Late Relapse and Reinfection in HCV Patients Treated with Direct-Acting Antiviral (DAA) Drugs.

The risk of hepatitis C virus (HCV) recurrence after direct-acting antiviral (DAA) treatment is <0.5%. However, the distinction between HCV RNA late relapse and reinfection still represents a challenge in virological diagnostics. The aim of this study was to employ next-generation sequencing (NGS) to investigate HCV RNA recurrence in patients achieving a sustained virologic response (SVR) at least six months post-treatment. NGS was performed on plasma samples from six HCV-positive patients (Pt1-6) treated with DAA. NGS of HCV NS5B was analyzed before treatment (T0), after HCV RNA rebound (T1), and, for Pt3, after a second rebound (T2). Reinfection was confirmed for Pt5, and for the first rebound observed in Pt3. Conversely, viral relapse was observed when comparing T0 and T1 for Pt6 and T1 and T2 for Pt3. Z-scores were calculated and used to predict whether HCV-positive patient samples at different time points belonged to the same quasispecies population. A low Z-score of <2.58 confirmed that viral quasispecies detected at T0 and T1 were closely related for both Pt1 and Pt2, while the Z-score for Pt4 was suggestive of possible reinfection. NGS data analyses indicate that the Z-score may be a useful parameter for distinguishing late relapse from reinfection.

Clinical Relevance of Torque Teno Virus (TTV) in HIV/HCV Coinfected and HCV Monoinfected Patients Treated with Direct-Acting Antiviral Therapy.

Torque Teno virus (TTV) is a ubiquitous virus that causes chronic infection in humans with unknown clinical consequences. Here, we investigated the influence of TTV infection on HCV direct-acting antiviral (DAA) efficacy in HIV/HCV coinfected and HCV monoinfected patients as controls. Of 92 study patients, 79.3% were TTV DNA positive; untreated patients exhibited a significantly higher proportion of TTV DNA-positivity vs. sustained virological response (SVR) patients (100.0% vs. 65.2%, p < 0.001), while TTV positivity was not significant in DAA failure patients vs. SVR patients despite HIV/HCV coinfection. TTV DNA viral load was higher among HCV monoinfected patients vs. HIV/HCV coinfected, although marginally significant (p = 0.074) and no significant viral load difference was detected between DAA failures and SVR patients, while untreated vs. SVR patients had a significantly higher viral load (19,884, IQR 5977-333,534, vs. 469, IQR 10-4124, p = 0.004). Alpha-genogroup 3 TTV was the most prevalent genetic group, and no specific strain or genogroup was observed in relapser patients. Among HIV/HCV patients with HCV RNA detectable at end of treatment (EOT), TTV DNA was detected in 9/17 treatment responder patients and 3/5 relapser patients, thus, TTV infection does not appear to influence the control HCV viremia after EOT. Levels of IL-6 IL-4, and CD14 were not significantly different between TTV PCR-positive and -negative patients. These results suggest no association between TTV DNA positivity or viral load and HCV DAA failure whether patients were HIV/HCV coinfected or HCV monoinfected.

Short Communication: HIV Viral Load Trends During the Coronavirus Disease 2019 Pandemic in a Reference Center for HIV in Rome, Italy.

Coronavirus disease 2019 (COVID-19) pandemic has reduced the access of HIV patients to reference centers. However, retention-in-care is critical to maintain adherence to therapy and viral suppression. During lockdown in Italy, our center implemented several measures to ensure HIV-care continuum. To assess whether these efforts were successful, we investigated HIV viral load trend for a 1-year period (September 2019-August 2020), which included lockdown and partial lockdown months in our country. No significant changes overtime in the proportion of undetectable HIV-RNA were observed. Continuity of service made it possible to maintain viral suppression in our patients.

Effectiveness and Safety of Interferon-Free Direct-Acting Antiviral Hepatitis C Virus Therapy in HIV/Hepatitis C Virus Coinfected Individuals: Results From a Pan-European Study.

OBJECTIVES: To investigate the effectiveness, safety, and reasons for premature discontinuation of direct-acting antivirals (DAAs) in a diverse population of HIV/hepatitis C virus (HCV) coinfected individuals in Europe. METHODS: All HIV/HCV coinfected individuals in the EuroSIDA study that started interferon free DAA treatment between January 6, 2014, and January 3, 2018, with ≥12 weeks of follow-up after treatment stop were included in this analysis. Sustained virological response (SVR) was defined as a negative HCV-RNA result ≥12 weeks after stopping treatment (SVR12). Logistic regression was used to explore factors associated with SVR12. RESULTS: 1042 individuals started interferon-free DAA treatment after 1/6/2014 and were included, 862 (82.2%) had a known response to treatment, and 789 [91.5%, 95% confidence interval (CI): 89.7 to 93.4] of which achieved SVR12. There were no differences in SVR12 across regions of Europe (P = 0.84). After adjustment, the odds of achieving SVR12 was lower in individuals that received sofosbuvir/simeprevir ± ribavirin (RBV) [adjusted odds ratio 0.21 (95% CI: 0.08 to 0.53)] or ombitasvir/paritaprevir/dasabuvir ± RBV [adjusted odds ratio 0.46 (95% CI: 0.22 to 1.00)] compared with sofosbuvir/ledipasvir ± RBV. Forty-three (4.6%) individuals had one or more components of their HCV regimen stopped early, most commonly because of toxicity (n = 14); of these 14, 11 were treated with ribavirin. Increased bilirubin was the most common grade 3 or 4 laboratory adverse event (n = 15.3%) and was related to treatment with atazanavir and ribavirin. CONCLUSIONS: Our findings from real-world data on HIV/HCV coinfected individuals across Europe show DAA treatment is well tolerated and that high rates of SVR12 can be achieved in all regions of Europe.

Nonmelanoma skin cancer and melanoma in HIV-1-infected patients.

: In the cART era, the incidence of AIDS-defining cancers decreased, whereas a persistence of non-AIDS-defining cancers has been observed. In particular, concerning the risk of melanoma and nonmelanoma skin cancers in HIV patients, conflicting data are available. In this study, our aim was to assess the occurrence of cutaneous malignancies in 97 HIV-positive individuals visited in our Institute, and to evaluate the association with immunological parameters, as well as combination antiretroviral therapy (cART) duration.

Usefulness of bronchoalveolar lavage in the management of patients presenting with lung infiltrates and suspect COVID-19-associated pneumonia: A case report.

OBJECTIVE: To report a clinical case of a patient with a compatible HRCT scan and two negative SARS-CoV-2 RNA upper respiratory tract specimens but with a confirmed viral infection by BAL (19 days after symptom onset). METHODS: Revision of a patient's clinical charts with COVID-19 admitted at INMI L. Spallanzani Hospital RESULTS: Two oropharyngeal swab tests of SARS-CoV-2 by qualitative real-time reverse-transcriptase-polymerase-chain-reaction (RT-PCR) assay were performed at admission (17 days from symptoms onset) and a day apart and were found negative. BAL fluid collected 19 days after symptoms onset was positive for SARS-CoV-2. CONCLUSION: This case highlights importance of clinical suspicion of SARS-CoV-2 infection in diagnosis and infectivity assessment. We suggest collection of BAL fluid when consecutive nasopharyngeal swabs are negative, to confirm or exclude the diagnosis of COVID-19-associated pneumonia. Healthcare workers should perform aerosol-generating procedures in an adequately ventilated room and should wear adequate PPE.

Recreational drugs and STI diagnoses among patients attending an STI/HIV reference clinic in Rome, Italy.

BACKGROUND: An observational study was conducted to assess recreational drug use in association with recent STIs among clients of an STI/HIV reference centre in Rome, Italy. METHODS: Attendees self-compiled a questionnaire concerning sexual behaviours and drug use, including the nine drugs used for sex (amphetamines, poppers, cocaine, ketamine, erectile dysfunction agent (EDA), steroids and the three chemsex drugs, ie, chems: γ-hydroxybutyric acid/γ-butyrolactone, crystal and Mcat). RESULTS: Overall, 703 patients participated, with men who have sex with men (MSM) accounting for 50.4% of the total and 73.2% of HIV-positive patients. Apart from condylomatosis, whose prevalence was higher among females (38.8%) and non-MSM (45.8%) than MSM (14.4%), STIs were more frequent among MSM, particularly syphilis (14.1%), gonorrhoea (4.8%), urethritis (3.4%) and hepatitis A (6.5%). Recreational drug use was significantly more frequent among MSM (39.8% vs 17.6% in females and 22.7% in non-MSM). A total of 26.3% of MSM used at least one of the nine drugs and 5.1% at least one of the three chems. Cocaine (13.3%) and poppers (13.0%) were the most used sex drugs in MSM.The use of any of the nine drugs was associated with being MSM (adjusted OR (AOR): 1.94, 95% CI 1.05 to 3.58), sex with partner contacted online (1.99, 95% CI 1.14 to 3.45), group sex (4.08, 95% CI 2.40 to 6.93) and STI in the last year (1.65, 95% CI 1.05 to 2.61). Use of any of the nine chems among MSM was associated with condomless sex (2.24, 95% CI 1.21 to 4.14), group sex (2.08, 95% CI 1.01 to 4.31) and STI diagnosis in the last year (4.08, 95% CI 2.32 to 7.19). CONCLUSIONS: Our data suggest that recreational drug use is quite common among MSM in Italy. No evidence of association with STI was found among non-MSM and females, where only cannabis and cocaine use was reported. The use of chems is still limited, but cocaine, poppers and EDA are widely used among MSM. Recreational drug use appears associated with high-risk sexual behaviours and a higher risk of STI.

Prevalence of predicted resistance to doravirine in HIV-1-positive patients after exposure to non-nucleoside reverse transcriptase inhibitors.

This study investigated the prevalence of doravirine (DOR) resistance mutations in non-nucleoside reverse transcriptase inhibitor (NNRTI)-experienced patients. DOR resistance was assessed in samples from NNRTI-experienced patients who underwent genotypic testing for virological failure from the Antiretroviral Response Cohort Analysis (ARCA) database. Intermediate DOR resistance was defined as detection of any of V106A/M, Y188C/H, V108I, and K103N+P225H. High-level DOR resistance was defined as detection of any of Y188L, M230L, G190E, V106A/M+F227L, and V106A/M+L234I. Overall, 6893 patients were included in the study: 64.2% had experienced efavirenz (EFV), 54.4% nevirapine (NVP), 6.8% etravirine (ETR), 7.7% rilpivirine (RPV) and 0.7% delavirdine. Among NNRTI-experienced patients, 12.7% and 6.1% of subjects had intermediate and high-level DOR resistance, respectively. The most common DOR resistance mutation was Y188L. In multivariable analysis, previous EFV use (OR = 1.52, 95% CI 1.15-2.02) and ETR use (OR = 1.91, 95% CI 1.34-2.73) were associated with detection of high-level DOR resistance, whilst RPV use was associated with a lower probability of high-level DOR resistance (OR = 0.39, 95% CI 0.22-0.71). Moreover, EFV use (OR = 1.76, 95% CI 1.19-2.58) and ETR use (OR = 1.72, 95% CI 1.10-2.68) were associated with detection of the Y188L mutation, whereas RPV use was not (OR = 0.16, 95% CI 0.05-0.50). In Italy, DOR resistance is uncommon among NNRTI-experienced patients, confirming a distinguishing resistance pattern within NNRTIs. However, previous EFV and ETR experience poses a higher risk of DOR resistance. These results support the use of DOR in NNRTI-experienced patients.

Randomized clinical trial on efficacy of fixed-dose efavirenz/tenofovir/emtricitabine on alternate days versus continuous treatment.

OBJECTIVE: Antiretrovirals with long half-lives, such as tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) and efavirenz (EFV), are suitable for reduced frequency dosing, with potential for improved adherence and reduced toxicity and costs. The objective of this study was to investigate the noninferiority of the TDF/FTC/EFV fixed-dose combination on alternate-days versus standard regimen in virologically suppressed patients. DESIGN: A randomized-controlled open-label noninferiority trial enrolling HIV-1-infected patients treated for at least 6 months with TDF/FTC/EFV fixed-dose combination, virologically suppressed (<40 HIV-RNA copies/ml) with EFV plasma concentrations greater than 1000 ng/ml, were randomized to maintain TDF/FTC/EFV standard-of-care regimen (SOC, Arm A) or to switch to TDF/FTC/EFV on AlTernAte Days (ATAD, Arm B). METHODS: Primary end-point was the proportion of patients with less than 40 HIV-RNA copies/ml at week 48. RESULTS: One hundred and ninety-seven patients were randomized (98 in the SOC and 99 in the ATAD arm). One hundred and seventy-nine (90.3%) were men, median age 43.2 years, 133 (67.5%) MSM. CD4+ T-cell count at baseline was 706 cells/µl in SOC and 632 cells/µl in ATAD arm. At week 48, 95 (96.9%) patients in SOC and 93 (93.9%) in ATAD had a virological response (-3.0% overall risk difference, 95% CI: -8.86%/2.86%). Median change from baseline at week 48 in CD4+ T-cell count was 29.4 cells/µl (95% CI: 2.5/56.4) in SOC (P = 0.008) and 61.0 cells/µl (95% CI: 32.1/89.9) in ATAD (P < 0.001). Median change of EFV concentration at week 48 from baseline was -6.5 ng/ml (95% CI: -103/55) in SOC (P = 0.877) and -1124 ng/ml (95% CI: -1375/-928) in ATAD arm (P < 0.001). CONCLUSION: Despite a significant decrease of EFV exposure, TDF/FTC/EFV on ATAD was noninferior to SOC regimen through 48 weeks.

Vaccine-preventable anal infections by human papillomavirus among HIV-infected men who have sex with men.

AIM: HIV-infected men who have sex with men (MSM) show the highest prevalence of anal HPV infection. Anal prevalence of the HPVs targeted by the quadrivalent HPV vaccine (4vHPV) and nonavalent HPV vaccine (9vHPV) was estimated in this population. MATERIALS & METHODS: Anal specimens were collected from HIV-infected MSM attending a sexually transmitted infection/HIV center. Specimens were analyzed using the Linear Array HPV Genotyping Test. RESULTS: A total of 49.5 and 71.2% of the 313 enrolled MSM harbored at least one of the 4vHPV and 9vHPV types, respectively. A significantly decreasing trend was observed for the prevalence of both 4vHPV (p = 0.04) and 9vHPV types (p < 0.001) across age classes. CONCLUSION: A substantial proportion of HIV-infected MSM do not harbor a current anal infection with vaccine-preventable HPVs. The potential benefit of the 4vHPV versus 9vHPV vaccination in these subjects, including older MSM, should be investigated.

Impact of social determinants on antiretroviral therapy access and outcomes entering the era of universal treatment for people living with HIV in Italy.

BACKGROUND: Social determinants are known to be a driving force of health inequalities, even in high income countries. Aim of our study was to determine if these factors can limit antiretroviral therapy (ART) access, outcome and retention in care of people living with HIV (PLHIV) in Italy. METHODS: All ART naïve HIV+ patients (pts) of Italian nationality enrolled in the ICONA Cohort from 2002 to 2016 were included. The association of socio-demographic characteristics (age, sex, risk factor for HIV infection, educational level, occupational status and residency area) with time to: ART initiation (from the first positive anti-HIV test), ART regimen discontinuation, and first HIV-RNA < 50 cp/mL, were evaluated by Cox regression analysis, Kaplan Meier method and log-rank test. RESULTS: A total of 8023 HIV+ pts (82% males, median age at first pos anti-HIV test 36 years, IQR: 29-44) were included: 6214 (77.5%) started ART during the study period. Women, people who inject drugs (PWID) and residents in Southern Italy presented the lowest levels of education and the highest rate of unemployment compared to other groups. Females, pts aged > 50 yrs., unemployed vs employed, and people with lower educational levels presented the lowest CD4 count at ART initiation compared to other groups. The overall median time to ART initiation was 0.6 years (yrs) (IQR 0.1-3.7), with a significant decrease over time [2002-2006 = 3.3 yrs. (0.2-9.4); 2007-2011 = 1.0 yrs. (0.1-3.9); 2012-2016 = 0.2 yrs. (0.1-2.1), p < 0.001]. By multivariate analysis, females (p < 0.01) and PWID (p < 0.001), presented a longer time to ART initiation, while older people (p < 0.001), people with higher educational levels (p < 0.001), unemployed (p = 0.02) and students (p < 0.001) were more likely to initiate ART. Moreover, PWID, unemployed vs stable employed, and pts. with lower educational levels showed a lower 1-year probability of achieving HIV-RNA suppression, while females, older patients, men who have sex with men (MSM), unemployed had higher 1-year risk of first-line ART discontinuation. CONCLUSIONS: Despite median time to ART start decreased from 2002 to 2016, socio-demographic factors still contribute to disparities in ART initiation, outcome and durability.