Impact of Obefazimod on Viral Persistence, Inflammation, and Immune Activation in People With Human Immunodeficiency Virus on Suppressive Antiretroviral Therapy.

BACKGROUND: Persistence of viral reservoirs has been observed in people with human immunodeficiency virus (HIV), despite long-term antiretroviral therapy (ART), and likely contributes to chronic immune activation and inflammation. Obefazimod is a novel drug that inhibits human immunodeficiency virus type 1 (HIV-1) replication and reduces inflammation. Here we assess whether obefazimod is safe and might impact HIV-1 persistence, chronic immune activation, and inflammation in ART-suppressed people with HIV. METHODS: We evaluated obefazimod-related adverse events, changes in cell-associated HIV-1 DNA and RNA, residual viremia, immunophenotype, and inflammation biomarkers in blood and rectal tissue. We compared 24 ART-suppressed people with HIV who received daily doses of 50 mg obefazimod for 12 weeks (n = 13) or 150 mg for 4 weeks (n = 11) and 12 HIV-negative individuals who received 50 mg for 4 weeks. RESULTS: The 50- and 150-mg doses of obefazimod were safe, although the 150-mg dose showed inferior tolerability. The 150-mg dose reduced HIV-1 DNA (P = .008, median fold change = 0.6) and residual viremia in all individuals with detectable viremia at baseline. Furthermore, obefazimod upregulated miR-124 in all participants and reduced the activation markers CD38, HLA-DR, and PD-1 and several inflammation biomarkers. CONCLUSIONS: The effect of obefazimod by reducing chronic immune activation and inflammation suggests a potential role for the drug in virus remission strategies involving other compounds that can activate immune cells, such as latency-reversing agents.

Pharmacological Inhibition of IKK to Tackle Latency and Hyperinflammation in Chronic HIV-1 Infection.

HIV latent infection may be associated with disrupted viral RNA sensing, interferon (IFN) signaling, and/or IFN stimulating genes (ISG) activation. Here, we evaluated the use of compounds selectively targeting at the inhibitor of nuclear factor-κB (IκB) kinase (IKK) complex subunits and related kinases (TBK1) as a novel pathway to reverse HIV-1 latency in latently infected non-clonal lymphoid and myeloid cell in vitro models. IKK inhibitors (IKKis) triggered up to a 1.8-fold increase in HIV reactivation in both, myeloid and lymphoid cell models. The best-in-class IKKis, targeting TBK-1 (MRT67307) and IKKß (TCPA-1) respectively, were also able to significantly induce viral reactivation in CD4+ T cells from people living with HIV (PLWH) ex vivo. More importantly, although none of the compounds tested showed antiviral activity, the combination of the distinct IKKis with ART did not affect the latency reactivation nor blockade of HIV infection by ART. Finally, as expected, IKKis did not upregulate cell activation markers in primary lymphocytes and innate immune signaling was blocked, resulting in downregulation of inflammatory cytokines. Overall, our results support a dual role of IKKis as immune modulators being able to tackle the HIV latent reservoir in lymphoid and myeloid cellular models and putatively control the hyperinflammatory responses in chronic HIV-1 infection.

Prevalence of HPV-DNA and E6 mRNA in lung cancer of HIV-infected patients.

HIV-infected individuals could be at a greater risk for developing lung cancer than the general population due to the higher prevalence in the former of human papillomavirus (HPV) in the oral cavity and higher smoking rates. Our aim was to assess HPV prevalence and E6 viral oncogene transcription in lung cancer samples from HIV-infected individuals. This was a single-center, retrospective study of a cohort of HIV-1-infected patients diagnosed with and treated for lung cancer. Pathological lung samples archived as smears or formalin-fixed paraffin-embedded blocks were subjected to HPV genotyping, detection of human p16 protein and assessment for HPV E6 mRNA expression. Lung cancer samples from 41 patients were studied, including squamous cell carcinoma (32%), adenocarcinoma (34%), non-small cell cancer (27%), and small cell cancer (7%). HPV DNA was detected in 23 out of 41 (56%, 95% CI 41-70%) of samples and high-risk (HR)-HPV types were detected in 16 out of 41 (39%, 95% CI 26-54%), HPV-16 being the most prevalent [13/16 (81.3%, 95% CI 57.0-93%]. In samples with sufficient material left: expression of p16 was detected in 3 out of 10 (30%) of HR-HPV DNA-positive tumors and in 3 out of 7 (43%) of the negative ones; and E6 mRNA was detected in 2 out of 10 (20%) of HPV-16-positive samples (squamous lung cancers). These two patients had a background of a previous HPV-related neoplasia and smoking. HR-HPV DNA detection was prevalent in lung cancers in HIV-infected patients. However, viral oncogene expression was limited to patients with previous HPV-related cancers.

Incidence of Recurrent High-Grade Anal Dysplasia in HIV-1-Infected Men and Women Following Infrared Coagulation Ablation: A Retrospective Cohort Study.

This single-center, retrospective cohort study sought to estimate the cumulative incidence in HIV-1-infected patients of biopsy-proven high-grade anal intraepithelial neoplasia (HGAIN) recurrence after infrared coagulation (IRC) treatment. The study was based on data from a prospectively compiled database of 665 HIV-1-infected outpatients who attended a hospital Clinical Proctology/HIV Unit between January 2012 and December 2015. Patient records were checked to see which ones had received IRC treatment but later experienced a recurrence of HGAIN. Cytology samples were also checked for the presence of human papilloma virus (HPV). A total of 81 of the 665 patients (12%, 95%CI: 10-15%), of whom 65 were men and 16 women, were diagnosed with HGAIN and again treated with IRC. Of these 81, 20 (25%) experienced recurrent HGAIN, this incidence being true of both men (16/65, 95%CI: 19-57%) and women (4/16, 95%CI: 10-50%). The median time to recurrence was 6 (2-19) months overall, 6 (2-19) months in men, and 4 (2-6) months in women. HPV infection was detected in all patients except two, with HPV-16 being the most common genotype. This rate of incidence of recurrent HGAIN following IRC treatment is consistent with other reports and highlights the importance of continued post-treatment surveillance, particularly in the first year.

Routine Screening of Anal Cytology in Persons With Human Immunodeficiency Virus and the Impact on Invasive Anal Cancer: A Prospective Cohort Study.

BACKGROUND: The efficacy of screening programs to prevent anal cancer in persons with human immunodeficiency virus 1 (HIV-1) is unclear. METHODS: To examine the impact of a screening program to detect anal cancer precursors on the incidence of cases of invasive anal squamous-cell carcinoma (IASCC) in persons with HIV-1, we performed a single-center, retrospective analysis of a prospective cohort of outpatients with HIV-1 attending a reference HIV unit from January 2005 onward. All participants were invited to participate in a continued structured screening program for anal cancer prevention. We estimated the incidence of IASCC and performed a comparative analysis between subjects enrolled in the screening program (screening group) and those who declined to participate (nonscreening group). To reduce any selection bias, a propensity score analysis was applied. RESULTS: We included 3111 persons with HIV-1 (1596 men-who-have-sex-with-men [MSM], 888 men-who-have-sex-with-women [MSW], 627 women; mean age, 41 years), with a median follow-up of 4.7 years (14 595 patient-years of follow-up); 1691 (54%) participated in the screening program. Ten patients were diagnosed with IASCC: 2 (MSM) in the screening group and 8 (4 MSM, 2 MSW, and 2 women) in the nonscreening group. The incidence rates of IASCC were 21.9 (95% confidence interval [CI], 2.7-70.3) and 107.0 (95% CI, 46.2-202.0) per 100 000 person-years, respectively. After a propensity score adjustment, the difference was significant in favor of the screening group (hazard ratio, 0.17; 95% CI, .03-.86). CONCLUSIONS: The number of cases of IASCC was significantly lower in persons with HIV engaged in an anal cytology screening program. These results should be validated in a randomized clinical trial.

ADAR1 function affects HPV replication and is associated to recurrent human papillomavirus-induced dysplasia in HIV coinfected individuals.

Infection by human papillomavirus (HPV) alters the microenvironment of keratinocytes as a mechanism to evade the immune system. A-to-I editing by ADAR1 has been reported to regulate innate immunity in response to viral infections. Here, we evaluated the role of ADAR1 in HPV infection in vitro and in vivo. Innate immune activation was characterized in human keratinocyte cell lines constitutively infected or not with HPV. ADAR1 knockdown induced an innate immune response through enhanced expression of RIG-I-like receptors (RLR) signaling cascade, over-production of type-I IFNs and pro-inflammatory cytokines. ADAR1 knockdown enhanced expression of HPV proteins, a process dependent on innate immune function as no A-to-I editing could be identified in HPV transcripts. A genetic association study was performed in a cohort of HPV/HIV infected individuals followed for a median of 6 years (range 0.1-24). We identified the low frequency haplotype AACCAT significantly associated with recurrent HPV dysplasia, suggesting a role of ADAR1 in the outcome of HPV infection in HIV+ individuals. In summary, our results suggest that ADAR1-mediated innate immune activation may influence HPV disease outcome, therefore indicating that modification of innate immune effectors regulated by ADAR1 could be a therapeutic strategy against HPV infection.

Natural History of Anal Squamous Intraepithelial Lesions in HIV-Positive Men with Normal Baseline Cytology.

The natural history of squamous intraepithelial lesions (SILs) in the anal canal of HIV-infected men is incompletely understood. We assessed the incidence and factors associated with SIL and invasive anal squamous cell carcinoma (IASCC) among HIV-infected men with normal cytology at baseline. We performed a single-center prospective cohort study [men who have sex with men (MSM) and men who have sex with women (MSW)]. The incidence of anal canal SIL (low grade and high grade) and IASCC were estimated and predictive factors analyzed. The study population comprised 297 HIV-infected men with a normal cytology result and no anal human papillomavirus (HPV)-related diseases. Of these, 251 (85%) had at least one evaluable set of cytology data during follow-up (172 MSM, 79 MSW). The median follow-up time was 4 years. The cumulative incidence of SIL was 43% (107/251): 52% in MSM (90/172) and 22% in MSW (17/79), p < 0.0001. The incidence rate of SILs was 109 (95% confidence interval = 90-132) per 1000 person-years: 142 in MSM and 49 in MSW, p < 0.0001. HPV infection, receiving antiretroviral treatment (ART), and being MSM were independently associated risk factors. The incidence of IASCC was 0.15 per 1000 person-years among MSM and 0 in MSW. HIV-infected men, both MSM and MSW, are at high risk of developing SIL despite having a normal anal cytology at baseline. The incidence of anal canal SIL was higher among MSM, but was also remarkable among MSW. Independent risk factors associated with SIL were being HIV-infected MSM at high risk for acquisition of STIs, time on ART, and HPV infection.

Incidence of cervical high-grade squamous intraepithelial lesions in HIV-1-infected women with no history of cervical pathology: up to 17 years of follow-up.

Currently, Papanicolaou smears are proposed at three-year intervals for cervical screening to all women living with HIV. The aim of this retrospective cohort study was to provide data on the incidence of cervical high-grade squamous intraepithelial lesions (HSIL) in cervical smear confirmed by histology in HIV-1-infected women (two consecutive normal Papanicolaou smears at baseline) after a long-term follow-up. Sixty-seven women (recruited between March 1999 and January 2003) were analyzed. The median period of follow-up was 13.2 years (range: 7.4-17.1 years) with a total of 583 Papanicolaou smears. Twenty-seven percent of these HIV-1-infected women had poorly-controlled HIV. Cumulative incidence of HSIL was 18% (12/67; 95%CI: 11-29%) of which one was an invasive squamous cell carcinoma and two were carcinoma in situ. These women had not been well-engaged with the annual Papanicolaou smear screening program and had poor adherence to antiretroviral therapy. Development of HSIL was associated with high-risk-HPV infection (OR: 14.9; 95%CI: 3.0, 75.1). At last Papanicolaou smear, prevalence of high-risk-HPV infection was 30% (20/66, 95%CI: 21-42%). In conclusion, the incidence of cervical HSIL in HIV-1-infected women with poor antiretroviral therapy adherence or poor immunological status reinforces the need to identify those HIV-1-infected women at risk of developing cervical cancer.

Low nadir CD4+ T-cell counts predict gut dysbiosis in HIV-1 infection.

Human immunodeficiency virus (HIV)-1 infection causes severe gut and systemic immune damage, but its effects on the gut microbiome remain unclear. Previous shotgun metagenomic studies in HIV-negative subjects linked low-microbial gene counts (LGC) to gut dysbiosis in diseases featuring intestinal inflammation. Using a similar approach in 156 subjects with different HIV-1 phenotypes, we found a strong, independent, dose-effect association between nadir CD4+ T-cell counts and LGC. As in other diseases involving intestinal inflammation, the gut microbiomes of subjects with LGC were enriched in gram-negative Bacteroides, acetogenic bacteria and Proteobacteria, which are able to metabolize reactive oxygen and nitrogen species; and were depleted in oxygen-sensitive methanogenic archaea and sulfate-reducing bacteria. Interestingly, subjects with LGC also showed increased butyrate levels in direct fecal measurements, consistent with enrichment in Roseburia intestinalis despite reductions in other butyrate producers. The microbiomes of subjects with LGC were also enriched in bacterial virulence factors, as well as in genes associated with beta-lactam, lincosamide, tetracycline, and macrolide resistance. Thus, low nadir CD4+ T-cell counts, rather than HIV-1 serostatus per se, predict the presence of gut dysbiosis in HIV-1 infected subjects. Such dysbiosis does not display obvious HIV-specific features; instead, it shares many similarities with other diseases featuring gut inflammation.

Effectiveness of physically ablative and pharmacological treatments for anal condyloma in HIV-infected men.

BACKGROUND: There is limited information on the effectiveness of available treatments for anal condyloma acuminata in HIV-1-infected men. AIM: To provide data on the effectiveness of electrosurgical excision, infrared coagulation and pharmacological (imiquimod) treatments for anal condyloma acuminata (peri-anal and/or intra-anal) in HIV-1-infected men based on authors' practice. METHODS: Single-center, retrospective descriptive analysis of HIV-1-infected men, 18 years or older treated for anal condyloma acuminata. Standard treatments were offered: electrosurgery excision, infrared coagulation and topical imiquimod. Effectiveness was evaluated by the recurrence rate at 1 year after treatment. Recurrence was defined as any anal condyloma acuminata diagnosed after 3 months of condyloma-free survival post-treatment. Anal cytology and human-papillomavirus-infection (HPV) was assessed. RESULTS: Between January 2005 and May 2009, 101 men were treated for anal condyloma acuminata: 65 (64%) with electrosurgery, 27 (27%) with infrared coagulation and 9 (9%) with imiquimod. At 1 year after treatment, the cumulative recurrence rate was 8% (4/65, 95%CI: 2-15%) with electrosurgery excision, 11% (3/27, 95%CI: 4-28%) with infrared coagulation and 11% (1/9, 95%CI: 2-44%) with imiquimod treatment. No predictive factors were associated with recurrence. Anal HPV-6 or HPV-11 was detectable in 98 (97%) patients and all had high-risk HPV genotypes, and 89 (88%) patients had abnormal anal canal cytology. Limitations: this was a retrospective descriptive analysis; limited to a single center; it cannot know if the recurrence is related to new infection. CONCLUSION: Recurrence of anal condyloma after any treatment was common. Abnormal anal cytology and high-risk HPV-infection were highly prevalent in this population, therefore at high-risk of anal cancer, and warrants careful follow-up.

RNA editing by ADAR1 regulates innate and antiviral immune functions in primary macrophages.

ADAR1-dependent A-to-I editing has recently been recognized as a key process for marking dsRNA as self, therefore, preventing innate immune activation and affecting the development and resolution of immune-mediated diseases and infections. Here, we have determined the role of ADAR1 as a regulator of innate immune activation and modifier of viral susceptibility in primary myeloid and lymphoid cells. We show that ADAR1 knockdown significantly enhanced interferon, cytokine and chemokine production in primary macrophages that function as antiviral paracrine factors, rendering them resistant to HIV-1 infection. ADAR1 knockdown induced deregulation of the RLRs-MAVS signaling pathway, by increasing MDA5, RIG-I, IRF7 and phospho-STAT1 expression, an effect that was partially rescued by pharmacological blockade of the pathway. In summary, our results demonstrate a role of ADAR1 in regulating innate immune function in primary macrophages, suggesting that macrophages may play an essential role in disease associated to ADAR1 dysfunction. We also show that viral inhibition is exclusively dependent on innate immune activation consequence of ADAR1 knockdown, pointing towards ADAR1 as a potential target to boost antiviral immune response.

Gut Microbiota Linked to Sexual Preference and HIV Infection.

The precise effects of HIV-1 on the gut microbiome are unclear. Initial cross-sectional studies provided contradictory associations between microbial richness and HIV serostatus and suggested shifts from Bacteroides to Prevotella predominance following HIV-1 infection, which have not been found in animal models or in studies matched for HIV-1 transmission groups. In two independent cohorts of HIV-1-infected subjects and HIV-1-negative controls in Barcelona (n = 156) and Stockholm (n = 84), men who have sex with men (MSM) predominantly belonged to the Prevotella-rich enterotype whereas most non-MSM subjects were enriched in Bacteroides, independently of HIV-1 status, and with only a limited contribution of diet effects. Moreover, MSM had a significantly richer and more diverse fecal microbiota than non-MSM individuals. After stratifying for sexual orientation, there was no solid evidence of an HIV-specific dysbiosis. However, HIV-1 infection remained consistently associated with reduced bacterial richness, the lowest bacterial richness being observed in subjects with a virological-immune discordant response to antiretroviral therapy. Our findings indicate that HIV gut microbiome studies must control for HIV risk factors and suggest interventions on gut bacterial richness as possible novel avenues to improve HIV-1-associated immune dysfunction.

Lung cancer in HIV-infected patients in the combination antiretroviral treatment era.

The advent of combination antiretroviral treatment (cART) has been followed by a decrease in HIV-associated morbidity and mortality, but also by an apparent increase in the incidence of non-AIDS-defining cancers (NADCs). The risk of lung cancer is substantially higher in HIV-infected patients than in the general population, in part due to aging and tobacco use, and it is the most frequent NADC. The management of lung cancer in HIV-infected patients has some peculiarities that need to be taken into account. This review focuses on the epidemiology, risk factors, and clinical management of lung cancer in HIV-infected patients. In addition, screening tools and future perspectives are also discussed.

Prevalence of ischemic heart disease and management of coronary risk in daily clinical practice: results from a Mediterranean cohort of HIV-infected patients.

BACKGROUND: There are conflicting data on the prevalence of coronary events and the quality of the management of modifiable cardiovascular risk factors (CVRF) in HIV-infected patients. METHODS: We performed a retrospective descriptive study to determine the prevalence of coronary events and to evaluate the management of CVRF in a Mediterranean cohort of 3760 HIV-1-infected patients from April 1983 through June 2011. RESULTS: We identified 81 patients with a history of a coronary event (prevalence 2.15%); 83% of them suffered an acute myocardial infarction. At the time of the coronary event, CVRF were highly prevalent (60.5% hypertension, 48% dyslipidemia, and 16% diabetes mellitus). Other CVRF, such as smoking, hypertension, lack of exercise, and body mass index, were not routinely assessed. After the coronary event, a significant decrease in total cholesterol (P = 0.025) and LDL-cholesterol (P = 0.004) was observed. However, the percentage of patients who maintained LDL-cholesterol > 100 mg/dL remained stable (from 46% to 41%, P = 0.103). Patients using protease inhibitors associated with a favorable lipid profile increased over time (P = 0.028). CONCLUSIONS: The prevalence of coronary events in our cohort is low. CVRF prevalence is high and their management is far from optimal. More aggressive interventions should be implemented to diminish cardiovascular risk in HIV-infected patients.

Incidence and clinical management of oral human papillomavirus infection in men: a series of key short messages.

Oral human papillomavirus (HPV) infections are less prevalent than genital and anal infections. However, the incidence of oropharyngeal squamous cell carcinomas has increased significantly over the last 2 decades in several countries. At least 90% of these cancers are associated with oncogenic type HPV16. Oral HPV infections are notably more frequent in men than in women, and the incidence of HPV-positive oropharyngeal squamous cell carcinomas has increased, predominantly among mid-adult men. Nevertheless, little is known about the progression of oral HPV infection to cancer, and it remains unclear which medical interventions should be applied to modify the natural history of the disease. This narrative review aimed at non-experts in HPV infection provides an update on oral HPV infection and its clinical management in men. Furthermore, using the cervix as a reference anatomical site, the lessons learned from investigations on cervical HPV infection are also addressed.

Randomised study to assess the efficacy and safety of once-daily etravirine-based regimen as a switching strategy in HIV-infected patients receiving a protease inhibitor-containing regimen. Etraswitch study.

BACKGROUND: Etravirine (ETR) was approved for patients with virological failure and antiretroviral resistance mutations. It has also shown antiviral efficacy in antiretroviral-naïve patients. However, data on the switching from protease inhibitors (PI) to ETR are lacking. METHODS: HIV-1-infected patients with suppressed viral load (VL) during a PI-containing regimen (>12 months) and no previous virological failure were randomized to switch from the PI to ETR (400 mg/day, dissolved in water) (ETR group, n = 22) or to continue with the same regimen (control group, n = 21). Percentage of patients with VL ≤ 50 copies/mL were assessed at week 48, as well as changes in CD4 T-cell counts and metabolic profile. RESULTS: We included 43 patients [72.9% male, 46.3 (42.2; 50.6) years]. Two patients receiving ETR (grade-1 diarrhea and voluntary discontinuation) and another in the control group (simplification) discontinued therapy early. No patients presented virological failure (two consecutive VL>50 copies/mL); treatment was successful in 95.2% of the control group and 90.9% of the ETR group (intention-to-treat analysis, missing = failure) (p = 0.58). CD4+ T-cell counts did not significantly vary [+49 cells/µL in the ETR group (p = 0.25) and -4 cells/µL in the control group (p = 0.71)]. The ETR group showed significant reductions in cholesterol (p<0.001), triglycerides (p = <0.001), and glycemia (p = 0.03) and higher satisfaction (0-10 scale) (p = 0.04). Trough plasma concentrations of ETR were similar to observed in studies using ETR twice daily. CONCLUSION: Switch from a PI-based regimen to a once-daily combination based on ETR maintained undetectable VL during 48 weeks in virologically suppressed HIV-infected patients while lipid profile and patient satisfaction improved significantly. TRIAL REGISTRATION: ClinicalTrials.gov NCT01034917.

Cribado de la neoplasia intraepitelial anal / Screening of intraepithelial anal neoplasm

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