HPTN 071 (PopART): A Cluster-Randomized Trial of the Population Impact of an HIV Combination Prevention Intervention Including Universal Testing and Treatment: Mathematical Model

Background

The HPTN 052 trial confirmed that antiretroviral therapy (ART) can nearly eliminate HIV transmission from successfully treated HIV-infected individuals within couples. Here, we present the mathematical modeling used to inform the design and monitoring of a new trial aiming to test whether widespread provision of ART is feasible and can substantially reduce population-level HIV incidence.

Methods and Findings

The HPTN 071 (PopART) trial is a three-arm cluster-randomized trial of 21 large population clusters in Zambia and South Africa, starting in 2013. A combination prevention package including home-based voluntary testing and counseling, and ART for HIV positive individuals, will be delivered in arms A and B, with ART offered universally in arm A and according to national guidelines in arm B. Arm C will be the control arm. The primary endpoint is the cumulative three-year HIV incidence.We developed a mathematical model of heterosexual HIV transmission, informed by recent data on HIV-1 natural history. We focused on realistically modeling the intervention package. Parameters were calibrated to data previously collected in these communities and national surveillance data.We predict that, if targets are reached, HIV incidence over three years will drop by >60% in arm A and >25% in arm B, relative to arm C. The considerable uncertainty in the predicted reduction in incidence justifies the need for a trial. The main drivers of this uncertainty are possible community-level behavioral changes associated with the intervention, uptake of testing and treatment, as well as ART retention and adherence.

Conclusions

The HPTN 071 (PopART) trial intervention could reduce HIV population-level incidence by >60% over three years. This intervention could serve as a paradigm for national or supra-national implementation. Our analysis highlights the role mathematical modeling can play in trial development and monitoring, and more widely in evaluating the impact of treatment as prevention.     

Hidden Drug Resistant HIV to Emerge in the Era of Universal Treatment Access in Southeast Asia

Background

Universal access to first-line antiretroviral therapy (ART) for HIV infection is becoming more of a reality in most low and middle income countries in Asia. However, second-line therapies are relatively scarce.

Methods and Findings

We developed a mathematical model of an HIV epidemic in a Southeast Asian setting and used it to forecast the impact of treatment plans, without second-line options, on the potential degree of acquisition and transmission of drug resistant HIV strains. We show that after 10 years of universal treatment access, up to 20% of treatment-naïve individuals with HIV may have drug-resistant strains but it depends on the relative fitness of viral strains.

Conclusions

If viral load testing of people on ART is carried out on a yearly basis and virological failure leads to effective second-line therapy, then transmitted drug resistance could be reduced by 80%. Greater efforts are required for minimizing first-line failure, to detect virological failure earlier, and to procure access to second-line therapies.     

Universal precautions to prevent HIV transmission to health care workers: an economic analysis.

The universal precautions recommended by the US Centers for Disease Control (CDC), Atlanta, for the prevention of HIV (human immunodeficiency virus) transmission to health care workers are widely accepted, despite little documentation of their effectiveness and efficiency. We reviewed the evidence on the risk of HIV transmission to hospital workers and the effectiveness of the universal precautions. We also evaluated the costs of implementing the recommendations in a 450-bed acute care teaching hospital in Hamilton, Ont. On the basis of aggregated results from six prospective studies the risk of HIV seroconversion among hospital workers after a needlestick injury involving a patient known to have AIDS (acquired immune deficiency syndrome) is 0.36% (upper 95% confidence limit 0.67%); the risk after skin and mucous membrane exposure to blood or other body fluids of AIDS patients is 0% (upper 95% confidence limit 0.38%). We estimated that 0.038 cases of HIV seroconversion would be prevented annually in the study hospital if the CDC recommendations were followed. The incremental cost of implementing the universal precautions was estimated to be about $315,000 per year, or over $8 million per case of HIV seroconversion prevented. If all HIV-infected workers were assumed to have AIDS within 10 years of infection the of the program would be about $565,000 per life-year saved. When less conservative, more probable assumptions were applied the best estimate of the implementation cost was $128,862,000 per case of HIV seroconversion prevented. The universal precautions implemented in the study hospital were not found to be efficacious or cost-effective. To minimize the already small risk of HIV transmission in hospitals the sources of risk of percutaneous injury should be better defined and the design of percutaneous lines, needles and surgical equipment as well as techniques improved. Preventive measures recommended on the basis of demonstrated efficacy and aimed at routes of exposure that represent true risk are needed.     

CD4 Counts at Entry to HIV Care in Mexico for Patients under the “Universal Antiretroviral Treatment Program for the Uninsured Population,” 2007–2014

In Mexico, public health services have provided universal access to antiretroviral therapy (ART) since 2004. For individuals receiving HIV care in public healthcare facilities, the data are limited regarding CD4 T-lymphocyte counts (CD4e) at the time of entry into care. Relevant population-based estimates of CD4e are needed to inform strategies to maximize the impact of Mexico’s national ART program, and may be applicable to other countries implementing universal HIV treatment programs. For this study, we retrospectively analyzed the CD4e of persons living with HIV and receiving care at state public health facilities from 2007 to 2014, comparing CD4e by demographic characteristics and the marginalization index of the state where treatment was provided, and assessing trends in CD4e over time. Our sample included 66,947 individuals who entered into HIV care between 2007 and 2014, of whom 79% were male. During the study period, the male-to-female ratio increased from 3.0 to 4.3, reflecting the country''s HIV epidemic; the median age at entry decreased from 34 years to 32 years. Overall, 48.6% of individuals entered care with a CD4≤200 cells/μl, ranging from 42.2% in states with a very low marginalization index to 52.8% in states with a high marginalization index, and from 38.9% among individuals aged 18–29 to 56.5% among those older than 50. The adjusted geometric mean (95% confidence interval) CD4e increased among males from 135 (131,142) cells/μl in 2007 to 148 (143,155) cells/μl in 2014 (p-value<0.0001); no change was observed among women, with a geometric mean of 178 (171,186) and 171 (165,183) in 2007 and 2014, respectively. There have been important gains in access to HIV care and treatment; however, late entry into care remains an important barrier in achieving optimal outcomes of ART in Mexico. The geographic, socioeconomic, and demographic differences observed reflect important inequities in timely access to HIV prevention, care, and treatment services, and highlight the need to develop contextual and culturally appropriate prevention and HIV testing strategies and linkage programs.     

Cytokine therapies in HIV infection

The theoretical objectives of cytokine therapies in HIV infection are to impact T cell homeostasis and/or to improve immune functions or the mobilization of the HIV reservoir. Among cytokines, IL-2 and IL-7 are promising agents under clinical evaluation. Intermittent administration of IL-2 is by far the furthest studied strategy in HIV infection. This cytokine increases CD4 T lymphocytes in HIV-infected individuals. Recent clinical data showed that this effect is sustained over years. IL-2 therapy induces a peripheral expansion of T cells as a consequence of prolonged survival of T cells and decreased immune activation. These effects suggest that a cytokine therapy may interfere with critical factors of HIV disease. Recent data provide arguments that IL-2 therapy improves immune functions in HIV-infected patients. Whether these effects may be translated into clinical benefits is under evaluation in ongoing phase III studies. The potential interest of IL-7 in the treatment of HIV-infection is based on its crucial role on T cell homeostasis both in thymic output and peripheral T proliferation and survival. Although no data in human are still available, recent studies provide arguments to assess this cytokine in HIV infection. Phase I studies are ongoing or planned.     

Modeling the epidemiological impact of the UNAIDS 2025 targets to end AIDS as a public health threat by 2030

BackgroundUNAIDS has established new program targets for 2025 to achieve the goal of eliminating AIDS as a public health threat by 2030. This study reports on efforts to use mathematical models to estimate the impact of achieving those targets.Methods and findingsWe simulated the impact of achieving the targets at country level using the Goals model, a mathematical simulation model of HIV epidemic dynamics that includes the impact of prevention and treatment interventions. For 77 high-burden countries, we fit the model to surveillance and survey data for 1970 to 2020 and then projected the impact of achieving the targets for the period 2019 to 2030. Results from these 77 countries were extrapolated to produce estimates for 96 others. Goals model results were checked by comparing against projections done with the Optima HIV model and the AIDS Epidemic Model (AEM) for selected countries. We included estimates of the impact of societal enablers (access to justice and law reform, stigma and discrimination elimination, and gender equality) and the impact of Coronavirus Disease 2019 (COVID-19). Results show that achieving the 2025 targets would reduce new annual infections by 83% (71% to 86% across regions) and AIDS-related deaths by 78% (67% to 81% across regions) by 2025 compared to 2010. Lack of progress on societal enablers could endanger these achievements and result in as many as 2.6 million (44%) cumulative additional new HIV infections and 440,000 (54%) more AIDS-related deaths between 2020 and 2030 compared to full achievement of all targets. COVID-19–related disruptions could increase new HIV infections and AIDS-related deaths by 10% in the next 2 years, but targets could still be achieved by 2025. Study limitations include the reliance on self-reports for most data on behaviors, the use of intervention effect sizes from published studies that may overstate intervention impacts outside of controlled study settings, and the use of proxy countries to estimate the impact in countries with fewer than 4,000 annual HIV infections.ConclusionsThe new targets for 2025 build on the progress made since 2010 and represent ambitious short-term goals. Achieving these targets would bring us close to the goals of reducing new HIV infections and AIDS-related deaths by 90% between 2010 and 2030. By 2025, global new infections and AIDS deaths would drop to 4.4 and 3.9 per 100,000 population, and the number of people living with HIV (PLHIV) would be declining. There would be 32 million people on treatment, and they would need continuing support for their lifetime. Incidence for the total global population would be below 0.15% everywhere. The number of PLHIV would start declining by 2023.

John Stover and co-workers assess the potential health impacts of UNAIDS’ HIV/AIDS targets.     

Elimination of HIV in South Africa through Expanded Access to Antiretroviral Therapy: A Model Comparison Study

Background

Expanded access to antiretroviral therapy (ART) using universal test and treat (UTT) has been suggested as a strategy to eliminate HIV in South Africa within 7 y based on an influential mathematical modeling study. However, the underlying deterministic model was criticized widely, and other modeling studies did not always confirm the study''s finding. The objective of our study is to better understand the implications of different model structures and assumptions, so as to arrive at the best possible predictions of the long-term impact of UTT and the possibility of elimination of HIV.

Methods and Findings

We developed nine structurally different mathematical models of the South African HIV epidemic in a stepwise approach of increasing complexity and realism. The simplest model resembles the initial deterministic model, while the most comprehensive model is the stochastic microsimulation model STDSIM, which includes sexual networks and HIV stages with different degrees of infectiousness. We defined UTT as annual screening and immediate ART for all HIV-infected adults, starting at 13% in January 2012 and scaled up to 90% coverage by January 2019. All models predict elimination, yet those that capture more processes underlying the HIV transmission dynamics predict elimination at a later point in time, after 20 to 25 y. Importantly, the most comprehensive model predicts that the current strategy of ART at CD4 count ≤350 cells/µl will also lead to elimination, albeit 10 y later compared to UTT. Still, UTT remains cost-effective, as many additional life-years would be saved. The study''s major limitations are that elimination was defined as incidence below 1/1,000 person-years rather than 0% prevalence, and drug resistance was not modeled.

Conclusions

Our results confirm previous predictions that the HIV epidemic in South Africa can be eliminated through universal testing and immediate treatment at 90% coverage. However, more realistic models show that elimination is likely to occur at a much later point in time than the initial model suggested. Also, UTT is a cost-effective intervention, but less cost-effective than previously predicted because the current South African ART treatment policy alone could already drive HIV into elimination. Please see later in the article for the Editors'' Summary     

Need for Timely Paediatric HIV Treatment within Primary Health Care in Rural South Africa

Background

In areas where adult HIV prevalence has reached hyperendemic levels, many infants remain at risk of acquiring HIV infection. Timely access to care and treatment for HIV-infected infants and young children remains an important challenge. We explore the extent to which public sector roll-out has met the estimated need for paediatric treatment in a rural South African setting.

Methods

Local facility and population-based data were used to compare the number of HIV infected children accessing HAART before 2008, with estimates of those in need of treatment from a deterministic modeling approach. The impact of programmatic improvements on estimated numbers of children in need of treatment was assessed in sensitivity analyses.

Findings

In the primary health care programme of HIV treatment 346 children <16 years of age initiated HAART by 2008; 245(70.8%) were aged 10 years or younger, and only 2(<1%) under one year of age. Deterministic modeling predicted 2,561 HIV infected children aged 10 or younger to be alive within the area, of whom at least 521(20.3%) would have required immediate treatment. Were extended PMTCT uptake to reach 100% coverage, the annual number of infected infants could be reduced by 49.2%.

Conclusion

Despite progress in delivering decentralized HIV services to a rural sub-district in South Africa, substantial unmet need for treatment remains. In a local setting, very few children were initiated on treatment under 1 year of age and steps have now been taken to successfully improve early diagnosis and referral of infected infants.     

Late entry into HIV care: estimated impact on AIDS mortality rates in Brazil, 2003-2006

Background

Worldwide, a high proportion of HIV-infected individuals enter into HIV care late. Here, our objective was to estimate the impact that late entry into HIV care has had on AIDS mortality rates in Brazil.

Methodology/Principal Findings

We analyzed data from information systems regarding HIV-infected adults who sought treatment at public health care facilities in Brazil from 2003 to 2006. We initially estimated the prevalence of late entry into HIV care, as well as the probability of death in the first 12 months, the percentage of the risk of death attributable to late entry, and the number of avoidable deaths. We subsequently adjusted the annual AIDS mortality rate by excluding such deaths. Of the 115,369 patients evaluated, 50,358 (43.6%) had entered HIV care late, and 18,002 died in the first 12 months, representing a 16.5% probability of death in the first 12 months (95% CI: 16.3–16.7). By comparing patients who entered HIV care late with those who gained timely access, we found that the risk ratio for death was 49.5 (95% CI: 45.1–54.2). The percentage of the risk of death attributable to late entry was 95.5%, translating to 17,189 potentially avoidable deaths. Averting those deaths would have lowered the 2003–2006 AIDS mortality rate by 39.5%. Including asymptomatic patients with CD4⁺ T cell counts >200 and ≤350 cells/mm³ in the group who entered HIV care late increased this proportion by 1.8%.

Conclusions/Significance

In Brazil, antiretroviral drugs reduced AIDS mortality by 43%. Timely entry would reduce that rate by a similar proportion, as well as resulting in a 45.2% increase in the effectiveness of the program for HIV care. The World Health Organization recommendation that asymptomatic patients with CD4⁺ T cell counts ≤350 cells/mm³ be treated would not have a significant impact on this scenario.     

Designing equitable antiretroviral allocation strategies in resource-constrained countries

Background

Recently, a global commitment has been made to expand access to antiretrovirals (ARVs) in the developing world. However, in many resource-constrained countries the number of individuals infected with HIV in need of treatment will far exceed the supply of ARVs, and only a limited number of health-care facilities (HCFs) will be available for ARV distribution. Deciding how to allocate the limited supply of ARVs among HCFs will be extremely difficult. Resource allocation decisions can be made on the basis of many epidemiological, ethical, or preferential treatment priority criteria.

Methods and Findings

Here we use operations research techniques, and we show how to determine the optimal strategy for allocating ARVs among HCFs in order to satisfy the equitable criterion that each individual infected with HIV has an equal chance of receiving ARVs. We present a novel spatial mathematical model that includes heterogeneity in treatment accessibility. We show how to use our theoretical framework, in conjunction with an equity objective function, to determine an optimal equitable allocation strategy (OEAS) for ARVs in resource-constrained regions. Our equity objective function enables us to apply the egalitarian principle of equity with respect to access to health care. We use data from the detailed ARV rollout plan designed by the government of South Africa to determine an OEAS for the province of KwaZulu–Natal. We determine the OEAS for KwaZulu–Natal, and we then compare this OEAS with two other ARV allocation strategies: (i) allocating ARVs only to Durban (the largest urban city in KwaZulu–Natal province) and (ii) allocating ARVs equally to all available HCFs. In addition, we compare the OEAS to the current allocation plan of the South African government (which is based upon allocating ARVs to 17 HCFs). We show that our OEAS significantly improves equity in treatment accessibility in comparison with these three ARV allocation strategies. We also quantify how the size of the catchment region surrounding each HCF, and the number of HCFs utilized for ARV distribution, alters the OEAS and the probability of achieving equity in treatment accessibility. We calculate that in order to achieve the greatest degree of treatment equity for individuals with HIV in KwaZulu–Natal, the ARVs should be allocated to 54 HCFs and each HCF should serve a catchment region of 40 to 60 km.

Conclusion

Our OEAS would substantially improve equality in treatment accessibility in comparison with other allocation strategies. Furthermore, our OEAS is extremely different from the currently planned strategy. We suggest that our novel methodology be used to design optimal ARV allocation strategies for resource-constrained countries.     

Influence of Municipality-Level Mean Income on Access to Aortic Valve Surgery: A Cross-Sectional Observational Study under Japan's Universal Health-Care Coverage

Background

Universal health-care coverage has attracted the interest of policy makers as a way of achieving health equity. However, previous reports have shown that despite universal coverage, socioeconomic disparity persists in access to high-tech invasive care, such as cardiac treatment. In this study, we aimed to investigate the association between socioeconomic status and care of aortic stenosis in the context of Japan''s health-care system, which is mainly publicly funded.

Methods

We chose aortic stenosis in older people as a target because such patients are likely to be affected by socioeconomic disparity. Using a large Japanese claim-based inpatient database, we identified 12,893 isolated aortic stenosis patients aged over 65 years who were hospitalized between July 2010 and March 2012. Municipality socioeconomic status was represented by the mean household income of the patients'' residential municipality, categorized into quartiles. The likelihood of undergoing aortic valve surgery and in-hospital mortality was regressed against socioeconomic status level with adjustments for hospital volume, regional number of cardiac surgeons per 1 million population, and patients'' clinical status.

Results

We found no significant differences between the highest and lowest quartile groups in surgical indication (odds ratio, 0.84; 95% confidence interval, 0.69–1.03) or in-hospital mortality (1.00; 0.68–1.48). Hospital volume was significantly associated with lower postoperative mortality (odds ratio of the highest volume tertile to the lowest, 0.49; 0.34–0.71).

Conclusions

Under Japan''s current universal health-care coverage, municipality socioeconomic status did not appear to have a systematic relationship with either treatment decision for surgical intervention or postoperative survival following aortic valve surgery among older patients. Our results imply that universal health-care coverage with high publicly funded coverage offers equal access to high-tech cardiovascular care.     

Towards malaria elimination in Savannakhet,Lao PDR: mathematical modelling driven strategy design

Background

The number of Plasmodium falciparum malaria cases around the world has decreased substantially over the last 15 years, but with the spread of resistance against anti-malarial drugs and insecticides, this decline may not continue. There is an urgent need to consider alternative, accelerated strategies to eliminate malaria in countries like Lao PDR, where there are a few remaining endemic areas. A deterministic compartmental modelling tool was used to develop an integrated strategy for P. falciparum elimination in the Savannakhet province of Lao PDR. The model was designed to include key aspects of malaria transmission and integrated control measures, along with a user-friendly interface.

Results

Universal coverage was the foundation of the integrated strategy, which took the form of the deployment of community health workers who provided universal access to early diagnosis, treatment and long-lasting insecticidal nets. Acceleration was included as the deployment of three monthly rounds of mass drug administration targeted towards high prevalence villages, with the addition of three monthly doses of the RTS,S vaccine delivered en masse to the same high prevalence sub-population. A booster dose of vaccine was added 1 year later. The surveillance-as-intervention component of the package involved the screening and treatment of individuals entering the simulated population.

Conclusions

In this modelling approach, the sequential introduction of a series of five available interventions in an integrated strategy was predicted to be sufficient to stop malaria transmission within a 3-year period. These interventions comprised universal access to early diagnosis and adequate treatment, improved access to long-lasting insecticidal nets, three monthly rounds of mass drug administration together with RTS,S vaccination followed by a booster dose of vaccine, and screening and treatment of imported cases.

     

Mathematical Analysis of the Transmission Dynamics of HIV Syphilis Co-infection in the Presence of Treatment for Syphilis

The re-emergence of syphilis has become a global public health issue, and more persons are getting infected, especially in developing countries. This has also led to an increase in the incidence of human immunodeficiency virus (HIV) infections as some studies have shown in the recent decade. This paper investigates the synergistic interaction between HIV and syphilis using a mathematical model that assesses the impact of syphilis treatment on the dynamics of syphilis and HIV co-infection in a human population where HIV treatment is not readily available or accessible to HIV-infected individuals. In the absence of HIV, the syphilis-only model undergoes the phenomenon of backward bifurcation when the associated reproduction number (\({\mathcal {R}}_{T}\)) is less than unity, due to susceptibility to syphilis reinfection after recovery from a previous infection. The complete syphilis–HIV co-infection model also undergoes the phenomenon of backward bifurcation when the associated effective reproduction number (\({\mathcal {R}}_{C}\)) is less than unity for the same reason as the syphilis-only model. When susceptibility to syphilis reinfection after treatment is insignificant, the disease-free equilibrium of the syphilis-only model is shown to be globally asymptotically stable whenever the associated reproduction number (\({\mathcal {R}}_{T}\)) is less than unity. Sensitivity and uncertainty analysis show that the top three parameters that drive the syphilis infection (with respect to the associated response function, \({\mathcal {R}}_{T}\)) are the contact rate (\(\beta _S\)), modification parameter that accounts for the increased infectiousness of syphilis-infected individuals in the secondary stage of the infection (\(\theta _1\)) and treatment rate for syphilis-only infected individuals in the primary stage of the infection (\(r_1\)). The co-infection model was numerically simulated to investigate the impact of various treatment strategies for primary and secondary syphilis, in both singly and dually infected individuals, on the dynamics of the co-infection of syphilis and HIV. It is observed that if concerted effort is exerted in the treatment of primary and secondary syphilis (in both singly and dually infected individuals), especially with high treatment rates for primary syphilis, this will result in a reduction in the incidence of HIV (and its co-infection with syphilis) in the population.     

CD4+CD8+ T cells represent a significant portion of the anti-HIV T cell response to acute HIV infection

Previous studies have revealed that HIV-infected individuals possess circulating CD4(+)CD8(+) double-positive (DP) T cells specific for HIV Ags. In the present study, we analyzed the proliferation and functional profile of circulating DP T cells from 30 acutely HIV-infected individuals and 10 chronically HIV-infected viral controllers. The acutely infected group had DP T cells that showed more proliferative capability and multifunctionality than did both their CD4(+) and CD8(+) T cells. DP T cells were found to exhibit greater proliferation and higher multifunctionality compared with CD4 T cells in the viral controller group. The DP T cell response represented 16% of the total anti-HIV proliferative response and >70% of the anti-HIV multifunctional response in the acutely infected subjects. Proliferating DP T cells of the acutely infected subjects responded to all HIV Ag pools with equal magnitude. Conversely, the multifunctional response was focused on the pool representing Nef, Rev, Tat, VPR, and VPU. Meanwhile, the controllers' DP T cells focused on Gag and the Nef, Rev, Tat, VPR, and VPU pool for both their proliferative and multifunctional responses. Finally, we show that the presence of proliferating DP T cells following all HIV Ag stimulations is well correlated with proliferating CD4 T cells whereas multifunctionality appears to be largely independent of multifunctionality in other T cell compartments. Therefore, DP T cells represent a highly reactive cell population during acute HIV infection, which responds independently from the traditional T cell compartments.     

Safety and Efficacy of Co-Trimoxazole for Treatment and Prevention of Plasmodium falciparum Malaria: A Systematic Review

Introduction

Cotrimoxazole (CTX) has been used for half a century. It is inexpensive hence the reason for its almost universal availability and wide clinical spectrum of use. In the last decade, CTX was used for prophylaxis of opportunistic infections in HIV infected people. It also had an impact on the malaria risk in this specific group.

Objective

We performed a systematic review to explore the efficacy and safety of CTX used for P.falciparum malaria treatment and prophylaxis.

Result

CTX is safe and efficacious against malaria. Up to 75% of the safety concerns relate to skin reactions and this increases in HIV/AIDs patients. In different study areas, in HIV negative individuals, CTX used as malaria treatment cleared 56%–97% of the malaria infections, reduced fever and improved anaemia. CTX prophylaxis reduces the incidence of clinical malaria in HIV-1 infected individuals from 46%–97%. In HIV negative non pregnant participants, CTX prophylaxis had 39.5%–99.5% protective efficacy against clinical malaria. The lowest figures were observed in zones of high sulfadoxine-pyrimethamine resistance. There were no data reported on CTX prophylaxis in HIV negative pregnant women.

Conclusion

CTX is safe and still efficacious for the treatment of P.falciparum malaria in non-pregnant adults and children irrespective of HIV status and antifolate resistance profiles. There is need to explore its effect in pregnant women, irrespective of HIV status. CTX prophylaxis in HIV infected individuals protects against malaria and CTX may have a role for malaria prophylaxis in specific HIV negative target groups.     

HIV Self-Testing Could “Revolutionize Testing in South Africa,but It Has Got to Be Done Properly”: Perceptions of Key Stakeholders

South Africa bears the world’s largest burden of HIV with over 6.4 million people living with the virus. The South African government’s response to HIV has yielded remarkable results in recent years; over 13 million South Africans tested in a 2012 campaign and over 2 million people are on antiretroviral treatment. However, with an HIV & AIDS and STI National Strategic Plan aiming to get 80 percent of the population to know their HIV status by 2016, activists and public health policy makers argue that non-invasive HIV self-testing should be incorporated into the country HIV Counseling and Testing [HCT] portfolios. In-depth qualitative interviews (N = 12) with key stakeholders were conducted from June to July 2013 in South Africa. These included two government officials, four non-governmental stakeholders, two donors, three academic researchers, and one international stakeholder. All stakeholders were involved in HIV prevention and treatment and influenced HCT policy and research in South Africa and beyond. The interviews explored: interest in HIV self-testing; potential distribution channels for HIV self-tests to target groups; perception of requirements for diagnostic technologies that would be most amenable to HIV self-testing and opinions on barriers and opportunities for HIV-linkage to care after receiving positive test results. While there is currently no HIV self-testing policy in South Africa, and several barriers exist, participants in the study expressed enthusiasm and willingness for scale-up and urgent need for further research, planning, establishment of HIV Self-testing policy and programming to complement existing facility-based and community-based HIV testing systems. Introduction of HIV self-testing could have far-reaching positive effects on holistic HIV testing uptake, giving people autonomy to decide which approach they want to use for HIV testing, early diagnosis, treatment and care for HIV particularly among hard-to reach groups, including men.     

HLA-B63 presents HLA-B57/B58-restricted cytotoxic T-lymphocyte epitopes and is associated with low human immunodeficiency virus load

Several HLA class I alleles have been associated with slow human immunodeficiency virus (HIV) disease progression, supporting the important role HLA class I-restricted cytotoxic T lymphocytes (CTL) play in controlling HIV infection. HLA-B63, the serological marker for the closely related HLA-B*1516 and HLA-B*1517 alleles, shares the epitope binding motif of HLA-B57 and HLA-B58, two alleles that have been associated with slow HIV disease progression. We investigated whether HIV-infected individuals who express HLA-B63 generate CTL responses that are comparable in breadth and specificity to those of HLA-B57/58-positive subjects and whether HLA-B63-positive individuals would also present with lower viral set points than the general population. The data show that HLA-B63-positive individuals indeed mounted responses to previously identified HLA-B57-restricted epitopes as well as towards novel, HLA-B63-restricted CTL targets that, in turn, can be presented by HLA-B57 and HLA-B58. HLA-B63-positive subjects generated these responses early in acute HIV infection and were able to control HIV replication in the absence of antiretroviral treatment with a median viral load of 3,280 RNA copies/ml. The data support an important role of the presented epitope in mediating relative control of HIV replication and help to better define immune correlates of controlled HIV infection.     

Inaccurate Diagnosis of HIV-1 Group M and O Is a Key Challenge for Ongoing Universal Access to Antiretroviral Treatment and HIV Prevention in Cameroon

Background

Increased access to HIV testing is essential in working towards universal access to HIV prevention and treatment in resource-limited countries. We here evaluated currently used HIV diagnostic tests and algorithms in Cameroon for their ability to correctly identify HIV infections.

Methods

We estimated sensitivity, specificity, and positive and negative predictive values of 5 rapid/simple tests, of which 3 were used by the national program, and 2 fourth generation ELISAs. The reference panel included 500 locally collected samples; 187 HIV -1 M, 10 HIV-1 O, 259 HIV negative and 44 HIV indeterminate plasmas.

Results

None of the 5 rapid assays and only 1 ELISA reached the current WHO/UNAIDS recommendations on performance of HIV tests of at least 99% sensitivity and 98% specificity. Overall, sensitivities ranged between 94.1% and 100%, while specificities were 88.0% to 98.8%. The combination of all assays generated up to 9% of samples with indeterminate HIV status, because they reacted discordantly with at least one of the different tests. Including HIV indeterminate samples in test efficiency calculations significantly decreased specificities to a range from 77.9% to 98.0%. Finally, two rapid assays failed to detect all HIV-1 group O variants tested, with one rapid test detecting only 2 out of 10 group O specimens.

Conclusion

In the era of ART scaling-up in Africa, significant proportions of false positive but also false negative results are still observed with HIV screening tests commonly used in Africa, resulting in inadequate treatment and prevention strategies. Depending on tests or algorithms used, up to 6% of HIV-1 M and 80% of HIV-1 O infected patients in Cameroon do not receive ART and adequate counseling to prevent further transmission due to low sensitivities. Also, the use of tests with low specificities could imply inclusion of up to 12% HIV negative people in ART programs and increase budgets in addition to inconveniences caused to patients.     

Exploring the Potential Health Impact and Cost-Effectiveness of AIDS Vaccine within a Comprehensive HIV/AIDS Response in Low- and Middle-Income Countries

Background

The Investment Framework Enhanced (IFE) proposed in 2013 by the Joint United Nations Programme on HIV/AIDS (UNAIDS) explored how maximizing existing interventions and adding emerging prevention options, including a vaccine, could further reduce new HIV infections and AIDS-related deaths in low- and middle-income countries (LMICs). This article describes additional modeling which looks more closely at the potential health impact and cost-effectiveness of AIDS vaccination in LMICs as part of UNAIDS IFE.

Methods

An epidemiological model was used to explore the potential impact of AIDS vaccination in LMICs in combination with other interventions through 2070. Assumptions were based on perspectives from research, vaccination and public health experts, as well as observations from other HIV/AIDS interventions and vaccination programs. Sensitivity analyses varied vaccine efficacy, duration of protection, coverage, and cost.

Results

If UNAIDS IFE goals were fully achieved, new annual HIV infections in LMICs would decline from 2.0 million in 2014 to 550,000 in 2070. A 70% efficacious vaccine introduced in 2027 with three doses, strong uptake and five years of protection would reduce annual new infections by 44% over the first decade, by 65% the first 25 years and by 78% to 122,000 in 2070. Vaccine impact would be much greater if the assumptions in UNAIDS IFE were not fully achieved. An AIDS vaccine would be cost-effective within a wide range of scenarios.

Interpretation

Even a modestly effective vaccine could contribute strongly to a sustainable response to HIV/AIDS and be cost-effective, even with optimistic assumptions about other interventions. Higher efficacy would provide even greater impact and cost-effectiveness, and would support broader access. Vaccine efficacy and cost per regimen are critical in achieving cost-effectiveness, with cost per regimen being particularly critical in low-income countries and at lower efficacy levels.     

Autonomous targeting of infectious superspreaders using engineered transmissible therapies

Infectious disease treatments, both pharmaceutical and vaccine, face three universal challenges: the difficulty of targeting treatments to high-risk 'superspreader' populations who drive the great majority of disease spread, behavioral barriers in the host population (such as poor compliance and risk disinhibition), and the evolution of pathogen resistance. Here, we describe a proposed intervention that would overcome these challenges by capitalizing upon Therapeutic Interfering Particles (TIPs) that are engineered to replicate conditionally in the presence of the pathogen and spread between individuals--analogous to 'transmissible immunization' that occurs with live-attenuated vaccines (but without the potential for reversion to virulence). Building on analyses of HIV field data from sub-Saharan Africa, we construct a multi-scale model, beginning at the single-cell level, to predict the effect of TIPs on individual patient viral loads and ultimately population-level disease prevalence. Our results show that a TIP, engineered with properties based on a recent HIV gene-therapy trial, could stably lower HIV/AIDS prevalence by ～30-fold within 50 years and could complement current therapies. In contrast, optimistic antiretroviral therapy or vaccination campaigns alone could only lower HIV/AIDS prevalence by <2-fold over 50 years. The TIP's efficacy arises from its exploitation of the same risk factors as the pathogen, allowing it to autonomously penetrate superspreader populations, maintain efficacy despite behavioral disinhibition, and limit viral resistance. While demonstrated here for HIV, the TIP concept could apply broadly to many viral infectious diseases and would represent a new paradigm for disease control, away from pathogen eradication but toward robust disease suppression.