Longitudinal evolution of the HIV effective reproduction number following sequential expansion of treatment as prevention and pre-exposure prophylaxis in British Columbia, Canada: a population-level programme evaluation.

BACKGROUND: Treatment as prevention and pre-exposure prophylaxis (PrEP) are key strategies in the control of HIV/AIDS. We aimed to characterise the longitudinal effects of antiretroviral therapy (ART), followed by treatment as prevention and the addition of PrEP, on the HIV effective reproduction number (Re) in British Columbia, Canada. METHODS: This population-level programme evaluation used data from the Drug Treatment Program of the British Columbia Centre for Excellence in HIV/AIDS (Vancouver, British Columbia, Canada). We also used estimates of HIV incidence and prevalence from the Public Health Agency of Canada, data on the number of new HIV diagnoses per year from the British Columbia Centre for Disease Control, and mortality data from the British Columbia Vital Statistics Agency. Data were obtained from 1985 until 2022, depending on the database source. Outcomes were the annual HIV prevalence, HIV incidence, number of new HIV diagnoses, number of people living with HIV on ART, HIV/AIDS-related and all-cause mortality rates, the HIV incidence-to-all-cause-mortality ratio, and Re. We calculated the modified effective reproduction number (Rme) using two thresholds of viral suppression and compared these values with Re. FINDINGS: We found a 95% decline in HIV/AIDS-related mortality and a 91% decrease in HIV incidence over the study period. The Re progressively declined from 1996 to 2022; however, from 1996 to 2017, Rme remained stable (>1) when calculated for people living with HIV with unsuppressed viraemia, suggesting that treatment as prevention reduces HIV incidence by decreasing the pool of individuals who are potentially able to transmit the virus. From 2018 to 2022, a decline in the estimated Re and Rme (<1) was observed regardless of whether we considered all people living with HIV or only those who were virologically unsuppressed. This finding suggests that PrEP decreases HIV incidence by reducing the number of susceptible individuals in the community, independently of viral suppression. INTERPRETATION: Our results show the synergy between generalised treatment as prevention and targeted PrEP in terms of decreasing HIV incidence. These findings support the incorporation of longitudinal monitoring of Re at a programmatic level to identify opportunities for the optimisation of treatment-as-prevention and PrEP programmes. FUNDING: British Columbia Ministry of Health, Health Canada, Public Health Agency of Canada, Vancouver Coastal Health, Vancouver General Hospital Foundation, Genome British Columbia, and the Canadian Institutes of Health Research.

Update on treatment as prevention of HIV illness, death, and transmission: sub-Saharan Africa HIV financing and progress towards the 95-95-95 target.

PURPOSE OF REVIEW: After over 40 years, the HIV pandemic is amongst the deadliest in history - 100% fatal without treatment, HIV has infected over 84 million people, and has caused over 40 million deaths. Global HIV spending between 2000 and 2015 totaled over a half trillion dollars. Delays in harnessing scientific advances, including 'test and treat' and treatment as prevention of illness, death, and transmission (TasP) provide a cautionary tale applicable to other pandemics. Resource allocation has also been problematic with many highest burden countries spending less than 50% on care and treatment. RECENT FINDINGS: Between 2002 and 2021, over $94 billion was budgeted for HIV in 40 sub-Saharan African countries, with 19 countries over $1 billion. In 2021, 8.1 million (32%) People Living with HIV (PLHIV) are still not on treatment; viral suppression data, the most important programme success indicator, is unavailable for 50% of countries. Of 19 countries with at least one billion dollars budgeted, seven have below 80% ART coverage, leaving 3.5 million (29%) of PLHIV off treatment and vulnerable to illness, death, and transmitting the virus to partners and children. SUMMARY: With additional funding and improved efficiency, achieving the 95-95-95 target to diagnose 95% of all HIV-positive individuals, provide antiretroviral therapy (ART) for 95% of those diagnosed and achieve viral suppression for 95% of those treated by 2030 is feasible and the humane pathway towards ending the HIV pandemic.

Deep Convolutional Neural Networks With Ensemble Learning and Generative Adversarial Networks for Alzheimer's Disease Image Data Classification.

Recent advancements in deep learning (DL) have made possible new methodologies for analyzing massive datasets with intriguing implications in healthcare. Convolutional neural networks (CNN), which have proven to be successful supervised algorithms for classifying imaging data, are of particular interest in the neuroscience community for their utility in the classification of Alzheimer's disease (AD). AD is the leading cause of dementia in the aging population. There remains a critical unmet need for early detection of AD pathogenesis based on non-invasive neuroimaging techniques, such as magnetic resonance imaging (MRI) and positron emission tomography (PET). In this comprehensive review, we explore potential interdisciplinary approaches for early detection and provide insight into recent advances on AD classification using 3D CNN architectures for multi-modal PET/MRI data. We also consider the application of generative adversarial networks (GANs) to overcome pitfalls associated with limited data. Finally, we discuss increasing the robustness of CNNs by combining them with ensemble learning (EL).

A deleterious mutation in the ALMS1 gene in a naturally occurring model of hypertrophic cardiomyopathy in the Sphynx cat.

BACKGROUND: Familial hypertrophic cardiomyopathy is a common inherited cardiovascular disorder in people. Many causal mutations have been identified, but about 40% of cases do not have a known causative mutation. Mutations in the ALMS1 gene are associated with the development of Alstrom syndrome, a multisystem familial disease that can include cardiomyopathy (dilated, restrictive). Hypertrophic cardiomyopathy has not been described. The ALMS1 gene is a large gene that encodes for a ubiquitously expressed protein. The function of the protein is not well understood although it is believed to be associated with energy metabolism and homeostasis, cell differentiation and cell cycle control. The ALMS1 protein has also been shown to be involved in the regulation of cell cycle proliferation in perinatal cardiomyocytes. Although cardiomyocyte cell division and replication in mammals generally declines soon after birth, inhibition of ALMS1 expression in mice lead to increased cardiomyocyte proliferation, and deficiency of Alstrom protein has been suggested to impair post-natal cardiomyocyte cell cycle arrest. Here we describe the association of familial hypertrophic cardiomyopathy in Sphynx cats with a novel ALMS1 mutation. RESULTS: A G/C variant was identified in exon 12 (human exon 13) of the ALMS1 gene in affected cats and was positively associated with the presence of hypertrophic cardiomyopathy in the feline population (p < 0.0001). The variant was predicted to change a highly conserved nonpolar Glycine to a positively charged Arginine. This was predicted to be a deleterious change by three in silico programs. Protein prediction programs indicated that the variant changed the protein structure in this region from a coil to a helix. Light microscopy findings included myofiber disarray with interstitial fibrosis with significantly more nuclear proliferative activity in the affected cats than controls (p < 0.0001). CONCLUSION: This study demonstrates a novel form of cardiomyopathy associated with ALMS1 in the cat. Familial hypertrophic cardiomyopathy is a disease of genetic heterogeneity; many of the known causative genes encoding for sarcomeric proteins. Our findings suggest that variants in genes involved with cardiac development and cell regulation, like the ALMS1 gene, may deserve further consideration for association with familial hypertrophic cardiomyopathy.

Isoniazid preventive therapy plus antiretroviral therapy for the prevention of tuberculosis: a systematic review and meta-analysis of individual participant data.

BACKGROUND: Isoniazid preventive therapy prevents active tuberculosis in people with HIV, but previous studies have found no evidence of benefit in people with HIV who had a negative tuberculin skin test, and a non-significant effect on mortality. We aimed to estimate the effect of isoniazid preventive therapy given with antiretroviral therapy (ART) for the prevention of tuberculosis and death among people with HIV across population subgroups. METHODS: We searched PubMed, Embase, the Cochrane database, and conference abstracts from database inception to Jan 15, 2019, to identify potentially eligible randomised trials. Eligible studies were trials that enrolled HIV-positive adults (age ≥15 years) taking ART who were randomly assigned to either daily isoniazid preventive therapy plus ART or ART alone and followed up longitudinally for outcomes of incident tuberculosis and mortality. We approached all authors of included trials and requested individual participant data: coprimary outcomes were relative risk of incident tuberculosis and all-cause mortality. We did a single-stage meta-analysis of individual participant data using stratified Cox-proportional hazards models. We did prespecified subgroup analyses by sex, CD4 cell count, and evidence of immune sensitisation to tuberculosis (indicated by tuberculin skin test or interferon-γ release assays [IGRAs]). We also assessed the relative risk of liver injury in an additional prespecified analysis. This study is registered with PROSPERO, CRD42019121400. FINDINGS: Of 838 records, we included three trials with data for 2611 participants and 8584·8 person-years of follow-up for the outcome of incident tuberculosis, and a subset of 2362 participants with 8631·6 person-years of follow-up for the coprimary outcome of all-cause mortality. Risk for tuberculosis was lower in participants given isoniazid preventive therapy and ART than participants given ART alone (hazard ratio [HR] 0·68, 95% CI 0·49-0·95, p=0·02). Risk of all-cause mortality was lower in participants given isoniazid preventive therapy and ART than participants given ART alone, but this difference was non-significant (HR 0·69, 95% CI 0·43-1·10, p=0·12). Participants with baseline CD4 counts of less than 500 cells per µL had increased risk of tuberculosis, but there was no significant difference in the benefit of isoniazid preventive therapy with ART by sex, baseline CD4 count, or results of tuberculin skin test or IGRAs. 65 (2·5%) of 2611 participants had raised alanine aminotransferase, but data were insufficient to calculate an HR. INTERPRETATION: Isoniazid preventive therapy with ART prevents tuberculosis across demographic and HIV-specific and tuberculosis-specific subgroups, which supports efforts to further increase use of isoniazid preventive therapy with ART broadly among people living with HIV. FUNDING: National Institutes of Health and National Institute of Allergy and Infectious Diseases.

The scale and dynamics of COVID-19 epidemics across Europe.

The number of COVID-19 deaths reported from European countries has varied more than 100-fold. In terms of coronavirus transmission, the relatively low death rates in some countries could be due to low intrinsic (e.g. low population density) or imposed contact rates (e.g. non-pharmaceutical interventions) among individuals, or because fewer people were exposed or susceptible to infection (e.g. smaller populations). Here, we develop a flexible empirical model (skew-logistic) to distinguish among these possibilities. We find that countries reporting fewer deaths did not generally have intrinsically lower rates of transmission and epidemic growth, and flatter epidemic curves. Rather, countries with fewer deaths locked down earlier, had shorter epidemics that peaked sooner and smaller populations. Consequently, as lockdowns were eased, we expected, and duly observed, a resurgence of COVID-19 across Europe.

Treatment as prevention trials and ending AIDS: what do we know, when did we know it, and what do we do now?

PURPOSE OF REVIEW: HIV remains a significant global public health problem. Treatment as prevention of HIV and TB illness, death and transmission was proposed in 2006 as a means to end the HIV epidemic. We review the results of the treatment as prevention trials. RECENT FINDINGS: Some of the trials struggled with delivering services, however, most demonstrate that it is feasible to achieve at least the 90-90-90 target by scaling access to test-and-treat at the community level and by extension at the district or national level. Patients, if offered, will start and stay on immediate treatment even without symptoms. Community-based multidisease prevention campaigns have significant impact, especially for hard-to-reach men. Earlier treatment impacts illness and death including from HIV-associated tuberculosis. Test-and treat impacts transmission, however, some of the community cluster trials had difficulty showing an impact on incidence. Most trials showed incidence reduction in line with the level of viral suppression and suggest that achieving 95-95-95 is an important means to accelerate the end of the epidemic. SUMMARY: TasP trial findings, HIV and TB program data, and PHIA study trend data will likely confirm that reaching at least 95-95-95 is both feasible and a key element in ending the epidemic.

HIV control strategies for sex worker-client contact networks.

Controlling the spread of HIV among hidden, high-risk populations such as survival sex workers and their clients is becoming increasingly important in the ongoing fight against HIV/AIDS. Several sociological and structural factors render general control strategies ineffective in these settings; instead, focused prevention, testing and treatment strategies which take into account the nature of survival sex work are required. Using a dynamic bipartite network model of sexual contacts, we investigate the optimal distribution of treatment and preventative resources among sex workers and their clients; specifically, we consider control strategies that randomly allocate antiretroviral therapy and pre-exposure prophylaxis within each subpopulation separately. Motivated by historical data from a South African mining community, three main asymmetries between sex workers and clients are considered in our model: relative population sizes, migration rates and partner distributions. We find that preventative interventions targeted at female sex workers are the lowest cost strategies for reducing HIV prevalence, since the sex workers form a smaller population and have, on average, more sexual contacts. However, the high migration rate among survival sex workers limits the extent to which prevalence can be reduced using this strategy. To achieve a further reduction in HIV prevalence, testing and treatment in the client population cannot be ignored.

Tuberculosis decline in populations affected by HIV: a retrospective study of 12 countries in the WHO African Region.

OBJECTIVE: To investigate which of the World Health Organization recommended methods for tuberculosis control have had the greatest effect on case incidence in 12 countries in the World Health Organization (WHO) African Region that carry high burdens of tuberculosis linked to human immunodeficiency virus (HIV) infection. METHODS: We obtained epidemiological surveillance, survey and treatment data on HIV and tuberculosis for the years 2003 to 2016. We used statistical models to examine the effects of antiretroviral therapy (ART) and isoniazid preventive therapy in reducing the incidence of tuberculosis among people living with HIV. We also investigated the role of tuberculosis case detection and treatment in preventing Mycobacterium tuberculosis transmission and consequently reducing tuberculosis incidence. FINDINGS: Between 2003 and 2016, ART provision was associated with the decline of tuberculosis in each country, and with differences in tuberculosis decline between countries. Inferring that ART was a cause of tuberculosis decline, ART prevented 1.88 million (95% confidence interval, CI: 1.65 to 2.11) tuberculosis cases in people living with HIV, or 15.7% (95% CI: 13.8 to 17.6) of the 11.96 million HIV-positive tuberculosis cases expected. Population coverage of isoniazid preventive therapy was too low (average 1.0% of persons eligible) to have a major effect on tuberculosis decline, and improvements in tuberculosis detection and treatment were either weakly associated or not significantly associated with tuberculosis decline. CONCLUSION: ART provision is associated with tuberculosis decline in these 12 countries. ART should remain central to tuberculosis control where rates of tuberculosis-HIV coinfection are high, but renewed efforts to treat tuberculosis are needed.

Epidemiological metrics and benchmarks for a transition in the HIV epidemic.

Peter Godfrey-Faussett and colleagues present six epidemiological metrics for tracking progress in reducing the public health threat of HIV.

High risk exposure to HIV among sexually active individuals who tested negative on rapid HIV Tests in the Tshwane District of South Africa-The importance of behavioural prevention measures.

OBJECTIVE: To assess the prevalence of HIV risk behaviour among sexually active HIV sero-negative individuals in the Tshwane district of South Africa (SA). METHODS: Demographic and HIV risk behaviour data were collected on a questionnaire from participants of a cross-sectional study that screened for early HIV infection using pooled nucleic acid amplification testing (NAAT). The study enrolled individuals who tested negative on rapid HIV tests performed at five HIV counseling and testing (HCT) clinics, which included four antenatal clinics and one general HCT clinic. RESULTS: The study enrolled 9547 predominantly black participants (96.6%) with a median age of 27 years (interquartile range [IQR]: 23-31). There were 1661 non-pregnant and 7886 pregnant participants largely enrolled from the general and antenatal HCT clinics, respectively. NAAT detected HIV infection in 61 participants (0.6%; 95% confidence interval [CI]: 0.4-0.8) in the whole study. A high proportion of study participants, 62.8% and 63.0%, were unaware of their partner's HIV status; and also had high prevalence, 88.5% and 99.5%, of recent unprotected sex in the general and pregnant population, respectively. Consistent use of condoms was associated with protection against HIV infection in the general population. Trends of higher odds for HIV infection were observed with most demographic and HIV risk factors at univariate analysis, however, multivariate analysis did not show statistical significance for almost all these factors. A significantly lower risk of HIV infection was observed in circumcised men (p <0.001). CONCLUSIONS: These data show that a large segment of sexually active people in the Tshwane district of SA have high risk exposure to HIV. The detection of newly diagnosed HIV infections in all study clinics reflects a wide distribution of individuals who are capable of sustaining HIV transmission in the setting where HIV risk behaviour is highly prevalent. A questionnaire that captures HIV risk behaviour would be useful during HIV counselling and testing to ensure that there is a systematic way of identifying HIV risk factors and that counselling is optimised for each individual. HIV risk behaviour surveillance could be used to inform relevant HIV prevention interventions that could be implemented at a community or population level.

Dynamics and control of infections on social networks of population types.

Random mixing in host populations has been a convenient simplifying assumption in the study of epidemics, but neglects important differences in contact rates within and between population groups. For HIV/AIDS, the assumption of random mixing is inappropriate for epidemics that are concentrated in groups of people at high risk, including female sex workers (FSW) and their male clients (MCF), injecting drug users (IDU) and men who have sex with men (MSM). To find out who transmits infection to whom and how that affects the spread and containment of infection remains a major empirical challenge in the epidemiology of HIV/AIDS. Here we develop a technique, based on the routine sampling of infection in linked population groups (a social network of population types), which shows how an HIV/AIDS epidemic in Can Tho Province of Vietnam began in FSW, was propagated mainly by IDU, and ultimately generated most cases among the female partners of MCF (FPM). Calculation of the case reproduction numbers within and between groups, and for the whole network, provides insights into control that cannot be deduced simply from observations on the prevalence of infection. Specifically, the per capita rate of HIV transmission was highest from FSW to MCF, and most HIV infections occurred in FPM, but the number of infections in the whole network is best reduced by interrupting transmission to and from IDU. This analysis can be used to guide HIV/AIDS interventions using needle and syringe exchange, condom distribution and antiretroviral therapy. The method requires only routine data and could be applied to infections in other populations.

Progress and prospects for the control of HIV and tuberculosis in South Africa: a dynamical modelling study.

BACKGROUND: In September, 2016, South Africa adopted a policy of providing antiretroviral treatment to everyone infected with HIV irrespective of their CD4 cell count. Studies of universal treatment and expanded prevention of HIV differ widely in their projections of effects and the associated costs, so we did this analysis to attempt to find a consensus. METHODS: We used data on HIV from the Joint UN Programme on HIV and AIDS (UNAIDS) from 1988 to 2013 and from data from WHO on tuberculosis from 1980 to to 2013 to fit a dynamical model to time trends in HIV prevalence, antiretroviral therapy (ART) coverage, and tuberculosis notification rates in South Africa. We then used the model to estimate current trends and project future patterns in HIV prevalence and incidence, AIDS-related mortality, and tuberculosis notification rates, and we used data from the South African National AIDS Council to assess current and future costs under different combinations of treatment and prevention approaches. We considered two treatment strategies: the Constant Effort strategy, in which people infected with HIV continue to start treatment at the rate in 2016, and the Expanded Treatment and Prevention (ETP) strategy, in which testing rates are increased, treatment is started immediately after HIV is detected, and prevention programmes are expanded. FINDINGS: Our estimates show that HIV incidence among adults aged 15 years or older fell from 2·3% per year in 1996 to 0·65% per year in 2016, AIDS-related mortality decreased from 1·4% per year in 2006 to 0·37% per year in 2016, and both continue to fall at a relative rate of 17% per year. Our model shows that maintenance of Constant Effort will have a substantial effect on HIV but will not end AIDS, whereas ETP could end AIDS by 2030, with incidence of HIV and AIDs-related mortality rates both at less than one event per 1000 adults per year. Under ETP the annual cost of health care and prevention will increase from US$2·3 billion in 2016 to $2·9 billion in 2018, then decrease to $1·7 billion in 2030 and $0·9 billion in 2050. Over the next 35 years, the expansion of treatment will avert an additional 3·8 million new infections, save 1·1 million lives, and save $3·2 billion compared with continuing Constant Effort up to 2050. Expansion of prevention, including provision of pre-exposure prophylaxis, condom distribution, and male circumcision, could avert a further 150 000 new infections, save 5000 lives, and cost an additional $5·7 billion compared with Constant Effort. INTERPRETATION: Our results suggest that South Africa is on track to reduce HIV incidence and AIDS-related mortality substantially by 2030, saving both lives and money. Success will depend on high rates of HIV testing, ART delivery and adherence, good patient monitoring and support, and data to monitor progress. FUNDING: None.