HIV-1 infection among women in Israel, 2010–2018

Introduction Although women comprise 33% of the HIV-1-carriers in Israel, they have not previously been considered a risk group requiring special attention. Immigration waves from countries in Africa and in East Europe may have changed the local landscape of women diagnosed with HIV-1. Here, we aimed to assess viral and demographic characteristics of HIV-1-positive women identified in Israel between 2010 and 2018. Methods All > 16 year-old, HIV-1-infected women, diagnosed in Israel in 2010–2018, (n = 763) registered in the National HIV reference laboratory were included in this cross-sectional study. Demographic and clinical characteristics were extracted from the database. Viral subtypes and transmitted drug resistance mutations (TDRM) were determined in 337 (44.2%) randomly selected samples collected from treatment-naive women. Results Median age at diagnosis was 38 years. Most (73.3%) women were immigrants from the former Soviet Union (FSU) (41.2%, 314) or sub-Saharan Africa (SSA) (32.2%, 246) and carried subtype A (79.7%) or C (90.3%), respectively. Only 11.4% (87) were Israeli-born women. Over the years, the prevalence of women from SSA decreased while that of women from FSU increased significantly (p < 0.001). The median CD4+ cell count was 263 cells/mm3, and higher (391 cells/mm3) in Israeli-born women. TDRM were identified in 10.4% of the tested samples; 1.8, 3 and 7.1% had protease inhibitors (PI), nucleotide reverse transcriptase inhibitors (NRTI) and non-nucleoside reverse transcriptase inhibitors (NNRTI) TDRM, respectively. The prevalence of women with NNRTI TDRM significantly increased from 4.9% in 2010–2012 to 13.3% in 2016–2018. Israeli-born women had the highest prevalence (16.3%) of NNRTI TDRM (p = 0.014). NRTI A62 (5.6%), NNRTI E138 and K103 (5.6 and 4.2%, respectively) were the most prominent mutated sites. Conclusions Most HIV-1-positive women diagnosed in Israel in 2010–2018 were immigrants, with the relative ratio of FSU immigrants increasing in recent years. The high proportion of women diagnosed with resistance mutations, particularly, the yearly increase in the frequency of NNRTI mutations, support the national policy of resistance testing at baseline

High Prevalence of Hypertension in Ethiopian and Non-Ethiopian HIV-Infected Adults

Objectives. Prevalence of hypertension has not been studied in the Ethiopian HIV-infected population, which represents 60% of the patients in our AIDS unit. Our aim was to identify risk factors and characterize the prevalence of hypertension in the population monitored at our unit. Methods. A retrospective chart review categorized subjects according to their blood pressure levels. Hypertension prevalence was determined and stratified according to variables perceived to contribute to elevated blood pressure. Results. The prevalence of hypertension in our study population was significantly higher compared to the general population (53% versus 20%, P<0.0001) and was associated with known risk factors and not with patients’ viral load and CD4 levels. Ethiopian HIV-infected adults had a prominently higher rate of blood pressure rise over time as compared to non-Ethiopians (P=0.016). Conclusions. The high prevalence of hypertension in this cohort and the rapid increase in blood pressure in Ethiopians are alarming. We could not attribute high prevalence to HIV-related factors and we presume it is part of the metabolic syndrome. The lifelong cardiovascular risk associated with HIV infection mandates hypertension screening and close monitoring in this population

Rituximab identified as an independent risk factor for severe PJP: A case-control study.

ObjectivePneumocystis jirovecii pneumonia (PJP) was reported among immunosuppressed patients with deficits in cell-mediated immunity and in patients treated with immunomodulatory drugs. The aim of this study was to identify risk-factors for PJP in noninfected HIV patients.MethodsThis retrospective, test negative, case-control study was conducted in six hospitals in Israel, 2006-2016. Cases were hospitalized HIV-negative patients with pneumonia diagnosed as PJP by bronchoalveolar lavage. Controls were similar patients negative for PJP.ResultsSeventy-six cases and 159 controls were identified. Median age was 63.7 years, 65% males, 34% had hematological malignancies, 11% inflammatory diseases, 47% used steroids and 9% received antilymphocyte monoclonal antibodies. PJP was independently associated with antilymphocyte monoclonal antibodies (OR 11.47, CI 1.50-87.74), high-dose steroid treatment (OR 4.39, CI 1.52-12.63), lymphopenia (OR 8.13, CI 2.48-26.60), low albumin (OR 0.15, CI 0.40-0.54) and low BMI (OR 0.80, CI 0.68-0.93).ConclusionIn conclusion, rituximab, which is prescribed for a wide variety of malignant and inflammatory disorders, was found to be significant risk-factor for PJP. Increased awareness of possible PJP infection in this patient population is warranted

Transmission patterns of HIV-subtypes A/AE versus B: inferring risk-behavior trends and treatment-efficacy limitations from viral genotypic data obtained prior to and during antiretroviral therapy.

BACKGROUND: HIV subtypes A and CRF01_AE (A/AE) became prevalent in Israel, first through immigration of infected people, mostly intravenous-drug users (IVDU), from Former Soviet-Union (FSU) countries and then also by local spreading. We retrospectively studied virus-transmission patterns of these subtypes in comparison to the longer-established subtype B, evaluating in particular risk-group related differences. We also examined to what extent distinct drug-resistance patterns in subtypes A/AE versus B reflected differences in patient behavior and drug-treatment history. METHODS: Reverse-transcriptase (RT) and protease sequences were retrospectively analyzed along with clinical and epidemiological data. MEGA, ClusalX, and Beast programs were used in a phylogenetic analysis to identify transmission networks. RESULTS: 318 drug-naive individuals with A/AE or patients failing combination antiretroviral therapy (cART) were identified. 61% were IVDU. Compared to infected homosexuals, IVDU transmitted HIV infrequently and, typically, only to a single partner. 6.8% of drug-naive patients had drug resistance. Treatment-failing, regimen-stratified subtype-A/AE- and B-patients differed from each other significantly in the frequencies of the major resistance-conferring mutations T215FY, K219QE and several secondary mutations. Notably, failing boosted protease-inhibitors (PI) treatment was not significantly associated with protease or RT mutations in either subtype. CONCLUSIONS: While sizable transmission networks occur in infected homosexuals, continued HIV transmission among IVDU in Israel is largely sporadic and the rate is relatively modest, as is that of drug-resistance transmission. Deviation of drug-naive A/AE sequences from subtype-B consensus sequence, documented here, may subtly affect drug-resistance pathways. Conspicuous differences in overall drug-resistance that are manifest before regimen stratification can be largely explained in terms of treatment history, by the different efficacy/adherence limitations of older versus newer regimens. The phenomenon of treatment failure in boosted-PI-including regimens in the apparent absence of drug-resistance to any of the drugs, and its relation to adherence, require further investigation

Epidemiology and Transmitted HIV-1 Drug Resistance among Treatment-Na&iuml;ve Individuals in Israel, 2010&ndash;2018

Despite the low prevalence of HIV-1 in Israel, continuous waves of immigration may have impacted the local epidemic. We characterized all people diagnosed with HIV-1 in Israel in 2010&ndash;2018. The demographics and clinical data of all individuals (n = 3639) newly diagnosed with HIV-1 were retrieved. Subtypes, transmitted drug-resistance mutations (TDRM), and phylogenetic relations, were determined in &gt;50% of them. In 39.1%, HIV-1 transmission was through heterosexual contact; 34.3% were men who have sex with men (MSM); and 10.4% were people who inject drugs. Many (&gt;65%) were immigrants. Israeli-born individuals were mostly (78.3%) MSM, whereas only 9% of those born in Sub-Saharan Africa (SSA), Eastern Europe and Central Asia (EEU/CA), were MSM. The proportion of individuals from SSA decreased through the years 2010&ndash;2018 (21.1% in 2010&ndash;2012; 16.8% in 2016&ndash;2018) whereas those from EEU/CA increased significantly (21% in 2010&ndash;2012; 27.8% in 2016&ndash;2018, p &lt; 0.001). TDRM were identified in 12.1%; 3.7, 3.3 and 6.6% had protease inhibitors (PI), nucleotide reverse transcriptase inhibitors (NRTI), and non-nucleoside reverse transcriptase inhibitors (NNRTI) TDRM, respectively, with the overall proportion remaining stable in the studied years. None had integrase TDRM. Subtype B was present in 43.9%, subtype A in 25.2% (A6 in 22.8 and A1 in 2.4%) and subtype C in 17.1% of individuals. Most MSM had subtype B. Subtype C carriers formed small clusters (with one unexpected MSM cluster), A1 formed a cluster mainly of locally-born patients with NNRTI mutations, and A6 formed a looser cluster of individuals mainly from EEU. Israelis, &lt;50 years old, carrying A1, had the highest risk for having TDRM. In conclusion, an increase in immigrants from EEU/CA and a decrease in those from SSA characterized the HIV-1 epidemic in 2010&ndash;2018. Baseline resistance testing should still be recommended to identify TDRM, and improve surveillance and care

Resistance Mutations in the Protease of drug-naive and drug-treated individuals.

<p>250 samples from 234 drug-naive patients and 115 samples from 78 treated A/AE patients were genotyped. 31 patients were sampled both prior to treatment and after treatment failure. PI mutations found in all A/AE naive patients were compared to those found in A/AE drug-treated ones and to samples from 254 drug naive and 60 drug treated B individuals diagnosed since 2001. The first available sample from each drug-naive individual was used for analysis. For mutation-frequency analysis of drug-treated patients each mutation was counted once. Only mutations showing statistically significant differences between drug-naive and drug-treated patients and/or between A/AE and B frequencies are included.</p><p>Mutations in the Protease: The PI mutations L23I, L24I, D30N, V32I, M46I/L, I47A, G48V, I50L/V, I54V, V82A/S, I84V/A/C, N88S/T and L90M were considered major mutations. Secondary PI mutations included L10V/I/F/M, K20R, L33F, M36I, F53L, A71V/I and G73S/T/C/A.</p><p>N – NRTIs; NN – NNRTIs; NNRTIs – Non-nucleosides reverse transcriptase inhibitors; NS – Not significant; NRTIs – Nucleosides reverse transcriptase inhibitors; PI – Protease inhibitors;</p>a<p>Subtyping was performed using the Stanford Database Rapid Subtyping Tool <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0057789#pone.0057789-Rhee1" target="_blank">[23]</a>–<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0057789#pone.0057789-Rhee2" target="_blank">[24]</a>. According to that classification 192 patients had virus containing protease of subtype A and RT most similar to CRF01_AE; for 70 both the protease and the RT were CRF01_AE; 52 were of subtype A; and four had protease classified as CRF01_AE and RT classified as A. Other subtyping tools such as Geno2Pheno (<a href="http://www.geno2pheno.org/" target="_blank">http://www.geno2pheno.org/</a>) or the Rega Subtyping Tool (<a href="http://jose.med.kuleuven.be/subtypetool/html/" target="_blank">http://jose.med.kuleuven.be/subtypetool/html/</a>) <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0057789#pone.0057789-deOliveira1" target="_blank">[57]</a> vary to some extent in the classification of variants.</p

Mutations found in patients failing regiments containing LPV/r or NNRTIs.

<p>Mutations found in patients failing regiments containing LPV/r or NNRTIs.</p><p>The Table classifies patients failing on LPV/r or NNRTI containing regimens according to the number of mutations conferring resistance to the different drug classes. “+” indicates presence of mutations, but for some patients the actual mutations are listed. “–” indicates “no mutations” or also “no previous PI-containing regimens”.</p><p>EFV – efavirenz; IDV – indinavir; LPV/r – lopinovir/ritonavir; NFV – nelfinavir; NNRTIs – Non-nucleosides reverse transcriptase inhibitors; NRTIs – Nucleosides reverse transcriptase inhibitors; NVP – nevirapine; SQV – saquinavir; PIs – protease inhibitors.</p

First-administrated and actual drug regimens while failing treatment.

a<p>All except 5 received NRTIs as part of the first regimen. A few received mono- or duo-therapy or combinations of PIs and NNRTIs.</p>b<p>All 78 treatment-failing patients received NRTI backbone. Thirty-four received also PI and 39 NNRTI as additional drug.</p><p>3TC – lamivudine; EFV – efavirenz; FTC – emtricitabine; LPV/r – lopinavir/r; NNRTI – Non-Nucleoside Reverse Trancriptase Inhibitor; NRTI – Nucleoside Reverse Trancriptase Inhibitor; NVP – nevirapine; PI – Protease inhibitor; r – ritonavir; TDF – tenofovir; ZDV – zidovudine.</p

Phylogenetic tree of Pr-RT sequences from A/AE-HIV samples.

<p>Neighbor-joint analysis of A/AE protease and RT sequences, combined (918 nucleotides). The first available sequence from 216 drug-naive and 65 drug-treated individuals was used. Trees were colored according to: A. Birth place and infection site: red lines – born and infected in FSU; blue lines – born and infected in Israel; turquoise lines – born in FSU and infected in Israel; yellow lines – born in Israel and infected in Thailand; green lines – reference sequences. B. Transmission groups: red lines – IVDU; blue lines – MSM; turquoise lines – Hetero; green lines – reference sequences. Insert: red lines – posterior probability>0.95 of having a common ancestor. Major drug-resistance mutations in drug naive individuals: Red circles – K103N; Green triangle – M184V; orange rhombus – protease M46I. Reference sequences used in constructing the tree: Subtype-A/AE variants: subtype A – AF193275, subtype CRF01_AE – AF197340 and AF447851.1; subtype CRF03_AB – AF193276; subtype B – K03455, subtype C – AF286233 and AY585268; subtype D – AY322189; subtype F – AJ249238. Cl. – cluster. Clusters having more than 4 members with posterior probability>0.95 of having a common ancestor are marked with arrows.</p