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AimCombined antiretroviral treatment (cART) traditionally consists of three antiretroviral medications, while two-drug regimens (2DR), historically used infrequently, recently been suggested to be non-inferior to three-drug regimens, is emerging as a potential treatment option and is currently a recommended option for treatment initiation in many guidelines.PurposeCharacterize the indications and clinical efficacy of 2DR use at a real-life setting in a nation-wide survey.MethodsA cross-sectional survey of Israeli patients treated by 2DR until July 2019, included demographic, immunologic, virologic, genotypic and biochemical/metabolic parameters at diagnosis, ART initiation, 2DR initiation and following 24, 48, 96 and 144 weeks of 2DR treatment.Results176 patients were included in the study. In contrast to historical data implicating ART resistance and adverse effects as the major reasons leading to 2DR switching, treatment simplification was the main reason leading to 2DR treatment in 2019. 2DR that included INSTI and PI were more commonly used in cases of drug resistance, while a combination of INSTI and NNRTI was used in all other 2DR indications. A switch to 2DR induced a mean CD4 T cell increase from 599 cells/μl at treatment initiation to 680 cells/μl at 96 weeks of treatment pConclusions2DR in a large-scale real-life nation-wide survey proved to be safe and effective. Most 2DRs, other than PI and INSTI, were similarly effective in suppressing HIV viremia and in elevating CD4 T cell counts.

OBJECTIVE To determine the rate of grade 4, potentially life-threatening events not attributable to AIDS, cardiovascular disease (CVD), or non-AIDS cancer among participants on antiretroviral therapy and to describe associations of these events with interleukin-6 (IL-6) and D-dimer. DESIGN Cohort study. METHODS HIV-infected participants on antiretroviral therapy (N = 3568) with an HIV-RNA level ≤ 500 copies/mL were followed for grade 4, AIDS, CVD, non-AIDS cancer, and all-cause mortality events. Grade 4 events were further classified masked to biomarker levels as reflecting chronic inflammation-related disease (ChrIRD) or not (non-ChrIRD). Associations of baseline IL-6 and D-dimer with events were studied using Cox models. RESULTS Over a median follow-up of 4.3 years, 339 participants developed a grade 4 event (22.9 per 1000 person-years); 165 participants developed a ChrIRD grade 4 event (10.7 per 1000 person-years). Grade 4 events were more common than AIDS (54 participants), CVD (132), and non-AIDS cancer (80) events, any of which developed in 252 participants (17.1 per 1000 person-years). Grade 4 and AIDS events were associated with similar risks of death. Higher IL-6 [hazard ratio (HR) = 1.19 per doubling of biomarker; P = 0.003] and D-dimer (HR = 1.23; P < 0.001) levels were associated with an increased risk of grade 4 events. IL-6 associations were stronger for ChrIRD (HR = 1.38; P < 0.001) than non-ChrIRD grade 4 events (HR = 1.11; P = 0.21). CONCLUSIONS Morbidity and mortality associated with activation of inflammatory and coagulation pathways include conditions other than AIDS, CVD, and non-AIDS cancer events. Effective inflammation-dampening interventions could greatly affect the health of people with HIV.

Background Randomized trials have shown increased risk of suicidality associated with efavirenz (EFV). The START (Strategic Timing of Antiretroviral Treatment) trial randomized treatment-naive human immunodeficiency virus (HIV)-positive adults with high CD4 cell counts to immediate vs deferred antiretroviral therapy (ART). Methods The initial ART regimen was selected prior to randomization (prespecified). We compared the incidence of suicidal and self-injurious behaviours (suicidal behavior) between the immediate vs deferred ART groups using proportional hazards models, separately for those with EFV and other prespecified regimens, by intention to treat, and after censoring participants in the deferred arm at ART initiation. Results Of 4684 participants, 271 (5.8%) had a prior psychiatric diagnosis. EFV was prespecified for 3515 participants (75%), less often in those with psychiatric diagnoses (40%) than without (77%). While the overall intention-to-treat comparison showed no difference in suicidal behavior between arms (hazard ratio [HR], 1.07, P = .81), subgroup analyses suggest that initiation of EFV, but not other ART, is associated with increased risk of suicidal behavior. When censoring follow-up at ART initiation in the deferred group, the immediate vs deferred HR among those who were prespecified EFV was 3.31 (P = .03) and 1.04 (P = .93) among those with other prespecified ART; (P = .07 for interaction). In the immediate group, the risk was higher among those with prior psychiatric diagnoses, regardless of prespecified treatment group. Conclusions Participants who used EFV in the immediate ART group had increased risk of suicidal behavior compared with ART-naive controls. Those with prior psychiatric diagnoses were at higher risk.

The K65R mutation in HIV-1 reverse transcriptase (RT) can be selected by the RT inhibitors tenofovir (TDF), abacavir (ABC), and didanosine (DDI). Recently, in vitro studies have shown that K65R is selected in tissue culture more rapidly with subtype C than subtype B viruses. The prevalence of K65R in viruses sequenced at the Tel-Aviv AIDS Center was evaluated. This study analyzed retrospectively sequences from 1999 to 2007 in patients treated with TDF, ABC, and/or DDI and compared rates of mutational prevalence between subtypes. Fisher's exact test was used to determine statistical significance. Forty-four sequences from patients treated with the three above-cited drugs were analyzed. Subtypes A (n = 1), CRF01_AE (n = 4), CRF02_AG (n = 2), B (n = 21), C (n = 11), D (n = 1), F (n = 3), and G (n = 1) were represented. Seven non-B viruses had the K65R mutation, which was only found in one subtype B virus. Of these seven samples four were subtype C, one was subtype CRF01_AE, and two were subtype CRF02_AG. None of the eight viruses with K65R harbored thymidine analogue mutations. In this study, non-subtype B viruses possessed the K65R mutation at higher incidence than subtype B viruses. Subtype C viruses may be especially prone to develop this mutation. Larger studies are needed to confirm these data. Efforts should be intensified to understand better differences in drug resistance between various HIV subtypes.

Background HIV in Israel started with a subtype-B epidemic among men who have sex with men, followed in the 1980s and 1990s by introductions of subtype C from Ethiopia (predominantly acquired by heterosexual transmission) and subtype A from the former Soviet Union (FSU, most often acquired by intravenous drug use). The epidemic matured over the last 15 years without additional large influx of exogenous infections. Between 2005 and 2013 the number of infected men who have sex with men (MSM) increased 2.9-fold, compared to 1.6-fold and 1.3-fold for intravenous drug users (IVDU) and Ethiopian-origin residents. Understanding contemporary spread is essential for effective public health planning. Methods We analyzed demographic and virologic data from 1,427 HIV-infected individuals diagnosed with HIV-I during 1998–2012. HIV phylogenies were reconstructed with maximum-likelihood and Bayesian methods. Results Subtype-B viruses, but not A or C, demonstrated a striking number of large clusters with common ancestors having posterior probability ≥0.95, including some suggesting presence of transmission networks. Transmitted drug resistance was highest in subtype B (13%). MSM represented a frequent risk factor in cross-ethnic transmission, demonstrated by the presence of Israeli-born with non-B virus infections and FSU immigrants with non-A subtypes. Conclusions Reconstructed phylogenetic trees demonstrated substantial grouping in subtype B, but not in non-MSM subtype-A or in subtype-C, reflecting differences in transmission dynamics linked to HIV transmission categories. Cross-ethnic spread occurred through multiple independent introductions, with MSM playing a prevalent role in the transmission of the virus. Such data provide a baseline to track epidemic trends and will be useful in informing and quantifying efforts to reduce HIV transmission.

We retrospectively studied the effect of the lamivudine-induced reverse transcription mutation M184V on selection of thymidine analog mutations (TAMs) in HIV subtype C-infected children and on clinical outcome.We genotyped 135 blood samples from 55 children. TAMs accumulation, viral load and clinical outcome were compared in children maintained on zidovudine/stavudine + lamivudine + protease inhibitor/nonnucleoside reverse transcriptase inhibitor (PI/NNRTI) despite loss of viral suppression and in children treated with, or switched to, other nucleoside reverse transcriptase inhibitors (NRTIs). Drug susceptibility and replication capacity of selected samples were measured.M184V developed in 18 of 22 of children who had received only zidovudine/stavudine + lamivudine + PI/NNRTI during a mean of 23.2 +/- 3.2 months versus in 3 of 14 children treated with other drugs and/or having multiple regimen changes (P = 0.001). TAMs appeared, respectively, in 2 of 22 versus 12 of 14 (P0.0001). The 2 groups did not differ significantly in baseline HIV-RNA or CD4 count, sampling time, and follow-up period. In M184V-containing samples, we found large reductions in susceptibility to lamivudine and emtricitabine but not to other NRTIs. When T215Y was present without M184V, susceptibility to zidovudine was reduced 8-fold. When both M184V + T215Y occurred, susceptibility to zidovudine was substantially increased. Average inhibition concentration 50 values were similar to those documented in the Stanford database for subtype B HIV with these mutation patterns.Maintaining a thymidine analog + lamivudine-based regimen reduced accumulation of TAMs and increased zidovudine susceptibility. This is likely the result of an increased susceptibility to thymidine analog (zidovudine) in the context of M184V documented here for the first time in subtype C-infected children. This retrospective study supports the strategy of maintaining lamivudine-containing therapy in subtype C-infected children. This strategy may be beneficially applied in the treatment of children in Africa, where thymidine analog + lamivudine-based regimen became available recently but further options are limited.

Since the introduction of new and efficient antiretroviraL treatment (ART), mortality and morbidity due to HIV infections have been greatly reduced. However, there is a growing incidence of chronic diseases, such as cardiovascular, metabolic, bone and renal diseases.To examine the impact of HIV infection on renal functions over time and to define risk factors which contribute to the change in renal functions.We screened 600 out of the 800 patients who are registered in the Institute for Immunology, Allergy and AIDS at the Rambam Medical Center, Haifa. We collected data from the typed and computerized medical fites of the patients. Finally, for 136 patients under surveillance between the years 2005-2010 there was sufficient data to meet the inclusion and exclusion criteria. We followed the renal function, presented by the estimated glomerular filtration rate (eGFR) and quantified the change in GFR each year. Then, we determined the risk factors contributing to the change in renal function, by using a multi-variant model.We found an average yearly decline of 4.83 mt/ min/1.73 m2 body surface area during the period 2005- 2010. We also found that co-infection with HCV and treatment by the antiretrovirat drug Tenofovir are significantly associated with the decline in renal function among our patients [p=0. 0.14 and 0.045 respectively).There is a persistent decline in renal function, overtime, in HIV patients. This decline is significantly higher than the change observed in age- and sex-matched healthy general populations. Co-infection with HCV and treatment by the antiretroviral drug Tenofovir are substantial risk factors for eGFR.

Highly active antiretroviral treatment (HAART), the increase in life expectancy and improved HIV viral detection methods, have all led to a change in attitude towards fertility in people living with HIV. There is now acknowledgment of the fundamental rights of HIV patients to parenthood and growing implementation of assisted fertility in this group. The aims of fertility treatment are prevention of infection in HIV-discordant couples, and treatment for fertility problems, identical to the general population. We review the influence of HIV on the reproduction systems of males and females, conditions requiring fertility intervention, various methods that are possible and describe the optional treatment existing in Israel for patients with viral infection, and specifically HIV.

Decreased bone mineral density (BMD) was reported in HIV infected patients. Mechanisms leading to this decrease are poorly understood.To assess factors relating to BMD in young HIV infected Israeli women of Ethiopian and Caucasian origin.75 young HIV infected women aged 34.5 ± 8.5 followed up at the Institute of Allergy, Clinical ImmunologyAIDS filled a questionnaire about sun exposure, daily calcium intake and dress habits. Data about HIV status and treatment regimens were collected from the patients' charts. Serum hydroxyvitamin D [25(OH)D] levels, bone turnover markers and bone densitometry were evaluated.28 (65%) of Ethiopians and 2 (6.25%) of Caucasians had 25(OH)D serum levels10 ng/ml (vitamin D deficiency), p = 0.001. 21 (67.7%) Ethiopians and 16 (39%) Caucasians avoided sun exposure, p = 0.019. Mean daily calcium intake was 491 ± 268.6 mg and 279 ± 252.6 mg, respectively, p = 0.001. Z scores-1 found at Lumbar spine in 26 (89.7%), at Femoral neck in 20 (69%) at Total hip in 17 (58.6%) of vitamin D deficient patients compared to 20 (48.8%), 17 (41.5%), 9 (22%), in patients with 25(OH)D10 ng/ml, p0.01,0.03,0.001, respectively. Significantly more Ethiopian than Caucasian women covered their face (32.3% and 9.5%, p = 0.003) and hands (58.1% and 30.9%, p = 0.03). There was no difference in bone turnover markers levels.Poorer vitamin D status was observed in Ethiopian women might be one of the important factors related to lower BMD in this group.

Iatrogenic Cushing's syndrome (CS) is caused by exposure to glucocorticoids and may be promoted by interaction with additional drugs. It is well known in asthmatic human immunodeficiency virus (HIV)-infected patients treated with inhaled fluticasone with ritonavir-containing antiretroviral regimen (cART).The authors present an asthmatic HIV-infected Ethiopian woman, treated with fluticasone/salmeterol, commencing cART with tenofovir, emtricitabine, and lopinavir/ritonavir. During 7 months she gained 9 kg and hyperpigmentation, mild edema, marked abdominal striae, and increase in blood pressure were noted. Plasma am and urine free cortisol levels confirmed CS diagnosis and fluticasone was discontinued. Complete resolution of CS occurred within 2 months. However, frequent asthma symptoms required resumption of inhaled corticosteroid (ICS) treatment, and budesonide/formeterol was prescribed. Soon reemergence of symptomatic CS was noted. Ritonavir dose was halved, but CS symptoms continued to develop. Budesonide was stopped and montelukast initiated. Resolution of cushingoid symptoms was observed within weeks.Corticosteroids are metabolized by cytochrome P450 3A4 (CYP3A4). Fluticasone has the longest glucocorticoid receptor-binding half-life and is 300 times more lipophilic than budesonide. Inhaled fluticasone possesses a high suppression rate of hypothalamic-pituitary-adrenal axis. Ritonavir, a potent CYP3A4 inhibitor, may inhibit corticosteroid degradation and increase its accumulation. Inhaled budesonide is less likely to cause adrenal suppression. Diagnosing Cushing's syndrome presents a clinical challenge due to similarities with clinical manifestations and side effects related to cART. In patients treated with inhaled or intranasal corticosteroids together with cART there may be a higher incidence of iatrogenic CS. CS should be looked for, and management considered carefully.

Although it has been widely suggested that oxidative stress contributes to the pathogenesis of HIV infection, salivary composition and its oxidative related aspects have never been studied in HIV patients, both HAART-treated and untreated. Human saliva and serum were collected and analyzed for various biochemical, redox related and immunological parameters from 43 consenting HIV-infected patients (20 untreated and 23 treated with HAART) and 20 healthy controls, age and gender matched. Saliva composition of HIV infected patients was completely altered but returned to normal following HAART. HIV patients had significantly-increased levels of oxidative stress damaging markers, compared to healthy controls. Carbonyl levels increased by 110% (p=0.005), and superoxide dismutase enzyme (SOD) and antioxidant capacity (ImAnOx) levels by 45% and 16% (0.035) respectively, but returned to normal levels in treated patients (p=0.005, p=0.03 and 0.02 respectively). Also, the significantly-altered salivary composition (pH and lactate dehydrogenase (LDH) enzyme) and concentration (calcium (Ca), magnesium (Mg), albumin, salivary total protein, secretory IgA) of HIV-infected patients reverted to normal following HAART treatment. Salivary analysis may be used for assessing patient status: treated vs untreated, based on the increase or decrease in the concentration of a given salivary parameter in the HIV-untreated group vs controls, and a return to normal following the HAART treatment. Salivary collection is simple, non-invasive and not associated with risk of infection spread. Antioxidants in HIV patients may be recommended, as well as local oral means aimed at resuming salivary functions compromised in HIV patients.