No transmitted drug resistance to HIV integrase strand-transfer inhibitors after their scale-up in Estonia in 2017.

OBJECTIVES: In Eastern Europe, HIV-1 transmitted drug resistance (TDR) data, especially in the integrase (IN) region, are limited. In Estonia, INSTI (integrase strand transfer inhibitors) TDR has been studied only prior to the INSTI scale-up in late 2010s. The current study aimed to determine the levels of protease (PR), reverse transcriptase (RT) and IN surveillance drug resistance mutations (SDRMs) among newly diagnosed patients in Estonia in 2017. METHODS: The study included 216 newly diagnosed HIV-1 individuals from 1 January until 31 December 2017 in Estonia. Demographic and clinical data were obtained from the Estonian Health Board, the Estonian HIV Cohort Study (E-HIV) and clinical laboratories' databases. The PR-RT and IN regions were sequenced and analysed for SDRMs and subtype determination. RESULTS: Seventy-one percent (151/213) of available HIV-positive samples were successfully sequenced. The overall level of TDR was 7.9% (12/151; 95% CI 4.4%-13.8%); no dual or triple class resistance was detected. No major INSTI mutations were found. The distribution of SDRMs for NNRTI, NRTI and PI was 5.9% (9/151), 1.3% (2/151) and 0.7% (1/151), respectively. The predominant NNRTI mutation was K103N. CRF06_cpx was the predominant variant (59%) in the Estonian HIV-1 population, followed by subtype A (9%) and subtype B (8%). CONCLUSION: Although no major INSTI mutations were found, close monitoring of INSTI SDRMs is needed considering the extensive use of the first- and second-generation INSTIs. PR-RT TDR is slowly rising in Estonia, indicating the need for continuous surveillance in the future. Low genetic barrier NNRTIs should be avoided in the treatment regimens.

Dynamics of hepatitis C epidemic among people living with HIV in Estonia based on Estonian HIV cohort study.

BACKGROUND: Estonia has a typical Eastern European HIV epidemic where the most frequent co-infection is chronic hepatitis C (HCV). We aimed to describe the changes in HCV prevalence, the distribution of HCV genotypes (GT), and HCV treatment in Estonian people living with HIV over 15 years. METHODS: We used data of subjects included to the Estonian HIV Cohort Study (E-HIV) before 31st of December 2015. We compared two time periods-first, 1st of January 2000 to 31st of December 2008 when the HIV epidemic was mostly spreading among people who inject drugs (PWID) and second, 1st of January 2009 to 31st of December 2015 when HIV started to emerge to the general population. RESULTS: Of 4422 HIV positives 3708 (84%) had information about their HCV serostatus; 2706 (61%) were HCV seropositive, of latter 1625 (60%) were HCV RNA positive, 239 (9%) had their HCV GT determined, and 141 (5%) received treatment for HCV. The dominating subtypes were 1b (42%) and 3a (37%) followed by 1a (16%), and the few cases of 2 (1.5%). HCV prevalence was 1.5 times (95% CI 1.4-1.6) higher in subjects diagnosed with HIV in first as compared to those diagnosed in second period (84% vs 56%, respectively). There were more men and the median age at HIV diagnosis was lower in HIV/HCV co-infected than in HIV mono-infected patients (70% vs 47% and 24 years vs. 30 years, respectively; both p < 0.001). CONCLUSION: There is a decrease in HCV prevalence but it remains high among HIV positive PWID, suggesting that there is need for improvement of harm reduction programs among PWID.

The concordance of the limiting antigen and the Bio-Rad avidity assays in persons from Estonia infected mainly with HIV-1 CRF06_cpx.

BACKGROUND: Serological assays to determine HIV incidence have contributed to estimates of HIV incidence, monitoring of HIV spread, and evaluation of prevention strategies. Two frequently used incidence assays are the Sedia HIV-1 LAg-Avidity EIA (LAg) and the Bio-Rad avidity incidence (BRAI) assays with a mean duration of recent infection (MDRI) of 130 and 240 days for subtype B infections, respectively. Little is known about how these assays perform with recombinant HIV-1 strains. We evaluated the concordance of these assays in a population infected mainly with HIV-1 CRF06_cpx. MATERIAL/METHODS: Remnant serum samples (n = 288) collected from confirmed, newly-diagnosed HIV-positive persons from Estonia in 2013 were tested. Demographic and clinical data were extracted from clinical databases. LAg was performed according to the manufacturer's protocol and BRAI testing was done using a validated protocol. Samples with LAg-pending or BRAI-invalid results were reclassified as recent if they were from persons with viral loads <1000 copies/mL or were reclassified as long-term if presenting with AIDS. RESULTS: In total 325 new HIV infections were diagnosed in 2013 in Estonia. Of those 276 persons were tested with both LAg and BRAI. Using assay results only, the recency rate was 44% and 70% by LAg and BRAI, respectively. The majority of samples (92%) recent by LAg were recent by BRAI. Similarly, 89% of samples long-term by BRAI were long-term by LAg. After clinical information was included in the analysis, the recency rate was 44% and 62% for LAg and BRAI, respectively. The majority of samples (86%) recent by LAg were recent by BRAI and 91% of long-term infections by BRAI were long-term by LAg. CONCLUSIONS: Comparison of LAg and BRAI results in this mostly CRF06_cpx-infected population showed good concordance for incidence classification. Our finding of a higher recency rate with BRAI in this population is likely related to the longer MDRI for this assay.

Stable level of HIV transmitted drug resistance in Estonia despite significant scale-up of antiretroviral therapy.

BACKGROUND: Due to the widespread use of non-nucleoside reverse transcriptase inhibitors (NNRTI) as part of first-line therapies to curb the human immunodeficiency virus (HIV) epidemic in Eastern-European countries, transmitted drug resistance (TDR) is of serious concern in this region. Therefore, TDR and its associated risk factors were investigated among newly diagnosed HIV-1 subjects in Estonia. METHODS: This nationwide observational study included all newly diagnosed HIV-1 subjects from January 1 until December 31, 2013. Demographic and clinical data were collected using the national surveillance system and the Estonian HIV-positive patient database (E-HIV). Starting from RNA, the HIV-1 protease (PR) and reverse transcriptase (RT) region was sequenced and surveillance drug resistance mutations (SDRM) were determined. Sequences from previous studies in Estonia and from public databases were included to study epidemic trends and to determine TDR clusters by phylogenetic analysis. RESULTS: Out of 325 newly diagnosed HIV-1 infections, 224 were successfully sequenced (68%). As in previous studies from Estonia, the circulating recombinant form CRF06_cpx was the most prevalent HIV subtype (164/224, 74%). Fifteen strains displayed SDRM, giving a TDR rate of 6.7% (95% CI 3.9; 11.0). The most common SDRMs were associated with NNRTI (10/15, 4.5%), followed by PI (3/15, 1.3%) and NRTI (2/15, 0.9%). K103 N (8/15, 53%) was the most common SDRM. The level of TDR and mutational patterns were comparable to previous years. Twenty-six transmission clusters containing Estonian sequences were observed, of which 23/26 belonged to CRF06_cpx and 2/26 displayed evidence of TDR. The only risk factor associated with the presence of TDR was imprisonment (OR 5.187, CI 1.139-25.565, p = 0.034). CONCLUSIONS: TDR remained stable at a moderate level in Estonia, K103N is the main SDRM with only one transmission-pair detected. We suggest screening for TDR at the time of diagnosis or prior to antiretroviral treatment initiation to tailor first-line regimens accordingly. SUMMARY: The third consecutive transmitted drug resistance (TDR) study demonstrated a stable TDR in Estonia. TDR reached 6.7% (moderate level) in 2013, with imprisonment being the only associated risk factor. Few drug resistance-associated transmission clusters were identified.

Design and structure of the Estonian HIV Cohort Study (E-HIV).

BACKGROUND: Estonia is experiencing the new Eastern Europe human immunodeficiency virus (HIV) epidemic, with the highest incidence of new infections in the EU. We describe demographic changes, HIV-related laboratory parameters and co-infections during the concentrated HIV epidemic using the Estonian HIV Cohort Study (E-HIV) database, founded in 2009. METHODS: All 3750 subjects in the E-HIV database on December 31, 2013 were included. Subjects were divided into risk groups: people who inject drugs (PWIDs), sexual transmission (heterosexual/homosexual), and other (perinatal) or unknown risk group. Subjects diagnosed before 2009 (first period) and after (second period) were analyzed separately. RESULTS: The mean age at diagnosis has increased from 22.8 years (interquartile range (IQR) = 19.5-27.2) to 29.7 years (IQR = 25.3-36.2) (p < 0.001) between the first and second periods. PWIDs were younger than other transmission groups (23.2 vs 27.1; p < 0.001). There is a statistical difference in the route of transmission among genders, with overall increasing sexual transmission. The most common AIDS-defining illness was tuberculosis (0.5%). HIV/hepatitis C (HCV) co-infection was diagnosed in 42% of cases. The population median CD4 + cell count at diagnosis has declined over the years; in total 53% have been late presenters. Half of the patients are receiving antiretroviral treatment (cART). The most common combinations are nucleoside reverse transcriptase inhibitor (NRTI) backbone plus protease inhibitors (PIs) (57%) or NRTI backbone + non-NRTIs (42%). CONCLUSION: The E-HIV enables us to fill the gap in the lack of data on the course of the new Eastern European HIV epidemic. These data demonstrate that the HIV epidemic in Estonia is moving from PWIDs to the general population, suggesting that prevention measures and testing guidelines should be revised.