Current HIV Research - Volume 18, Issue 4, 2020

Iran has been one of the active countries fighting against HIV/AIDS in the Middle East during the last decades. Moreover, there is a strong push to strengthen the national health management system concerning HIV prevention and control. In Iran, HIV disease has its unique features, from changes in modes of transmission to improvement in treatment and care programs, which can make it a good case for closer scrutiny. The present review describes the HIV epidemic in Iran from the first case diagnosed until prevention among different groups at risk and co-infections. Not only we addressed the key populations and community-based attempts to overcome HIV-related issues in clinics, but we also elaborated on the efforts and trends in society and the actual behaviors related to HIV/AIDS. Being located in the Middle East and North Africa (MENA) region, given the countryspecific characteristics, and despite all the national efforts along with other countries in this region, Iran still needs to take extra measures to reduce HIV transmission, especially in health education. Although Iran is one of the pioneers in implementing applicable and appropriate policies in the MENA region, including harm reduction services to reduce HIV incidence, people with substance use disorder continue to be the majority of those living with HIV in the country. Similar to other countries in this region, the HIV prevention and control programs aim at 90-90-90 targets to eliminate HIV infection and reduce the transmission, especially the mother-to-child transmission and among other key populations.

Background: Lipid-based formulations have been confirmed to lower some side effects of drugs and can be tailor-made to offer sustained drug release of drugs with short half-life like stavudine. Aim: This study aimed to evaluate the immunomodulatory properties of stavudine-loaded solid lipid microparticles (SLMs) using immunocompromised Wistar rats. Methods: The SLMs were formulated by the homogenization method. The optimized batches were used for further in vivo studies. The effect of formulation on the CD4 count and the haematological properties of immunocompromised Wistar rats were studied. Results: The particle size range was 4 -8 μm, EE range was 85-93 % and maximum drug release was observed at 10 h. The CD4 cells increased from 115 ± 3.17 cell/mm3 at day zero to 495 ± 5.64 cell/mm3 at day 14 of treatment and 538 ± 6.31 cell/mm3 at day 21. The red blood cells increased from 2.64 ± 1.58 (x 106/mm3) at day zero to 6.96 ± 3.47 (x 106/mm3) at day 14 and 7.85 ± 3.64 (x 106/mm3) at day 21. PCV increased significantly (p < 0.05) to about 42-50 % at day 21 in the groups that received the SLMs formulations. White blood cells (WBC) also were 12 x 103/mm3, for SLM formulations, while the rats that received plain stavudine exhibited WBC of 9.6 x 103/mm3 at day 21. The histopathological studies revealed that oral stavudine-loaded SLMs had no significant damage to the kidney, liver, spleen and the brain of Wistar rats. Conclusion: The formulations exhibited significantly higher immunomodulatory properties than plain stavudine (p<0.05) and showed good properties for once daily oral administration and could be a better alternative to plain stavudine tablets for the management of patients living with HIV.

Background: Vertebral pathological compression fracture involving extra-nodal lymphoma impacts negatively on the quality of life of HIV-positive patients. The choice of a safe and effective approach to palliative care in this condition remains a challenge. Objective: The purpose of this study was to investigate the safety and efficacy of percutaneous kyphoplasty (PKP) in the treatment of vertebral pathological compression fracture of extra-nodal lymphoma in HIV-positive patients. Methods: A retrospective analysis, from January 2016 to August 2019, was performed on 7 HIVpositive patients, 3 males and 4 females, with extra-nodal lymphoma with a vertebral pathological compression fracture. The patients were treated using percutaneous kyphoplasty in our hospital. Preoperative assessment of the patients was conducted regarding their hematological profile, biochemical indicators, liver and kidney function, blood coagulation function, CD4+T lymphocyte count and viral load. Subsequently, the patients were placed on highly active antiretroviral therapy (HAART) and rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (RCHOP) regimen. Besides, antibiotics, nutritional support and immune-modulating drugs were also administered, rationally. Postoperatively, the height of the anterior edge of the injured vertebrae, Visual Analogue Scale (VAS) and Oswestry Disability Index (ODI) values were evaluated. Patients were also monitored for any complications related to the operation. Results: The average CD4+T cell count for the patients was 164 (range 114 ~247 / ul), while the viral load was 26,269 (range 5,765 ~82,321 copies/ul). All patients received nutritional and immune support and registered significant improvements in the levels of ALB and Hb (P<0.05). In all cases, the operation was uneventful with neither cement leakage nor toxic reactions observed. Similarly, no opportunistic infections, other complications or deaths were reported. The height of the anterior vertebral body and the ODI score of the injured vertebrae were significantly improved immediately after surgery (P<0.05). Compared to the preoperative VAS (7.71±1.11), postoperative values were significantly reduced immediately after surgery (3.85±0.90) and at 2 weeks, 1 month and 6 months post-surgery: 2.71±0.76, 3.29±1.11, and 4.00±0.82, respectively (P<0.01). Conclusion: Supported with appropriate perioperative treatment measures, PKP is safe and effective in the treatment of pathological vertebral compression fracture due to extra-nodal lymphoma in HIV-positive patients.

Objective: The aim of this study was to analyze the temporal trends of HIV epidemiology in Turkey from 2011 to 2016. Methods: Thirty-four teams from 28 centers at 17 different cities participated in this retrospective study. Participating centers were asked to complete a structured form containing questions about epidemiologic, demographic and clinical characteristics of patients presented with new HIV diagnosis between 2011 and 2016. Demographic data from all centers (complete or partial) were included in the analyses. For the cascade of care analysis, 15 centers that provided full data from 2011 to 2016 were included. Overall and annual distributions of the data were calculated as percentages and the Chi square test was used to determine temporal changes. Results: A total of 2,953 patients between 2011 and 2016 were included. Overall male to female ratio was 5:1 with a significant increase in the number of male cases from 2011 to 2016 (p<0.001). The highest prevalence was among those aged 25-34 years followed by the 35-44 age bracket. The most common reason for HIV testing was illness (35%). While the frequency of sex among men who have sex with men increased from 16% to 30.6% (p<0.001) over the study period, heterosexual intercourse (53%) was found to be the most common transmission route. Overall, 29% of the cases presented with a CD4 count of >500 cells/mm3 while 46.7% presented with a CD4 T cell count of <350 cells/mm3. Among newly diagnosed cases, 79% were retained in care, and all such cases initiated ART with 73% achieving viral suppression after six months of antiretroviral therapy. Conclusion: The epidemiologic profile of HIV infected individuals is changing rapidly in Turkey with an increasing trend in the number of newly diagnosed people disclosing themselves as MSM. New diagnoses were mostly at a young age. The late diagnosis was found to be a challenging issue. Despite the unavailability of data for the first 90, Turkey is close to the last two steps of 90-90-90 targets.

Background: Tuberculous meningitis (TbM) is the most severe complication of extra pulmonary tuberculosis (Tb). There is a higher frequency of positive cerebrospinal fluid (CSF) cultures for Mycobacterium tuberculosis (MTb) in samples from human immunodeficiency virus (HIV) co-infected patients than in those from HIV-negative patients. We hypothesized that real time PCR assays for MTb (MTb qPCR) using CSF would be more sensitive in HIV co-infected patients owing to a greater MTb burden. The present study aimed to verify the diagnostic performance of MTb qPCR in CSF of TbM patients who either were co-infected with HIV or were HIVnegative. Methods: A total of 334 consecutive participants with suspected TbM were divided into two groups: HIV co-infected and HIV-negative; each group was categorized into definite TbM, probable TbM, possible TbM, and TbM-negative subgroups based on clinical, laboratory and imaging data. We evaluated the diagnostic characteristics of MTb qPCR analysis to detect TbM in CSF by comparing the results to those obtained for definite TbM (i.e., positive MTb culture) and/or probable TbM in CSF, as gold standard. Results: The sensitivity of MTb qPCR in the definite and probable subgroups of the HIV coinfected participants (n = 14) was 35.7%, with a specificity of 93.8%, negative predictive value (NPV) of 94.4%, and negative clinical utility index (CUI−) of 0.89. Results of the HIV-negative group (n = 7) showed lower sensitivity (14.3%) and similar specificity, NPV, and CUI−. Conclusion: The findings confirmed our hypothesis, despite the low sensitivity. MTb qPCR may significantly contribute to diagnosis when associated with clinical criteria and complementary examinations.

Background: Disseminated Kaposi sarcoma (DKS) is present in patients with advanced HIV infection in whom co-infection with other opportunistic pathogens can occur. Bone marrow (BM) aspirate and biopsy comprise a robust diagnostic tool in patients with fever, cytopenias, and abnormal liver tests. However, the yield in patients with DKS has not been determined. Objective: The aim of this study was to evaluate the utility of BM aspirate and biopsy in patients with DKS. Methods: We included 40 male patients with a recent diagnosis of DKS. BM aspirate and biopsy was performed as part of the workup to rule out co-infections. Results: In four patients, Mycobacterium avium complex (MAC) was recovered from culture. In other four patients, intracellular yeasts were observed in the Grocott stain, diagnosed as Histoplasma. The yield of BM was calculated in 20%. Only 12 patients (30%) had fever and 11 (27.5%) had pancytopenia. Alkaline phosphatase (ALP) above normal values and C-reactive protein (CRP) were higher in patients with positive results for BM than in those with negative results (63% vs. 21.9%, and 3.0 vs. 1.2 mg/L; p = 0.03 in both comparisons). No differences were found when complete blood-count abnormalities were compared. Conclusion: We recommend performing a BM aspirate for stains, culture, and biopsy in all HIV patients with DKS, as this will permit the early diagnosis of co-infections and prevent further complications in those who receive chemotherapy.

Background: Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are used in combination with antiretroviral therapy to suppress viral loads in HIV patients. The chemical design of NNRTIs has changed in recent years in response to resistance-associated mutations (RAMs) and resistance. NNRTIs are chemically diverse compounds that bind an allosteric site of HIV RT. Resistance- associated mutations (RAMs) identified in HIV patients are associated with NNRTI resistance. RAMs confer amino acid changes that alter both structural and physiochemical properties of the allosteric site. Ultimately, these changes reduce NNRTI affinity. Previously, we used a combination of computational and experimental methods to analyze and validate RAMs for 3 diarylpyrimidine (DAPY) NNRTIs. Objective: The objective of this study is to apply these methods to other chemically diverse, non- DAPY NNRTIs. Materials and Methods: We selected MIV-150 (experimental microbicide) and doravirine for this study. A computational and molecular modeling strategy was used to evaluate the effects of RAMs. Calculated changes in drug affinity and stability (ΔS + ΔA) were used to determine overall resistance levels: susceptible, low, intermediate, and high. The ΔS + ΔA values for K101P suggest that this mutation confers intermediate/high-level resistance to MIV-150, but remains susceptible to doravirine. Based on the determined resistance levels, we analyzed the models and used Molecular Dynamics (MD) to compare the interactions of MIV-150/doravirine with RT wild-type (WT) and RT (K101P). From MD, we found that key interactions were lost with RT (K101P), but were retained with doravirine. To experimentally validate our findings, we conducted a fluorescence-based reverse transcription assay for MIV-150 with RT (WT) and RT (K101P). IC50 values determined in assays showed a 101-fold change in potency for MIV-150, but essentially no change for doravirine. Results: Our computational and experimental results are also consistent with antiviral data reported in the literature. Conclusion: We believe that this approach is effective for analyzing mutations to determine resistance profiles for chemically diverse NNRTIs in development.

Background: The association between subclinical atherosclerosis and traditional cardiovascular disease (CVD) risk factors, inflammatory and metabolic biomarkers has been demonstrated around the world and specifically Brazilian human immunodeficiency virus type 1 (HIV-1)- infected individuals. However, the association between subclinical atherosclerosis and these aforementioned factors combined with anti-inflammatory biomarkers has not been examined in these populations. Objectives: To evaluate the association of the carotid intima-media thickness (cIMT) with CVD risk factors, inflammatory, metabolic and HIV-1 infection markers combined with adiponectin and interleukin (IL)-10 as anti-inflammatory variables. Methods: In this case-control study, 49 HIV-1-infected patients on combined antiretroviral therapy (cART) and 85 controls were compared for traditional CVD risk factors, inflammatory, metabolic, and anti-inflammatory variables. Further, we compared HIV-1-infected patients according to their cIMT (as continuous and categorized <0.9 or ≥0.9 mm variable) visualized by carotid ultrasonography doppler (USGD). Results: Twenty-four (48.9%) HIV-1-infected patients showed cIMT ≥0.9 mm. The patients had higher levels of C reactive protein on high sensitivity assay (hsCRP), tumor necrosis factor α, IL-6, IL-10, triglycerides, and insulin, and lower levels of adiponectin, total cholesterol and low-density lipoprotein cholesterol than controls (all p<0.05). Low levels of adiponectin were negatively associated with cIMT ≥0.9 mm (p=0.019), and explained 18.7% of the cIMT variance. Age (p=0.033) and current smoking (p=0.028) were positively associated with cIMT values, while adiponectin levels (p=0.008) were negatively associated with cIMT values; together, these three variables explained 27.3% of cIMT variance. Conclusion: Low adiponectin was associated with higher cIMT in HIV-1-infected patients on cART. Low adiponectin levels in combination with age and smoking could explain, in part, the increased subclinical atherosclerosis observed in these patients. Adiponectin may be a good candidate for predicting subclinical atherosclerosis in the management of HIV-1-infected patients in public health care, especially where USGD is not available.