleic acid. Both ALT and HBV DNA were monitored during therapy. After 12 months of therapy, 24 of 34 patients (70.6%) showed evidence of HBV DNA clearance and normal ALT levels; 22 of 34 (64.7%) and 19 of 34 (55.8%) patients maintained a complete response after 2 and 3 years of therapy, respectively. The long-term LAM therapy (>1 year) was not associated with an increase in the response of intially nonresponder patients. The YMDD variant emerged in 17.6% of patients in the first year, in 35.2% during the second year, and 52.9% during the third year of treatment. LAM was well tolerated during the 3-year therapy in all patients. Patients with chronic active anti-HBe–positive hepatitis demonstrated that the LAM response rate tends to decrease over time due to the emergence of YMDD variants.

Role of HCV infection in the development of carotid atherosclerosis in a cohort of HIV-infected patients

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