Assessment of epidemic projections using recent HIV survey data in South Africa: a validation analysis of ten mathematical models of HIV epidemiology in the antiretroviral therapy era

Background Mathematical models are widely used to simulate the eff ects of interventions to control HIV and to project future epidemiological trends and resource needs. We aimed to validate past model projections against data from a large household survey done in South Africa in 2012. Methods We compared ten model projections of HIV prevalence, HIV incidence, and antiretroviral therapy (ART) coverage for South Africa with estimates from national household survey data from 2012. Model projections for 2012 were made before the publication of the 2012 household survey. We compared adult (age 15–49 years) HIV prevalence in 2012, the change in prevalence between 2008 and 2012, and prevalence, incidence, and ART coverage by sex and by age groups between model projections and the 2012 household survey. Findings All models projected lower prevalence estimates for 2012 than the survey estimate (18·8%), with eight models’ central projections being below the survey 95% CI (17·5–20·3). Eight models projected that HIV prevalence would remain unchanged (n=5) or decline (n=3) between 2008 and 2012, whereas prevalence estimates from the household surveys increased from 16·9% in 2008 to 18·8% in 2012 (diff erence 1·9, 95% CI –0·1 to 3·9). Model projections accurately predicted the 1·6 percentage point prevalence decline (95% CI –0·3 to 3·5) in young adults aged 15–24 years, and the 2·2 percentage point (0·5 to 3·9) increase in those aged 50 years and older. Models accurately represented the number of adults on ART in 2012; six of ten models were within the survey 95% CI of 1·54–2·12 million. However, the diff erential ART coverage between women and men was not fully captured; all model projections of the sex ratio of women to men on ART were lower than the survey estimate of 2·22 (95% CI 1·73–2·71). Interpretation Projections for overall declines in HIV epidemics during the ART era might have been optimistic. Future treatment and HIV prevention needs might be greater than previously forecasted. Additional data about service provision for HIV care could help inform more accurate projections

Antigen-Displaying Lipid-Enveloped PLGA Nanoparticles as Delivery Agents for a Plasmodium vivax Malaria Vaccine

The parasite Plasmodium vivax is the most frequent cause of malaria outside of sub-Saharan Africa, but efforts to develop viable vaccines against P. vivax so far have been inadequate. We recently developed pathogen-mimicking polymeric vaccine nanoparticles composed of the FDA-approved biodegradable polymer poly(lactide-co-glycolide) acid (PLGA) “enveloped” by a lipid membrane. In this study, we sought to determine whether this vaccine delivery platform could be applied to enhance the immune response against P. vivax sporozoites. A candidate malaria antigen, VMP001, was conjugated to the lipid membrane of the particles, and an immunostimulatory molecule, monophosphoryl lipid A (MPLA), was incorporated into the lipid membranes, creating pathogen-mimicking nanoparticle vaccines (VMP001-NPs). Vaccination with VMP001-NPs promoted germinal center formation and elicited durable antigen-specific antibodies with significantly higher titers and more balanced Th1/Th2 responses in vivo, compared with vaccines composed of soluble protein mixed with MPLA. Antibodies raised by NP vaccinations also exhibited enhanced avidity and affinity toward the domains within the circumsporozoite protein implicated in protection and were able to agglutinate live P. vivax sporozoites. These results demonstrate that these VMP001-NPs are promising vaccines candidates that may elicit protective immunity against P. vivax sporozoites.United States. Dept. of Defense (contract W911NF-07-D-0004)Ragon Institute of MGH, MIT and Harvar

Health benefi ts, costs, and cost-eff ectiveness of earlier eligibility for adult antiretroviral therapy and expanded treatment coverage: a combined analysis of 12 mathematical models

Background New WHO guidelines recommend initiation of antiretroviral therapy for HIV-positive adults with CD4 counts of 500 cells per μL or less, a higher threshold than was previously recommended. Country decision makers have to decide whether to further expand eligibility for antiretroviral therapy accordingly. We aimed to assess the potential health benefi ts, costs, and cost-eff ectiveness of various eligibility criteria for adult antiretroviral therapy and expanded treatment coverage. Methods We used several independent mathematical models in four settings—South Africa (generalised epidemic, moderate antiretroviral therapy coverage), Zambia (generalised epidemic, high antiretroviral therapy coverage), India (concentrated epidemic, moderate antiretroviral therapy coverage), and Vietnam (concentrated epidemic, low antiretroviral therapy coverage)—to assess the potential health benefi ts, costs, and cost-eff ectiveness of various eligibility criteria for adult antiretroviral therapy under scenarios of existing and expanded treatment coverage, with results projected over 20 years. Analyses assessed the extension of eligibility to include individuals with CD4 counts of 500 cells per μL or less, or all HIV-positive adults, compared with the previous (2010) recommendation of initiation with CD4 counts of 350 cells per μL or less. We assessed costs from a health-system perspective, and calculated the incremental cost (in US$) per disability-adjusted life-year (DALY) averted to compare competing strategies. Strategies were regarded very cost eff ective if the cost per DALY averted was less than the country’s 2012 per-head gross domestic product (GDP; South Africa:$8040; Zambia: $1425; India:$1489; Vietnam: $1407) and cost eff ective if the cost per DALY averted was less than three times the per-head GDP. Findings In South Africa, the cost per DALY averted of extending eligibility for antiretroviral therapy to adult patients with CD4 counts of 500 cells per μL or less ranged from$237 to $1691 per DALY averted compared with 2010 guidelines. In Zambia, expansion of eligibility to adults with a CD4 count threshold of 500 cells per μL ranged from improving health outcomes while reducing costs (ie, dominating the previous guidelines) to$749 per DALY averted. In both countries results were similar for expansion of eligibility to all HIV-positive adults, and when substantially expanded treatment coverage was assumed. Expansion of treatment coverage in the general population was also cost eff ective. In India, the cost for extending eligibility to all HIV-positive adults ranged from $131 to$241 per DALY averted, and in Vietnam extending eligibility to patients with CD4 counts of 500 cells per μL or less cost $290 per DALY averted. In concentrated epidemics, expanded access for key populations was also cost eff ective. Interpretation Our estimates suggest that earlier eligibility for antiretroviral therapy is very cost eff ective in lowincome and middle-income settings, although these estimates should be revisited when more data become available. Scaling up antiretroviral therapy through earlier eligibility and expanded coverage should be considered alongside other high-priority health interventions competing for health budgets

Community-based antiretroviral therapy versus standard clinic-based services for HIV in South Africa and Uganda (DO ART): a randomised trial

Background: Community-based delivery of antiretroviral therapy (ART) for HIV, including ART initiation, clinical and laboratory monitoring, and refills, could reduce barriers to treatment and improve viral suppression, reducing the gap in access to care for individuals who have detectable HIV viral load, including men who are less likely than women to be virally suppressed. We aimed to test the effect of community-based ART delivery on viral suppression among people living with HIV not on ART. / Methods: We did a household-randomised, unblinded trial (DO ART) of delivery of ART in the community compared with the clinic in rural and peri-urban settings in KwaZulu-Natal, South Africa and the Sheema District, Uganda. After community-based HIV testing, people living with HIV were randomly assigned (1:1:1) with mobile phone software to community-based ART initiation with quarterly monitoring and ART refills through mobile vans; ART initiation at the clinic followed by mobile van monitoring and refills (hybrid approach); or standard clinic ART initiation and refills. The primary outcome was HIV viral suppression at 12 months. If the difference in viral suppression was not superior between study groups, an a-priori test for non-inferiority was done to test for a relative risk (RR) of more than 0·95. The cost per person virally suppressed was a co-primary outcome of the study. This study is registered with ClinicalTrials.gov, NCT02929992. / Findings: Between May 26, 2016, and March 28, 2019, of 2479 assessed for eligibility, 1315 people living with HIV and not on ART with detectable viral load at baseline were randomly assigned; 666 (51%) were men. Retention at the month 12 visit was 95% (n=1253). At 12 months, community-based ART increased viral suppression compared with the clinic group (306 [74%] vs 269 [63%], RR 1·18, 95% CI 1·07–1·29; psuperiority=0·0005) and the hybrid approach was non-inferior (282 [68%] vs 269 [63%], RR 1·08, 0·98–1·19; pnon-inferiority=0·0049). Community-based ART increased viral suppression among men (73%, RR 1·34, 95% CI 1·16–1·55; psuperiority<0·0001) as did the hybrid approach (66%, RR 1·19, 1·02–1·40; psuperiority=0·026), compared with clinic-based ART (54%). Viral suppression was similar for men (n=156 [73%]) and women (n=150 [75%]) in the community-based ART group. With efficient scale-up, community-based ART could cost US$275–452 per person reaching viral suppression. Community-based ART was considered safe, with few adverse events. / Interpretation: In high and medium HIV prevalence settings in South Africa and Uganda, community-based delivery of ART significantly increased viral suppression compared with clinic-based ART, particularly among men, eliminating disparities in viral suppression by gender. Community-based ART should be implemented and evaluated in different contexts for people with detectable viral load. / Funding: The Bill & Melinda Gates Foundation; the University of Washington and Fred Hutch Center for AIDS Research; the Wellcome Trust; the University of Washington Royalty Research Fund; and the University of Washington King K Holmes Endowed Professorship in STDs and AIDS

Predicted effects of the introduction of long-acting injectable cabotegravir pre-exposure prophylaxis in sub-Saharan Africa: a modelling study

BACKGROUND: Long-acting injectable cabotegravir pre-exposure prophylaxis (PrEP) is recommended by WHO as an additional option for HIV prevention in sub-Saharan Africa, but there is concern that its introduction could lead to an increase in integrase-inhibitor resistance undermining treatment programmes that rely on dolutegravir. We aimed to project the health benefits and risks of cabotegravir-PrEP introduction in settings in sub-Saharan Africa. METHODS: With HIV Synthesis, an individual-based HIV model, we simulated 1000 setting-scenarios reflecting both variability and uncertainty about HIV epidemics in sub-Saharan Africa and compared outcomes for each with and without cabotegravir-PrEP introduction. PrEP use is assumed to be risk-informed and to be used only in 3-month periods (the time step for the model) when having condomless sex. We consider three groups at risk of integrase-inhibitor resistance emergence: people who start cabotegravir-PrEP after (unknowingly) being infected with HIV, those who seroconvert while on PrEP, and those with HIV who have residual cabotegravir drugs concentrations during the early tail period after recently stopping PrEP. We projected the outcomes of policies of cabotegravir-PrEP introduction and of no introduction in 2022 across 50 years. In 50% of setting-scenarios we considered that more sensitive nucleic-acid-based HIV diagnostic testing (NAT), rather than regular antibody-based HIV rapid testing, might be used to reduce resistance risk. For cost-effectiveness analysis we assumed in our base case a cost of cabotegravir-PrEP drug to be similar to oral PrEP, resulting in a total annual cost of USD$144 per year ($114 per year and $264 per year considered in sensitivity analyses), a cost-effectiveness threshold of$500 per disability-adjusted life years averted, and a discount rate of 3% per year. FINDINGS: Reflecting our assumptions on the appeal of cabotegravir-PrEP, its introduction is predicted to lead to a substantial increase in PrEP use with approximately 2·6% of the adult population (and 46% of those with a current indication for PrEP) receiving PrEP compared with 1·5% (28%) without cabotegravir-PrEP introduction across 20 years. As a result, HIV incidence is expected to be lower by 29% (90% range across setting-scenarios 6-52%) across the same period compared with no introduction of cabotegravir-PrEP. In people initiating antiretroviral therapy, the proportion with integrase-inhibitor resistance after 20 years is projected to be 1·7% (0-6·4%) without cabotegravir-PrEP introduction but 13·1% (4·1-30·9%) with. Cabotegravir-PrEP introduction is predicted to lower the proportion of all people on antiretroviral therapy with viral loads less than 1000 copies per mL by 0·9% (-2·5% to 0·3%) at 20 years. For an adult population of 10 million an overall decrease in number of AIDS deaths of about 4540 per year (-13 000 to -300) across 50 years is predicted, with little discernible benefit with NAT when compared with standard antibody-based rapid testing. AIDS deaths are predicted to be averted with cabotegravir-PrEP introduction in 99% of setting-scenarios. Across the 50-year time horizon, overall HIV programme costs are predicted to be similar regardless of whether cabotegravir-PrEP is introduced (total mean discounted annual HIV programme costs per year across 50 years is $151·3 million vs$150·7 million), assuming the use of standard antibody testing. With antibody-based rapid HIV testing, the introduction of cabotegravir-PrEP is predicted to be cost-effective under an assumed threshold of $500 per disability-adjusted life year averted in 82$144 per year, in 52% at $264, and in 87$114. INTERPRETATION: Despite leading to increases in integrase-inhibitor drug resistance, cabotegravir-PrEP introduction is likely to reduce AIDS deaths in addition to HIV incidence. Long-acting cabotegravir-PrEP is predicted to be cost-effective if delivered at similar cost to oral PrEP with antibody-based rapid HIV testing. FUNDING: Bill & Melinda Gates Foundation, National Institute of Allergy and Infectious Diseases of the National Institutes of Health

Comparison of empirically derived and model-based estimates of key population HIV incidence and the distribution of new infections by population group in sub-Saharan Africa

Background: The distribution of new HIV infections among key populations, including female sex workers (FSWs), gay men and other men who have sex with men (MSM), and people who inject drugs (PWID) are essential information to guide an HIV response, but data are limited in sub-Saharan Africa (SSA). We analyzed empirically derived and mathematical model-based estimates of HIV incidence among key populations and compared with the Joint United Nations Programme on HIV/AIDS (UNAIDS) estimates.Methods: We estimated HIV incidence among FSW and MSM in SSA by combining meta-analyses of empirical key population HIV incidence relative to the total population incidence with key population size estimates (KPSE) and HIV prevalence. Dynamic HIV transmission model estimates of HIV incidence and percentage of new infections among key populations were extracted from 94 country applications of 9 mathematical models. We compared these with UNAIDS-reported distribution of new infections, implied key population HIV incidence and incidence-to-prevalence ratios.Results: Across SSA, empirical FSW HIV incidence was 8.6-fold (95% confidence interval: 5.7 to 12.9) higher than total population female 15–39 year incidence, and MSM HIV incidence was 41.8-fold (95% confidence interval: 21.9 to 79.6) male 15–29 year incidence. Combined with KPSE, these implied 12% of new HIV infections in 2021 were among FSW and MSM (5% and 7% respectively). In sensitivity analysis varying KPSE proportions within 95% uncertainty range, the proportion of new infections among FSW and MSM was between 9% and 19%. Insufficient data were available to estimate PWID incidence rate ratios. Across 94 models, median proportion of new infections among FSW, MSM, and PWID was 6.4% (interquartile range 3.2%–11.7%), both much lower than the 25% reported by UNAIDS.Conclusion: Empirically derived and model-based estimates of HIV incidence confirm dramatically higher HIV risk among key populations in SSA. Estimated proportions of new infections among key populations in 2021 were sensitive to population size assumptions and were substantially lower than estimates reported by UNAIDS.</div

Gelsolin dysfunction causes photoreceptor loss in induced pluripotent cell and animal retinitis pigmentosa models

Mutations in the Retinitis Pigmentosa GTPase Regulator (RPGR) cause X-linked RP (XLRP), an untreatable, inherited retinal dystrophy that leads to premature blindness. RPGR localises to the photoreceptor connecting cilium where its function remains unknown. Here we show, using murine and human induced pluripotent stem cell models, that RPGR interacts with and activates the actin-severing protein gelsolin, and that gelsolin regulates actin disassembly in the connecting cilium, thus facilitating rhodopsin transport to photoreceptor outer segments. Disease-causing RPGR mutations perturb this RPGR-gelsolin interaction, compromising gelsolin activation. Both RPGR and Gelsolin knockout mice show abnormalities of actin polymerisation and mislocalisation of rhodopsin in photoreceptors. These findings reveal a clinically-significant role for RPGR in the activation of gelsolin, without which abnormalities in actin polymerisation in the photoreceptor connecting cilia cause rhodopsin mislocalisation and eventual retinal degeneration in XLRP.Mutations in the Retinitis Pigmentosa GTPase Regulator (RPGR) cause retinal dystrophy, but how this arises at a molecular level is unclear. Here, the authors show in induced pluripotent stem cells and mouse knockouts that RPGR mediates actin dynamics in photoreceptors via the actin-severing protein, gelsolin

Measuring HIV acquisitions among partners of key populations: estimates from HIV transmission dynamic models

BACKGROUND: Key populations (KPs), including female sex workers (FSWs), gay men and other men who have sex with men (MSM), people who inject drugs (PWID), and transgender women (TGW) experience disproportionate risks of HIV acquisition. The UNAIDS Global AIDS 2022 Update reported that one-quarter of all new HIV infections occurred among their non-KP sexual partners. However, this fraction relied on heuristics regarding the ratio of new infections that KPs transmitted to their non-KP partners to the new infections acquired among KPs (herein referred to as "infection ratios"). We recalculated these ratios using dynamic transmission models.SETTING: One hundred seventy-eight settings (106 countries).METHODS: Infection ratios for FSW, MSM, PWID, TGW, and clients of FSW were estimated from 12 models for 2020.RESULTS: Median model estimates of infection ratios were 0.7 (interquartile range: 0.5-1.0; n = 172 estimates) and 1.2 (0.8-1.8; n = 127) for acquisitions from FSW clients and transmissions from FSW to all their non-KP partners, respectively, which were comparable with the previous UNAIDS assumptions (0.2-1.5 across regions). Model estimates for female partners of MSM were 0.5 (0.2-0.8; n = 20) and 0.3 (0.2-0.4; n = 10) for partners of PWID across settings in Eastern and Southern Africa, lower than the corresponding UNAIDS assumptions (0.9 and 0.8, respectively). The few available model estimates for TGW were higher [5.1 (1.2-7.0; n = 8)] than the UNAIDS assumptions (0.1-0.3). Model estimates for non-FSW partners of FSW clients in Western and Central Africa were high (1.7; 1.0-2.3; n = 29).CONCLUSIONS: Ratios of new infections among non-KP partners relative to KP were high, confirming the importance of better addressing prevention and treatment needs among KP as central to reducing overall HIV incidence.</p

Surface topography regulates wnt signaling through control of primary cilia structure in mesenchymal stem cells

The primary cilium regulates cellular signalling including influencing wnt sensitivity by sequestering β-catenin within the ciliary compartment. Topographic regulation of intracellular actin-myosin tension can control stem cell fate of which wnt is an important mediator. We hypothesized that topography influences mesenchymal stem cell (MSC) wnt signaling through the regulation of primary cilia structure and function. MSCs cultured on grooves expressed elongated primary cilia, through reduced actin organization. siRNA inhibition of anterograde intraflagellar transport (IFT88) reduced cilia length and increased active nuclear β-catenin. Conversely, increased primary cilia assembly in MSCs cultured on the grooves was associated with decreased levels of nuclear active β-catenin, axin-2 induction and proliferation, in response to wnt3a. This negative regulation, on grooved topography, was reversed by siRNA to IFT88. This indicates that subtle regulation of IFT and associated cilia structure, tunes the wnt response controlling stem cell differentiation.We acknowledge funding from an EPSRC Platform grant which supported McMurray and a Wellcome Trust project grant which supported Wann and McMurray. Wann is now supported on an ARUK project grant. Thompson was funded by a BBSRC PhD studentshi

In vitro and in vivo mRNA delivery using lipid-enveloped pHresponsive polymer nanoparticles

Biodegradable core−shell structured nanoparticles with a poly(β-amino ester) (PBAE) core enveloped by a phospholipid bilayer shell were developed for in vivo mRNA delivery with a view toward delivery of mRNA-based vaccines. The pH-responsive PBAE component was chosen to promote endosome disruption, while the lipid surface layer was selected to minimize toxicity of the polycation core. Messenger RNA was efficiently adsorbed via electrostatic interactions onto the surface of these net positively charged nanoparticles. In vitro, mRNA-loaded particle uptake by dendritic cells led to mRNA delivery into the cytosol with low cytotoxicity, followed by translation of the encoded protein in these difficult-to-transfect cells at a frequency of 30%. Particles loaded with mRNA administered intranasally (i.n.) in mice led to the expression of the reporter protein luciferase in vivo as soon as 6 h after administration, a time point when naked mRNA given i.n. showed no expression. At later time points, luciferase expression was detected in naked mRNA-treated mice, but this group showed a wide variation in levels of transfection, compared to particle-treated mice. This system may thus be promising for noninvasive delivery of mRNA-based vaccines.United States. Dept. of Defense (Institute for Soldier Nanotechnology, contract W911NF-07-D-0004)Ragon Institute of MGH, MIT and HarvardSingapore. Agency for Science, Technology and ResearchHoward Hughes Medical Institute (Investigator