Magdalena Witak-Jędra

Transmitted HIV drug resistance in antiretroviral-treatment-naive patients from Poland differs by transmission category and subtype

OBJECTIVES The surveillance of HIV-transmitted drug resistance mutations (t-DRMs), including temporal trends across subtypes and exposure groups, remains a priority in the current management of the epidemic worldwide. METHODS A cross-sectional analysis of 833 treatment-naive patients from 9 of 17 Polish HIV treatment centres. Partial pol sequences were used to analyse drug resistance with a general time reversible (GTR)-based maximum likelihood algorithm used for cluster/pair identification. Mutation frequencies and temporal trends were investigated. RESULTS t-DRMs were observed in 9% of cases (5.8% for NRTI, 1.2% NNRTI and 2.0% PI mutations) and were more common among heterosexually infected (HET) individuals (13.4%) compared with MSM (8.3%, P = 0.03) or injection drug users (IDUs; 2.9%, P = 0.001) and in MSM compared with IDUs (P = 0.046). t-DRMs were more frequent in cases infected with the non-B variant (21.6%) compared with subtype B (6.6%, P < 0.001). With subtype B a higher mutation frequency was found in MSM compared with non-MSM cases (8.3% versus 1.8% for IDU + HET, P = 0.038), while non-B variants were associated with heterosexual exposure (30.4% for HET versus 4.8% for MSM, P = 0.019; versus 0 for IDU, P = 0.016). Trends in t-DRM frequencies were stable over time except for a decrease in NNRTI t-DRMs among MSM (P = 0.0662) and an NRTI t-DRM decrease in HET individuals (P = 0.077). With subtype B a higher frequency of sequence pairs/clusters in MSM (50.4%) was found compared with HET (P < 0.001) and IDUs (P = 0.015). CONCLUSIONS Despite stable trends over time, patterns of t-DRMs differed notably between transmission categories and subtypes: subtype B was associated with MSM transmission and clustering while in non-B clades t-DRMs were more common and were associated with heterosexual infections.

The temporal increase in HIV-1 non-R5 tropism frequency among newly diagnosed patients from northern Poland is associated with clustered transmissions

CCR5 (R5) tropic viruses are associated with early stages of infection, whereas CXCR4 (X4) HIV‐1 tropism has been associated with severe immunodeficiency. We investigated the temporal changes in the genotype‐predicted tropism frequency and the phylogenetic relationships between the R5 and non‐R5 clades.

Distribution and time trends of HIV-1 variants in Poland: Characteristics of non-B clades and recombinant viruses.

The spread of HIV-1 subtypes varies considerably both worldwide and within Europe, with non-B variants commonly found across various exposure groups. This study aimed to analyse the distribution and temporal trends in HIV-1 subtype variability across Poland. For analysis of the subtype distribution, 1219 partial pol sequences obtained from patients followed up in 9 of 17 Polish HIV treatment centres were used. Subtyping was inferred using the maximum likelihood method; recombination was assessed using the bootscanning and jumping profile hidden Markov model methods. Subtype B dominated in the studied group (n=1059, 86.9%); in 160 (13.1%) sequences, non-B variants were present [A1 (n=63, 5.2%), D (n=43, 3.5%), C (n=22, 1.8%), and F1 (n=2, 0.2%)]. In 25 (2.1%) cases circulating recombinant forms (CRFs) were found. Five A1 variants (0.4%) were unique AB recombinant forms (URF) not previously identified in Poland. Non-B clades were notably more common among females (n=73, 45.6%, p<0.001) and heterosexual individuals (n=103, 66.5%, p<0.001) and less frequent among men who have sex with men (MSM) (n=27, 17.42%, p<0.001). HIV-1 viral load at diagnosis was higher among non-B cases [median: 5.0 (IQR: 4.4-5.6)] vs. [median: 4.8 (IQR: 4.3-5.4) log copies/ml for subtype B (p<0.001)] with a lower CD4(+) lymphocyte count at baseline [median: 248 (IQR: 75-503) for non-B vs. median: 320 (IQR: 125-497) cells/μl for subtype B; p<0.001]. The frequency of the non-B subtypes proved stable from 2008 (11.5%) to 2014 (8.0%) [OR: 0.95 (95% CI: 0.84-1.07), p=0.4], with no temporal differences for exposure groups, gender, age and AIDS. Despite the predominance of subtype B, the variability of HIV in Poland is notable; both CRFs and URFs are present in the analysed population. Non-B variants are associated with heterosexual transmission, more advanced HIV disease and have stable temporal frequencies.

Time trends in HIV-1 transmitted drug resistance mutation frequency in Poland.

In Poland, the HIV epidemic has shifted recently from being predominantly related to injection drug use (IDU) to being driven by transmissions among men‐who‐have‐sex‐with‐men (MSM). The number of new HIV cases has increased in the recent years, while no current data on the transmitted drug resistance associated mutations (tDRM) frequency trend over time are available from 2010. In this study, we analyze the temporal trends in the spread of tDRM from 2008 to 2013.

Expanding HIV-1 subtype B transmission networks among men who have sex with men in Poland

Introduction Reconstruction of HIV transmission links allows to trace the spread and dynamics of infection and guide epidemiological interventions. The aim of this study was to characterize transmission networks among subtype B infected patients from Poland. Material and methods Maximum likelihood phylogenenetic trees were inferred from 966 HIV-1 subtype B protease/reverse transcriptase sequences from patients followed up in nine Polish HIV centers. Monophyletic clusters were identified using 3% within-cluster distance and 0.9 bootstrap values. Interregional links for the clusters were investigated and time from infection to onward transmission estimated using Bayesian dated MCMC phylogeny. Results Three hundred twenty one (33.2%) sequences formed 109 clusters, including ten clusters of ≥5 sequences (n = 81, 8.4%). Transmission networks were more common among MSM (234 sequences, 68.6%) compared to other infection routes (injection drug use: 28 (8.2%) and heterosexual transmissions: 59 (17.3%) cases, respectively [OR:3.5 (95%CI:2.6–4.6),p<0.001]. Frequency of clustering increased from 26.92% in 2009 to 50.6% in 2014 [OR:1.18 (95%CI:1.06–1.31),p = 0.0026; slope +2.8%/year] with median time to onward transmission within clusters of 1.38 (IQR:0.59–2.52) years. In multivariate models clustering was associated with both MSM transmission route [OR:2.24 (95%CI:1.38–3.65),p<0.001] and asymptomatic stage of HIV infection [OR:1.93 (95%CI:1.4–2.64),p<0.0001]. Additionally, interregional networks were linked to MSM transmissions [OR:4.7 (95%CI:2.55–8.96),p<0.001]. Conclusions Reconstruction of the HIV-1 subtype B transmission patterns reveals increasing degree of clustering and existence of interregional networks among Polish MSM. Dated phylogeny confirms the association between onward transmission and recent infections. High transmission dynamics among Polish MSM emphasizes the necessity for active testing and early treatment in this group.

Phylogeographic analysis on the travel-related introduction of HIV-1 non-B subtypes to Northern Poland

Phylodynamic, sequence data based reconstructions for the surveillance of the geographic spatial spread are a powerful tool in molecular epidemiology. In this study region of origin for the set of 57 partial pol sequences derived from the patients the history of travel-related HIV transmission was analyzed using phylogeographic approach. Maximum likelihood trees based on the sets of country-annotated reference sequences were inferred for identified non-B variants. Region of sequence import was assigned using on the highest approximate likelihood ratios. Import of the A1 clades was traced to the Eastern Europe and associated with immigration from this region. Subtype C infections clustered most frequently with sequences of the South African origin while majority of subtype Ds were similar to the European clades. Subtype G sequences clustered with Portuguese lineage, CRF01_AE with Eastern or South-Eastern Asian. Eastern European, Middle African or Western African lineage was assigned for the CFR02_AG. Rare circulating recombinants originated either from Central Africa (CRF11_cpx - Democratic Republic of Congo, CRF13_cpx - Central African Republic, CRF37_cpx - Cameroon) or South America (CRF28_BF and CRF46_BF - Brazil). Import of the HIV-1 non-B variants, including recombinant forms previously rarely found in Poland and Europe is frequent among travelers. Observed founder events result in the heterosexually-driven introduction of the novel HIV-1 variants into the population.

Hepatitis C coinfection adversely affects the life expectancy of people living with HIV in northwestern Poland

Introduction Hepatitis C (HCV) infection adversely affects survival among people living with HIV, increasing mortality risk due to liver-related causes. In Poland HCV is found among ~30% of HIV infected individuals, with only a small percentage successfully treated for this coinfection. This study aimed to analyze the HCV-associated influence on the life expectancy among HIV/HCV coinfected patients from northwestern Poland. Material and methods Longitudinal data of 701 (368 HIV monoinfected and 368 HIV/HCV coinfected) patients were investigated to assess the life expectancy and survival after HIV diagnosis. Kaplan-Meier and Cox analyses were used to assess the mortality risk in both unadjusted and multivariate models. Effect plots indicate the adjusted hazard ratio for HCV-associated survival. Results Overall mortality was significantly higher among HCV coinfected (22.52%) compared to HIV monoinfected (10.32%) cases (p < 0.001, OR = 2.52 (95% CI: 1.65–3.85)), with shorter life expectancy among HIV/HCV infected patients (median: 55.4 (IQR: 42.8–59.1) years) compared to HIV monoinfection (median 72.7 (IQR: 60.4–76.8) years, univariate HR = 4.15 (95% CI: 2.7–6.38), p < 0.0001, adjusted HR = 2.32 (95% CI: 1.47–3.65), p < 0.0001). After HIV diagnosis, HCV adversely influenced the survival after 15 years of follow-up, with a strengthened impact in the subsequent 5 years (univariate HR = 1.57 (95% CI: 1.05–2.34) p = 0.026 for the 20-year survival time point, adjusted HR = 2.21 (95% CI: 1.18–4.13), p = 0.013). Conclusions Among patients living with HIV, HCV coinfection is associated with a median life expectancy decrease of 17.3 years and low probability of surviving until the age of 65 years. In the era of directly acting anti-HCV drugs, treatment scale-up and immediacy of treatment are advisable in this cohort.

Temporal increase in HIV-1 non-R5 tropism frequency among antiretroviral-naive patients from northern Poland

Sequencing of the third hypervariable loop allows to identify genotype‐based HIV tropism. R5‐tropic viruses associated with early stages of infection are preferentially transmitted, while non‐R5 HIV‐1 tropism has been associated with severe immunodeficiency and lower lymphocyte CD4 nadir and may reflect delayed HIV diagnosis. In this study, we investigate the changes in tropism frequency from 2007 to 2013.