Early HAART Initiation May Not Reduce Actual Reproduction Number and Prevalence of MSM Infection: Perspectives from Coupled within- and between-Host Modelling Studies of Chinese MSM Populations

Having a thorough understanding of the infectivity of HIV, time of initiating treatment and emergence of drug resistant virus variants is crucial in mitigating HIV infection. There are many challenges to evaluating the long-term effect of the Highly Active Antiretroviral Therapy (HAART) on disease transmission at the population level. We proposed an individual based model by coupling within-host dynamics and between-host dynamics and conduct stochastic simulation in the group of men who have sex with men (MSM). The mean actual reproduction number is estimated to be 3.6320 (95% confidence interval: [3.46, 3.80]) for MSM group without treatment. Stochastic simulations show that given relatively high (low) level of drug efficacy after emergence of drug resistant variants, early initiation of treatment leads to a less (greater) actual reproduction number, lower (higher) prevalence and less (more) incidences, compared to late initiation of treatment. This implies early initiation of HAART may not always lower the actual reproduction number and prevalence of infection, depending on the level of treatment efficacy after emergence of drug resistant virus variants, frequency of high-risk behaviors and etc. This finding strongly suggests early initiation of HAART should be implemented with great care especially in the settings where the effective drugs are limited. Coupling within-host dynamics with between-host dynamics can provide critical information about impact of HAART on disease transmission and thus help to assist treatment strategy design and HIV/AIDS prevention and control.

Below:  Time series of susceptible and infected individuals

Below:  Histogram of the number of secondary cases induced by a single infected individual in a simulation

Full article at:   http://goo.gl/MHsHUH

By:  Xiaodan Sun,¹ Yanni Xiao,^1,* Sanyi Tang,² Zhihang Peng,³ Jianhong Wu,⁴ and Ning Wang^5,*

Gui-Quan Sun, Editor

¹Department of Applied Mathematics, Xi’an Jiaotong University, Xi’an, Shaanxi, China

²College of Mathematics and Information Science, Shaanxi Normal University, Xi’an, Shaanxi, China

³School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China

⁴Laboratory for Industrial and Applied Mathematics, Centre for Disease Modelling, York Institute for Health Research, York University, Toronto, ON, Canada

⁵National Center for AIDS/STD Prevention and Control, Chinese Center for Disease Control and Prevention, Beijing, China

Shanxi University, CHINA

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Missed Opportunities of Inclusion of HIV-Infected Children to Initiate Antiretroviral Treatment Before the Age of Two in West Africa, 2011 to 2013

INTRODUCTION:

The World Health Organization (WHO) 2010 guidelines recommended to treat all HIV-infected children less than two years of age. We described the inclusion process and its correlates of HIV-infected children initiated on early antiretroviral therapy (EART) at less than two years of age in Abidjan, Côte d'Ivoire, and Ouagadougou, Burkina Faso.

METHODS:

All children with HIV-1 infection confirmed with a DNA PCR test of a blood sample, aged less than two years, living at a distance less than two hours from the centres and whose parents (or mother if she was the only legal guardian or the legal caregiver if parents were not alive) agreed to participate in the MONOD ANRS 12206 project were included in a cohort to receive EART based on lopinavir/r. We used logistic regression to identify correlates of inclusion.

RESULTS:

Among the 217 children screened and referred to the MONOD centres, 161 (74%) were included and initiated on EART. The main reasons of non-inclusion were fear of father's refusal (48%), mortality (24%), false-positive HIV infection test (16%) and other ineligibility reasons (12%). Having previously disclosed the child's and mother's HIV status to the father (adjusted odds ratio (aOR): 3.20; 95% confidence interval (95% CI): 1.55 to 6.69) and being older than 12 months (aOR: 2.05; 95% CI: 1.02 to 4.12) were correlates of EART initiation. At EART initiation, the median age was 13.5 months, 70% had reached WHO Stage 3/4 and 57% had a severe immune deficiency.

CONCLUSIONS:

Fear of stigmatization by the father and early competing mortality were the major reasons for missed opportunities of EART initiation. There is an urgent need to involve fathers in the care of their HIV-exposed children and to promote early infant diagnosis to improve their future access to EART and survival.

Below:  Cohort profile ofthe ANRS 12206 MONOD study, Abidjan, Ouagadougou, May 2011 to February 2013

Full article at:   http://goo.gl/ILmMTv

By:  Dahourou DL1,2,3, Amorissani-Folquet M4,5, Coulibaly M1,2, Avit-Edi D4, Meda N1,6,7, Timite-Konan M8, Arendt V9, Ye D7,10, Amani-Bosse C4, Salamon R2,Lepage P11, Leroy V12; Monod Anrs 12206 Study Group.

• 1MONOD Project, ANRS 12206, Centre de Recherche Internationale pour la Santé, Ouagadougou, Burkina Faso.
• 2Inserm, U1219, Institut de Santé Publique, Epidémiologie et Développement, University of Bordeaux, Bordeaux, France.
• 3Centre Muraz, Bobo-Dioulasso, Burkina Faso; ddahourou@gmail.com; ddahourou@gmail.com.
• 4PACCI Programme, Site ANRS, Projet Monod, Abidjan, Côte d'Ivoire.
• 5Pediatric Department, CHU of Cocody, Abidjan, Côte d'Ivoire.
• 6Centre Muraz, Bobo-Dioulasso, Burkina Faso.
• 7University of Ouagadougou, Ouagadougou, Burkina Faso.
• 8Pediatric Department, Centre Hospitalier Universitaire (CHU) de Yopougon, Abidjan, Côte d'Ivoire.
• 9Department of Infection and Immunity, Luxembourg Institute of Health, Luxembourg.
• 10Pediatric Department, CHU Charles de Gaulle, Ouagadougou, Burkina Faso.
• 11Pediatric Department, Hôpital Universitaire des Enfants de la Reine Fabiola, Université Libre de Bruxelles, Brussels, Belgium.
• 12Inserm, U1027, Université Toulouse, Toulouse, France. 
• J Int AIDS Soc. 2016 Mar 23;19(1):20601. doi: 10.7448/IAS.19.1.20601.

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Diagnosis of HIV-Associated Oral Lesions in Relation to Early versus Delayed Antiretroviral Therapy

Oral mucosal lesions that are associated with HIV infection can play an important role in guiding the decision to initiate antiretroviral therapy (ART). The incidence of these lesions relative to the timing of ART initiation has not been well characterized. 

A randomized controlled clinical trial was conducted at the GHESKIO Center in Port-au-Prince, Haiti between 2004 and 2009. 816 HIV-infected ART-naïve participants with CD4 T cell counts between 200 and 350 cells/mm³ were randomized to either immediate ART initiation (early group; N = 408), or initiation when CD4 T cell count was less than or equal 200 cells/mm³ or with the development of an AIDS-defining condition (delayed group; N = 408). Every 3 months, all participants underwent an oral examination. 

The incidence of oral lesions was 4.10 in the early group and 17.85 in the delayed group (p-value <0.01). In comparison to the early group, there was a significantly higher incidence of candidiasis, hairy leukoplakia, herpes labialis, and recurrent herpes simplex in the delayed group. The incidence of oral warts in delayed group was 0.97 before therapy and 4.27 post-ART initiation (p-value <0.01). In the delayed group the incidence of oral warts post-ART initiation was significantly higher than that seen in the early group (4.27 versus 1.09; p-value <0.01). 

The incidence of oral warts increased after ART was initiated, and relative to the early group there was a four-fold increase in oral warts if ART was initiated following an AIDS diagnosis. Based upon our findings, candidiasis, hairy leukoplakia, herpes labialis, and recurrent herpes simplex indicate immune suppression and the need to start ART. In contrast, oral warts are a sign of immune reconstitution following ART initiation.

Below:

Full article at:   http://goo.gl/W2pd06

By:   

Ashita S. Batavia, Jean William Pape, Daniel W. Fitzgerald 
Weill Cornell Medical Center, New York, New York, United States of America

Rode Secours, Marc Antoine Jean Juste, Patrice Severe, Jean William Pape 

Groupe Haitien d’Etude du Sarcome de Kaposi et des Infections Opportunistes (GHESKIO), Port-au-Prince, Haiti

Patrice Espinosa

University of California San Francisco School of Dentistry, San Francisco, California, United States of America

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Early ART Results in Greater Immune Reconstitution Benefits in HIV-Infected Infants: Working with Data Missingness in a Longitudinal Dataset

Background

Early initiation of anti-retroviral treatment (ART) decreases mortality as compared to deferred treatment, but whether it preserves immune cells from early loss or promotes their recovery remains undefined. Determination of complex immunological endpoints in infants is often marred by missing data due to missed visits and/or inadequate sampling. Specialized methods are required to address missingness and facilitate data analysis.

Methods

We characterized the changes in cellular and humoral immune parameters over the first year of life in 66 HIV-infected infants (0–1 year of age) enrolled in the CHER study starting therapy within 12 weeks of birth (n = 42) or upon disease progression (n = 24). A convenience cohort of 23 uninfected infants aged 0–6 months born to mothers with HIV-1 infection was used as controls. Flow cytometry and ELISA were used to evaluate changes in natural killer (NK) cells, plasmacytoid dendritic cells (pDC), and CD4⁺ or CD8⁺ T-cell frequencies. Data missingness was assessed using Little's test. Complete datasets for analysis were created using Multiple Imputation (MI) or Bayesian modeling and multivariate analysis was conducted on the imputed datasets.

Results

HIV-1-infected infants had greater frequency of CD4⁺ T cells with naïve phenotype, as well as higher serum IL-7 levels than HIV exposed/uninfected infants. The elevated data missingness was completely at random, allowing the use of both MI and Bayesian modeling. Both methods indicate that early ART initiation results in higher CD4⁺ T cell frequency, lower expression of CD95 in CD8⁺ T cell, and preservation of naïve T cell subsets. In contrast, innate immune effectors appeared to be similar independently of the timing of ART initiation.

Conclusions

Early ART initiation in infants with perinatal HIV infection reduces immune activation and preserves an early expansion of naïve T-cells with undiminished innate cell numbers, giving greater immune reconstitution than achieved with deferred ART. Both statistical approaches concurred in this finding.

Below:  Statistical analysis summary.

The tree represents the statistical analyses applied in the order in which they were performed. Distribution assumptions are indicated. Statistical packages are listed; where not specified, tests were conducted using R.

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By:   

Livio Azzoni, Emmanouil Papasavvas, Luis J. Montaner

The Wistar Institute, Philadelphia, Pennsylvania, United States of America

Russell Barbour

Biostatistics Department, Yale School of Public Health, New Haven, Connecticut, United States of America

Deborah K. Glencross, Wendy S. Stevens

Department of Molecular Medicine and Hematology, University of the Witwatersrand and National Health Laboratory Service, Johannesburg, South Africa

Mark F. Cotton

Children’s Infectious Diseases Clinical Research Unit, Department of Paediatrics and Child Health, Stellenbosch University, Cape Town, South Africa

Avy Violari

Perinatal HIV Research Unit, University of the Witwatersrand, Johannesburg, South Africa

  

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Economic and Epidemiological Impact of Early Antiretroviral Therapy Initiation in India

Recent WHO guidance advocates for early antiretroviral therapy (ART) initiation at higher CD4 counts to improve survival and reduce HIV transmission. We sought to quantify how the cost-effectiveness and epidemiological impact of early ART strategies in India are affected by attrition throughout the HIV care continuum.

We constructed a dynamic compartmental model replicating HIV transmission, disease progression and health system engagement among Indian adults. Our model of the Indian HIV epidemic compared implementation of early ART initiation (i.e. initiation above CD4 ≥350 cells/mm³) with delayed initiation at CD4 ≤350 cells/mm³; primary outcomes were incident cases, deaths, quality-adjusted-life-years (QALYs) and costs over 20 years. We assessed how costs and effects of early ART initiation were impacted by suboptimal engagement at each stage in the HIV care continuum.

Assuming “idealistic” engagement in HIV care, early ART initiation is highly cost-effective ($442/QALY-gained) compared to delayed initiation at CD4 ≤350 cells/mm³ and could reduce new HIV infections to <15,000 per year within 20 years. However, when accounting for realistic gaps in care, early ART initiation loses nearly half of potential epidemiological benefits and is less cost-effective ($530/QALY-gained). We project 1,285,000 new HIV infections and 973,000 AIDS-related deaths with deferred ART initiation with current levels of care-engagement in India. Early ART initiation in this continuum resulted in 1,050,000 new HIV infections and 883,000 AIDS-related deaths, or 18% and 9% reductions (respectively), compared to current guidelines. Strengthening HIV screening increases benefits of earlier treatment modestly (1,001,000 new infections; 22% reduction), while improving retention in care has a larger modulatory impact (676,000 new infections; 47% reduction).

Early ART initiation is highly cost-effective in India but only has modest epidemiological benefits at current levels of care-engagement. Improved retention in care is needed to realize the full potential of earlier treatment.

Below: Model schematic of HIV transmission, disease progression and engagement in HIV care continuum. The Indian population is divided into compartments stratified by HIV serostatus, stage of HIV infection, and engagement with HIV care continuum. Each compartment is further stratified by gender and risk group (heterosexual, MSM, PWID and high-risk individuals [e.g. FSW]). The model incorporates HIV transmission through sexual intercourse and injection drug use. Arrows represent rates of flow between compartments; values are shown in Table 1. +, HIV-infected individuals; −, HIV-uninfected individuals; ART, HIV-infected individuals on first- or second-line antiretroviral therapy. At any point in the care continuum, PLWH can progress through stages of HIV from acute HIV to AIDS if not on ART (shown in inset). Individuals experience immunological recovery if on ART and virologically suppressed.

Below:  Sensitivity analysis for incremental cost-effectiveness ratio comparing early ART initiation with current practices of ART initiation (CD4 ≤350 cells/mm3) within the context of a “realistic” continuum of care. Solid vertical line represents base ICER ($530 per QALY-gained). Blue bars indicate low values of parameter range; red bars indicate high values of parameter range.

Below: Epidemiological impact of delayed ART initiation (CD4 ≤350 cells/mm3), early ART initiation and early ART initiation in combination with various interventions in the HIV care continuum. “Delayed ART initiation” represents current practice and incorporates the current HIV care continuum with suboptimal screening, linkage and retention in care. “Early ART initiation” represents increased rates of ART initiation at CD4 >350 cells/mm3, but assumes continuation of current levels of care-engagement. “Expanded screening” involves annual screening of high-risk groups, with 95% linkage to care. “Improved detection of virological failure” involves detecting ART failure and modifying treatment promptly (within six months of virological failure). “Improved retention in care” is defined as optimal retention of PLWH in care (annual disengagement rate of 2.5% and reengagement within one year of disengagement).

Full article at: http://goo.gl/AjmfmD

By: Manoj V Maddali,1 David W Dowdy,2 Amita Gupta,1,3 and Maunank Shah§,1

¹Division of Infectious Diseases, Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD, USA

²Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA

³Department of International Health, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA

  

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