Randomized-trial data on the risks and benefits of antiretroviral therapy (ART) as compared with zidovudine and single-dose nevirapine to prevent transmission of the human immunodeficiency virus (HIV) in HIV-infected pregnant women with high CD4 counts are lacking.

Data from randomized trials are lacking on the benefits and risks of initiating antiretroviral therapy in patients with asymptomatic human immunodeficiency virus (HIV) infection who have a CD4+ count of more than 350 cells per cubic millimeter.

Progressive immune dysfunction and the acquired immunodeficiency syndrome (AIDS) develop in most persons with untreated infection with human immunodeficiency virus type 1 (HIV-1) but in only approximately 20 to 30% of persons infected with HIV type 2 (HIV-2); among persons infected with both types, the natural history of disease progression is poorly understood.

Antiretroviral preexposure prophylaxis is a promising approach for preventing human immunodeficiency virus type 1 (HIV-1) infection in heterosexual populations.

The optimal time for the initiation of antiretroviral therapy for asymptomatic patients with human immunodeficiency virus (HIV) infection is uncertain.

There is considerable genetic diversity among viruses of different subtypes (designated A to J) in the major group of human immunodeficiency virus type 1 (HIV-1), the form of HIV that is dominant in the global epidemic. If available, HIV-1 sequences pre-dating the recognition of AIDS could be crucial in defining the time of origin and the subsequent evolution of these viruses in humans. The oldest known case of HIV-1 infection was reported to be that of a sailor from Manchester who died of an AIDS-like illness in 1959; however, the authenticity of this case has not been confirmed. Genetic analysis of sequences from clinical materials obtained from 1971 to 1976 from members of a Norwegian family infected earlier than 1971 showed that they carried viruses of the HIV-1 outlier group, a variant form that is mainly restricted to West Africa. Here we report the amplification and characterization of viral sequences from a 1959 African plasma sample that was previously found to be HIV-1 seropositive. Multiple phylogenetic analyses not only authenticate this case as the oldest known HIV-1 infection, but also place its viral sequence near the ancestral node of subtypes B and D in the major group, indicating that these HIV-1 subtypes, and perhaps all major-group viruses, may have evolved from a single introduction into the African population not long before 1959.

Olumuyiwa Omonaiye, Pat Nicholson, Elizabeth Manias, Mohammadreza Mohebbi, Snezana Kusljic

Charles Abongomera, Tullia Battaglioli, Cherinet Adera, Koert Ritmeijer

Rachel M. Arends, Erni J. Nelwan, Ratna Soediro, Reinout van Crevel, Bachti Alisjahbana, Herdiman T. Pohan, A. Katinka L. von Borries, Aart H. Schene, André J. A. M. van der Ven, Arnt F. A. Schellekens

by Rachel M. Arends, Erni J. Nelwan, Ratna Soediro, Reinout van Crevel, Bachti Alisjahbana, Herdiman T. Pohan, A. Katinka L. von Borries, Aart H. Schene, André J. A. M. van der Ven, Arnt F. A. Schellekens HIV, hepatitis B and C, and syphilis share common transmission routes of which primarily unsafe sexual contact and injecting drug use are important. Impulsivity is a major factor contributing to this transmission risk behavior; however comprehensive studies within female, prison, and Asian populations are scarce. This cross-sectional study aims to delineate the contributions of different aspects of impulsivity to risk behavior, among female inmates living in a prison in Jakarta (N = 214). The relationships between various aspects of impulsivity, risk behaviors and seropositivity were tested using analyses of variance and logistic regression analyses. Motor impulsivity was related to alcohol use, reward-related impulsivity to drug use, and cognitive/goal-directed impulsivity to sexual risk behavior. Finally, goal-directed impulsivity was also directly associated with seropositivity. Specific aspects of impulsivity are associated with different types of risk behavior in Indonesian female prisoners, which can be relevant for future studies on infection prevention strategies for such a population.

Abstract Background CD4 cell count has been identified to be an essential component in monitoring HIV treatment outcome. However, CD4 cell count monitoring sometimes fails to predict virological failure resulting in unnecessary switch of treatment lines which causes drug resistance and limitations of treatment options. This study assesses the use of both viral load (HIV RNA) and CD4 cell count in the monitoring of HIV/AIDS progression. Methods Time-homogeneous Markov models were fitted, one on CD4 cell count monitoring and the other on HIV RNA monitoring. Effects of covariates; gender, age, CD4 baseline, HIV RNA baseline and adherence to treatment were assessed for each of the fitted models. Assessment of the fitted models was done using prevalence plots and the likelihood ratio tests. The analysis was done using the “msm” package in R. Results Results from the analysis show that viral load monitoring predicts deaths of HIV/AIDS patients better than CD4 cell count monitoring. Assessment of the fitted models shows that viral load monitoring is a better predictor of HIV/AIDS progression than CD4 cell count. Conclusion From this study one can conclude that although patients take more time to achieve a normal CD4 cell count and less time to achieve an undetectable viral load, once the CD4 cell count is normal, mortality risks are reduced. Therefore, both viral load monitoring and CD4 count monitoring can be used to provide useful information which can be used to improve life expectance of patients living with HIV. However, viral load monitoring is a better predictor of HIV/AIDS progression than CD4 cell count and hence viral load is deemed superior.…

kula, Anna; Delacourt, Nadège; Bouchat, Sophie; Darcis, Gilles; Avettand-Fenoel, Veronique; Verdikt, Roxane; Corazza, Francis; Necsoi, Coca; Vanhulle, Caroline; Bendoumou, Maryam; Burny, Arsene; DE Wit, Stephane; Rouzioux, Christine; Rohr, Oliver; van Lint, Carine

Objectives: Few single latency-reversing agents (LRAs) have been tested in vivo and only some of them have demonstrated an effect, albeit weak, on the decrease of latent reservoir. Therefore, other LRAs and combinations of LRAs need to be assessed. Here, we evaluated the potential of combined treatments of therapeutically promising LRAs, disulfiram and romidepsin. Setting and methods: We assessed the reactivation potential of individual disulfiram or simultaneous or sequential combined treatments with romidepsin in vitro in latently-infected cell lines of T-lymphoid and myeloid origins and in ex vivo cultures of CD8+-depleted peripheral blood mononuclear cells (PBMCs) isolated from 18 HIV-1+ cART-treated individuals. Results: We demonstrated heterogeneous reactivation effects of disulfiram in vitro in various cell lines of myeloid origin and no latency reversal neither in vitro in T-lymphoid cells nor ex vivo, even if doses corresponding to maximal plasmatic concentration or higher were tested. Disulfiram+romidepsin combined treatments produced distinct reactivation patterns in vitro. Ex vivo, the combined treatments showed a modest reactivation effect when used simultaneously as opposed to no viral reactivation for the corresponding sequential treatment. Conclusions: Exclusive reactivation effects of disulfiram in myeloid latency cell lines suggest that disulfiram could be a potential LRA for this neglected reservoir. Moreover, distinct reactivation profiles pinpoint heterogeneity of the latent reservoir and confirm that the mechanisms that contribute to HIV latency are diverse. Importantly, disulfiram+romidepsin treatments are not potent ex vivo and most likely do not represent an effective drug combination to achieve high levels of latency reversal in vivo. Correspondance to Carine Van Lint, Service of Molecular Virology, Institut de Biologie et de Médecine Moléculaires (IBMM), Université Libre de Bruxelles (ULB), Rue des Professeurs Jeener et Brachet 12, 6041 Gosselies, Belgium. cvlint@ulb.ac.be The authors report no conflicts of interest related to this work. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Fearon, Elizabeth; Phillips, Andrew; Mtetwa, Sibongile; Chabata, Sungai T; Mushati, Phillis; Cambiano, Valentina; Busza, Joanna; Napierala, Sue; Hensen, Bernadette; Baral, Stefan; Weir, Sharon S; Rice, Brian; Cowan, Frances M; Hargreaves, James R

Background: ‘HIV prevention cascades’ have been proposed to support programmes by identifying gaps in demand for, access to and capability to adhere to HIV prevention tools, but there are few empirical examples to guide development. We apply a prevention cascade framework to examine prevention coverage and factors associated with condoms and/or PrEP adherence among female sex workers (FSW). Setting: Seven sites across Zimbabwe. Methods: Seven respondent-driven sampling (RDS) surveys from the intervention sites of a pragmatic cluster-randomised trial in Zimbabwe in 2016 were analysed, and 611/1439 women testing HIV-negative included. We operationalised key components of an HIV prevention cascade including demand, supply and capability to adhere to two tools for HIV prevention: condoms and Pre-Exposure Prophylaxis (PrEP). We used adjusted logistic regression to identify determinants of adherence to condoms and PrEP in turn, examining the effect of adherence to one tool on adherence to the other. Results: There were 343/611, 54.7%, women reporting adherence to condoms and/or PrEP, leaving almost half uncovered. While women were aware that condoms prevented HIV and reported good access to them, only 45·5% reported full adherence to condom use. For PrEP, a new technology, there were gaps along all three domains of demand, supply and adherence. Alcohol use decreased adherence to PrEP and condoms. Younger and newer entrants to sex work were less likely to take PrEP every day. Conclusion: HIV prevention programming among FSW in Zimbabwe could consider increasing awareness of PrEP alongside supply, alcohol use interventions, and approaches to engaging younger women. This is an open access article distributed under the terms of the Creative Commons Attribution License 4.0 (CC BY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Corresponding Author and requests for reprints: Dr Elizabeth FearonElizabeth.Fearon@lshtm.ac.uk +44 7927 2877 Department of Social and Environmental Health Research, Public Health and Policy, London School of Hygiene and Tropical Medicine 15-17 Tavistock Place, London WC1H 9SH Conflicts of Interest and Source of Funding: We have no conflicts of interest to report. These analyses were funded by the Bill and Melinda Gates Foundation via the Measurement and Surveillance of HIV Epidemics Consortium. The original trial from which data was collected was funded by DFID, Swedish SIDA and Irish Aid via Zimbabwe’s Integrated Support Programme, and UNFPA. Presented at IAS AIDS 2018 conference in Amsterdam, July 2018, not otherwise published. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Polanka, Brittanny M.; Kundu, Suman; So-Armah, Kaku A.; Freiberg, Matthew S.; Gupta, Samir K.; Bedimo, Roger J.; Budoff, Matthew J.; Butt, Adeel A.; Chang, Chung-Chou H.; Gottlieb, Stephen S.; Marconi, Vincent C.; Womack, Julie A.; Stewart, Jesse C.

Background: Insomnia is associated with increased cardiovascular disease (CVD) risk in the general population and is highly prevalent in people with HIV. The CVD risk conferred by insomnia in the HIV population is unknown. Methods: Using the Veterans Aging Cohort Study-Survey Cohort, insomnia symptoms were measured and dummy coded with the item, “Difficulty falling or staying asleep?” (5-point scale from no difficulty to bothers a lot). Incident CVD event ICD-9 codes (acute myocardial infarction, stroke, or coronary artery revascularization) were identified with VA and Medicare administrative data and VA fee-for-service data. Those with baseline CVD were excluded. Results: HIV-infected (N=3,108) veterans had a median follow-up time of 10.8 years, during which 267 CVD events occurred. Compared to HIV-infected veterans with no difficulty falling or staying asleep, HIV-infected veterans bothered a lot by insomnia symptoms had an increased risk of incident CVD after adjusting for demographics (HR=1.64, 95%CI=1.16-2.31, p=.005), CVD risk factors (HR=1.62, 95%CI=1.14-2.30, p=.007), additional potential confounders (hepatitis C infection, renal disease, anemia, alcohol use, cocaine use; HR=1.70, 95%CI=1.19-2.43, p=.003), and HIV-specific factors (HIV-1 RNA, CD4+ T-cell count, ART; HR=1.66, 95%CI=1.16-2.37, p=.005). Additional adjustment for non-benzodiazepine sleep medication (HR=1.62, 95%CI=1.13-2.32, p=.009) did not attenuate the association; however, it fell short of significance at p < .01 after adjustment for depressive symptoms (HR=1.51, 95%CI=0.98-2.32, p=.060) or antidepressant medication (HR=1.51, 95%CI=1.04-2.19, p=.031). Conclusion: Highly bothersome insomnia symptoms were significantly associated with incident CVD in HIV-infected veterans, suggesting that insomnia may be a novel, modifiable risk factor for CVD in HIV. Corresponding Author: Jesse C. Stewart, PhD, Department of Psychology, Indiana University-Purdue University Indianapolis (IUPUI), 402 N. Blackford St., LD 100E, Indianapolis, IN 46202. Telephone: (317) 274-6761. Fax: (317) 274-6756. Email address: jstew@iupui.edu Conflicts of Interest and Sources of Funding: Dr. Gupta reports funding from the National Institutes of Health, Indiana University, and Gilead Sciences; advisory board fees from Gilead Sciences and GlaxoSmithKline/ViiV; and travel support to present data at scientific conferences from Gilead Sciences and Bristol-Myers Squibb. Dr. Budoff reports funding from the National Institutes of Health and General Electric. Dr. Butt reports funding from Gilead and Merck. Dr. Stewart reports funding from the National Institutes of Health and Indiana University. The Veterans Aging Cohort Study was funded by grant U10AA13566 from the National Institute on Alcohol Abuse and Alcoholism and Veterans Health Administration Public Health Strategic Health Core Group. For the remaining authors none were declared. This analysis was funded in part by grant R01HL126557 from the National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the Department of Veterans Affairs or the National Institutes of Health. Previous Presentation: Oral presentation presented at the 76th annual meeting of the American Psychosomatic Society, March 7-10, 2018, Louisville, Kentucky. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Liu, Yongjian; Su, Bin; Zhang, Yu; Jia, Lei; Li, Hanping; Li, Zhen; Han, Jingwan; Zhang, Tong; Li, Tianyi; Wu, Hao; Wang, Xiaolin; Li, Jingyun; Li, Lin

Background: Unique recombinant forms (URFs) were generated in dually-infected or multiply-infected individuals, and some of URFs can be transmitted to many people resulting in the emergence of circulating recombinant forms (CRFs). We examined whether there was evidence for onward transmission of multiple URFs among men who have sex with men (MSM) in Beijing. Methods: A total of 146 MSM subjects with acute/early HIV-1 infection were recruited from the Beijing PRIMO clinical cohort between September 2010 and July 2012. HIV-1 full-length gag and partial pol, env genes were amplified and sequenced separately. Phylogenetic and recombination analysis were performed to determine the viral genotypes. Single genome amplification (SGA) and direct sequencing were used to confirm onward transmission of URFs Results: CRF01_AE was the most common genotype (51.9%), followed by CRF07_BC (23.0%), subtype B (14.8%), URFs (7.4%), CRF65_cpx (2.2%), CRF55_01B (0.7%). Multiple forms of URFs were identified, including CRF01_AE/BC, CRF01_AE/B and CRF01_AE/C. Nine of the ten individuals harboring URFs were infected by onward transmission of URFs. The remained one individual was co-infected with CRF01_AE and CRF07_BC variants. Conclusion: We introduced a new method to provide evidence for onward transmission of URF strains by examining the absence of inter-subtype co-infection among early infected individuals. Onward transmission of multiple URFs was found among MSM in Beijing, China. Our findings call for a program of continuous molecular surveillance and have implications to prevention programs among MSM in China. Correspondence to: Lin Li, PhD, Department of AIDS Research, State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, No.20 Dongda Street, Fengtai District, Beijing 100071, China (dearwood2001@yahoo.com). The authors declare no conflicts of interest. Yongjian Liu and Bin Su contributed equally to the work. Supported by the NSFC (81773493), Beijing Municipal S&T Project (D141100000314001), grant 2017YFC1200800, the State Key Laboratory of Pathogen and Biosecurity (AMMS), the Beijing Key Laboratory for HIV/AIDS Research (BZ0089). Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Benki-Nugent, Sarah F.; Martopullo, Ira I; Laboso, Tony; Tamasha, Nancy; Wamalwa, Dalton C.; Tapia, Kenneth; Langat, Agnes; Maleche-Obimbo, Elizabeth; Marra, Christina M.; Bangirana, Paul; Boivin, Michael J.; John-Stewart, Grace C.

Background: Monocyte activation may contribute to neuronal injury in aviremic HIV-infected adults; data are lacking in children. We examined the relation between monocyte activation markers and early and long-term neurodevelopmental outcomes in early-treated HIV-infected children. Setting: Prospective study of infant and child neurodevelopmental outcomes nested within a randomized clinical trial (NCT00428116) and extended cohort study in Kenya. Methods: HIV-infected infants (N=67) initiated ART at age…

Giovanni Guaraldi, Stefano Zona, Ana Rita Silva, Marianna Menozzi, Giovanni Dolci, Jovana Milic, Federica Carli, Cristina Mussini

by Giovanni Guaraldi, Stefano Zona, Ana Rita Silva, Marianna Menozzi, Giovanni Dolci, Jovana Milic, Federica Carli, Cristina Mussini Objective To investigate the association between current CD4+ T-cell count and CD4/CD8+ ratio with severity of frailty among people aging with HIV. Methods Cross-sectional observational study analysing data from all study visits in the ongoing prospective Modena HIV Metabolic Clinic Cohort between 2006 and 2015. Frailty severity was assessed using a frailty index (FI). We visualized the relationships between frailty index score and current CD4 cell count and CD4/CD8 ratio on two different curves adjusted for age, sex, and duration of HIV infection. Results Frailty index scores exhibited an inverse relationship with current CD4 count, up to 900 cells/μL. The CD4/CD8 ratio was inversely correlated with frailty index both below and above the cut-off of 900 CD4 cells/μL. Conclusions Frailty in PLWH is inversely associated with both immune-activation, depicted by CD4/CD8 ratio and immune-deficit depicted by CD4 count. The first association shows a linear shape while the second shows a hook-shape with a turning point at 900 cells. Above this cut off level CD4 do not represent a significant risk factor for frailty.…

Matteo Basilissi, Camilla Tincati, Esther Merlini, Giuseppe Ancona, Elisa Borghi, Francesca Borgo, Alessandra Barassi, Antonella d’Arminio Monforte, Giulia Marchetti

by Matteo Basilissi, Camilla Tincati, Esther Merlini, Giuseppe Ancona, Elisa Borghi, Francesca Borgo, Alessandra Barassi, Antonella d’Arminio Monforte, Giulia Marchetti HIV infection causes the progressive depletion of CD4+ T-lymphocytes and profound modifications of T-cell homeostasis, which persist despite virologically-suppressive treatment and have been linked to a worse clinical outcome. Enduring alterations of the gastrointestinal tract may represent the underlying pathogenic mechanisms of these phenomena. Twenty-six HIV-infected subjects were assessed over a 12-month period following the introduction of antiretroviral therapy. 18 uninfected individuals were enrolled as controls. Parameters of peripheral T-cell homeostasis (activation, maturation), gastrointestinal function (microbial translocation, gut inflammation, fecal microbiota composition) and mucosal immunity (CD4+CCR6+CD161+, CD4+CCR9+α4β7+, stem cell memory CD4+/CD8+ T-cells) were assessed. CD4+CCR6+CD161+ cells were depleted in HIV-infected untreated subjects and maintained significantly lower levels compared to controls, despite the introduction of effective antiviral treatment. The frequency of gut-homing CD4+CCR9+α4β7+ cells was also impaired in untreated infection and correlated with the HIV RNA load and CD4+HLADR+CD38+; during therapy, we observed a contraction of this pool in the peripheral blood and the loss of its correlation with antigenic exposure/immune activation. A partial correction of the balance between stem cell memory pools and T-cell homeostasis was registered following treatment. In HIV-infected subjects with moderate immune-suppression, antiretroviral therapy has a marginal impact on mucosal immune populations which feature distinctive kinetics in the periphery, possibly reflecting their diverse recruitment from the blood to the mucosa. The persistent defects in mucosal immunity may fuel peripheral T-cell abnormalities through diverse mechanisms, including the production of IL-17/IL-22, cellular permissiveness to infection and regulation of T-lymphocyte maturation.

Susan Jaffe

The unexpected announcement in the State of the Union address could set the start of a realistic agenda to end HIV/AIDS in the USA, provided funds are secured. Susan Jaffe reports.

Salazar-Vizcaya L, Kouyos R, Metzner K, et al.

AbstractBackgroundScale-up of direct-acting antiviral(DAA) therapy is expected to abate HCV incidence among HIV-positive men-who-have-sex-with-men(MSM). Treatment programs in neighbouring countries may influence each other’s outcomes through international transmission.We aimed at classifying HCV infections in HIV-positive MSM as either domestically or internationally acquired, and at estimating how this classification changed over time. MethodsHCV subtype 1a (the most frequent subtype among MSM) genomes from 99 persons enrolled in the Swiss-HIV-Cohort-Study(SHCS) and diagnosed with replicating HCV infections between 1999 and 2016, were sequenced. Sixty-six of these sequences were from MSM. We inferred maximum-likelihood phylogenetic-trees and time-trees containing a fragment of the NS5B region of these and other 374 circulating strains retrieved from national and international databases. We inferred transmission clusters from these trees and used the country composition of such clusters to attribute infections to domestic or international transmission. ResultsFifty to 80% of HCV transmissions were classified as domestic depending on the classification criterion. Between 2000 and 2007, the fraction attributable to domestic transmission was 54%[range:0%-75%]. It increased to 85%[range:67%-100%] between 2008 and 2016. ConclusionsInternational and domestic transmission have played major roles in the epidemic. While international transmission persists, local transmission has established as the main source of infections.

Abstract Background HIV-associated neurocognitive disorder (HAND) remains prevalent in the era of combination antiretroviral therapy (cART). The prevalence of HAND in Hong Kong is not known. Methods Between 2013 and 2015, 98 treatment-naïve HIV-1-infected individuals were referred to and screened by the AIDS Clinical Service, Queen Elizabeth Hospital with (1) the International HIV Dementia Scale (IHDS), a screening tool that targets moderate to severe HAND, (2) the Montreal Cognitive Assessment (MoCA), a frequently used cognitive screening test and (3) the Patient Health Questionnare-9 (PHQ-9), a 9-item questionnaire that evaluates depression symptoms. Within the study period, 57 of them completed the second set of IHDS and MoCA at 6 months after baseline assessment. Results Most participants were male (94%), with a median age of 31 years. At baseline, 38 (39%) and 25 (26%) of them scored below the IHDS (≤10) and MoCA (25/26) cut-offs respectively. Poor IHDS performers also scored lower on MoCA (p = 0.039) but the correlation between IHDS and MoCA performance was weak (r = 0.29, p = 0.004). Up to a third of poor IHDS performers (13/38) showed moderate depression (PHQ-9 > 9). In the multivariable analysis, a lower education level (p = 0.088), a history of prior psychiatric illness (p = 0.091) and the presence of moderate depression (p = 0.079) tended to be significantly associated with poor IHDS performance. At follow-up, 54 out of 57 were on cART, of which 46 (85%) had achieved viral suppression. Their blood CD4+ T-lymphocytes and IHDS scores were higher at follow-up compared to baseline values (both p 

Imagine a daily pill that prevents an unwanted consequence of sexual intercourse. Does it give users a "license for promiscuity"? Will its widespread availability lead to "sexual anarchy"? These questions were posed more than a half-century ago about oral contraceptive pills, which enabled……

Zhigang Zheng, Jinying Lin, ZhenZhen Lu, Jinming Su, Jianjun Li, Guangjie Tan, Chongxing Zhou, Wenkui Geng

by Zhigang Zheng, Jinying Lin, ZhenZhen Lu, Jinming Su, Jianjun Li, Guangjie Tan, Chongxing Zhou, Wenkui Geng To evaluate the mortality risk in the HIV-positive population, we conducted an observational cohort study involving routine data collection of HIV-positive patients who presented at HIV clinics and multiple treatment centers throughout Guangxi province, Southern China in 2011. The patients were screened for tuberculosis (TB) and tested for hepatitis B (HBV) and C (HCV) virus infections yearly. Following the registration, the cohort was followed up for a 60-month period till the end-point (December 31, 2015). Univariable and multivariable Cox proportional hazards regression models were used to analyze the hazard ratio (HR) and 95% confidence interval (95% CI) for mortality after adjusting for confounding factors stratified by patients’ sociodemographic and behavioral characteristics. HRs were compared within risk-factor levels. With the median follow-up of 3.7-person years for each individual, 5,398 (37.8%) (of 14,293 patients with HIV/AIDS) died; among whom, 78.4% were antiretroviral therapy (ART)-naïve; 43.6% presented late; and 12.2% and 3.3% of patients had Mycobacterium tuberculosis (MTB) and HBV and HCV co-infection, respectively. Of individuals with CD4 counts, those with CD4 count >350 cells/μL formed 14.0% of those who died. Furthermore, gender [multivariable HR (95% CI):1.94 (1.68–2.25)], Han ethnicity [2.15 (1.07–4.32)], illiteracy [3.28 (1.96–5.5)], elementary education [2.91 (1.8–4.72)], late presentation [2.89 (2.46–3.39)], and MTB co-infection [1.28 (1.10–1.49)] strongly increased the all-cause mortality risk of HIV-positive individuals. The HR for ART-based stratification was 0.08 (0.07–0.09); and for HBV and HCV co-infection, HR was 1.02 (0.86–1.21). The findings emphasized that accessibility to HIV testing among high-risk populations and screening for viral hepatitis and TB co-infection are important for the survival of HIV-positive individuals. Initiating early ART, even for individuals with higher CD4 counts, is advisable to help increase the prolongation of lives within the community.

Yee, K. L., Ouerdani, A., Claussen, A., de Greef, R., Wenning, L.

Doravirine is a novel non-nucleoside reverse transcriptase inhibitor for the treatment of human immunodeficiency virus 1 (HIV-1). A population pharmacokinetic (PK) model was developed for doravirine using pooled data from densely sampled Phase 1 trials and from sparsely sampled Phase 2b and Phase 3 trials evaluating doravirine administered orally as a single entity or as part of a fixed-dose combination of doravirine/lamivudine/tenofovir disoproxil fumarate. A one-compartment model with linear clearance from the central compartment adequately described the clinical PK of doravirine. While weight, age, and healthy versus HIV-1 status were identified as statistically significant covariates affecting doravirine PK, the magnitude of their effects was not clinically meaningful. Other intrinsic factors (gender, body mass index, race, ethnicity, and renal function) did not have statistically significant or clinically meaningful effects on doravirine PK. Individual exposure estimates for individuals in the Phase 2b and 3 trials obtained from the final model were used for subsequent exposure–response analyses for virologic response (proportion of individuals achieving

Feng, H.-P., Caro, L., Fandozzi, C., Chu, X., Guo, Z., Talaty, J., Panebianco, D., Dunnington, K., Du, L., Hanley, W. D., Fraser, I. P., Mitselos, A., Denef, J.-F., De Lepeleire, I., de Hoon, J. N., Vandermeulen, C., Marshall, W. L., Jumes, P., Huang, X., Martinho, M., Valesky, R., Butterton, J. R., Iwamoto, M., Yeh, W. W.

The combination of the hepatitis C virus (HCV) NS5A inhibitor elbasvir and NS3/4A protease inhibitor grazoprevir is a potent, once-daily therapy indicated for the treatment of chronic HCV infection in individuals coinfected with human immunodeficiency virus-1 (HIV). We explored the pharmacokinetic interactions of elbasvir and grazoprevir with ritonavir and ritonavir–boosted HIV protease inhibitors in three phase 1 trials. Drug–drug interaction trials in healthy participants were conducted to evaluate the effect of ritonavir on the pharmacokinetics of grazoprevir (N = 10) and the potential 2-way pharmacokinetic interaction of elbasvir (N = 30) or grazoprevir (N = 39) when coadministered with ritonavir-boosted atazanavir, lopinavir, or darunavir. Coadministration of ritonavir with grazoprevir increased grazoprevir exposure: geometric mean ratio (GMR) for grazoprevir + ritonavir versus grazoprevir alone area under the concentration-time curve from 0 to 24 h (AUC0-24) was 1.91 (90% confidence interval [CI]; 1.31 to 2.79). Grazoprevir exposure was markedly increased with coadministration of atazanavir/ritonavir, lopinavir/ritonavir, and darunavir/ritonavir, with GMRs for grazoprevir AUC0-24 of 10.58 (7.78 to 14.39), 12.86 (10.25 to 16.13), and 7.50 (5.92 to 9.51), respectively. Elbasvir exposure was increased with coadministration of atazanavir/ritonavir, lopinavir/ritonavir, and darunavir/ritonavir, with GMRs for elbasvir AUC0-24 of 4.76 (4.07 to 5.56), 3.71 (3.05 to 4.53), and 1.66 (1.35 to 2.05), respectively. Grazoprevir and elbasvir had little effect on atazanavir, lopinavir, and darunavir pharmacokinetics. Coadministration of elbasvir/grazoprevir with atazanavir/ritonavir, lopinavir/ritonavir, or darunavir/ritonavir is contraindicated owing to an increase in grazoprevir exposure. As such, HIV treatment regimens without HIV protease inhibitors should be considered in HCV/HIV-coinfected individuals who are treated with elbasvir/grazoprevir.…

Abstract Background Access to qualitative HIV PCRs for early infant diagnosis (EID) is restricted in resource-limited settings due to cost. We hypothesised that pooling of dried blood spots (DBS), defined as combining multiple patient samples in a single test with subsequent individual testing of positive pools, would be cost saving while retaining clinical accuracy compared to individual patient testing. Methods Cost savings: A model was developed to simulate reagent and consumable cost saving of pooled compared to individual sample testing. Daily sample/result data of a public health laboratory in South Africa were used to illustrate outputs from the model. Samples were randomly allocated to pools and the process was repeated 1000 times to measure variation in estimates due to this stochasticity. Clinical accuracy: 1170 patient samples were tested using the Roche CAP/CTM Qual assay in pools of five 50 μl DBS. Negative pools comprised DBS previously tested in single reactions; positive pools included 1 positive sample. Results Pooling would have saved 64% of laboratory costs in 2015. The model is published as an R-based web tool, into which the user enters sample/positivity estimates and workflow management parameters to obtain cost saving estimates at an optimal pool size. Sensitivity of pooled testing was 98.8% overall; 100% for strongly reactive pools. One pool tested false positive which would not impact clinical specificity as individual patient testing is performed prior to reporting. Conclusions Pooled PCR testing for EID remains accurate and dramatically reduces costs in settings with moderate to low prevalence rates and sufficient sample numbers.…

Abstract Background Empirical treatment of tuberculosis (TB) may be necessary in patients with negative or no Xpert MTB/RIF results. In a context with access to Xpert, we assessed mortality in the 6 months after the initial TB consultation among HIV-positive and HIV-negative patients who received empirical TB treatment or TB treatment based on bacteriological confirmation and we compared it with the mortality among those who did not receive TB treatment. Methods This prospective cohort study included consecutively adult patients with signs and symptoms of TB attending an outpatient TB clinic in Western Kenya. At the first consultation, patients received a clinical exam and chest X-ray. Sputum was collected for microscopy, Xpert and Mycobacterium tuberculosis complex (MTB) culture. Patients not started on TB treatment were reassessed after 5 days. All patients bacteriologically confirmed (positive Xpert or culture) received TB treatment. Empirical treatment was defined as a decision to start TB treatment without bacteriological confirmation. Patients were reassessed after 6 months. Results Of 606 patients included, 344/606 (56.8%) were women. Median age was 35 years [Interquartile Range (IQR):27–47] and 398/594 (67.0%) were HIV-positive. In total, 196/606 (32.3%) patients were Xpert- or culture-positive and 331/606 (54.6%) started TB treatment. Overall, 100/398 (25.1%) HIV-positive and 31/196 (15.8%) HIV-negative patients received empirical treatment. Mortality in the 6 months following the first consultation was 1.6 and 0.8/100 patient-months among HIV-positive and HIV-negative patients respectively. In the multivariate analyses, TB treatment - whether empirical or based on bacteriological confirmation- was not associated with increased mortality among HIV-positive patients (aHR:2.51, 95%CI:0.79–7.90 and aHR:1.25, 95%CI:0.37–4.21 respectively). However, HIV-negative patients who received empirical treatment had a higher risk of mortality (aHR:4.85, 95%CI:1.08–21.67) compared to those not started on treatment. HIV-negative patients treated for TB based on bacteriological confirmation did not have a different risk of mortality (aHR:0.77, 95%CI:0.08–7.41). Conclusions Our findings suggest that in a context with access to Xpert, clinicians should continue using empirical TB treatment in HIV-positive patients with signs and symptoms of TB and negative Xpert results. However, differential diagnoses other than TB should be actively sought before initiating empirical TB treatment, particularly in HIV-negative patients.…