Immune and virologic responses to Truvada or Combivir as a first-line therapy of HIV-infected, treatment-naïve patients

Methods 107 HIV-infected, ARV-naive patients were prospectively enrolled and treated with TVD (300 mg TDF + 200 mg FTC QD) or CBV (300 mg AZT + 150 mg 3TC BID) in combination with EFV (600 mg QD) or a PI (LPV/r, ATV/ r, fAPV/r and SQV/r). Twenty-seven patients received TVD-EFV, 33 received TVD-PI, 24 received CBV-EFV, and 23 received CBV-PI. Fifty-one of these patients have, so far, reached 12 months of therapy. Clinical, immunological and virologic parameters at baseline and after 12 months of therapy are presented

TLR Activation Pathways in HIV-1-Exposed Seronegative Individuals

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Plasma and PBMC miRNA profile in sexually HIV-1 exposed seronegative individuals

Background: MicroRNAs (miRNAs) are small 20- to 24-nt non-coding RNAs involved in the post-transcriptional regulation of gene expression which play important defensive roles in several viral infections. Global expression profiles of cellular miRNAs have identified alterations of specific miRNAs post-HIV-1 infection both in vitro and in different patient cohorts suggesting potential roles for miRNA in pathogenesis and disease progression. We therefore decided to verify if natural resistance to HIV-1 infection observed in seronegative individuals repeatedly exposed to HIV-1 (HESN) through unprotected sexual intercourse could be secondary to a different expression of their miRNA profile. Methods: Expression levels of 25 miRNAs selected according to their proven anti-HIV-1 properties were analyzed in plasma, basal PBMC and in in vitro HIV-1 infected macrophages isolated from 30 HESN, 30 HIV seropositive subjects (HIV + ) and 30 healthy controls (HC).Results: In plasma the expression of mir-155, mir-382, mir-28 and mir-198 was significantly augmented in both HIV + and HESN compared to HC probably as a consequence of viral exposure. Conversely the expression of mir-223 and mir-150 in plasma was significantly increased only in HESN and this result was also confirmed in basal PBMC suggesting a protective effect for these miRNAs in resistance to HIV-1 infection. Furthermore, the expression of mir-150 was significantly increased in HESN macrophages following HIV-1 infection. Conclusions: mir-223 and mir-150 can target the 3\ua2UTR of HIV-1 transcripts, and they have already been identified as anti-HIV-1 miRNAs. The higher expression of these miRNA in HESN samples could therefore represent a key protection mechanism against HIV infection

Antiretroviral treatment efficacy after mutations reversion during T20 monotherapy, an alternative strategy in multi-failed HIV-1 infected patients

Purpose of the study Monotherapy maintenance with 3TC after multiple therapeutic failure, helps in maintaining the number of CD4, but, at the same time, slows down the speed of reversion of mutations usually achieved during complete interruption of therapy. Monotherapy with enfuvirtide (T20) can be an interesting alternative to 3TC monotherapy, due to the CD4-enhancement typical of this drug even during therapeutic failure. Aim of this study was to assess, in a proof-of-concept study, the efficacy of T20-monotherapy to maintain the levels of CD4, to allow reversal of mutations in the pol gene, and eventually to favor long-term success of subsequent HAART

IL4 primes the dynamics of breast cancer progression via DUSP4 inhibition

The tumor microenvironment supplies proinflammatory cytokines favoring a permissive milieu for cancer cell growth and invasive behavior. Here we show how breast cancer progression is facilitated by IL4 secreted by adipose tissue and estrogen receptor-positive and triple-negative breast cancer cell types. Blocking autocrine and paracrine IL4 signaling with the IL4R\uce\ub1 antagonist IL4DM compromised breast cancer cell proliferation, invasion, and tumor growth by downregulating MAPK pathway activity. IL4DM reduced numbers of CD44+/CD24-cancer stem-like cells and elevated expression of the dual specificity phosphatase DUSP4by inhibiting NF-\uce\ubaB. Enforced expression of DUSP4 drove conversion of metastatic cells to nonmetastatic cells. Mechanistically, RNAi-mediated attenuation of DUSP4activated the ERKand p38 MAPK pathways, increased stem-like properties, and spawned metastatic capacity. Targeting IL4 signaling sensitized breast cancer cells to anticancer therapy and strengthened immune responses by enhancing the number of IFN\uce\ub3-positive CTLs. Our results showed the role of IL4 in promoting breast cancer aggressiveness and how its targeting may improve the efficacy of current therapies

Is HCV elimination among persons living with HIV feasible? Data from the NoCo study in the setting of the ICONA cohort

Background and Aims: Whether the HCV test-and-treat strategy impacted on the rate of new HCV infections among PLWH in Italy is unknown. Methods: Prospective study of PLWH in the ICONA network. At baseline, PLWH were tested for HCV-Ab; HCV-RNA (if HCV-Ab positive) and, if positive, treated with DAA. SVR12 indicated eradication. Seroconversions and re-infections were evaluated yearly in HCV-Ab neg and HCV-RNA neg at first screening. We estimated the following: HCV seroconversions, incidence of HCV reinfections, and access to DAA and SVR12 rates tighter with factors associated with each outcome. Data were analysed by Cox regression, Poisson regression and logistic regression models. Results: Sixteen thousand seven hundred and forty-three PLWH were included; 27.3% HCV-Ab positive; of these, 39.3% HCV-RNA positive. HCV seroconversion incidence:.48/100 PYFU (95% CI:.36–.65); re-infections incidence: 1.40/100 PYFU (95% CI:.91–2.04). The risk factor for HCV re-infection was young age: aIRR 1.85, 95% CI: 1.17–2.95) per 10 years younger. 86.4% of HCV viremic in follow-up started DAA. PWID vs. heterosexuals (aHR.75, 95% CI.62–.90), HIV-RNA >50 copies/mL (aHR.70, 95% CI.56–.87), HCV genotype other than G1, G2, G3, G4 or with multiple/missing HCV genotype and post-COVID-19 calendar periods were associated with lower DAA access. 922/965 (95.5%) PLWH achieved SVR12. We estimated 72% reduction of chance to achieve SVR12 in PLWH with a CD4 count <200/mm3 (vs. CD4 ≥200/mm3 aOR.18, 95% CI:.07–.46). 95.5% of DAA-treated individuals eradicated HCV, but they represent only 53.2% of HCV viremic PLWH and 66.4% of those in follow-up. HCV-RNA positivity by year decreased from 41.7% in 2017 to 11.7% in 2022. Conclusions: The screening-and-treat campaign implemented in Italy, even if only partially effective, resulted in a dramatic drop in HCV circulation in our cohort

Characterization and outcomes of difficult-to-treat patients starting modern first-line ART regimens: Data from the ICONA cohort

OBJECTIVE: Treatment failures to modern antiretroviral therapy (ART) raise concerns, as they could reduce future options. Evaluations of occurrence of multiple failures to modern ART are missing and their significance in the long run is unclear. METHODS: People with HIV (PWH) in the ICONA cohort who started a modern first-line ART were defined as ‘difficult to treat’ (DTT) if they experienced ≥1 among: i) ≥2 VF (2 viral loads, VL>200 copies/mL or 1 VL>1000 copies/mL) with or without ART change; ii) ≥2 treatment discontinuations (TD) due to toxicity/intolerance/failure; iii) ≥1 VF followed by ART change plus ≥1 TD due to toxicity/intolerance/failure. A subgroup of the DTT participants were matched to PWH that, after the same time, were non-DTT. Treatment response, analysing VF, TD, treatment failure, AIDS/death, and SNAE (Serious non-AIDS event)/death, were compared. Survival analysis by KM curves and Cox regression models were employed. RESULTS: Among 8061 PWH, 320 (4%) became DTT. Estimates of becoming DTT was 6.5% (95% CI: 5.8–7.4%) by 6 years. DTT PWH were significantly older, with a higher prevalence of AIDS and lower CD4+ at nadir than the non-DTT. In the prospective analysis, DTT demonstrated a higher unadjusted risk for all the outcomes. Once controlled for confounders, significant associations were confirmed for VF (aHR 2.23, 1.33–3.73), treatment failure (aHR 1.70, 1.03–2.78), and SNAE/death (aHR 2.79, 1.18–6.61). CONCLUSION: A total of 6.5% of PWH satisfied our definition of DTT by 6 years from ART starting. This appears to be a more fragile group who may have higher risk of failure