Diagnosis and Risk Factors of Prediabetes and Diabetes in People Living with HIV- Evaluation of Clinical and Microbiome Parameters.

Diabetes is more common among people living with HIV (PLWH), as compared with healthy individuals. In a prospective multicenter study (N = 248), we identified normoglycemic (48.7%), prediabetic (44.4%) and diabetic (6.9%) PLWH. HbA1c and fasting blood glucose (FBG) sensitivity in defining dysglycemia was 96.8%, while addition of oral glucose tolerance test led to reclassification of only 4 patients. Inclusion of 93 additional PLWH with known DM enabled identification of multiple independent predictors of dysglycemia or diabetes: older age, higher BMI, Ethiopian origin, HIV duration, lower integrase inhibitor exposure and advanced disease at diagnosis. Shotgun metagenomic microbiome analysis revealed 4 species that were significantly expanded with hyperglycemia/hyperinsulinemia, and 2 species that were differentially more prevalent in prediabetic/diabetic PLWH. Collectively, we uncover multiple potential host and microbiome predictors of altered glycemic status in PLWH, while demonstrating that FBG and HbA1C likely suffice for diabetes screening. These potential diabetic predictors merit future prospective validation.

Epidemiology, Clinical Characteristics and Risk Factors for Severity of Chronic Disseminated Candidiasis in Jerusalem, Israel.

Chronic disseminated candidiasis (CDC) occurs mostly in patients with acute hematologic malignancy and its clinical manifestations derive from immune reconstitution following neutrophil recovery. The aim of this study was to describe epidemiological and clinical characteristics of CDC and define risk factors for disease severity. Demographic and clinical data were collected from medical files of patients with CDC hospitalized in two tertiary medical centers in Jerusalem between 2005 and 2020. Associations between different variables and disease severity were evaluated, as well as characterization of Candida species. The study included 35 patients. CDC incidence slightly increased during study years and the average number of involved organs and disease duration was 3 ± 1.26 and 178 ± 123 days, respectively. Candida grew in blood in less than third of cases and the most common isolated pathogen was Candida tropicalis (50%). Histopathological or microbiological workup in patients who underwent an organ biopsy demonstrated Candida in about half of the patients. Nine months after starting antifungals, 43% of the patients still didn't have resolution of organ lesions in imaging modalities. Factors associated with protracted and extensive disease were prolonged fever prior to CDC and absence of candidemia. A C- Reactive Protein (CRP) cutoff level of 7.18 mg/dL was found to predict extensive disease. In conclusion, CDC incidence is increasing and the number of involved organs is higher than previously described. Clinical factors such as fever duration prior to CDC and absence of candidemia can predict severe course of disease and assist in treatment decisions and follow-up planning.

Acute diabetic foot in post kidney transplantation patients receiving chronic immunosuppression-clinical presentation and outcomes.

AIMS: Data regarding diabetic foot ulcers in patients after solid organ transplantation, particularly kidney transplantation, are limited. Chronic immunosuppression may be associated with impaired wound healing and a higher risk of amputations. In this study, we characterised the clinical presentation and outcomes of patients after kidney transplantation admitted to the diabetic foot unit, compared to non-kidney-transplant patients. MATERIALS AND METHODS: Data on the baseline characteristics, clinical presentation, and outcomes of all patients admitted to the diabetic foot unit of a large tertiary centre between the years 2014 and 2019 were collected. The most recent admission of each patient was considered. Primary outcomes were major amputations and 1 year mortality rate. RESULTS: During the study period, 537 patients were hospitalised, 18 of them were receiving immunosuppressive therapy due to kidney transplantation. Baseline characteristics of the patients were broadly similar, except that smoking was reported by 22.0% of the non-transplant patients and by none of the post-transplant patients (p = 0.01). Post-transplant patients tended to be younger (59.4 ± 11.1 vs. 65.3 ± 12.2; p = 0.07), were more likely to have type-1 diabetes (16.7% vs. 5.2%; p = 0.07) and had lower glucose levels upon admission (9.4 ± 4.3 vs. 12.0 ± 6.4 mmol/L; p = 0.07). Overall, 30% of the patients underwent major amputation, in-patient mortality rate was 9.3%, and 1 year mortality rate was 27.2%. Rates were similar in the post-transplant versus the non-post-transplant patients (p = 0.83, 1.00, 0.59, respectively). CONCLUSIONS: Post-transplant patients did not incur worse outcomes in spite of immunosuppressive therapy. Limb salvage efforts should be pursued in these patients similar to the overall population.

Healthcare-associated Pneumocystis jirovecii Pneumonia (PJP) Infection in HIV-negative Adults: a Multicenter Study.

BACKGROUND: Pneumocystis jirovecii pneumonia (PJP) is an opportunistic infection in immunocompromised patients. Clusters of PJP, especially among organ transplant recipients in clinic settings were described. Data regarding nosocomial PJP infection among inpatients are limited. OBJECTIVES: To assess the magnitude and characteristics of inpatient healthcare-associated PJP infection (HCA-PJP) in HIV-negative patients. METHODS: A retrospective chart review of hospitalized PJP patients was performed to identify HCA-PJP. The study was performed at six medical centers in Israel from 2006 to 2016. HCA-PJP was defined as cases of hospital-onset or those with documented contact with a PJP patient. We reviewed and cross-matched temporal and spatial co-locations of patients. Clinical laboratory characteristics and outcomes were compared. RESULTS: Seventy-six cases of PJP were identified. Median age was 63.7 years; 64% men; 44% hematological malignancies; 18% inflammatory diseases; and 61% steroid usage. Thirty-two patients (42%) were defined as HCA-PJP: 18/32 (23.6%) were hospitalized at onset and 14/32 (18.4%) had a previous encounter with a PJP patient. Time from onset of symptoms to diagnosis was shorter in HCA-PJP vs. community-PJP (3.25 vs. 11.23 days, P = 0.009). In multivariate analysis, dyspnea at presentation (odds ratio [OR] 16.79, 95% confidence interval [95%CI] 1.78-157.95) and a tendency toward higher rate of ventilator support (72% vs. 52%, P = 0.07, OR 5.18, 95%CI 0.7-30.3) were independently associated with HCA-PJP, implying abrupt disease progression in HCA-PJP. CONCLUSIONS: HCA-PJP was common. A high level of suspicion for PJP among selected patients with nosocomial respiratory infection is warranted. Isolation of PJP patients should be considered.

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.

Limited awareness of the effective timing of HIV post-exposure prophylaxis among people with high-risk exposure to HIV.

The effectiveness of post-exposure prophylaxis (PEP), a major strategy in the battle against HIV, depends on awareness of this modality and its proper timing among high-risk groups. While general awareness of PEP is improving, recently estimated to be 36-47% among men who have sex with men (MSM), PEP implementation remains disappointingly low and may be driven by limited awareness of effective PEP timing window. The level of detailed understanding of PEP timing and effectiveness among populations at risk has not been prospectively assessed to date. We prospectively evaluated, for the first time, actionable awareness regarding effective timing of PEP among a large cohort of individuals tested for HIV following unprotected sexual intercourse. Four hundred participants were assessed between December 2014 and February 2016. Overall awareness of the option of PEP was 60% and was significantly higher among male members of the LGBTQ community (75·5% as compared to 52·6% among heterosexual males) and those undergoing past HIV testing (67·1%). However, only 24% of individuals at risk were aware as to the proper timing of effective PEP treatment, thereby leading, in the majority of cases, to missing the window of opportunity for PEP treatment. This study highlights the lack of knowledge as to the specific requirements needed for effective PEP timing. Expanded advertising, better targeting of the heterosexual population, training of family physicians in the field of gender, sexuality, and LGBTQ medicine, may improve effective PEP availability, thereby reducing HIV transmission.

Association of HIV and syphilis seropositivity with transit stay in urban areas among Ethiopian immigrants to Israel.

BACKGROUND: Ethiopian immigration to Israel was initiated in 1981. Most immigrants were rural dwellers who migrated first to Addis Ababa or Gondar, where they waited for eligibility status from Israel to leave Ethiopia. Soon after arriving in Israel, all immigrants were offered screening tests for human immunodeficiency virus (HIV) and syphilis. OBJECTIVES: To evaluate the association of age, gender, marital status and length of time spent in urban areas in Ethiopia with the prevalence of HIV and syphilis seropositivity. METHODS: All adult Ethiopian immigrants who arrived at the Jerusalem immigration center between 1999 and 2002 and consented to HIV and syphilis screening tests were interviewed. RESULTS: Altogether, 678 immigrants (51% females) were screened; 39 (5.8%) were seropositive for HIV and 33 (4.9%) for syphilis. The length of time the immigrants spent in Ethiopian cities before leaving for Israel was significantly associated with HIV: odds ratio (OR) 2.76, 95% confidence interval (CI) 1.13-6.71, and syphilis seropositivity OR 3.87, 95%CI 1.56-9.62. CONCLUSIONS: The length of transit time Ethiopian immigrants from rural areas spend in Ethiopian cities is significantly associated with HIV and syphilis seropositivity. Efforts should be made to shorten this time in order to reduce the risk of infection

[Assessing cardiovascular risk factors among patients living with HIV/AIDS - survey of patients treated at the Hadassah Aids Center, Hadassah Ein Kerem, Jerusalem].

BACKGROUND: It has recently become evident that people living with HIV/AIDS have an increased cardiovascular risk. The reasons leading to this risk are multifactorial. In this study, we aimed to evaluate the cardiovascular risk (CVR) among patients treated at the Hadassah AIDS Center. MATERIALS AND METHODS: We conducted a cross-sectional study. CVR was calculated using the Framingham risk score (FRS). LDL-cholesterol optimal levels were defined using National Cholesterol Education Program (NCEP) criteria. RESULTS: We analyzed data from 150 patients during 2010. Their median age was 41 years and 60% were male. Nearly 52% of our patients were immigrants from Ethiopia. Most patients (90%) were on antiretroviral therapy (ART). The median time for ART exposure was 6.5 years. Rates of hypertension (HTN) (18.5%), diabetes (5.7%) and smoking (25%) were similar to the rates found in the general Israeli population (15%, 5.7% and 24%, respectively). Smoking was significantly less frequent among patients originating from Ethiopia (8%). Increased CVR (FRS >10%) was observed in 21% of the patients. Significantly lower rates were observed among Ethiopian patients (11%), compared with non-Ethiopians (39%). Increased CVR was correlated with increased age (p<0.05), male gender (p=0.034) and HTN (p=0.002), but not with smoking (p=0.53), change in CD4 (p=0.7) or viral suppression (p=0.64). CONCLUSION: Rates of hypertension, diabetes and smoking among patients living with HIV/AIDS were comparable to those found in the general Israeli population. Significantly lower rates of increased Framingham risk score (>or=10%) were observed among Ethiopian HIV/AIDS patients, than among non-Ethiopians. .

[Fertility treatment options for discordant couples living with HIV].

BACKGROUND: Serodiscordant couples live with the risk of HIV infection of the negative partner when attempting to become pregnant. Using density gradient centrifugation (DGC), spermatozoa can be separated from other seminal compartments. Isolated spermatozoa do not contain detectable HIV RNA. DGC followed by artificial insemination may significantly reduce the risk of infection. The Hadassah AIDS Center (HAC) has recently initiated a fertility center for serodiscordant couples. METHODS: Our patient population includes serodiscordant couples in which the male is HIV positive. The male semen is washed using the DGC procedure. Washed semen is tested for HIV by standard PCR methods. Intrauterine insemination (IUI) is attempted using the washed semen. RESULTS: A total of 55 couples have registered for this procedure. This includes 16 men who have sex with men, 7 who have hemophilia and 8 couples of Ethiopian origin. The average female age is 33 years. Seven (12%) men had inadequate sperm counts and were referred for IVF. Overall, 34 semen samples were tested for HIV. Only one was found to be positive. During the procedure, 22 couples underwent at least one IUI attempt and 16 (72%) females became pregnant, 3 of them after the first IUI attempt. All women tested for HIV after IUI were found to be negative. CONCLUSIONS: The pregnancy success rate during the first year of operation was 72%, similar to that reported by other centers in Europe. There were no seroconversions of the female partner. Serodiscordant couples living with HIV in Israel today may consider starting a family, while significantly reducing the risk of infecting the negative female partner.

Enterococci in Diabetic Foot Infections: Prevalence, Clinical Characteristics, and Outcomes.

Background: Diabetic foot infections (DFIs) are frequently polymicrobial, yet the relevance of each isolated pathogen, remains ill-defined. Specifically, the prevalence and pathogenicity of enterococcal DFIs and the impact of targeted antienterococcal treatment remain elusive. Methods: We collected demographic, clinical, and outcome-related data on patients admitted with DFIs to the Hadassah Medical Center diabetic foot unit between 2014 and 2019. The primary outcome was a composite of in-hospital death or major amputation. Secondary outcomes included any amputation, major amputation, length of stay (LOS), and 1-year major amputation or mortality rate. Results: Enterococci were isolated in 35% of 537 eligible DFI case patients, who were notable for a higher prevalence of peripheral vascular disease, increased levels of C-reactive protein, and higher Wagner scores. Infection in enterococci-positive individuals was mostly polymicrobial (96.8% vs 61.0% in non-enterococci-infected patients; P < .001). Enterococci-infected patients were more likely to undergo amputation (72.3% vs 50.1%; P < .001) and had longer hospital stays (median LOS, 22.5 vs 17 days; P < .001), but the primary end point of major amputation or in-hospital death did not differ between groups (25.5% vs 21.0%; P = .26). Appropriate antienterococcal antibiotics were used in 78.1% of enterococci-infected patients and, compared with results in untreated patients, were associated with a trend toward a lower rate of major amputations (20.4% vs 34.1%; P = .06) but longer hospitalization (median LOS, 24 vs 18 days; P = .07). Conclusions: Enterococci are common in DFIs and associated with higher rates of amputation and longer hospitalization. A reduction in major amputation rates with appropriate enterococci treatment is suggested retrospectively, meriting validation by future prospective studies.

Factors Associated with Virological Failure in First-Line Antiretroviral Therapy in Patients Diagnosed with HIV-1 between 2010 and 2018 in Israel.

Despite the progress in contemporary antiretroviral therapy (ART) and the continuous changes in treatment guidelines, virological failure (VF) is still an ongoing concern. The goal of this study was to assess factors related to VF after first-line ART. A longitudinal cohort retrospective study of individuals on first-line ART diagnosed with HIV-1 in 2010-2018 and followed-up for a median of two years was conducted. Demographics, baseline and longitudinal CD4 counts, treatment regimens, adherence and VF were recorded. The Cox proportional hazards regression and mixed models were used. A cohort of 1130 patients were included. Overall, 80% were males and 62% were Israeli-born individuals. Compared to individuals diagnosed in 2010-2014, when treatment was initiated according to CD4 levels, those diagnosed in 2015-2018 were older and had lower baseline CD4 counts. VF was recorded in 66 (5.8%) patients. Diagnosis with CD4 <200 cells/mmᶟ with AIDS-defining conditions (HR = 2.75, 95%CI:1.52-4.97, p < 0.001) and non-integrase strand transfer inhibitor regimens (non-INSTI, HR = 1.80, 95%CI:1.01-3.24, p = 0.047) increased VF risk. No impact of baseline resistance was observed. We concluded that the early detection of HIV-1 infection and usage of INSTI-based regimens are recommended to reduce VF.

An outbreak of achromobacter xylosoxidans associated with ultrasound gel used during transrectal ultrasound guided prostate biopsy.

PURPOSE: We describe an outbreak of Achromobacter xylosoxidans after transrectal ultrasound guided prostate biopsy at a urology unit at a tertiary care center as well as clinical and microbiological investigation, and intervention. MATERIALS AND METHODS: In September 2008, several days after undergoing transrectal ultrasound guided prostate biopsy, 4 patients were hospitalized with fever. We reviewed the procedure and infection control practices in the urology service. Environmental cultures were obtained from equipment and materials used for the procedure. Isolates were identified by routine laboratory procedures with molecular confirmation and characterized by pulsed field gel electrophoresis. RESULTS: A. xylosoxidans was isolated from the urine of 2 patients, of whom 1 also had a positive blood culture. Review of transrectal ultrasound guided prostate biopsy revealed that the lubricant gel used in the procedure, which the biopsy needle passes through, was held in a plastic container that was repeatedly refilled from a large bag. A. xylosoxidans was isolated from this container. Pulsed field gel electrophoresis showed that the isolates obtained from patients and the gel were identical. CONCLUSIONS: Contaminated lubricant gel was the cause of this outbreak. The practice of repeatedly refilling gel containers with nonsterile gel was replaced by the use of individual sterile gel sachets in each patient. No further cases occurred. During an invasive procedure involving a sterile body site, such as transrectal ultrasound guided prostate biopsy, using sterile gel is essential. Our experience emphasizes the crucial need to review all invasive procedures from an infection control perspective.

Predictors and outcomes of diabetic foot ulcer infection with ESBL-producing bacteria in a large tertiary center.

OBJECTIVES: The aim of this study was to describe the predictors and outcomes of infection with extended-spectrum beta-lactamase (ESBL)-producing bacteria in patients with an acute diabetic foot infection (DFI). METHODS: The records of patients admitted with acute DFI to a large tertiary hospital during the years 2014-2018 were reviewed. Demographic, clinical, and laboratory data were collected, as well as outcomes regarding amputations and mortality. Only cultures obtained during the first 2 weeks following admission were considered. RESULTS: Cultures were available for 493 patients; 121 (24.5%) included bacteria suspected of being ESBL producers. Patients infected with ESBL-producing bacteria were older, more likely to have peripheral vascular disease (PVD), and had higher SINBAD and Wagner scores upon admission. They were also more likely to have been hospitalized in the recent 6 months. Major amputations were more prevalent in patients with versus without an ESBL-producing bacterial infection (30.6% vs 19.4%; P = 0.010), yet overall amputations and mortality rates were similar. CONCLUSIONS: ESBL-producing bacteria are common pathogens in DFI, more prevalent in older patients with PVD, advanced ulcers, and recent hospitalization. They are associated with higher rates of major amputation. These considerations may support the choice of empirical antibiotic therapy in patients admitted with an acute DFI.

Epidemiology and Transmitted HIV-1 Drug Resistance among Treatment-Naïve Individuals in Israel, 2010-2018.

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 2010-2018. 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 >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 (>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 2010-2018 (21.1% in 2010-2012; 16.8% in 2016-2018) whereas those from EEU/CA increased significantly (21% in 2010-2012; 27.8% in 2016-2018, p < 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, <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 2010-2018. Baseline resistance testing should still be recommended to identify TDRM, and improve surveillance and care.

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

OBJECTIVE: Pneumocystis 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. METHODS: This 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. RESULTS: Seventy-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). CONCLUSION: In 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.

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.

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.