The characteristics of HIV-positive patients with mild/asymptomatic and moderate/severe course of COVID-19 disease-A report from Central and Eastern Europe.

BACKGROUND: There is currently no evidence suggesting that COVID-19 takes a different course in HIV-positive patients on antiretroviral treatment compared to the general population. However, little is known about the relation between specific HIV-related factors and the severity of the COVID-19 disease. METHODS: We performed a retrospective analysis of cases collected through an on-line survey distributed by the Euroguidelines in Central and Eastern Europe Network Group. In statistical analyses characteristics of HIV-positive patients, asymptomatic/moderate and moderate/severe course were compared. RESULTS: In total 34 HIV-positive patients diagnosed with COVID-19 were reported by 12 countries (Estonia, Czech Republic, Lithuania, Albania, Belarus, Romania, Serbia, Bosnia and Herzegovina, Poland, Russia, Hungary, Bulgaria). Asymptomatic courses of COVID-19 were reported in four (12%) cases, 11 (32%) patients presented with mild disease not requiring hospitalization, moderate disease with respiratory and/or systemic symptoms was observed in 14 (41%) cases, and severe disease with respiratory failure was found in five (15%) patients. The HIV-related characteristics of patients with an asymptomatic/mild course of COVID-19 were comparable to those with a moderate/severe course of COVID-19, except for the use of non-nucleoside reverse transcriptase inhibitors (NNRTIs) in cART regimen (0.0% vs. 31.6% respectively, p = 0.0239). CONCLUSIONS: In our analyses HIV viral suppression and immunological status were not associated with the course of COVID-19 disease. On the contrary the cART regimen could contribute to severity of SARS-CoV-2 infection. Large and prospective studies are necessary to further investigate this relationship.

Cross-sectional study on vaccination coverage in newly diagnosed HIV-infected persons in the Czech Republic.

OBJECTIVES: Individuals with HIV infection are at an increased risk for a number of infectious diseases, some of which are preventable by vaccination. Unfortunately, little is known about the attitudes of this population group to vaccination, therefore, we decided to find out vaccination coverage against 5 infections among newly diagnosed HIV-infected patients in the Czech Republic. METHODS: This cross-sectional study was conducted on newly diagnosed patients who started their follow-up care at the HIV Clinic of Na Bulovce Hospital during the two following years. Vaccination history data and results of serological tests were collected from all participants. RESULTS: Enrolled were 269 HIV-positive subjects (94.1% males) with a mean age of 34.4 years, 64 subjects (23.8%) had tertiary education, 229 (85.1%) were men having sex with men, 32 (11.9%) were heterosexual, and 8 (3.0%) were injection drug users. The mean CD4+ T-lymphocyte count was 556.2/µL, with 149 persons (55.4%) who had a CD4+ T-lymphocyte count > 500/µL, and 68 (25.3%) individuals were late presenters with CD4+ T-lymphocyte count < 350/µL. A vaccination against tetanus was reported by 262 subjects (97.4%), against influenza by 18 subjects (6.7%), against tick-borne encephalitis by 18 subjects (6.7%), against viral hepatitis A by 78 persons (29.0%), and against hepatitis B by 104 subjects (38.7%). For influenza, tick-borne encephalitis and hepatitis A, a significant positive impact of tertiary education was found (p-values < 0.001-0.044). Vaccination coverage against both types of hepatitis was significantly lower in late presenters (p = 0.044 and p = 0.004, respectively). CONCLUSIONS: Vaccination rates found in our cohort were except tetanus and hepatitis B in young people low, especially for influenza and tick-borne encephalitis. Higher level of education and less advanced HIV infection were associated with higher vaccination rates. To improve this unsatisfactory situation, more attention should be paid to vaccination.

Prevalence of Chlamydia trachomatis and Neisseria gonorrhoeae co-infections among patients with newly diagnosed syphilis: a single-centre, cross-sectional study.

OBJECTIVES: The aim of the study was to determine the prevalence of Chlamydia trachomatis and Neisseria gonorrhoeae co-infections among patients with newly diagnosed syphilis. METHODS: In patients with any stage of newly diagnosed syphilis swabs were performed from urethra, rectum, pharynx and cervix according to the gender and type of sexual intercourse. From these smears standard validated nucleic acid amplification tests (NAATs) for Chlamydia trachomatis and Neisseria gonorrhoeae infections were done. RESULTS: From 548 (488 men, 60 women) screened patients co-infection was detected in 15.9% of the cases. The majority of the co-infections (86.2%) were asymptomatic. The overall prevalence of chlamydial infection was 11.1% and 8.8% for gonococcal infections. In men who have sex with men (MSM) the prevalence of co-infections was significantly higher (20.0%) than in heterosexual men and women (4.2%) (p < 0.001). In MSM patients the presence of co-infection was significantly associated with HIV infection (p < 0.001). Among MSM 9.6% of the tests detected infection in anorectal site, while prevalence in urethral (2.8%) and pharyngeal (2.4%) localization was significantly lower. In heterosexual patients prevalence was less than 2.0% in all anatomic sites. CONCLUSIONS: The implementation of screening tests in case of sexually transmitted infections in patients with newly diagnosed syphilis is an important part in the management of this disease. These results suggest that screening of asymptomatic heterosexual patients leads to detection of minimum co-infections, but in MSM (especially HIV positive) should always be performed at least in anorectal site, where asymptomatic co-infections are common.

Expression of TIM-3 on Plasmacytoid Dendritic Cells as a Predictive Biomarker of Decline in HIV-1 RNA Level during ART.

Depletion and functional impairment of circulating plasmacytoid dendritic cells (pDCs) are characteristic attributes of HIV-1-infection. The mechanism of dysfunction of pDCs is unclear. Here, we studied the development of phenotype of pDCs in a cohort of HIV-1-infected individuals monitored before the initiation and during a 9-month follow up with antiretroviral therapy (ART). Using polychromatic flow cytometry, we detected significantly higher pDC-surface expression of the HIV-1 receptor CD4, regulatory receptor BDCA-2, Fcγ receptor CD32, pDC dysfunction marker TIM-3, and the marker of killer pDC, TRAIL, in treatment-naïve HIV-1-infected individuals before initiation of ART when compared to healthy donors. After 9 months of ART, all of these markers approached but did not reach the expression levels observed in healthy donors. We found that the rate of decline in HIV-1 RNA level over the first 3 months of ART negatively correlated with the expression of TIM-3 on pDCs. We conclude that immunogenic phenotype of pDCs is not significantly restored after sustained suppression of HIV-1 RNA level in ART-treated patients and that the level of the TIM-3 expressed on pDCs in treatment naïve patients could be a predictive marker of the rate of decline in the HIV-1 RNA level during ART.

Steady increase of lymphogranuloma venereum cases, Czech Republic, 2010 to 2015.

Since the notification of the first case of lymphogranuloma venereum (LGV) in the Czech Republic in 2010, the numbers of LGV cases have steadily increased in the country. In 2015, 40 LGV cases were diagnosed, bringing the total for 2010-2015, to 88 cases. The profile of the most affected group, HIV-positive men who have sex with men with a previous sexually transmitted infection, matches that of those described in LGV outbreaks in western Europe.

Development of 5' LTR DNA methylation of latent HIV-1 provirus in cell line models and in long-term-infected individuals.

BACKGROUND: Human immunodeficiency virus type 1 (HIV-1) latency represents the major barrier to virus eradication in infected individuals because cells harboring latent HIV-1 provirus are not affected by current antiretroviral therapy (ART). We previously demonstrated that DNA methylation of HIV-1 long terminal repeat (5' LTR) restricts HIV-1 reactivation and, together with chromatin conformation, represents an important mechanism of HIV-1 latency maintenance. Here, we explored the new issue of temporal development of DNA methylation in latent HIV-1 5' LTR. RESULTS: In the Jurkat CD4(+) T cell model of latency, we showed that the stimulation of host cells contributed to de novo DNA methylation of the latent HIV-1 5' LTR sequences. Consecutive stimulations of model CD4(+) T cell line with TNF-α and PMA or with SAHA contributed to the progressive accumulation of 5' LTR DNA methylation. Further, we showed that once established, the high DNA methylation level of the latent 5' LTR in the cell line model was a stable epigenetic mark. Finally, we explored the development of 5' LTR DNA methylation in the latent reservoir of HIV-1-infected individuals who were treated with ART. We detected low levels of 5' LTR DNA methylation in the resting CD4(+) T cells of the group of patients who were treated for up to 3 years. However, after long-term ART, we observed an accumulation of 5' LTR DNA methylation in the latent reservoir. Importantly, within the latent reservoir of some long-term-treated individuals, we uncovered populations of proviral molecules with a high density of 5' LTR CpG methylation. CONCLUSIONS: Our data showed the presence of 5' LTR DNA methylation in the long-term reservoir of HIV-1-infected individuals and implied that the transient stimulation of cells harboring latent proviruses may contribute, at least in part, to the methylation of the HIV-1 promoter.

HIV resistance testing and detected drug resistance in Europe.

OBJECTIVES: To describe regional differences and trends in resistance testing among individuals experiencing virological failure and the prevalence of detected resistance among those individuals who had a genotypic resistance test done following virological failure. DESIGN: Multinational cohort study. METHODS: Individuals in EuroSIDA with virological failure (>1 RNA measurement >500 on ART after >6 months on ART) after 1997 were included. Adjusted odds ratios (aORs) for resistance testing following virological failure and aORs for the detection of resistance among those who had a test were calculated using logistic regression with generalized estimating equations. RESULTS: Compared to 74.2% of ART-experienced individuals in 1997, only 5.1% showed evidence of virological failure in 2012. The odds of resistance testing declined after 2004 (global P < 0.001). Resistance was detected in 77.9% of the tests, NRTI resistance being most common (70.3%), followed by NNRTI (51.6%) and protease inhibitor (46.1%) resistance. The odds of detecting resistance were lower in tests done in 1997-1998, 1999-2000 and 2009-2010, compared to those carried out in 2003-2004 (global P < 0.001). Resistance testing was less common in Eastern Europe [aOR 0.72, 95% confidence interval (CI) 0.55-0.94] compared to Southern Europe, whereas the detection of resistance given that a test was done was less common in Northern (aOR 0.29, 95% CI 0.21-0.39) and Central Eastern (aOR 0.47, 95% CI 0.29-0.76) Europe, compared to Southern Europe. CONCLUSIONS: Despite a concurrent decline in virological failure and testing, drug resistance was commonly detected. This suggests a selective approach to resistance testing. The regional differences identified indicate that policy aiming to minimize the emergence of resistance is of particular relevance in some European regions, notably in the countries in Eastern Europe.

Immuno-virological discordance and the risk of non-AIDS and AIDS events in a large observational cohort of HIV-patients in Europe.

BACKGROUND: The impact of immunosuppression despite virological suppression (immuno-virological discordance, ID) on the risk of developing fatal and non-fatal AIDS/non-AIDS events is unclear and remains to be elucidated. METHODS: Patients in EuroSIDA starting at least 1 new antiretroviral drug with CD4<350 cells/µl and viral load (VL)>500 copies/mL were followed-up from the first day of VL< = 50 copies/ml until a new fatal/non-fatal non-AIDS/AIDS event. Considered non-AIDS events included non-AIDS malignancies, pancreatitis, severe liver disease with hepatic encephalopathy (>grade 3), cardio- and cerebrovascular events, and end-stage renal disease. Patients were classified over time according to whether current CD4 count was above (non-ID) or below (ID) baseline level. Relative rates (RR) of events were calculated for ID vs. non-ID using adjusted Poisson regression models. RESULTS: 2,913 patients contributed 11,491 person-years for the analysis of non-AIDS. 241 pre-specified non-AIDS events (including 84 deaths) and 89 AIDS events (including 10 deaths) occurred. The RR of developing pre-specified non-AIDS events for ID vs. non-ID was 1.96 (95% CI 1.37-2.81, p<0.001) in unadjusted analysis and 1.43 (0.94-2.17, p = 0.095) after controlling for current CD4 count. ID was not associated with the risk of AIDS events (aRR 0.76, 95% CI 0.41-1.38, p = 0.361). CONCLUSION: Compared to CD4 responders, patients with immuno-virological discordance may be at increased risk of developing non-AIDS events. Further studies are warranted to establish whether in patients with ID, strategies to directly modify CD4 count response may be needed besides the use of ART.

Incidence and clinical and immunological characteristics of primary Toxoplasma gondii infection in HIV-infected patients.

OBJECTIVES: To determine the incidence and laboratory characteristics of primary Toxoplasma gondii infection in HIV-infected individuals. METHODS: This retrospective study was conducted between 1988 and 2012 on a cohort of 1130 HIV-infected patients at the AIDS Center Prague. Toxoplasma serology, standard laboratory parameters, and health status were evaluated at 3-6-month intervals for all patients. RESULTS: The total person-time of follow-up of patients at risk of Toxoplasma seroconversion was 3046.3 years; there were 14 primary T. gondii infections, yielding an incidence rate of 0.0046 (95% confidence interval 0.0027-0.0078). Most of the subjects were clinically asymptomatic, but in one case seroconversion was accompanied by transient cervical lymphadenopathy. The CD4+ T-lymphocyte count geometric mean increased from 418 (95% confidence interval 303-579) cells/µl before seroconversion to 501 (95% confidence interval 363-691) cells/µl after seroconversion (p = 0.004), while other parameters (CD8+ T-lymphocytes, natural killer cells, viral load, beta2-microglobulin, total immunoglobulins) remained unchanged. As compared to the control group, patients with primary toxoplasmosis had higher initial levels of total immunoglobulins IgA and IgG and a tendency to higher CD8+ T lymphocyte counts. CONCLUSIONS: Neither the incidence nor the course of the primary Toxoplasma infection was influenced by the immune status of the patients. Immune parameters of patients with primary Toxoplasma infection did not differ from those of the controls.

[Lymphogranuloma venereum]. / Lymphogranuloma venereum.

Lymphogranuloma venereum is a sexually transmitted disease caused by serovars L1-3 of Chlamydia trachomatis. This infection was originally endemic in tropics and transmitted predominantly by heterosexual contact but since the beginning of the century it spreads in industrialized countries mainly among men having sex with men causing them severe proctitis. In the Czech Republic the first case was diagnosed in 2011. Lymphogranuloma venereum can resemble other forms of anorectal disorders inclusive inflammatory bowel diseases and thus it must be included into differential diagnostic considerations. Definitive diagnosis is based on detection of specific serovars of Chlamydia trachomatis by polymerase chain reaction. In patients with lymphogranuloma venereum it is also necessary to exclude other sexually transmitted diseases, particularly syphilis, HIV and also hepatitis C. The therapy of choice is doxycycline administered for three weeks.

Incidence, predisposing factors, and aetiology of infective endocarditis in the Czech Republic.

OBJECTIVES: The aim of this study was to evaluate the incidence and epidemiological characteristics of infective endocarditis (IE) in the Czech Republic. These results represent the first data on the epidemiology of IE from the post-communist countries. METHODS: This was a prospective multi-centre observational study monitoring the occurrence of IE in the catchment areas of 29 hospitals during a 12-month period. The total monitored territory involved a population of 3.9 million people (37.7% of the total Czech population). Patients were included in the study if they had a diagnosis of possible or definite endocarditis according to the modified Duke criteria. RESULTS: One hundred and thirty-four episodes of IE in 132 patients were reported. Thus the crude incidence of IE was 3.4 cases/100,000 inhabitants/y. Vegetations were most frequently found on the aortic and mitral valves. The most frequent agent was Staphylococcus aureus (29.9%). The aetiology remained unexplained in 33.6% of cases, mainly because of previous antibiotic therapy. Surgical intervention during antibiotic therapy was performed in 36 patients (27.5%). Thirty-six patients died during hospitalization (in-hospital mortality rate 27.5%). The most common predisposing cardiac factors were remote cardiac surgery (19.4%) and degenerative valvular changes (11.9%). The most common extracardiac factors were pyogenic infections of skin and soft tissues (13.0%) and chronic haemodialysis (8.2%). CONCLUSIONS: Our results document the changing epidemiological characteristics of IE, namely an increasing incidence of the disease and an increasing role of Staphylococcus aureus as a major pathogen. A shift was evident in predisposing factors for IE: almost 39% of IE episodes were associated with both cardiac and extracardiac modern medical procedures.

Prevalence of human leukocyte antigen HLA-B*57:01 in HIV-infected subjects in the Czech Republic.

The HLA-B*57:01 allele is associated with a hypersensitivity reaction to abacavir, and its prevalence varies in different populations. The aim of the study was to investigate HLA-B*57:01 prevalence in the Czech HIV-infected population. HLA-B*57:01 prevalence in our cohort was 5.33%, which is similar to the situation in other Central European countries.

[Our experience with maraviroc treatment in HIV positive patients]. / Nase zkusenosti s maravirocem u HIV pozitivních pacientu.

UNLABELLED: BACKGROUND; Although antiretroviral therapy has changed the clinical course of HIV infection, AIDS remains an incurable disease. Virus entry inhibitors, including maraviroc as the only registered representative of the class, represent a newly emerged group of anti-retrovirals with novel mechanism of action. The primary endpoint is to evaluate the clinical efficacy parameter of maraviroc by measuring viral load at the end of the 4 week treatment period. The secondary endpoint is to evaluate the effectiveness of the drug by monitoring the changes of the viral load values and CD4+ cell counts during the period of 125 weeks. Drug safety was also assessed. METHODS AND RESULTS: Data of 23 subjects were collected, 21 patients were from the Czech Republic and 2 patients from France. Decrease in viral load in the 4th, 24th and 48th week was more than two orders of magnitude (-2.136; -2.448; -2.452 log10 copies/ml). The CD4+ cell count increased (71.71, 143.00, 196.43 cells/mm3). Drug safety was assessed by monitoring the frequency of adverse effects. The data obtained were compared with the III. phase of clinical trials. CONCLUSIONS: Our experience with maraviroc was positive. Maraviroc proved to be an effective antiretroviral agent for a combination therapy of HIV infection.

[Exogenous Cushing's syndrome as a serious side-effect of therapy with ritonavir an inhaled fluticasone]. / Exogenni Gushinguv syndrom jako zavazny nezadouci ucinek lecby ritonavirem a inhalacnim flutikazonem.

Inhalation of fluticasone is usually devoid of systemic side-effects. The authors describe a case of a young HIV positive woman treated concomitantly with fluticasone and inhibitors of HIV protease ritonavir and lopinavir in which developed a serious endocrine side-effect - an iatrogenic Cushing's syndrome. Plasma concentration of cortisol < 5.5 nmol/l was very low (norm 250-650 nmol/l) and plasmatic ACTH was even not detectable. The administration of fluticasone and both inhibitors of HIV protease was stopped and substitution therapy with decreasing dose of hydrocortisone was initiated. Twenty weeks later resolved both clinical and laboratory symptoms of Cushing's syndrome, and the substitution therapy with hydrocortisone was terminated. Two years later became the patient pregnant and gave birth to a healthy child.

Estimating prevalence of accumulated HIV-1 drug resistance in a cohort of patients on antiretroviral therapy.

OBJECTIVES: Estimating the prevalence of accumulated HIV drug resistance in patients receiving antiretroviral therapy (ART) is difficult due to lack of resistance testing at all occasions of virological failure and in patients with undetectable viral load. A method to estimate this for 6498 EuroSIDA patients who were under follow-up on ART at 1 July 2008 was therefore developed by imputing data on patients with no prior resistance test results, based on the probability of detecting resistance in tested patients with similar profiles. METHODS: Using all resistance test results available, predicted intermediate/high-level resistance to specific drug classes [nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs)] was derived using the Stanford algorithm v5.1.2. Logistic regression models were then employed to estimate predicted probability of resistance to each drug class for given values of current viral load, history of virological failure and previous virological suppression. Based on these predicted probabilities and patients' covariate profiles, estimates of prevalence in 5355 patients with no prior test results were obtained. Overall prevalence of resistance was estimated by pooling these data with those observed in the remaining 1143 tested patients. RESULTS: Prevalence of NRTI, NNRTI and PI resistance was estimated as 43% (95% confidence interval: 39%-46%), 15% (13%-18%) and 25% (22%-28%), respectively. CONCLUSIONS: This method provides estimates for the proportion of treated patients in a cohort who harbour resistance on a given date, which are less likely to be affected by selection bias due to missing resistance data and will allow us to estimate prevalence of resistance to different drug classes at specific timepoints in HIV-infected populations on ART.

Bilateral Holmes-Adie syndrome as an early manifestation of the HIV neuropathy.

A 38-year-old HIV-1 infected woman affected with bilateral tonic pupils. Ophthalmologic examination confirmed Holmes-Adie syndrome (HAS), and peripheral distal polyneuropathy, orthostatic hypotension and leg hyperhidrosis were detected on further workup. The HAS can be either idiopathic or associated with neuropathy of various etiology (autoimmune, paraneoplastic and infectious). In our patient, the pupillotonia was the first and early symptom of hitherto unrecognized HIV neuropathy. HAS has been previously observed in association with syphilis, Lyme borreliosis, herpes simplex and parvovirus B19 infection. Our case is the first report of HAS in a case of HIV infection.

[Two types of CMV ocular complications in patients with HIV infection]. / Dva typy cytomegalovirového postizení oka u pacientu s HIV infekcí.

CMV retinitis is the most serious ocular complication of AIDS. Introduction of the combination antiretroviral therapy markedly reduced the occurrence of CMV retinitis, on the other hand it brought a new ocular complication - CMV uveitis. CMV uveitis is an immunopathological inflammatory reaction associated with the immune reconstitution inflammatory syndrome, which is a side effect of successfully initiated cART. These two forms of CMV ocular complications differ in pathogenesis, symptomatology and therapy. The CMV retinitis is treated with anti-CMV virostatics whereas the therapy of CMV uveitis is based on attenuation of the inflammatory reaction by administration of corticosteroids. The optimal prevention of both complications is an early initiation of cART before the CD4+ T lymphocytes drop below 200/microl.

[HIV retinopathy]. / HIV retinopatie.

HIV retinopathy is an ocular affection occurring especially in HIV positive patients with deep immunodeficiency. Because of benign character the HIV retinopathy does not require any specific therapy, but it must be carefully distinguished from other ocular diseases, which can seriously damage sight, e.g. CMV retinitis. The presence of HIV retinopathy can also be a symptom of progression of HIV infection and should be perceived as a signal for considering the initiation of antiretroviral therapy in treatment naive patients.

Acute appendicitis as a manifestation of the immune reconstitution inflammatory syndrome.

Acute appendicitis as a manifestation of the immune reconstitution inflammatory syndrome is repeatedly discussed in the literature, but only a few cases of acute appendicitis associated with the initiation of cART have been published as yet. We describe a case of a young HIV-infected man who suffered from acute appendicitis early after the successful switch of a failing cART regimen.

Successfully resuscitated sudden cardiac death in a young homosexual male with HIV myocarditis.

Successfully treated sudden cardiac death due to malignant arrhythmia related to HIV myocarditis in a young male with favorable clinical and virological profile is not described in current literature. HIV myocarditis as a possible cause of malignant ventricular arrhythmia and sudden cardiac death is discussed.