Estimation of the determinants for HIV late presentation using the traditional definition and molecular clock-inferred dates: Evidence that older age, heterosexual risk group and more recent diagnosis are prognostic factors.

OBJECTIVES: HIV late presentation (LP) has been increasing in recent years in Europe. Our aim was to investigate the characteristics of LP in Greece using in addition to the traditional definition for LP, the time interval between HIV infection and diagnosis. METHODS: Our nationwide sample included HIV-1 sequences generated from 6166 people living with HIV (PLWH) in Greece during the period 1999-2015. Our analysis was based on the molecularly inferred HIV-1 infection dates for PLWH infected within local molecular transmission clusters of subtypes A1 and B. RESULTS: Analysis of the determinants of LP was conducted using either CD4 counts or AIDS-defining condition at diagnosis or the time from infection to diagnosis. Older age, heterosexual transmission risk group and more recent diagnosis were associated with increased risk for LP. In contrast to previous studies, people who inject drugs (PWID) had a shorter median time to diagnosis (0.63 years) compared to men who have sex with men (MSM) (1.72 years) and heterosexuals (2.43 years). Using HIV infection dates that provide an unbiased marker for LP compared to CD4 counts at diagnosis, which are age-dependent, we estimated that the time to diagnosis increased gradually with age. Migrants infected regionally do not differ with respect to LP status compared to native Greeks. CONCLUSIONS: We demonstrate that older people and heterosexuals are among those at higher risk for LP; and given the growing number of older people among newly diagnosed cases, tailored interventions are needed in these populations.

Earlier treatment initiation is associated with a decreased number of HIV-1 subtype A1 transmissions in Greece.

OBJECTIVES: Subtypes A1 and B are the most prevalent HIV-1 clades in Greece. Subtype A1 epidemic is highly monophyletic and corresponds to transmissions that occurred locally. Our aim in this molecular epidemiology analysis was to investigate the role of early treatment in preventing new HIV-1 transmissions. METHODS: Our analysis focused on 791 subtype A1 sequences from treatment-naïve individuals in Greece. Estimation of infection dates was performed by molecular clock calculations using Bayesian methods. We estimated the time interval between (1) the infection and sampling dates (linkage to care window), (2) the sampling dates and antiretroviral therapy (ART) initiation (treatment window), and (3) the infection dates and ART initiation (transmissibility window) for the study population. We also inferred the putative source of HIV infections between individuals of different groups divided according to the length of treatment, linkage to care or transmissibility window. RESULTS: A significant decline was detected for the treatment window during 2014-2015 versus the 2 previous years (p=0.0273), while the linkage to care interval remained unchanged during the study period. Inference of the putative source of HIV infections suggested that individuals with a recent diagnosis or narrow transmissibility window (time period between HIV infection and ART initiation) were not sources of HIV infections to other groups. Contrarily, a significant number of HIV infections originated from individuals with longer transmissibility window interval. CONCLUSIONS: Our findings showed that the treatment window is decreasing over time, presumably due to the updated treatment guidelines. Our study also demonstrates that people treated earlier after infection do not transmit at high rates, thus documenting the benefits of early ART initiation in preventing ongoing HIV-1 transmission.

Dating the Origin and Estimating the Transmission Rates of the Major HIV-1 Clusters in Greece: Evidence about the Earliest Subtype A1 Epidemic in Europe.

Our aim was to estimate the date of the origin and the transmission rates of the major local clusters of subtypes A1 and B in Greece. Phylodynamic analyses were conducted in 14 subtype A1 and 31 subtype B clusters. The earliest dates of origin for subtypes A1 and B were in 1982.6 and in 1985.5, respectively. The transmission rate for the subtype A1 clusters ranged between 7.54 and 39.61 infections/100 person years (IQR: 9.39, 15.88), and for subtype B clusters between 4.42 and 36.44 infections/100 person years (IQR: 7.38, 15.04). Statistical analysis revealed that the average difference in the transmission rate between the PWID and the MSM clusters was 6.73 (95% CI: 0.86 to 12.60; p = 0.026). Our study provides evidence that the date of introduction of subtype A1 in Greece was the earliest in Europe. Transmission rates were significantly higher for PWID than MSM clusters due to the conditions that gave rise to an extensive PWID HIV-1 outbreak ten years ago in Athens, Greece. Transmission rate can be considered as a valuable measure for public health since it provides a proxy of the rate of epidemic growth within a cluster and, therefore, it can be useful for targeted HIV prevention programs.

A Nationwide Study about the Dispersal Patterns of the Predominant HIV-1 Subtypes A1 and B in Greece: Inference of the Molecular Transmission Clusters.

Our aim was to investigate the dispersal patterns and parameters associated with local molecular transmission clusters (MTCs) of subtypes A1 and B in Greece (predominant HIV-1 subtypes). The analysis focused on 1751 (28.4%) and 2575 (41.8%) sequences of subtype A1 and B, respectively. Identification of MTCs was based on phylogenetic analysis. The analyses identified 38 MTCs including 2-1518 subtype A1 sequences and 168 MTCs in the range of 2-218 subtype B sequences. The proportion of sequences within MTCs was 93.8% (1642/1751) and 77.0% (1982/2575) for subtype A1 and B, respectively. Transmissions within MTCs for subtype A1 were associated with risk group (Men having Sex with Men vs. heterosexuals, OR = 5.34, p < 0.001) and Greek origin (Greek vs. non-Greek origin, OR = 6.05, p < 0.001) and for subtype B, they were associated with Greek origin (Greek vs. non-Greek origin, OR = 1.57, p = 0.019), younger age (OR = 0.96, p < 0.001), and more recent sampling (time period: 2011-2015 vs. 1999-2005, OR = 3.83, p < 0.001). Our findings about the patterns of across and within country dispersal as well as the parameters associated with transmission within MTCs provide a framework for the application of the study of molecular clusters for HIV prevention.

Norwegian scabies presenting as erythroderma in HIV: A case report.

Crusted scabies is a rare and extreme manifestation of scabies that is observed mainly among immunosuppressed patients. We describe the case of a 55-year-old patient with a history of HIV infection and injection drug use. The patient was not on any antiretroviral therapy during the previous year, was malnourished and was living in unsanitary conditions. He had extensive, generalized, thick, hyperkeratotic, crusting, papular lesions, which had evolved over the previous month. Hyperkeratotic areas were fissured and linear excoriations were noted diffusely. The rash was distributed on the entire body from the scalp to the toes, with mild itching. Microscopic examination of the scale revealed numerous scabies mites and eggs. The patient was treated with topical scabicidal agents, which resulted in complete resolution. Because of the extremely contagious nature of crusted scabies, as well as its potential for complete cure with an appropriate therapy, there should be a high degree of suspicion for this disease in patients with AIDS, even when the lesions do not have the classical appearance. Nosocomial transmission of scabies from patients with AIDS is a risk, and protective measures, early diagnosis, and therapy are essential.

Evaluation of a convenient vaccination schedule against hepatitis B in HIV-patients with undetectable HIV viral load.

Vaccination against hepatitis B virus (HBV) is recommended for all HIV-positive individuals but the standard schedule is not satisfactory. High or more doses have also been studied with variable results. We compared a vaccination schedule with a higher dose but fewer shots to the standard scheme (HBVaxPro 40 µg versus Engerix 20 µg at 0, 1, and 6 months). Of the 63 patients vaccinated with HBVaxPro 79%, 65% and 47% seroconverted at month 1, 12 and 24 after vaccination, respectively. A total of 137 patients received Engerix and showed lower response rates (68%, 53% and 38%, respectively). Anti-HBs titers in the Engerix group were also lower with a statistically significant difference. In patients younger than 55 years HBVaxPro was 3 times more likely to provoke a response compared with Engerix (OR = 3, p = 0.006). In conclusion, HBVaxPro 40 µg at 3 doses could be proposed as a more robust and acceptable alternative.

Dermatological conditions associated with HIV medication in a cohort of Greek patients initiating antiretroviral therapy: 1988-2013.

Objectives: Treatment of HIV infection has evolved from a single antiretroviral agent to combination therapy, which has dramatically improved both the quality of life and life expectancy of affected patients. The aim of this study was to review HIV treatment-associated dermatological conditions observed in adult patients receiving antiretroviral therapy (ART) in a single tertiary care referral centre over time. Methods: We reviewed the files of HIV-positive patients seen at the Dermatology Department, AIDS Clinic of the Andreas Syggros Hospital, Athens, Greece who had initiated ART from 1988 to 2013, for evidence of dermatological conditions commonly associated with HIV-related medication. Results: Among a cohort of 1329 HIV-positive patients (1155 men and 174 women), 352 (299 men and 53 women) presented with at least one dermatological condition, with a total of 423 conditions diagnosed that could be attributed to HIV-related medication. Lipodystrophy (47.42%), and maculopapular (MP) rash (40.6%) were most commonly diagnosed. There were three incidence peaks for these reactions, which reflected the different types of ART and HIV-related drugs commonly used at the time. After 2006, the number of these dermatological conditions declined (15.1% of cases) with the availability of newer ART regimens. Conclusions: Early ART was accompanied with a high incidence of adverse skin reactions, which have decreased over time in association with overall better tolerated treatment regimens for HIV infection.

Suicidal behaviour in HIV-infected patients in Greece.

This study investigated suicide completion and suicide attempts by HIV-infected patients in Greece, which, from the existing literature, are more frequent than those among the general population. The study sample comprised HIV-infected patients who had been monitored for a minimum period of six months from 1992 through 2012 at the "Andreas Sygros" University Hospital in Athens. Among the 1884 patients who were monitored during the study period, 37 suicides were attempted by 28 (1.48%) patients (27 men and 1 woman). Six of them were fatal (0.3%, 52/100,000 person-years) while over the study, 397 patients died. No significant differences concerning main characteristics were recorded among patients with an attempted and those with a completed suicide. Seventeen of the 28 patients (60.71%) demonstrated psychiatric morbidities. Suicide attempts were more numerous before the advent of combined antiretroviral therapy (cART), whereas there was no difference in attempts before and after the Greek financial crisis in 2009. The suicide frequency was higher than that of the general population for the same period. However, it decreased after the introduction of cART. Special attention is required in recording coexisting mental disorders and providing specialized psychiatric care to HIV-infected patients.

Transmission Dynamics of HIV-1 Drug Resistance among Treatment-Naïve Individuals in Greece: The Added Value of Molecular Epidemiology to Public Health.

The presence of human immunodeficiency virus type 1 (HIV-1) drug resistance among drug-naïve patients remains stable, although the proportion of patients with virological failure to therapy is decreasing. The dynamics of transmitted resistance among drug-naïve patients remains largely unknown. The prevalence of non-nucleoside reverse transcriptase inhibitors (NNRTI) resistance was 16.9% among treatment-naïve individuals in Greece. We aimed to investigate the transmission dynamics and the effective reproductive number (Re) of the locally transmitted NNRTI resistance. We analyzed sequences with dominant NNRTI resistance mutations (E138A and K103N) found within monophyletic clusters (local transmission networks (LTNs)) from patients in Greece. For the K103N LTN, the Re was >1 between 2008 and the first half of 2013. For all E138A LTNs, the Re was >1 between 1998 and 2015, except the most recent one (E138A_4), where the Re was >1 between 2006 and 2011 and approximately equal to 1 thereafter. K103N and E138A_4 showed similar characteristics with a more recent origin, higher Re during the first years of the sub-epidemics, and a declining trend in the number of transmissions during the last two years. In the remaining LTNs the epidemic was still expanding. Our study highlights the added value of molecular epidemiology to public health.

Early syphilis affects markers of HIV infection.

The objective of this study was to investigate if early syphilis infection affects markers of HIV infection; CD4 T cells and viral load (VL). A retrospective study was performed on 160 HIV-positive patients (111 receiving antiretroviral therapy [ART] and 49 without ART). Early syphilis diagnosis was made in HIV patients during their follow-up at the HIV/AIDS Unit at a Greek Dermatology and Venereology Unit. The patients' blood tests were available at the time of diagnosis, as well as before and 12 weeks after early syphilis diagnosis. CD4 T cell counts and VL levels were measured. It was found that syphilis infection had a negative impact on the CD4 T cell counts in both groups, with reduced CD4 T cell counts observed in 84.6% (99/111) and 79.5% (39/49) of patients receiving and not receiving ART, respectively. After treatment for syphilis, CD4 T cell counts returned to pre-treatment levels in most patients, especially those receiving ART. There was a slight and transient VL increase. Patients receiving ART had a 27% increase in VL, compared to 71.4% among patients not receiving ART. Although the VL increase was slight (41-14,000 copies/ml) in the group under treatment, 4-5% (5/111) patients did not return to pre-treatment levels. Moreover, viral mutations associated with treatment resistance were identified in these patients. Early syphilis accelerates and complicates the progression of HIV infection. Early diagnosis and treatment of syphilis may prevent infection-associated complications in most instances. Consequently, prevention of syphilis and other sexually transmitted infections is of great importance for patients infected with HIV.

Adherence to hepatitis A virus vaccination in HIV-infected men who have sex with men.

Although vaccination against hepatitis A virus (HAV) is essential for human immunodeficiency virus (HIV)-infected patients, the uptake of HAV vaccine is reported to be very low. From 2007 to 2012, 912 HIV-infected men in Athens, Greece were screened for exposure to HAV. Two doses of an HAV vaccine were recommended to 569 eligible patients. Reminder cards with scheduled vaccination visits were given to each patient. Among eligible patients, 62.2% (354/569) received both doses. Patients who were fully vaccinated compared with non-adherent patients were natives, older, had undetectable HIV viral load, higher CD4 T cell counts and lower nadir CD4 T cell counts. Multivariate logistic regression revealed that the patient's country of origin (p = 0.024; OR = 2.712; 95% CI, 1.139-6.457), CD4 T cell count (p < 0.001) and nadir CD4 T cell count (p < 0.001) were factors directly associated with adherence. In conclusion, adherence to HAV vaccination was better than in previously published data. Because many of the factors related to vaccination completion are parameters of HIV infection, it appears that physician interest in HIV care and vaccination planning is crucial to enhancing vaccine uptake.

Prevalence and titre of antibodies against Hepatitis A virus in HIV-infected men having sex with men in Greece.

Hepatitis A remains a serious vaccine-preventable disease for HIV patients. We tested 897 HIV-infected men having sex with men (MSM) for antibodies against hepatitis A virus (anti-HAV) and measured the geometric mean antibody titres (GMTs) in a group of patients who received a hepatitis A vaccine and in patients with immunity to HAV due to infection in childhood. In all, 320 patients (35%) had positive anti-HAV antibodies. Multivariate analysis showed that only age (p 0.001) and ethnic origin (OR 20.029, p 0.001) had a statistically significant effect on the presence of antibodies. In addition, age was a fairly sensitive (68.4%) and specific (64.2%) marker, patients being separated by the 36.5 years cut-off point. The response rate of patients who get vaccinated (n 383), one month following the administration of the second dose of the vaccine, was 76%. The GMT of the vaccinated patients was 305 mIU/ml versus 7105 mIU/ml of patients with past infection. The vast majority of HIV-infected MSM patients in Greece is susceptible to HAV. Immunity to HAV in newly vaccinated patients, unlike patients with natural immunity, is low and probably requires monitoring.

Patterns of drug resistance among newly diagnosed HIV-1 infected patients in Greece during the last decade: the crucial role of transmission networks.

INTRODUCTION: The prevalence of drug resistance is approximately 10% in Europe and North America among newly infected patients. We aim to investigate the temporal patterns of resistance among drug naive HIV-infected individuals in Greece and also to determine transmission networking among those with resistant strains. MATERIALS AND METHODS: Protease (PR) and partial reverse transcriptase (RT) sequences were determined from 2499 newly diagnosed HIV-1 patients, in Greece, during 2003-2013. Genotypic drug resistance was estimated using the HIVdb: Genotypic Resistance Interpretation Algorithm. We identified transmission clusters of resistant strains on the basis of a large collection of HIV-1 sequences from 4024 seropositives in Greece. Phylodynamic analysis was performed using a Bayesian method. RESULTS: We estimated drug resistance levels among naïve patients on the basis of all resistance mutations in PR and partial RT. The overall prevalence of resistance was 19.6% (490/2499). Resistance to NNRTIs was the most common (397/2499, 15.9%) followed by PIs (116/2499, 4.6%) and NRTIs (79/2499, 3.2%). We found a significant trend for decreasing resistance to NRTIs over time (6.7%-1.6%). There was no time trend for the overall PI and NNRTI resistance. The most frequently observed major resistant sites in PR were V82 (2.0%) and L90 (1.8%). In RT, we found E138 (58.6%), K103 (13.1%), V179 (8.4%) and T215 (7.1%), M41 (4.7%) associated with resistance to NNRTIs and NRTIs, respectively. The prevalence of K103N and E138Q were significantly increased during 2003-2013. Crucially, we found that both K103N, E138Q are associated with transmission networking within men having sex with men (MSM) and intravenous drug user (IDU) local networks. The K103N network included seropositives across Greece, while the latter only from the recent IDU outbreak in Athens metropolitan area (1). Phylodynamic analyses revealed that the exponential growth for K103N network started in 2009 (Figure 1) and for the E138Q in 2010. CONCLUSIONS: The overall resistance has been stable in Greece over time; however, specific NNRTI resistance patterns are increasing. Notably, they are associated with local transmission networking, thus suggesting that this is the cause for the increased patterns of NNRTI resistance and not multiple transmissions of resistant strains from different sources among treated individuals. Our study highlights the advance of molecular epidemiology for understanding the dynamics of resistance.

Hepatitis A vaccination and immunological parameters in HIV-infected patients.

Vaccination against hepatitis A is an important intervention to prevent disease in HIV-patients. There are insufficient data on the association of the response to hepatitis A vaccine with immunological parameters, including subpopulations of T-cells. We studied HIV-infected adults with CD4 T-cells>200 cells/mm(3) who received two doses of hepatitis A vaccine (Havrix or Vaqta). The counts of CD3, CD4, CD8, CD4+T-cells, NK, NK CD8+, NK CD8 - cells, and HIV RNA were measured at the time of first dose administration and one month after the end of the vaccination period. The geometric mean titer of antibodies to hepatitis A virus (anti-HAV) and factors affecting response were evaluated. 113 patients (50 antiretroviral treatment-naïve and 63 treatment-experienced) were enrolled in the study. There was no change in the immunological parameters and in the HIV-RNA post-vaccination, except for a decrease in CD8 and in double positive CD4+CD8+t-cell count. The immune response and geometric mean titer of anti-HAV were similar among treated and naïve patients (78% vs. 76% and 237 mIU/mL vs. 158 mIU/mL). Vaccine response was achieved in 71% of patients with CD4=200-499 cells/mm(3) compared with 80% of participants with CD4 ≥500 cells/mm(3) (p>0.05). Logistic regression revealed that immunological cells tested do not affect response differently in treatment-naïve vs. experienced patients. The only factor affecting response is the CD4 T-cell count at vaccination (OR 1.320; 95% CI 1.052-1.656; p=0.016). Patients with CD4 T-cell count ≥500 cells/mm(3) were 4.3 times more likely to respond to the vaccine than patients with CD4 T-cell count 200-499 cells/mm(3) (p=0.005). In conclusion, successful vaccination is associated with CD4 T-cells. The count of other immune cells or the administration of antiretroviral therapy does not predict response to hepatitis A vaccine in HIV patient with baseline CD4 T-cell>200 cells/mm(3).

Adherence to antiretroviral therapy among HIV-infected prisoners.

Adherence, the act of following a course of medication in exactly the manner prescribed, is critical for the success of therapy. Adherence is influenced by many behavioural and social factors and incarceration might be one such factor. This study determined the level of adherence and reasons for non-adherence to antiretroviral therapy among 93 HIV-infected prisoners. Up to 56% of these patients had poor adherence. A similar rate of adherence was detected in prisoners after release. Problems with antiretroviral adherence among prisoners appear to be mostly linked to their deviant behaviour. Inmates with poor adherence had higher HIV-related morbidity and mortality. Age and country of origin were also associated with adherence.