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Overcoming the global health threat of HIV infection requires continuous pipelines of novel drug candidates. We identified the γ-pyrone polyketides Aureothin/Neoaureothin as potent hits by anti-HIV screening of an extensive natural compound collection. Total synthesis of a structurally diverse group of Aureothin-derivatives successfully identified a lead compound (#7) superior to Aureothin that combines strong anti-HIV activity (IC 90 <45 nM), photostability and improved cell safety. Compound #7 inhibited de novo virus production from integrated proviruses by blocking the accumulation of HIV RNAs that encode the structural components of virions and include viral genomic RNAs. Thus, the mode-of-action displayed by compound #7 is different from those of all current clinical drugs. Proteomic analysis indicated that compound #7 does not affect global protein expression in primary blood cells and may modulate cellular pathways linked to HIV infection. Compound #7 inhibited multiple HIV genotypes, including HIV-type 1 and 2 and synergistically inhibited HIV in combination with clinical reverse transcriptase and integrase inhibitors. We conclude that compound #7 represents a promising new class of HIV inhibitors that will facilitate the identification of new virus-host interactions exploitable for antiviral attack and holds promise for further drug development.

Background: Cryptococcal meningitis (CCM) is a common and deadly disease among HIV-infected patients. Notable about CCM is its association with the immune reconstitution inflammatory syndrome (IRIS). Though it has been posited a switch from first to second-line antiretroviral therapy (ART) can induce CCM IRIS, a case presentation of CCM IRIS has not been published., Case Presentation: A 10-year-old, HIV-infected girl who initially presented with severe headache and new-onset seizures, with cerebrospinal fluid that returned antigen, India Ink, and culture positive for Cryptococcus neoformans. Notably, 8 weeks prior to seizures, she had switched from first line to second-line ART (abacavir-lamivudine-efavirenz to zidovudine-lamivudine-lopinavir/ritonavir) due to virologic failure, with a viral load of 224,000 copies/milliliter. At time of seizures and 8 weeks on second-line ART, her viral load had reduced to 262 copies/milliliter. Her hospital course was prolonged, as she had ongoing headaches and developed bilateral cranial nerve VI palsies despite clearance of Cryptococcus from cerebrospinal fluid on antifungal therapy and therapeutic lumbar punctures. However, symptoms stabilized, and she was discharged with oral fluconazole. Cranial nerve palsies resolved 10 weeks post discharge and she has remained disease free., Conclusions: We describe a case of CCM IRIS in a 10-year-old HIV infected child after changing to second-line ART. This case provides evidence that screening for cryptococcal antigenaemia prior to switch from first-line to second-line ART could be an important measure to prevent cryptococcal disease.

A series of indazolyl-substituted piperidin-4-yl-aminopyrimidines (IPAPYs) were designed from two potent HIV-1 NNRTIs piperidin-4-yl-aminopyrimidine 3c and diaryl ether 4 as the lead compounds by molecular hybridization strategy. The target molecules 5a-q were synthesized and evaluated for their anti-HIV activities and cytotoxicities in MT-4 cells. 5a-q displayed moderate to excellent activities against wild-type (WT) HIV-1 with EC 50 values ranging from 1.5 to 0.0064 μM. Among them, 5q was regarded as the most excellent compound against WT HIV-1 (EC 50  = 6.4 nM, SI = 2500). And also, it displayed potent activities against K103 N (EC 50  = 0.077 μM), Y181C (EC 50  = 0.11 μM), E138K (EC 50  = 0.057 μM), and moderate activity against double mutants RES056 (EC 50  = 8.7 μM). Moreover, the structure-activity relationships (SARs) were summarized, and the molecular docking was performed to investigate the binding mode of IPAPYs and HIV-1 reverse transcriptase., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Introduction: Use of tenofovir based anti-retroviral therapy (ART) in HIV patients is associated with low bone mineral density (BMD). Low BMD predisposes people living with HIV (PLWHIV) to fractures thereby increasing morbidity and mortality. Since the introduction of tenofovir based ARV regimens in 2011, information on the prevalence of low BMD in PLWHIV and receiving ART is still scarce in Malawi. This study aimed to determine the prevalence and associated factors of low BMD among adults living with HIV and receiving ART in Blantyre, Malawi., Methodology: This was a cross sectional study involving 282 HIV-positive adults of whom 102 (36%) were males. The participants aged 18-45 years were recruited from three primary and one tertiary health care facilities. Patients with no other comorbidities or conditions associated with low BMD and on ART >12 months were included. Data on BMD (femoral neck and lumbar spine) were collected using Dual-Energy X-ray Absorptiometry (DEXA). The International Physical Activity Questionnaire (IPAQ) was used to assess the physical activity (PA) levels. Participants' body weight (kg) and height (m) were also measured. Descriptive statistics, Chi-Square test and multivariable logistic regression were used to analyse data., Results: Mean age of participants was 37(± 6.4) years, mean duration on ART was 5(± 3.5) years and mean body mass index (BMI) was 23(± 4.5) kg/m2. Twenty percent (55) had reduced BMD. More males (28%) had reduced BMD than females (14%) (p = 0.04). There was a significant association between lumbar BMD and femoral neck BMD (r = 0.66,p<0.001). However, on average, lumbar BMD (g/cm2) was significantly lower than the femoral BMD (p < 0.001). Participants with low PA level (OR 1.23,p = 0.6) had higher odds of having reduced BMD compared to those with high PA level., Conclusions and Recommendation: Prevalence of reduced BMD is high among PLWHIV in Malawi especially male Malawian adults. Occurrence of low BMD is associated with low PA level. There is need for health care providers to routinely monitor BMD and PA levels of this population., Competing Interests: The authors have declared that no competing interests exist.

Global Human Immunodeficiency Virus (HIV) statistics by the World Health Organization (WHO) for the year 2017 was estimated to be 36.9 (31.1-43.9) million. Antiviral drug resistance poses a serious threat to public health and requires immediate action. Retroviral Integrase (IN), a component enzyme in the retroviral pre-integration complex (PIC) enables a retrovirus to incorporate its genetic material into the host DNA. Development of resistance by the current integrases invites immediate attention of the drug discovery community for the development of new second-generation Integrase Strand Transfer Inhibitors (INSTIs). It will exhibit greater efficacy against Elvitegravir (EVG) and Raltegravir (RAL) resistant strains of HIV. This review focuses on the mechanism, importance of integrase structure, function and current research on small molecule inhibitors of integrase to overcome drug resistance. The molecular mechanism of retroviral integrase inhibition and the evolution of resistance are also explored., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

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., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

HIV-positive patients have a 60- to 200-fold increased incidence of Non-Hodgkin Lymphomas (NHL) because of their impaired cellular immunity. Some NHL are considered Acquired Immunodeficiency Syndrome (AIDS) defining conditions. Diffuse large B-cell Lymphoma (DLBC) and Burkitt Lymphoma (BL) are the most commonly observed, whereas Primary Effusion Lymphoma (PEL), Central Nervous System Lymphomas (PCNSL), Plasmablastic Lymphoma (PBL) and classic Hodgkin Lymphoma (HL) are far less frequent. Multicentric Castleman disease (MCD) is an aggressive lymphoproliferative disorder highly prevalent in HIV-positive patients and strongly associated with HHV-8 virus infection. In the pre-Combination Antiretroviral Therapy (CART) era, patients with HIV-associated lymphoma had poor outcomes with median survival of 5 to 6 months. By improving the immunological status, CART extended the therapeutic options for HIV positive patients with lymphomas, allowing them to tolerate standard chemotherapies regimen with similar outcomes to those of the general population. The combination of CART and chemotherapy/ immuno-chemotherapy treatment has resulted in a remarkable prolongation of survival among HIVinfected patients with lymphomas. In this short communication, we briefly review the problems linked with the treatment of lymphoproliferative diseases in HIV patients. Combination Antiretroviral Therapy (CART) not only reduces HIV replication and restores the immunological status improving immune function of the HIV-related lymphomas patients but allows patients to deal with standard doses of chemotherapies. The association of CART and chemotherapy allowed to obtain better results in terms of overall survival and complete responses. In the setting of HIVassociated lymphomas, many issues remain open and their treatment is complicated by the patient's immunocompromised status and the need to treat HIV concurrently., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Fibroblast Growth Factor 21 (FGF21) serum levels are associated with insulin resistance and metabolic syndrome in HIV patients., Objective: To quantify FGF21 levels in HIV patients using antiretroviral therapy (ART) and to analyze a possible association between serum FGF21 levels and lipid profile, levels of proinflammatory cytokines, and atherogenic risk factors., Materials and Methods: Twenty patients with HIV infection, who received ART in a scheme consisting of Tenofovir/Emtricitabine+Lopinavir/Ritonavir, were enrolled in this study. The serum levels of FGF21, inflammatory parameters (IL-6 and IL-1β), glucose, cholesterol, triglycerides, and insulin were determined at baseline and after 36 weeks of treatment. The homeostatic model assessment for insulin resistance (HOMA-IR) and the atherogenic risk factor were also calculated., Results: After 36 weeks, serum FGF21 levels decreased significantly (p=0.011), whereas IL-6 levels (r=0.821, p=0.0001) and the CD4+ T cell count (r=0.446, p=0.048), showed a positive correlation with the decrease in FGF21 levels. There was an increase in total cholesterol (r=-0.483, p=0.031), LDL (r=-0.496, p=0.026), VLDL (r=-0.320, p=0.045), and the atherogenic index factor (r=-0.539, p=0.014), these values showed a negative correlation with FGF21 levels., Conclusion: The decrease of serum FGF21 levels due to ART is associated with the alteration in lipid profile and an increased risk for cardiovascular diseases. These variations are predictors of inflammatory status in HIV patients using antiretroviral therapy., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Introduction: Structural modulation of previously identified lead spiro-β-lactams with antimicrobial activity was carried out., Objective: The main objective of this work was to synthesize and evaluate the biological activity of novel spiro-lactams based on previously identified lead compounds with antimicrobial activity., Methods: The target chiral spiro-γ-lactams were synthesized through 1,3-dipolar cycloaddition reaction of a diazo-γ-lactam with electron-deficient dipolarophiles. In vitro activity against HIV and Plasmodium of a wide range of spiro-β-lactams and spiro-γ-lactams was evaluated. Among these compounds, one derivative with good anti-HIV activity and two with promising antiplasmodial activity (IC50 < 3.5 µM) were identified., Results: A novel synthetic route to chiral spiro-γ-lactams has been established. The studied β- and γ- lactams were not cytotoxic, and three compounds with promising antimicrobial activity were identified, whose structural modulation may lead to new and more potent drugs., Conclusion: The designed structural modulation of biologically active spiro-β-lactams involved the replacement of the four-membered β-lactam ring by a five-membered γ-lactam ring. Although conformational and superimposition computational studies revealed no significant differences between β- and γ- lactam pharmacophoric features, the studied structural modulation did not lead to compounds with a similar biological profile. The observed results suggest that the β-lactamic core is a requirement for the activity against both HIV and Plasmodium., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The use of Antiretroviral drugs in treating HIV/ AIDS patients has enormously increased their life spans with serious disadvantages. The virus infection still remains a public health problem worldwide with no cure and vaccine for the viral agent until now. The use of nanoparticles (NPs) for the treatment and prevention of HIV/AIDS is an emerging technology of the 21st century. NPs are solid and colloid particles with 10 nm to <1000 nm size range; although, less than 200 nm is the recommended size for nanomedical usage. There are NPs with therapeutic capabilities such as liposomes, micelles, dendrimers and nanocapsules. The particle enters the body mainly via oral intake, direct injection and inhalation. It has been proven to have potentials of advancing the prevention and treatment of the viral agent. Certain NPs have been shown to have selftherapeutic activity for the virus in vitro. Strategies that are novel are emerging which can be used to improve nanotechnology, such as genetic treatment and immunotherapy. In this review, nanoparticles, the types and its characteristics in drug delivery were discussed. The light was furthermore shed on its implications in the prevention and treatment of HIV/AIDS., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Whether HIV-positive injecting drug users (IDUs) are at higher risk of developing drug resistance mutations (DRMs) after methadone maintenance therapy (MMT) than any other HIV-positive population is unclear., Objective: To compare the incidence of new DRMs in two population groups: antiretroviraltreatment (ART) HIV-positive IDUs and non-drug users., Methods: A prospective cohort of ART HIV-positive patients including IDUs who received MMT (MMT group) and non-drug users (N-MMT group) was established from April 2016 to December 2017 in Guangxi, China., Results: Of the 80 participants, 43 were in the MMT group and 37 were in the N-MMT group. Compared with the N-MMT group, the HRs of PIs, NRTIs and NNRTIs for new DRMs in the MMT group was 1.55 (95%CI: 0.28-8.64; P = 0.616), 1.51 (95%CI: 0.44-5.20; P = 0.512) and 0.45 (95%CI: 0.15-1.35; P = 0.155), respectively. There was no dose-response relationship between MMT and new DRMs for PIs, NRTIs and NNRTIs (P > 0.05). The new DRM incidence for NRTIs (138.23 per 104 person-months) was higher than for PIs (94.16 per 104 person-months) and NNRTIs (95.41per 104 person-months) in the MMT group, while the new DRM incidence for NNRTIs (208.24 per 104 person-months) was higher than for PIs (44.13 per 104 person-months) and NRTIs (91.78 per 104 person-months) in the N-MMT group., Conclusion: Among ART HIV-positive patients, there is no significant difference in the incidence of new DRMs between IDUs receiving MMT and non-drug users. MMT has little impact on the development of DRMs among IDUs., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Serum cytokine levels over the course of HIV infection usually increase with immunosuppression and decrease after antiretroviral treatment (ART)., Objectives: The aim of the study is to compare cytokine levels between HIV-infected patients (HIP) and controls and investigate the relationship between CD4+T cell count, HIV-RNA levels, and cytokine levels., Methods: The study subjects comprised ART-naive HIP (n=30) with no comorbidities and age-and sex-matched healthy controls. We measured levels of IL-6, IL-1β, TNF-α, and IFN-γ in serum samples of HIP at the beginning and at month 6 of ART and in controls., Results: The mean age of the study subjects was 38.7 ±10.3 years, with men making up 86.7% of the study subjects (n=26). IL-6, IL-1β, and TNF-α levels were significantly higher in both ART-naive (p<0.001, p=0.002, p=0.001) and ART-experienced HIP (p<0.001) than controls. The IFN-γ level was lower in both ART-naive and ART-experienced HIP compared to controls (p=0.082 and p=0.002). There was a positive correlation between the CD4+T cell count and serum concentration of IFN- γ(r=0.320, p<0.05). While the serum IFN-γ concentration showed a negative correlation with the HIVRNA level(r=-0.412, p<0.001), the serum IL-1β, IL-6, and TNF-α concentrations showed a positive correlation with the HIV-RNA level (r=0.349, p<0.001; r:0.54, p<0.001; r:0.438, p<0.00)., Conclusion: Although serum concentrations of IL-6, IL-1β and TNF-α showed a significant decrease after ART, they were still significantly higher than the controls. IFN-γ responded differently to ART compared to the other cytokines, indicating that it may play a distinct and important role in the pathogenesis of HIV infection., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Evidence regarding the association between HIV viral load (VL) and hypertension is inconsistent. In this study, we investigated the relationship using viremia copy-years (VCY), a cumulative measure of HIV plasma viral burden., Methods: Data were analyzed for 686 PLWH in the Florida Cohort Study, who had at least five years of VL data before the baseline. VL data were extracted from Enhanced HIV/AIDS Reporting System (eHARS) and used to define peak VL (pVL), recent VL (rVL), and undetectable VL (uVL: rVL<50copies/mL). A five-year VCY (log10 copy × years/mL) before the baseline investigation, was calculated and divided into 5 groups (≤2.7, 2.8-3.7, 3.8-4.7, 4.8-5.7 and >5.7) for analysis. Hypertension was determined based on hypertension diagnosis from medical records. Multivariable logistic regression was used for association analysis., Results: Of the total sample, 277 (40.4%) participants were hypertensive. Compared to the participants with lowest VCY (≤2.7 log10 copy × years/mL), the odds ratios (OR) and 95% confidence interval [95% CI] for hypertension of the remaining four groups, in order, were 1.91 [1.11, 3.29], 1.91 [1.03, 3.53], 2.27 [1.29, 3.99], and 1.25 [0.65, 2.42], respectively, controlling for confounders. The association was independent of pVL, rVL, and uVL, each of which was not significantly associated with hypertension., Conclusion: Persistent HIV infection is a risk factor for hypertension among PLWH. Information provided by VCY is more effective than single time-point VL measures in investigating HIV infection- hypertension relationship. The findings of this study support the significance of continuous viral suppression in hypertension prevention among PLWH., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized by pulmonary vascular remodeling, elevated pulmonary arterial pressure, and right heart failure. Human immunodeficiency virus (HIV)-infected individuals have a higher incidence of PAH than the non-HIV infected population and evidence suggests a role for systemic and pulmonary inflammation in the pathogenesis of HIV-associated PAH. Due to their pleiotropic effects, including immune-modulatory and anti-inflammatory effects, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) have been considered for the treatment of PAH, with conflicting results. The effects of statins on HIV-associated PAH have not been specifically evaluated. We have developed a non-human primate (NHP) model of HIV-associated PAH that closely mimics HIV-PAH using simian immunodeficiency virus (SIV)-infected rhesus macaques (Macaca mulatta). We determined that treatment of healthy macaques with atorvastatin prior to and throughout SIV infection prevented the development of SIV-associated PAH. Additionally, SIV-infected macaques that initiated atorvastatin treatment during the early chronic disease stage had reduced incidence of PAH compared to untreated animals. Statin treatment reduced inflammatory mediators TGF-β, MIP-1α, and TNF-α and the numbers of CD14 dim CD16 + non-classical monocytes, and CD14 + CCR7 - CD163 - CD206 + alveolar macrophages previously shown to be associated with SIV-PAH. These results support the concept that statins reduce inflammatory processes that contribute to PAH and may provide a safe and effective prophylactic strategy for the prevention of PAH in HIV-infected individuals.

We evaluated the performance of a fourth-generation antigen/antibody (Ag/Ab) assay for detecting HIV-1 infection on dried blood spots (DBS) both in a conventional laboratory environment and in an epidemiological survey corresponding to a real-life situation. Although a 2-log loss of sensitivity compared to that with plasma was observed when using DBS in an analytical analysis, the median delay of positivity between DBS and crude serum during the early phase postacute infection was 7 days. The performance of the fourth-generation assay on DBS was approximately similar to that of a third-generation (antibody only) assay using crude serum samples. Among 2,646 participants of a cross-sectional study in a population of men having sex with men, 428 DBS were found reactive, but negative results were obtained from 5 DBS collected from individuals who self-reported a positive HIV status, confirmed by detection of antiretroviral (ARV) drugs in their DBS. The data generated allowed us to estimate a sensitivity of 98.8% of the fourth-generation assay/DBS strategy in a high-risk population, even including a broad majority of individuals on ARV treatment among those HIV positive. Our study brings additional proofs that DBS testing using a fourth-generation immunoassay is a reliable strategy able to provide alternative approaches for both individual HIV testing and surveillance of various populations., (Copyright © 2019 American Society for Microbiology.)

Background: This study was aimed to assess immunological recovery, failure, and factors associated with CD-4 T-cells progression over time, among adolescents and adults living with HIV on Antiretroviral Therapy in Northern Ethiopia., Methods: A retrospective cross sectional study was done on 19,525 HIV patients on ART. Data were collected using a data retrieval checklist from a database. All eligible data in the database were exported to Microsoft excel 2010 and then data verification and filtration were done before exporting to STATA 14.0 for analysis. Factors associated with recent CD-4 count were modeled by using Generalized Linear Model poison family., Results: Among the patients with advanced HIV infection (< 200 CD-4 T-cell/ mm3) at baseline, only 28.35%, 95% CI (27.45-29.26) of them had immunological recovery (≥ 500 T-cells/mm3). Only 2.14%, 95%CI (1.94%- 2.35%) of the patients had immunological failure. Baseline CD-4 count (Incidence Rate Ratio (IRR) = 1.0007, 95%CI = 1.00069-1.00078), patients from military health care facility (IRR = 1.11, 95%CI = 1.06-1.16), good adherence (IRR = 1.12, 95%CI = 1.04-1.21) and viral load suppression (IRR = 1.31, 95%CI = 1.28-1.33) were positively associated with recent CD-4 count in the full model. Whereas, being male (IRR = 0.85, 95%CI = 0.83-0.86), patients with on Anti-Retroviral Therapy (ART) regimen of 1e (TDF-3TC-EFV), 2f (AZT-3TC-ATV/r), and 2h (TDF-3TC-ATV/r) (IRR = 0.92, 95%CI = 0.91-0.94), (IRR = 0.65, 95%CI = 0.55-0.76) and (IRR = 0.71, 95%CI = 0.63-0.81) respectively were negatively associated with the recent CD-4 count in the full model., Conclusions: Immunological recovery was achieved by 1/3 of the patients despite being on highly active ART (HAART). Therefore, intensive adherence counseling, follow-up and support should be focused on patients with viral non suppression to enhance immunological recovery., Competing Interests: The authors have declared that no competing interest exist.

Objectives: Sexualized intravenous drug use, also known as slamsex, seems to be increasing among HIV-positive men who have sex with men (MSM). Physical and psychopathological symptoms have previously been reported in this population, although research on the subject of slamsex is scarce. The objectives of our study were to describe the psychopathological background of a sample of HIV-positive MSM who engaged in slamsex during the previous year and to compare physical, psychopathological, and drug-related symptoms between these participants and those who engaged in non-injecting sexualized drug use., Design and Methods: Participants (HIV-positive MSM) were recruited from the U-Sex study in 22 HIV clinics in Madrid during 2016-17. All participants completed an anonymous cross-sectional online survey on sexual behavior and recreational drug use. When participants met the inclusion criteria, physicians offered them the opportunity to participate and gave them a card with a unique code and a link to access the online survey. The present analysis is based on HIV-positive MSM who had engaged in slamsex and non-injecting sexualized drug use., Results: The survey sample comprised 742 participants. Of all the participants who completed the survey, 216 (29.1%) had engaged in chemsex, and of these, 34 (15.7%) had engaged in slamsex. Participants who engaged in slamsex were more likely to have current psychopathology (depression, anxiety, and drug-related disorders) than participants who engaged in non-injecting sexualized drug use. In addition, participants who engaged in slamsex more frequently reported high-risk sexual behaviors and polydrug use and were more often diagnosed with sexually transmitted infections (STIs) and hepatitis C than those who did not inject drugs. Compared with participants who did not inject drugs, participants who engaged in slamsex experienced more severe drug-related symptoms (withdrawal and dependence), symptoms of severe intoxication (loss of consciousness), and severe psychopathological symptoms during or after slamsex (eg, paranoid thoughts and suicidal behaviors)., Conclusion: Slamsex is closely associated with current psychiatric disorders and severe drug-related and psychiatric symptoms., Competing Interests: The authors have declared that no competing interests exist.

Background: Globally, ten percent of new HIV infections are among children and most of these children acquire infection through mother-to-child transmission. To prevent this, lifelong ART among pregnant and breast feeding (PBF) women living with HIV, irrespective of the WHO clinical stage, was adopted (option B+). There is limited cohort-wise assessment of VL testing among women on 'option B+'., Objective: Among a pregnancy cohort on antiretroviral therapy in public hospitals and clinics of Mazowe district, Zimbabwe (2017), to determine the i) proportion undergoing VL testing anytime up to six months post child birth and associated factors; ii) turnaround time (TAT) from sending the specimen to results receipt and VL suppression among those undergoing VL testing., Methods: This was a cohort study involving secondary programme data. Modified Poisson regression using robust variance estimates was used to determine the independent predictors of VL testing., Results: Of 1112 women, 354 (31.8%, 95% CI: 29.2-34.6) underwent VL testing: 113 (31.9%) during pregnancy, 124 (35%) within six months of child birth and for 117 (33.1%), testing period was unknown. Of 354, VL suppression was seen in 334 (94.4%) and 13 out of 20 with VL non-suppression underwent repeat VL testing. Among those with available dates (125/354), the median TAT was 93 days (IQR 19.3-255). Of 1112, VL results were available between 32 weeks and child birth in 31 (2.8%) women. When compared to hospitals, women registered for antenatal care in clinics were 36% less likely to undergo VL testing [aRR: 0.64 (95% CI: 0.53, 0.76)]., Conclusion: Among women on option B+, the uptake of HIV VL testing was low with unacceptably long TAT. VL suppression among those tested was satisfactory. There is an urgent need to prioritize VL testing among PBF women and to consider use of point of care machines. There is a critical need to strengthen the recording and local utilisation of routine clinic data in order to successfully monitor progress of healthcare services provided., Competing Interests: None of the authors have any competing interests. The contents of this paper do not necessarily reflect the views of the Government or Non-Governmental Organizations or Academic institutions or The Union.

The paper focussed on a step-by-step structural modification of a cycloheptathiophene-3-carboxamide derivative recently identified by us as reverse transcriptase (RT)-associated ribonuclease H (RNase H) inhibitor. In particular, its conversion to a 2-aryl-cycloheptathienoozaxinone derivative and the successive thorough exploration of both 2-aromatic and cycloheptathieno moieties led to identify oxazinone-based compounds as new anti-RNase H chemotypes. The presence of the catechol moiety at the C-2 position of the scaffold emerged as critical to achieve potent anti-RNase H activity, which also encompassed anti-RNA dependent DNA polymerase (RDDP) activity for the tricyclic derivatives. Benzothienooxazinone derivative 22 resulted the most potent dual inhibitor exhibiting IC 50 s of 0.53 and 2.90 μM against the RNase H and RDDP functions. Mutagenesis and docking studies suggested that compound 22 binds two allosteric pockets within the RT, one located between the RNase H active site and the primer grip region and the other close to the DNA polymerase catalytic centre.

In Gordts et al. (2015), we have shown that lignosulfonic acid, a commercially available lignin derivative, possesses broad antiviral activity against human immunodeficiency virus (HIV) and Herpes simplex virus (HSV) by preventing viral entry into susceptible target cells. Because of the interesting safety profile as potential microbicide, we now determined the antiviral activity of a series of lignosulfonates in order to understand better which molecular features can contribute to their antiviral activity. Here, 24 structurally different lignosulfonates were evaluated for their capacity to inhibit HIV and HSV transmission and replication in various cellular assays. These derivatives differ in origin (hardwood or softwood), counter-ion used during sulphite processing (Na + , Ca 2+ , or NH 4 + ), sulphur content, carboxylic acid percentage, and molecular weight fraction, which allowed to determine structure-activity relationships. We demonstrate that the broad antiviral activity of lignosulfonates is mainly dependent on their molecular weight and that their mechanism of action is based on interactions with the viral envelope glycoproteins. This makes the lignosulfonates a potential low-cost microbicide that protects women from sexual HIV and HSV transmission and thus prevents life-long infection., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Polyethyleneimine (PEI) is a chemical compound that used is as a carrier in gene therapy/delivery. Some studies have investigated the microbicidal potential and antiviral activity (prophylactic or therapeutic) of PEI and its derivatives. The aim of this study was to investigate the effect of branched polyethyleneimine (bPEI) on human immunodeficiency virus (HIV) replication. Infected cells were treated with bPEI for 36 hours, and the concentration of the viral protein P24 (as a virus replication marker) was determined in cell culture supernatants. This study indicated that bPEI increased HIV replication and decreased the viability of infected cells through cytotoxicity. The toxicity of bPEI its association with and cell death (apoptosis, autophagy and necrosis) have been reported in several studies. To investigate bPEI-induced cytotoxicity, we examined apoptosis and autophagy in cells treated with bPEI, and a significant increase in HIV viral load, the P24 antigen level, autophagy, and necrosis observed. Thus, treatment with bPEI leads to cytotoxicity and higher HIV virus yield.

Feminizing hormone therapy (FHT) may interact with human immunodeficiency virus preexposure prophylaxis (PrEP). We found that transgender women who took FHT exhibited a 7-fold lower rectal tissue ratio of PrEP's active metabolites vs competing deoxynucleotides compared to cisgender women and men (P = .03) that inversely correlated with estradiol (ρ = -0.79; P < .05). Thus, FHT may negatively impact PrEP efficacy. Clinical Trials Registration . NCT02983110., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: HIV programs are increasingly confronted with failing antiretroviral therapy (ART), including second-line regimens. WHO has provided guidelines on switching to third-line ART. In a Médecins Sans Frontières clinic in Mumbai, India, receiving referred presumptive second-line ART failure cases, an evidence-based protocol consisting of viral load (VL) testing, enhanced adherence counselling (EAC) and genotype for switching was implemented., Objective: To document the outcome and genotype of presumptive second-line ART failure cases switched to third-line or maintained on second-line ART., Design: Retrospective cohort study of patients referred between January 2011 and September 2017., Results: The cases (n = 120) were complex with median 9.2 years of ART exposure, poor adherence at baseline, and exposure to multiple ART regimens other than recommended by WHO. Out of 90 evaluated cases, 39(43%) were maintained on second-line ART. Forty-nine (54%) were ever switched to third-line ART. Twelve months virological suppression was 72% in the second-line and 93% in the third-line ART cohort, while retention in care was 80% and 94% respectively. Genotyping showed 62% resistance for PIs, and 52% triple class resistance to NRTIs, NNRTIs and PIs. Resistance was noted for the new class of integrase inhibitors, and for different drugs without any documented previous exposure to the same drug., Conclusion: Adopting WHO guidelines on switching ART regimens and provision of EAC can prevent unnecessary switching/exposure to third-line ART regimens. Genotyping is urgently required in national HIV programs, which currently use only the exposure history of patients for switching to third-line ART regimens., Competing Interests: The authors have declared that no competing interests exist.

Cardiovascular disease is an important cause of morbidity and mortality in people living with HIV (PLWH), who commonly experience lipid disturbances. The aim of this study was to determine whether the plasma lipidomic profile differs between PLWH receiving a darunavir-based ART and those receiving integrase inhibitor-based ART. This was a cross-sectional study of unselected patients for whom metabolomic analysis was performed using ultra-high-performance liquid chromatography coupled to mass spectrometry. Data for the two subgroups were compared by calculating the log2 of the fold change for each metabolite and then grouping these into the main lipid families. Sixty-two PLWH aged 49.3 ± 8.6 years (82% men) were included: 12 patients (19.4%) had hypertension, 8 (12.9%) had type 2 diabetes, 25 (41.0%) had dyslipidaemia and 9 (14.5%) were taking statins, without significant differences in all these variables between the two groups. Twenty-five (40.3%) received darunavir-based ART and 37 (59.7%) integrase inhibitor-based ART. Although the differences were not statistically significant, patients treated with darunavir-based ART had higher concentrations of total cholesterol (211 mg/dL vs 194 mg/dL), LDL-cholesterol (132 mg/dL vs 117 mg/dL) and triglycerides (155 mg/dL vs 122 mg/dL), and lower HDL-cholesterol concentration (50 mg/dL vs 52 mg/dL). The main lipid families and metabolites differed slightly between groups (log2-fold change; P-value): ceramides (-0.07; 0.49), phosphatidylinositols (-0.05; 0.63), diacylglycerols (0.10; 0.64), phosphatidylethanolamines (0.03; 0.78), triacylglycerols (0.27; 0.18) and lysophosphatidylethanolamines (0.03; 0.83). In the integrase inhibitor-based group, the use of tenofovir alafenamide fumarate significantly increases the majority of lipid fractions, when compared with tenofovir disoproxil fumarate. The lipidomic profile did not differ between PLWH treated with darunavir-based or integrase inhibitor-based ART. This was especially true for ceramides, which are involved in cardiovascular disease. Further studies are needed to study the impact of ART in lipidomic profile.

Objective: The purpose of this work was to conduct an in-depth analysis to understand patients' experiences using a real-time medication monitoring pill bottle linked to an HIV self-management app., Methods: A descriptive qualitative study design was used. In-depth interviews were conducted using a semi-structured interview guide at the 3-month follow-up visit during a trial of the app for improving medication adherence which began in January 2018. Eligibility criteria were HIV-positive, over the age of 18, ownership of a smartphone, able to speak and understand English and self-report less than 80% adherence to medications in the past 30 days or a viral load of over 20 copies/mL (detectable). All interviews were audio-recorded and transcribed. Using thematic analysis, we explored emerging themes with similar patterns across interviews and organized the themes according to the constructs of the Fit between Individuals, Task and Technology (FITT) framework., Results: Thirty-eight persons living with HIV (PLWH), who were randomized to the intervention arm of the study trial, participated in the interviews. 79.0% of participants reported their race as African American/Black, 63.2% had completed some high school or less, and 79.0% reported an annual median income of less than $20,000. Data was collected until saturation was reached. A total of nine major themes organized by the FITT framework were identified. Three themes related to the fit between individuals and task were: motivation for strict medication adherence, self-efficacy for overall health management, and engagement with medication reminders. Four themes related to the fit between individual and technology were: ease of use, HIV-related stigma and disclosure of HIV status, customized alert of medication time windows based on individual routine set-up, and preference for device design. Two themes related to the fit between task and technology were: system functionality of data transfer from the electronic pill bottle to the app and self-awareness of system syncing signals., Conclusions: This study demonstrated that tracking medication adherence and receiving push-notification medication reminders through the electronic pill bottle connected to the app encourages and supports PLWH in adhering to their medication regimens. Findings from this work highlight the importance of adequate consideration of the needs of intended users in designing customizable mobile health technology, including HIV-related stigma, disclosure of HIV status and antiretroviral therapy regimens., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Dopaminergic dysfunction has long been connected to the development of HIV infection in the CNS. Our previous data showed that dopamine increases HIV infection in human macrophages by increasing the susceptibility of primary human macrophages to HIV entry through stimulation of both D1-like and D2-like receptors. These data suggest that, in macrophages, both dopamine receptor subtypes may act through a common signaling mechanism. To define better the mechanism(s) underlying this effect, this study examines the specific signaling processes activated by dopamine in primary human monocyte-derived macrophages (hMDM). In addition to confirming that the increase in entry is unique to dopamine, these studies show that dopamine increases HIV entry through a PKA insensitive, Ca 2+ dependent pathway. Further examination demonstrated that dopamine can signal through a previously defined, non-canonical pathway in human macrophages. This pathway involves both Ca 2+ release and PKC phosphorylation, and these data show that dopamine mediates both of these effects and that both were partially inhibited by the G q/11 specific inhibitor YM-254890. Studies have shown that G q/11 preferentially couples to the D1-like receptor D5, indicating an important role of the D1-like receptors in mediating these effects. These data indicate a role for Ca 2+ flux in the HIV entry process, and suggest a distinct signaling mechanism mediating some of the effects of dopamine in macrophages. Together, the data indicate that targeting this alternative dopamine signaling pathway might provide new therapeutic options for individuals with elevated CNS dopamine suffering from NeuroHIV., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose of Review: Although cities present opportunities for infectious pathogens such as HIV to spread, public health infrastructure within these cities also provides opportunities to design effective approaches to eliminate transmission of these pathogens. The HIV Transmission Elimination AMsterdam (H-TEAM) Initiative, a consortium of relevant stakeholders involved in HIV prevention and care, designed an integrated approach to curb the HIV epidemic in Amsterdam, including providing preexposure prophylaxis (PrEP), increasing awareness of acute HIV infection, offering same-day test and treat, and improving indicator disease-driven HIV testing., Recent Findings: In 2013, approximately 230 people in Amsterdam were newly diagnosed with HIV, largely belonging to one of two key affected populations, namely MSM and people with a migration background. Since the start of H-TEAM in 2014, a decrease in new diagnoses was observed (130 in 2017), with an increasing proportion of MSM who had been diagnosed with a recent infection., Summary: The H-TEAM shows that a city-based concerted effort is feasible. However, major challenges remain, such as reducing the number of late HIV diagnoses, and identifying and providing appropriate services to a diminishing group of individuals who are likely the source of transmission.

Purpose of Review: More than half of new HIV diagnoses occur in the Southern United States where the epidemic disproportionately affects persons of color. Although other areas of the country are seeing dramatic declines in the number of new cases, the progress in the South lags behind. This review will examine the reasons for that disparity. Many are unique to the South., Recent Findings: Despite advances in antiretroviral therapy for HIV, many in the South are not benefiting from these medications, at either a personal or public health level. The reasons are complex and include lack of access to healthcare, lower levels of funding than other areas of the country, stigma, structural racism, increased barriers due to social determinants of health, coexisting mental health disorders, substance use disorders and sexually transmitted diseases and insufficient workforce capacity to meet the needs of those living with HIV., Summary: These findings should underline the need for investment in the South for a holistic healthcare approach to persons living with HIV including supporting basic needs such as access to food, transportation and housing. Prioritization among politicians for policy and systems changes and approaches to decrease stigma and enhance education about HIV will be key.

Purpose of Review: To summarize recent trends in knowledge of HIV status, care and viral suppression, and the status of implementation of relevant contextual requirements for the United States to achieve the 90-90-90 goals. Recently, the US government announced a plan to decrease HIV incidence by over 90% by 2030. Reaching this goal may require higher targets than 90-90-90., Recent Findings: The United States is on course to reach 90-90-90 goals in the near future, with 86% of persons with HIV aware of their infection, 74% of persons with diagnosed infection in care, and 83% of persons in care with viral suppression in 2016. Some high-burden subnational jurisdictions have already achieved these goals., Summary: The United States is likely to reach 90-90-90 targets in the near future. However, to reduce HIV incidence by at least 90% by 2030, the United States will need to rapidly meet the new 95-95-95 targets and deploy a comprehensive strategy with novel approaches to testing, retaining persons with HIV on treatment, and preventing new infections with preexposure prophylaxis and comprehensive syringe services programs.

Ribonucleases H (RNases H) are endonucleolytic enzymes, evolutionarily related to retroviral integrases, DNA transposases, resolvases and numerous nucleases. RNases H cleave RNA in RNA/DNA hybrids and their activity plays an important role in the replication of prokaryotic and eukaryotic genomes, as well as in the replication of reverse-transcribing viruses. During reverse transcription, the RNase H activity of human immunodeficiency virus (HIV) and hepatitis B virus (HBV) degrades the viral genomic RNA to facilitate the synthesis of viral double-stranded DNA. HIV and HBV reverse transcriptases contain DNA polymerase and RNase H domains that act in a coordinated manner to produce double-stranded viral DNA. Although RNase H inhibitors have not been developed into licensed drugs, recent progress has led to the identification of a number of small molecules with inhibitory activity at low micromolar or even nanomolar concentrations. These compounds can be classified into metal-chelating active site inhibitors and allosteric inhibitors. Among them, α-hydroxytropolones, N-hydroxyisoquinolinediones and N-hydroxypyridinediones represent chemotypes active against both HIV and HBV RNases H. In this review we summarize recent developments in the field including the identification of novel RNase H inhibitors, compounds with dual inhibitory activity, broad specificity and efforts to decrease their toxicity., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Home-based human immunodeficiency virus (HIV) testing and education has increased HIV test uptake and access to health services among men. We studied how a home-based antenatal intervention influenced male partner utilization of clinic-based HIV and sexually transmitted infection (STI) services, linkage to HIV care and medical circumcision., Methods: We conducted a secondary analysis within a randomized controlled trial of pregnant women attending antenatal care in Kenya. Women and their male partners received either a home-based couple intervention or an invitation letter for clinic-based couple HIV testing. The home-based intervention included education on STI symptoms, STI and HIV treatment and male circumcision for HIV prevention. Male self-reported outcomes were compared using relative risks at 6 months postpartum., Results: Among 525 women, we reached 487 (93%) of their male partners; 247 men in the intervention arm and 240 men in the control arm. Men who received the intervention were more likely to report an STI consultation (n = 47 vs. 16; relative risk, 1.59; 95% confidence interval, 1.33-1.89). Among 23 men with newly diagnosed HIV, linkage to HIV care was reported by 4 of 15 in the intervention (3 men had missing linkage data) and 3 of 5 men in the control arms (relative risk, 0.66; 95% confidence interval, 0.34-1.29). Although the intervention identified 3 times more men with new HIV infection, the study lacked power to find significant differences in linkage to HIV care. Few eligible men sought medical circumcision (4 of 72 intervention and 2 of 88 control)., Conclusions: Home-based couple education and testing increased STI consultations among male partners of pregnant women, but appeared insufficient to overcome the barriers involved in linkage to HIV care and medical circumcision.

Background: Anal squamous cell carcinoma (ASCC) is one of the most frequent non-AIDS-defining neoplasias in HIV patients, mainly in MSM, and it has been associated with chronic infection with high-risk human papilloma virus (HR-HPV). Our main objective was to determine HR-HPV clearance and acquisition rates and related factors and their relationship with the incidence of HSILs and ASCC in anal mucosa of HIV+ MSM., Patients and Methods: The study included consecutive HIV-infected MSM between May 2010 and December 2018. Data were gathered at baseline and annually on their sexual behavior, CD4 and CD8 levels, plasma HIV viral load, and results of anal cytology, HPV PCR, and high-resolution anoscopy., Results: Out of the 405 patients studied, 34.9% of patients cleared oncogenic genotypes (IQR: 37-69) within 49 months, and 42.9% acquired new genotypes within 36 months (IQR:12-60). In multivariate analysis, clearance was only significantly influenced by the duration of antiretroviral therapy (ART) (OR: 1.016, 95% CI 1.003-1.030). The incidence of HSILs was 30.86/1,000 patient-years and that of ASCC was 81.22/100,000 patient-years; these incidences were not influenced by the acquisition (acquired: 14.9% vs. non-acquired: 10.4%; p = 0.238) or clearance (cleared 11.4% vs. non-cleared: 13.2%; p = 0.662) rates of these viruses., Conclusions: The duration of ART appears to positively affect oncogenic genotype clearance in the anal mucosa of HIV+ MSM, although this clearance does not affect the incidence of HSILs or ASCC. The reduction in HSIL+ rate observed in our patients may be attributable to the bundle of measures adopted at our center., Competing Interests: The authors have declared that no competing interests exist.

Cancer is the leading cause of death for HIV-infected persons in economically developed countries, even in the era of antiretroviral therapy (ART). Lymphomas remain a leading cause of cancer morbidity and mortality for HIV-infected patients and have increased incidence even in patients optimally treated with ART. Even limited interruptions of ART can lead to CD4 cell nadirs and HIV viremia, and increase the risk of lymphoma. The treatment of lymphoma is now similar for HIV-infected patients and the general population: patients with good HIV control can withstand intensive therapies appropriate to the lymphoma, including autologous and even allogeneic hematopoietic stem cell transplantation. Nonetheless, HIV-related lymphomas have unique aspects, including differences in lymphoma pathogenesis, driven by the presence of HIV, in addition to coinfection with oncogenic viruses. These differences might be exploited in the future to inform therapies. The relative incidences of lymphoma subtypes also differ in the HIV-infected population, and the propensity to advanced stage, aggressive presentation, and extranodal disease is higher. Other unique aspects include the need to avoid potential interactions between ART and chemotherapeutic agents, and the need for HIV-specific supportive care, such as infection prophylaxis. Despite these specific challenges for cancer treatment in the setting of HIV infection, the care of these patients has progressed sufficiently that recent guidelines from the American Society of Clinical Oncology advocate the inclusion of HIV-infected patients alongside HIV- patients in cancer clinical trials when appropriate., (© 2019 by The American Society of Hematology.)

Background: Integration of feminizing hormone therapy (FHT) and antiretroviral therapy (ART) is critical in providing gender-affirming HIV care for transgender (trans) women living with HIV. However, interpersonal communications with HIV providers who are not competent with FHT may complicate this integration., Methods: We conducted semi-structured interviews with trans women (n = 9) who self-reported as HIV-positive and their HIV providers (n = 15) from community-based venues (e.g., clinics) in Manila, Philippines., Results: We identified five key themes from our qualitative data: (1) provider's concerns; (2) patient's goals; (3) affirmative vs. non-affirmative provider rhetoric; (4) alignment vs. misalignment of provider rhetoric to patient goals; and (5) FHT and ART-related decisions. Based on these themes, we describe a gender-affirmative HIV care framework to understand FHT-ART decisions among trans women living with HIV. Based on our data, this framework shows that provider-patient communications regarding ART and FHT consists primarily of provider concerns and patient goals regarding FHT. These communications can take on a gender-affirmative or non-affirmative style of rhetoric that either aligns or misaligns with patient goals and may lead to differences in FHT and ART-related decisions among trans women living with HIV., Conclusion: There exist mixed regimens and beliefs about taking FHT and ART among this sample of trans women. While trans participants' main source of health information is their HIV provider, providers are likely to communicate non-affirmative rhetoric that negatively impacts trans women's decision to take FHT and ART. Research is needed to elucidate co-prescriptions of gender-affirmative services with HIV care among this group in the Philippines., Competing Interests: The authors have declared that no competing interests exist.

Background: The cost of direct-acting antivirals (DAAs) for hepatitis C virus (HCV) prompted many payers to restrict treatment to patients who met non-evidence-based criteria. These restrictions have implications for survival of people with HCV, especially for people with human immunodeficiency virus (HIV)/HCV coinfection who are at high risk for liver disease progression. The goal of this work was to estimate the effects of DAA access policies on 10-year all-cause mortality among people with HIV., Methods: The study population included 3056 adults with HIV in the Women's Interagency HIV Study and Multicenter AIDS Cohort Study from 1 October 1994 through 30 September 2015. We used the parametric g-formula to estimate 10-year all-cause mortality under DAA access policies that included treating (i) all people with HCV; (ii) only people with suppressed HIV; (iii) only people with severe fibrosis; and (iv) only people with HIV suppression and severe fibrosis., Results: The 10-year risk difference of treating all coinfected persons with DAAs compared with no treatment was -3.7% (95% confidence interval [CI], -9.1% to .6%). Treating only those with suppressed HIV and severe fibrosis yielded a risk difference of -1.1% (95% CI, -2.8% to .6%), with 51% (95% CI, 38%-59%) of coinfected persons receiving DAAs. Treating a random selection of 51% of coinfected persons at baseline decreased the risk by 1.9% (95% CI, -4.7% to .3%)., Conclusions: Restrictive DAA access policies may decrease survival compared to treating similar proportions of people with HIV/HCV coinfection with DAAs at random. These findings suggest that lives could be saved by thoughtfully revising access policies., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Currently, an increasing number of drugs are becoming available to clinics for the treatment of HIV infection. Even if this targeted therapy is highly effective at suppressing viral replication, caregivers are facing growing therapeutic failures in patients, due to resistance with or without treatment adherence concerns. Accordingly, it is important to continue to discover small molecules that have a novel mechanism of inhibition. In this work, HIV integrase inhibitors were selected by high-throughput screening. Chemical structure comparisons enabled the identification of stilbene disulfonic acids as a potential new chemotype. Biochemical characterization of the lead compound stilbenavir (NSC34931) and a few derivatives was performed. Stilbene disulfonic acid derivatives exhibit low to sub-micromolar antiviral activity, and they inhibit integrase through DNA-binding inhibition. They probably bind to the C -terminal domain of integrase, in the cavity normally occupied by the noncleaved strand of the viral DNA substrate. Because of this original mode of action compared to active site strand transfer inhibitors, they do not exhibit cross-resistance to the three main resistance pathways to integrase inhibitors (G140S-Q148H, N155H, and Y143R). Further structure-activity optimization should enable the development of more active and less toxic derivatives with potential clinical relevance.

Treatment of individuals coinfected with hepatitis C virus (HCV) and human immunodeficiency virus (HIV) requires careful consideration of potential drug-drug interactions. We evaluated the pharmacokinetic interaction of the direct-acting antiviral agents elbasvir and grazoprevir coadministered with the nucleotide reverse transcriptase inhibitor tenofovir disoproxil fumarate (TDF). Three open-label, multidose studies in healthy adults were conducted. In the first study (N = 10), participants received TDF 300 mg once daily, elbasvir 50 mg once daily, and elbasvir coadministered with TDF. In the second study (N = 12), participants received TDF 300 mg once daily, grazoprevir 200 mg once daily, and grazoprevir coadministered with TDF. In the third study (N = 14), participants received TDF 300 mg once daily and TDF 300 mg coadministered with coformulated elbasvir/grazoprevir 50 mg/100 mg once daily. Pharmacokinetics and safety were evaluated. Following coadministration, the tenofovir area under the plasma concentration-time curve to 24 hours and maximum plasma concentration geometric mean ratios (90% confidence intervals) for tenofovir and coadministered drug(s) versus tenofovir were 1.3 (1.2, 1.5) and 1.5 (1.3, 1.6), respectively, when coadministered with elbasvir; 1.2 (1.1, 1.3) and 1.1 (1.0, 1.2), respectively, when coadministered with grazoprevir; and 1.3 (1.2, 1.4) and 1.1 (1.0, 1.4), respectively, when coadministered with the elbasvir/grazoprevir coformulation. TDF had minimal effect on elbasvir and grazoprevir pharmacokinetics. Elbasvir and/or grazoprevir coadministered with TDF resulted in no clinically meaningful tenofovir exposure increases and was generally well tolerated, with no deaths, serious adverse events (AEs), discontinuations due to AEs, or laboratory AEs reported. No dose adjustments for elbasvir/grazoprevir or TDF are needed for coadministration in HCV/HIV-coinfected people., (© 2019, The American College of Clinical Pharmacology.)

Combination antiretroviral therapy (ART) has significantly reduced the morbidity and mortality resulting from HIV infection. ART is, however, unable to eradicate HIV, which persists latently in several cell types and tissues. Phylogenetic analyses suggested that the proliferation of cells infected before ART initiation is mainly responsible for residual viremia, although controversy still exists. Conversely, it is widely accepted that drug resistance mutations (DRMs) do not appear during ART in patients with suppressed viral loads. Studies based on sequence clustering have in fact indicated that, at least in developed countries, HIV-infected ART-naive patients are the major source of drug-resistant viruses. Analysis of longitudinally sampled sequences have also shown that DRMs have variable fitness costs, which are strongly influenced by the viral genetic background., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Objective: Evaluation of prevalence and risk factors of cervical dysplasia among Human Immunodeficiency Virus sero-positive (HIV+ve) females on Highly Active Antiretroviral Therapy (HAART) attending HIV clinic at University of Nigeria Teaching Hospital (UNTH) Enugu, Southeastern, Nigeria., Methods: Structured questionnaire was used to obtain socio-demographic and risk factors data. Cervical specimens were collected from 105 HIV +ve females on HAART and 104 HIV seronegative (HIV-ve) females. Pap smears were collected using cytobrush and Ayre's spatula in a secluded place. Smears were made on slides and placed in 95% ethyl alcohol for conventional Pap staining and the cytobrush washed into the preservative containers for later Immunocytochemistry staining. Blood samples were used for HIV screening. Immunocytochemistry activity using anti-P16INK4A was carried out on the Pap smears that were positive for cervical dysplasia., Results: Pap staining showed prevalence of cervical dysplasia among HIV+ve on HAART 19.05%, (ASCUS 14.29%, LSIL 3.81%, HSIL 0.95%) whereas HIV-ve was 6.73%, p = 0.008. Only the HSIL 0.95% was positive for P16INK4A. Odds ratios at 95% Confident Interval of the risk factors of cervical dysplasia were thus; HIV+ve, 3.26 (1.31-8.09), education less than secondary school 3.23 (1.25-8.37), polygamy 3.23 (1.25-8.37), smoking 1.36 (0.15-12.10), married 2.08 (0.43-2.31), grand multi gravidity 1.72 (0.72-4.11), grand multi parity 1.54 (0.66-3.61), positive history of sexually transmitted diseases 2.49 (1.06-5.80). Uptake of cervical cancer screening was low in both study groups, 7 (6.7%) among HIV+ve on HAART and 14 (13.5%) among HIV-ve females, P = 0.102., Conclusion: HAART had cytoprotective effect against cervical dysplasia in HIV+ve females, by reducing progression of ASCUS to LSIL, HSIL and cervical cancer. Progression from normal to ASCUS increased which could be due to latency or/and prolonged persistent high risk HPV and HIV infections, of the most sexually active age group before diagnosed of HIV.

Background: Optimization of combination antiretroviral therapy (cART) can impact the human immunodeficiency virus (HIV) reservoir. We evaluated the effect on the HIV reservoir in peripheral blood and ileum biopsies in patients switching from boosted protease inhibitor (PI/r)-based therapy to dolutegravir (DTG)-based therapy., Methods: Impact of Integrase-inhibitor DOlutegravir On the viral Reservoir (INDOOR) is a phase 4 open-label clinical trial that randomly included 42 HIV type 1-infected individuals on effective cART: 20 who switched from PI/r-based to DTG-based cART (switch group), and 22 who remained in PI/r-based regimens (control group). We analyzed blood and ileum biopsies to quantify episomal, total, and integrated HIV DNA, cell-associated HIV RNA, residual plasma viremia, T-cell subsets, cell activation, and inflammation markers., Results: There were no related adverse events or treatment discontinuations due to drug intolerance. The HIV reservoir was consistently larger in ileal than in peripheral CD4+ T cells in both groups (P < .01). Residual viremia in plasma decreased in the switch group (P = .03). However, we did not observe significant longitudinal changes in low-level viral replication, total and integrated HIV reservoir, HIV transcription, T-cell maturation subsets, immunoactivation markers, inflammatory soluble proteins, or cellular markers of latently infected cells., Conclusions: The INDOOR study is the first evaluation of changes in HIV reservoir size in ileum biopsies and in peripheral blood in individuals switched from PI/r- to DTG-based cART. Although this switch was safe and well tolerated, it had no impact on a large array of immunological and inflammatory markers or on HIV reservoir markers in peripheral or in ileal CD4+ T cells., Clinical Trials Registration: EudraCT 2014-004331-39., (© The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America.)

HIV persistence during combination antiretroviral therapy (cART) is the principal obstacle to cure. Mechanisms responsible for persistence remain uncertain; infections may be maintained by persistence and clonal expansion of infected cells or by ongoing replication in anatomic locations with poor antiretroviral penetration. These mechanisms require different strategies for eradication, and determining their contributions to HIV persistence is essential. We used phylogenetic approaches to investigate, at the DNA level, HIV populations in blood, lymphoid, and other infected tissues obtained at colonoscopy or autopsy in individuals who were on cART for 8 to 16 years. We found no evidence of ongoing replication or compartmentalization of HIV; we did detect clonal expansion of infected cells that were present before cART. Long-term persistence, and not ongoing replication, is primarily responsible for maintaining HIV. HIV-infected cells present when cART is initiated represent the only identifiable source of persistence and is the appropriate focus for eradication., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)

Background: The global transition to use of dolutegravir (DTG) in WHO-preferred regimens for HIV treatment is limited by lack of knowledge on use in pregnancy. Here we assessed the relationship between drug concentrations (pharmacokinetics, PK), including in breastmilk, and impact on viral suppression when initiated in the third trimester (T3)., Methods and Findings: In DolPHIN-1, HIV-infected treatment-naïve pregnant women (28-36 weeks of gestation, age 26 (19-42), weight 67kg (45-119), all Black African) in Uganda and South Africa were randomised 1:1 to dolutegravir (DTG) or efavirenz (EFV)-containing ART until 2 weeks post-partum (2wPP), between 9th March 2017 and 16th January 2018, with follow-up until six months postpartum. The primary endpoint was pharmacokinetics of DTG in women and breastfed infants; secondary endpoints included maternal and infant safety and viral suppression. Intensive pharmacokinetic sampling of DTG was undertaken at day 14 and 2wPP following administration of a medium-fat breakfast, with additional paired sampling between maternal plasma and cord blood, breastmilk and infant plasma. No differences in median baseline maternal age, gestation (31 vs 30 weeks), weight, obstetric history, viral load (4.5 log10 copies/mL both arms) and CD4 count (343 vs 466 cells/mm3) were observed between DTG (n = 29) and EFV (n = 31) arms. Although DTG Ctrough was below the target 324ng/mL (clinical EC90) in 9/28 (32%) mothers in the third trimester, transfer across the placenta (121% of plasma concentrations) and into breastmilk (3% of plasma concentrations), coupled with slower elimination, led to significant infant plasma exposures (3-8% of maternal exposures). Both regimens were well-tolerated with no significant differences in frequency of adverse events (two on DTG-ART, one on EFV-ART, all considered unrelated to drug). No congenital abnormalities were observed. DTG resulted in significantly faster viral suppression (P = 0.02) at the 2wPP visit, with median time to <50 copies/mL of 32 vs 72 days. Limitations related to the requirement to initiate EFV-ART prior to randomisation, and to continue DTG for only two weeks postpartum., Conclusion: Despite low plasma DTG exposures in the third trimester, transfer across the placenta and through breastfeeding was observed in this study, with persistence in infants likely due to slower metabolic clearance. HIV RNA suppression <50 copies/mL was twice as fast with DTG compared to EFV, suggesting DTG has potential to reduce risk of vertical transmission in mothers who are initiated on treatment late in pregnancy., Trial Registration: clinicaltrials.gov NCT02245022., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: ML declared research grants from ViiV, Janssen and personal fees from Mylan.

The budding of HIV from infected cells is driven by the protein-protein interaction between the p6 domain of the HIV Gag protein and the UEV domain of the human TSG101 protein. We report the development of a cyclic peptide inhibitor of the p6/UEV interaction, from a non cell-permeable parent that was identified in a SICLOPPS screen. Amino acids critical for the activity of the parent cyclic peptide were uncovered using alanine-scanning, and a series of non-natural analogues synthesized and assessed. The most potent molecule disrupts the p6/UEV interaction with an IC 50  of 6.17 ± 0.24 μM by binding to UEV with a K d of 11.9 ± 2.8 μM. This compound is cell permeable and active in a cellular virus-like particle budding assay with an IC 50  of ∼2 μM. This work further demonstrates the relative simplicity with which the potency and activity of cyclic peptides identified from SICLOPPS libraries can be optimized.

Background: Dipeptidyl peptidase-4 (DPP-4) inhibitors have pleotropic anti-inflammatory and immune regulatory effects in addition to glucoregulation. We evaluated inflammation and immune markers in suppressed human immunodeficiency virus (HIV) infection during treatment with the DPP-4 inhibitor sitagliptin., Methods: Virologically suppressed adults with HIV without diabetes on stable antiretroviral therapy (ART) with ≥100/μL CD4 cells were randomized to 16 weeks of sitagliptin 100 mg/day vs placebo in a multicenter trial. The primary endpoint was the change in plasma soluble CD14 (sCD14) from baseline to week 15-16., Results: Ninety participants were randomized, and 42 from each arm were included in per-protocol analyses. Participants were 45% non-Hispanic white, 38% non-Hispanic black, and 15% Hispanic, with a median age of 51 years; 83% were male; and the median CD4 count was 602 cells/μL. At week 15-16, there was no difference in sCD14 change between the 2 arms (P = .69). Relative to placebo, the sitagliptin arm had 47% greater decline in CXCL10 (95% confidence interval, -57% to -35%) at week 15 (P < .001). There were no significant between-arm differences in other soluble biomarkers, total CD4 and CD8 counts, or markers of lymphocyte or monocyte activation. Sitagliptin was well tolerated., Conclusions: Sixteen weeks of sitagliptin had no effect on sCD14 levels in virologically suppressed participants with HIV. CXCL10, a chemokine involved in atherogenesis that predicts non-AIDS events during ART, declined markedly with sitagliptin. This suggests that DPP-4 inhibition has the potential to reduce cardiovascular morbidity in treated HIV infection., Clinical Trials Registration: NCT01426438., (© The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Recently, the US Food and Drug Administration and European Medicines Agency issued warnings on the use of dolutegravir and darunavir/cobicistat for treatment of pregnant women living with human immunodeficiency virus (HIV). It took 3-5 years to identify the risks associated with the use of these antiretroviral drugs, during which time pregnant women were exposed to these drugs in clinical care, outside of controlled clinical trial settings. Across all antiretroviral drugs, the interval between registration of new drugs and first data on pharmacokinetics and safety in pregnancy becoming available is around 6 years. In this viewpoint, we provide considerations for clinical pharmacology research to provide safe and effective treatment of pregnant and breastfeeding women living with HIV and their children. These recommendations will lead to timelier availability of safety and pharmacokinetic information needed to develop safe treatment strategies for pregnant and breastfeeding women living with HIV, and are applicable to other chronic disease areas requiring medication during pregnancy., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America.)

Based on the potent anti-HIV activity of L-2',3'-dideoxycytidine (L-ddC), L-2',3'-dideoxy-4'-selenonucleosides (L-4'-Se-ddNs) have been synthesized from natural chiral template, L-glutamic acid, using Pummerer-type condensation as a key step. All synthesized compounds were assayed for anti-HIV-1 activity, but none of them did show any significant antiviral activity up to 100 μM, probably due to conformational differences between L-ddC and L-4'-Se-ddC, induced by the bulky selenium atom, which might play an important role in phosphorylation by cellular kinase.

Approximately 20% of people with HIV in the United States prescribed antiretroviral therapy are not virally suppressed. Thus, optimal management of virologic failure has a critical role in the ability to improve viral suppression rates to improve long-term health outcomes for those infected and to achieve epidemic control. This article discusses the causes of virologic failure, the use of resistance testing to guide management after failure, interpretation and relevance of HIV drug resistance patterns, considerations for selection of second-line and salvage therapies, and management of virologic failure in special populations., (Copyright © 2019 Elsevier Inc. All rights reserved.)

While scientific advances have led to large-scale production and widespread distribution of vaccines and antiviral drugs, viruses still remain a major cause of human diseases today. The ever-increasing reports of viral resistance and the emergence and re-emergence of viral epidemics pressure the health and scientific community to constantly find novel molecules with antiviral potential. This search involves numerous different approaches, and the use of antimicrobial peptides has presented itself as an interesting alternative. Even though the number of antimicrobial peptides with antiviral activity is still low, they already show immense potential to become pharmaceutically available antiviral drugs. Such peptides can originate from natural sources, such as those isolated from mammals and from animal venoms, or from artificial sources, when bioinformatics tools are used. This review aims to shed some light on antimicrobial peptides with antiviral activities against human viruses and update the data about the already well-known peptides that are still undergoing studies, emphasizing the most promising ones that may become medicines for clinical use.