Implementation of EACS vaccination recommendations among people living with HIV.

OBJECTIVES: With modern combination antiretroviral Treatment (cART) a normal life expectancy among people living with HIV (PLWH) has become reality if started early enough prior to the onset of more pronounced immunodeficiency. Therefore, prevention measures against other infectious diseases among this vulnerable group have gained increased attention. Indeed, the EACS guidelines recommend vaccinations against HAV, HBV, HPV, Influenza, Neisseria meningitidis, Streptococcus pneumoniae and VZV in HIV-infected adults. METHODS: All PLWH under cART attending our ID outpatient clinic between April to June 2018, were assessed during consultation for vaccination status regarding pneumococcus, Hepatitis A and B, influenza, varicella, meningococcus and HPV using a pre-defined questionnaire, vaccination certificates and medical records. In addition, the cohort database was screened for Hepatitis A and B serology and HIV surrogate markers. RESULTS: A total of 305 PLWH (82.3% male, 17.7% female) was included, median age was 48 years (IQR 47-51). Median CD4 + T cell count was 543 (IQR 304-770), and for 297 (97.4%) PLWH CD4 + T cell count was ≥ 200/ul. The viral load was undetectable (< 40 copies/ml) in 289 (94.8%) cases. Highest vaccination rates were observed for HAV (87.4%), Streptococcus pneumoniae (77.4%) and Influenza (76.5%). 64.3% PLWH got vaccinated against HBV, whereas VZV vaccination only played a minor role, in the context of the high rate of cleared infections (99.0%). Lowest vaccination rates were detected for HPV (0%) and Neisseria meningitidis (3.0%). CONCLUSIONS: Our data suggest that vaccination rates among PLWH are higher compared to the general German population. Implementation of EACS guidelines into daily routine though is not fully executed and the need for improving vaccination rates has to be emphasized. Centrally organized vaccination registers as well as electronic medical records could be helpful tools to detect a lack of vaccination coverage and send digital vaccination reminders particularly among risk groups.

Mitochondrial Dysfunction Contributes to Impaired Cytokine Production of CD56bright Natural Killer Cells From Human Immunodeficiency Virus-Infected Individuals Under Effective Antiretroviral Therapy.

Human immunodeficiency virus (HIV) infection is associated with impaired natural killer (NK) cell activity, which is only incompletely restored under antiretroviral therapy. Analyzing the bioenergetics profiles of oxygen consumption, we observed that several parameters were significantly reduced in HIV+ NK cells, indicating a mitochondrial defect. Accordingly, we found HIV+ CD56bright NK cells to display a decreased mitochondrial membrane potential and mitochondrial mass. Both parameters were positively correlated with interferon gamma (IFN-γ) production of NK cells. Finally, we demonstrated that stimulation of HIV+ NK cells with MitoTEMPO, a mitochondria-targeting antioxidant, significantly improved IFN-γ production. We identified mitochondrial dysfunction as a mechanism that contributes to impaired NK cell function.

HPV-associated anal lesions in HIV+ patients: long-term results regarding quality of life.

PURPOSE: HIV infection and concomitant HPV-associated anal lesions may significantly impact on patients' quality of life (QoL), as they are predicted to have negative effects on health, psyche, and sexuality. MATERIAL AND METHODS: Fifty-two HIV+ patients with HPV-associated anal lesions were enrolled in a survey approach after undergoing routine proctologic assessment and therapy for HPV-associated anal lesions if indicated over a time span of 11 years (11/2004-11/2015). Therapy consisted of surgical ablation and topic treatment. QoL was analyzed using the SF-36 and the CECA questionnaires. RESULTS: Fifty-two of 67 patients (77.6%) were successfully contacted and 29/52 provided full information. The mean age was 43.8 ± 12.8 years. The median follow-up from treatment to answering of the questionnaire was 34 months. Twenty-one percent (6/29) of the patients reported suffering from recurrence of condyloma acuminata, three patients from anal dysplasia (10.3%). In the SF-36, HIV+ patients did not rate their QoL as significantly different over all items after successful treatment of HPV-associated anal lesions. In the CECA questionnaire, patients with persisting HPV-associated anal lesions reported significantly higher emotional stress levels and disturbance of everyday life compared to patients who had successful treatment (71.9/100 ± 18.7 vs. 40.00/100 ± 27.4, p = 0.004). Importantly, the sexuality of patients with anal lesions was significantly impaired (59.8/100 ± 30.8 vs. 27.5/100 ± 12.2, p = 0.032). CONCLUSION: HPV-associated anal lesions impact significantly negative on QoL in HIV+ patients. Successful treatment of HPV-associated anal lesions in HIV+ patients improved QoL. Specific questionnaires, such as CECA, seem to be more adequate than the SF-36 in this setting.

Circulating levels of PRO-C3 reflect liver fibrosis and liver function in HIV positive patients receiving modern cART.

BACKGROUND AND AIMS: Although combined antiretroviral treatment (cART) has improved overall survival of HIV infected patients, liver fibrosis and liver related-mortality still constitute major challenges in HIV positive patients. Collagen accumulates in the liver during fibrogenesis. Recent studies showed that circulating levels of extracellular matrix (ECM) fragments might reflect degree of portal hypertension and fibrosis stage in liver disease. In this study, we analyzed the correlation between liver fibrosis assessed by Fibroscan and levels of the formation and degradation markers of type III and IV collagen in HIV positive patients receiving cART. METHODS: 116 HIV positive patients (82.7% male, median age 47 years) were enrolled into the study. Liver stiffness and liver fat content were determined using a Fibroscan with integrated CAP function. We quantified ECM formation and degradation fragments of collagen III and IV: PRO-C3, PRO-C4, C3M and C4M. These fragments were measured in peripheral serum by using specific ELISAs. RESULTS: Fifteen (12.9%) out of the 116 HIV positive patients had relevant fibrosis with a liver stiffness ≥ 7.1 kPa, and 79 patients had relevant steatosis with a CAP value > 248 dB/m. Circulating PRO-C3 levels significantly correlated with increasing degree of liver fibrosis assessed by Fibroscan (p = 0.0005), as well as with APRI score (p = 0.015). Interestingly, circulating PRO-C3 levels were significantly correlated with bilirubin (p = 0.022), reduced platelet count (p = 0.0008) and low albumin levels (p = 0.001), suggesting the association of type III collagen deposition with impaired liver function. None of the other measured ECM components significantly correlated with fibrosis or steatosis. CONCLUSION: The formation marker of type III collagen, PRO-C3 not only reflects liver fibrosis, but might also mirror liver dysfunction in HIV positive patients receiving cART. Therefore, the circulating levels of PRO-C3 might be suitable to monitor progression of liver fibrosis and deterioration of liver function in HIV positive patients receiving cART.

[Treatment of HPV-associated Anal Lesions in HIV-positive Patients - Comparison of Surgical Treatment and Topical Therapy with Imiquimod]. / Behandlung HPV-assoziierter analer Läsionen bei HIV-positiven Patienten ­ chirurgische Abtragung vs. topische Therapie mit Imiquimod.

OBJECTIVES: In HIV+-patients, routine proctological assessment is warranted due to the high incidence of human papilloma virus (HPV) infection-related anogenital lesions, such as Condylomata acuminata (C. ac.), anal intraepithelial dysplasia (AIN) and anal cancer. For C. ac. and AIN, surgical resection and topical therapy with imiquimod have been discussed as treatment options. BACKGROUND: In this study, we contrasted surgical resection and topical imiquimod therapy of HPV-associated anal lesions in HIV+-patients, with a focus on healing rates and clinical outcome. We also analysed whether a synergistic treatment effect was detectable. METHODS: This was a retrospective analysis of 97 HIV+ patients who underwent proctological evaluation and treatment over a 10-year period (11/2004 - 11/2015) at our centre. Initial success of surgical treatment, topical imiquimod therapy and the combination of the two strategies were compared. RESULTS: In 53/97 patients (54%), HPV-associated anal disease was diagnosed upon the first visit. In approx. 50% of the patients, the HIV infection was adequately controlled (52 patients with viral load < 40 copies [53.6%]) under cART. The mean age was 41.0 ± 11.6 years. In 7/53 patients with macroscopic C. ac., low-grade and in 18/53 patients high-grade AIN were additionally confirmed. Success rates of surgical resection, imiquimod treatment and the combination of the two were compared. Complete remission of C. ac. and AIN four weeks after treatment was considered a therapeutic success. For C. ac., success rates with imiquimod were 5/25 (20.0%) vs. surgery* 30/57 (52.6%, Mann-Whitney U test p < 0.05) vs. surgery+imiquimod 7/15 (46.7%). For AIN, success rates with imiquimod were 4/24 (16.7%) vs. surgery* 47/83 (56.7%, Mann-Whitney U test p < 0.05) vs. surgery+imiquimod 9/21 (42.8%). In 7/92 (13%) of surgical treatments, complications were reported: four minor and two significant bleeding episodes and one perianal thrombosis. No side effects of imiquimod were documented besides skin irritation. CONCLUSION: Surgery is more effective than topical imiquimod as initial therapy of HPV-related anogenital disease in HIV+-patients. A synergistic effect could not be demonstrated. On this basis, we recommend surgical treatment of C. ac. and AIN in HIV+-patients as first line treatment.

Moderate endurance training (marathon-training) - effects on immunologic and metabolic parameters in HIV-infected patients: the 42 KM cologne project.

BACKGROUND: Improved treatment options of HIV have resulted in regular physical activities of many HIV-infected patients. However, data on effects of sports in HIV-patients are scarce. METHODS: 21 HIV-infected persons were monitored prospectively while preparing for a marathon run. Multiple parameters with regard to immunology, quality of life and metabolism were measured at 4 time points (at baseline 1 year before the marathon run, 3 and 6 months after beginning of training, and immediately before marathon). RESULTS: 13 out of 21 participants completed the marathon (12 male, 1 female; median age 42 years [27-50]; CD4 = 620/µl [146-1268]; 11 were on ART since 3.5 years [1-7]). 8 participants ceased training early. All reasons for stopping (besides one pre-existing metatarsal fracture) were not regarded as training-related (e.g. time limitation n = 3; newly diagnosed anal cancer n = 1; personal reasons/unknown n = 3). We observed a significant increase in absolute CD4-T-cells (620/µl [146-1268] vs. 745 [207-1647]; p = 0.001) with simultaneous decrease of CD4-T-cell apoptosis (53% [47-64] vs. 32% [14-42]); p < 0.01). No effects on viral load independent of ART occurred. Systolic blood pressure and cholesterol improved significantly, although moderate and normal at baseline (cholesterol 185 mg/dl [98-250] vs. 167 [106-222], p = 0.02; RRsys 125 mmHg [100-145] vs. 120 [100-140], p = 0.01). Blood count, liver enzymes, creatinine and CK remained unchanged. CONCLUSIONS: The results of this pilot study indicated improved metabolic and immunologic parameters in HIV-infected patients undergoing moderate endurance training. Although training effects or ART cannot be ultimately separated as underlying mechanisms, we conclude that marathon training is safe for HIV-infected patients and potentially improves general health. TRIAL REGISTRATION: DRKS00011592 (retrospectively registered on February 9th 2017).

microRNA-200a: A stage-dependent biomarker and predictor of steatosis and liver cell injury in human immunodeficiency virus patients.

Nonalcoholic fatty liver disease contributes to liver-related mortality and has a high prevalence among patients with human immunodeficiency virus (HIV). The early detection of steatosis could prevent disease progression through life-style changes. However, as the common serum markers are nonspecific and the gold standard for the detection of nonalcoholic fatty liver disease remains the invasive liver biopsy, its verification is limited. Therefore, the search for novel biomarkers is essential. Several studies have emphasized the role of microRNAs (miRNAs) as biomarkers for certain liver diseases. With our study, we aimed to investigate the potential of miR-200a as a biomarker for liver injury, fibrosis, and steatosis in HIV patients. The study cohort consisted of 89 HIV patients. Clinical and laboratory parameters were assessed twice, within a median follow-up period of 12 months. miR-200a serum levels were determined by real-time polymerase chain reaction and normalized to spiked-in RNA (SV40). miR-200a serum levels showed a significant correlation with the patients' controlled attenuation parameter scores and their body weight at baseline and with alanine aminotransferase serum levels at follow-up. At baseline, we observed a stage-dependent increase in miR-200a serum levels according to the degree of steatosis. More importantly, patients with higher baseline levels of miR-200a recorded a progression of steatosis at follow-up. Remarkably, miR-200a not only reveals a prognostic value for steatosis but possibly also for liver damage and metabolic adaptions as patients with an increase in alanine aminotransferase/aspartate aminotransferase serum levels over time also recorded higher baseline miR-200a levels. Conclusion : Our study reveals miR-200a not only to be a stage-dependent biomarker of steatosis but also to be a predictor of steatosis progression and probably liver cell injury in HIV patients. (Hepatology Communications 2017;1:36-45).

Liver Fibrosis in HIV Patients Receiving a Modern cART: Which Factors Play a Role?

Liver-related death in human immunodeficiency virus (HIV)-infected individuals is about 10 times higher compared with the general population, and the prevalence of significant liver fibrosis in those with HIV approaches 15%. The present study aimed to assess risk factors for development of hepatic fibrosis in HIV patients receiving a modern combination anti-retroviral therapy (cART). This cross-sectional prospective study included 432 HIV patients, of which 68 (16%) patients were anti-hepatitis C virus (HCV) positive and 23 (5%) were HBsAg positive. Health trajectory including clinical characteristics and liver fibrosis stage assessed by transient elastography were collected at inclusion. Liver stiffness values >7.1 kPa were considered as significant fibrosis, while values >12.5 kPa were defined as severe fibrosis. Logistic regression and Cox regression uni- and multivariate analyses were performed to identify independent factors associated with liver fibrosis. Significant liver fibrosis was detected in 10% of HIV mono-infected, in 37% of HCV co-infected patients, and in 18% of hepatitis B virus co-infected patients. The presence of diabetes mellitus (odds ratio [OR] = 4.6) and FIB4 score (OR = 2.4) were independently associated with presence of significant fibrosis in the whole cohort. Similarly, diabetes mellitus (OR = 5.4), adiposity (OR = 4.6), and the FIB4 score (OR = 3.3) were independently associated with significant fibrosis in HIV mono-infected patients. Importantly, cumulative cART duration protected, whereas persistent HIV viral replication promoted the development of significant liver fibrosis along the duration of HIV infection. Our findings strongly indicate that besides known risk factors like metabolic disorders, HIV may also have a direct effect on fibrogenesis. Successful cART leading to complete suppression of HIV replication might protect from development of liver fibrosis.

A phase 1 study to evaluate the safety and immunogenicity of a recombinant HIV type 1 subtype C adeno-associated virus vaccine.

A novel prophylactic AIDS vaccine candidate, consisting of single-stranded DNA for HIV-1 subtype C gag, protease, and part of reverse transcriptase genes, enclosed within a recombinant adeno-associated virus serotype-2 protein capsid (tgAAC09) induced T cell responses and antibodies in nonhuman primates. In this randomized, dose escalation phase I trial, HIV-uninfected healthy volunteers (50 in Europe, 30 in India) received a single intramuscular injection of tgAAC09 at 3 x 10(9) DNase resistant particles (DRP) (n = 16), 3 x 10(10) DRP (n = 23), 3 x 10(11) DRP (n = 25), or placebo (n = 16). Twenty-one participants in Europe received a second (boost) dose of 3 x 10(11) DRP tgAAC09 or placebo at least 24 weeks after the first injection. The vaccine was safe and well-tolerated after initial and boost vaccination. Local and systemic reactogenicity was experienced by 13-25% of participants and was not dose related. No vaccine-related serious adverse events were reported. Modest HIV-specific T cell responses were detected in 7/64 vaccinees (40-385 SFC/10(6) PBMC), with 16% (4/25) responders in the highest dose group. All responses were to Gag epitopes. tgAAC09 appears to be safe, well-tolerated, and modestly immunogenic. Further evaluation of higher doses of tgAAC09 and boost injections is ongoing in Africa.