Risk compensation after HIV-1 vaccination may accelerate viral adaptation and reduce cost-effectiveness: a modeling study.

Pathogen populations can evolve in response to selective pressure from vaccine-induced immune responses. For HIV, models predict that viral adaptation, either via strain replacement or selection on de novo mutation, may rapidly reduce the effectiveness of an HIV vaccine. We hypothesized that behavioral risk compensation after vaccination may accelerate the transmission of vaccine resistant strains, increasing the rate of viral adaptation and leading to a more rapid decline in vaccine effectiveness. To test our hypothesis, we modeled: (a) the impact of risk compensation on rates of HIV adaptation via strain replacement in response to a partially effective vaccine; and (b) the combined impact of risk compensation and viral adaptation on vaccine-mediated epidemic control. We used an agent-based epidemic model that was calibrated to HIV-1 trends in South Africa, and includes demographics, sexual network structure and behavior, and within-host disease dynamics. Our model predicts that risk compensation can increase the rate of HIV viral adaptation in response to a vaccine. In combination, risk compensation and viral adaptation can, under certain scenarios, reverse initial declines in prevalence due to vaccination, and result in HIV prevalence at 15 years equal to or greater than prevalence without a vaccine.

The Time Is Now to End the HIV Epidemic.

In his State of the Union Address on February 5, 2019, President Donald J. Trump announced his administration's goal to end the domestic HIV epidemic. Following the announcement of the Ending the HIV Epidemic: A Plan for America initiative, the president proposed $291 million in new funding for the fiscal year 2020 Department of Health and Human Services (HHS) budget to implement a new initiative to reduce the number of new HIV infections by 75% in the next five years (2025) and by 90% in the next 10 years (2030). This is in addition to the $20 billion the US government already spends each year, domestically, for HIV prevention and care.With this initiative, HHS recognizes that the time to end the HIV epidemic is now: we have the right data, the right biomedical and behavioral tools, and the right leadership. With the new resources, the goal is achievable.This article outlines how this initiative will be accomplished through the implementation of four fundamental strategies that will be tailored by local communities on the basis of their own needs and strengths.

The future of a partially effective HIV vaccine: assessing limitations at the population level.

OBJECTIVES: Mathematical models have unanimously predicted that a first-generation HIV vaccine would be useful and cost-effective to roll out, but that its overall impact would be insufficient to reverse the epidemic. Here, we explore what factors contribute most to limiting the impact of such a vaccine. METHODS: Ranging from a theoretical ideal to a more realistic regimen, mirroring the one used in the currently ongoing trial in South Africa (HVTN 702), we model a nested hierarchy of vaccine attributes such as speed of scale-up, efficacy, durability, and return rates for booster doses. RESULTS: The predominant reasons leading to a substantial loss of vaccine impact on the HIV epidemic are the time required to scale up mass vaccination, limited durability, and waning of efficacy. CONCLUSIONS: A first-generation partially effective vaccine would primarily serve as an intermediate milestone, furnishing correlates of immunity and platforms that could serve to accelerate future development of a highly effective, durable, and scalable next-generation vaccine capable of reversing the HIV epidemic.

Acceptability of vaccination against HIV: A mapping of Togolese people's positions.

In anticipation of a future HIV vaccine, we mapped the different personal positions regarding HIV vaccination of people in Togo. In early 2014, 363 adults indicated their willingness to receive a future HIV vaccine under different conditions varying as a function of five factors: perceived susceptibility to HIV, vaccine effectiveness, perceived severity of AIDS, vaccine cost, and family's influence. We found five qualitatively different positions: unconditional acceptance (49%), depends on cost/effectiveness ratio (20%), depends on cost (18%), total indecision (10%), and complete reluctance (3%). Accordingly, HIV vaccination strategies in Togo and elsewhere in Africa need to be multifaceted and tailored.

Projected economic evaluation of the national implementation of a hypothetical HIV vaccination program among adolescents in South Africa, 2012.

BACKGROUND: Adolescents in South Africa are at high risk of acquiring HIV. The HIV vaccination of adolescents could reduce HIV incidence and mortality. The potential impact and cost-effectiveness of a national school-based HIV vaccination program among adolescents was determined. METHOD: The national HIV disease and cost burden was compared with (intervention) and without HIV vaccination (comparator) given to school-going adolescents using a semi-Markov model. Life table analysis was conducted to determine the impact of the intervention on life expectancy. Model inputs included measures of disease and cost burden and hypothetical assumptions of vaccine characteristics. The base-case HIV vaccine modelled cost at US$ 12 per dose; vaccine efficacy of 50 %; duration of protection of 10 years achieved at a coverage rate of 60 % and required annual boosters. Incremental cost-effectiveness ratios (ICER) were calculated using life years gained (LYG) serving as the outcome measure. Sensitivity analyses were conducted on the vaccine characteristics to assess parameter uncertainty. RESULTS: The HIV vaccination model yielded an ICER of US$ 5 per LYG (95 % CI ZAR 2.77-11.61) compared with the comparator, which is considerably less than the national willingness-to-pay threshold of cost-effectiveness. This translated to an 11 % increase in per capita costs from US$ 80 to US$ 89. National implementation of this intervention could potentially result in an estimated cumulative gain of 23.6 million years of life (95 % CI 8.48-34.3 million years) among adolescents age 10-19 years that were vaccinated. The 10 year absolute risk reduction projected by vaccine implementation was 0.42 % for HIV incidence and 0.41 % for HIV mortality, with an increase in life expectancy noted across all age groups. The ICER was sensitive to the vaccine efficacy, coverage and vaccine pricing in the sensitivity analysis. CONCLUSIONS: A national HIV vaccination program would be cost-effective and would avert new HIV infections and decrease the mortality and morbidity associated with HIV disease. Decision makers would have to discern how these findings, derived from local data and reflective of the South African epidemic, can be integrated into the national long term health planning should a HIV vaccine become available.

Statistical methods for the analysis of clinical trials data containing many zeros: An application in vaccine development.

In recent years, many vaccines have been developed for the prevention of a variety of diseases. Many of these vaccines, like the one for herpes zoster, are supposed to act in a multilevel way. Ideally, they completely prevent expression of the virus, but failing that they help to reduce the severity of the disease. A simple approach to analyze these data is the so-called burden-of-illness test. The method assigns a score, say W, equal to 0 for the uninfected and a post-infection outcome X > 0 for the infected individuals. One of the limitations of this test is the potential low power when the vaccine efficacy is close to 0. To overcome this limitation, we propose a Fisher adjusted test where we combine a statistic for infection with a statistic for post-infection outcome adjusted for selection bias. The advantages and disadvantages of different methods proposed in the literature are discussed. We compared the methods via simulations in herpes zoster, HIV, and malaria vaccine trial settings. In addition, we applied these methods to published data on HIV vaccine. The paper ends with some recommendations and conclusions.

Socioeconomic status and HIV vaccine preparedness studies in North America.

Educational level, employment, and income are key components of socioeconomic status (SES). This article is a systematic review of SES variables in North American countries, and their relationship to willingness to participate (WTP) and retention in a hypothetical preventive phase 3 HIV vaccine trial and in actual HIV vaccine trials. Men who have sex with men (MSM) tended to have higher educational levels, be more employed, and had higher income levels than injection drug users (IDU) and women at heterosexual risk (WAHR). In large part, there was no relationship between educational level and WTP, as well as between educational level and retention. Similarly, there was no relationship between employment and WTP. In WAHR who were African-American, those employed were less likely than others to complete the study at 18 months. The exact occupations of participants analyzed have not been specified, and specification of these occupations may help determine whether enhanced retention (ER) strategies are required.

Safety, immunogenicity and efficacy assessment of HIV immunotherapy in a multi-centre, double-blind, randomised, Placebo-controlled Phase Ib human trial.

BACKGROUND: Combination antiretroviral therapy (cART) is the main therapeutic management tool for HIV/AIDS. Despite its success in controlling viral load and disease progression, cART is expensive, associated with a range of significant side effects and depends for its efficacy on the patient's life-long commitment to high levels of treatment adherence. Immunotherapeutic agents can provide potential solutions to these shortcomings. Here we describe a Phase Ib trial of HIV-v, a synthetic immunotherapy that elicits T- and B-cell effector responses against HIV infected cells. METHODS: Fifty-nine cART-naive HIV-infected males aged 18-50 years with viral load of 5000-500,000 copies/ml and CD4 counts >350/µl were recruited for this multi-centre, randomised, double blind study. Volunteers received one low (250 µg) or high (500 µg) dose of HIV-v, either alone or adjuvanted (ISA-51). Safety, immunogenicity, CD4 count and viral load were monitored over 168 Days. RESULTS: HIV-v was well tolerated and the adjuvanted formulations elicited IgG responses in up to 75% of volunteers. The high adjuvanted dose also elicited cellular responses in 45% of tested volunteers. In these responding subjects viral loads were reduced by over 1 log (p=0.04) compared to Placebo and non-responders. No changes in CD4 count were observed. CONCLUSIONS: HIV-v is safe and can elicit T- and B-cell responses in ART-naive HIV patients that significantly reduce viral load. Improved dosing regimens and further research on long term efficacy are required, but HIV-v appears to have potential as an immunotherapeutic anti-viral agent. Trial registered as EudraCT-2009-010593-37 (ClinicalTrials.gov Identifier: NCT01071031).

Enhanced retention strategies and willingness to participate among hard-to-reach female sex workers in Barcelona for HIV prevention and vaccine trials.

The potential for implementation of HIV vaccine trials in hard-to-reach female sex workers in an inner city area of Barcelona, Spain was assessed via a study of HIV risk, willingness to participate and the success of retention strategies. In 130 women, serological HIV status, behavioral risk exposures and willingness to participate in future HIV vaccine trials were recorded every six months using a confidential questionnaire. An enhanced retention (ER) strategy was compared with a control retention (CR) strategy comprising the recording of data on appointment cards. HIV seroincidence and retention rates were estimated. Retention rates after 6 and 12 mo of follow-up in the ER group were 76% and 69% respectively compared with 16% and 13% in the CR group. Among the ER group 97% were willing to participate in HIV vaccine trials at baseline and, after 12 mo of follow-up. Willingness was significantly associated with higher HIV risk exposure, and higher education level. Successfully retaining these cohorts over time in settings with a high HIV seroincidence rate is an ongoing challenge that will need to be addressed to ensure participation in future trials. Furthermore, as we have demonstrated, the fact that retaining hard-to-reach populations is difficult should not exclude this target population for HIV vaccine and prevention trials.

A social vaccine? Social and structural contexts of HIV vaccine acceptability among most-at-risk populations in Thailand.

A safe and efficacious preventive HIV vaccine would be a tremendous asset for low- and middle-income country (LMIC) settings, which bear the greatest global impact of AIDS. Nevertheless, substantial gaps between clinical trial efficacy and real-world effectiveness of already licensed vaccines demonstrate that availability does not guarantee uptake. In order to advance an implementation science of HIV vaccines centred on LMIC settings, we explored sociocultural and structural contexts of HIV vaccine acceptability among most-at-risk populations in Thailand, the site of the largest HIV vaccine trial ever conducted. Cross-cutting challenges for HIV vaccine uptake - social stigma, discrimination in healthcare settings and out-of-pocket vaccine cost - emerged in addition to population-specific barriers and opportunities. A 'social vaccine' describes broad sociocultural and structural interventions - culturally relevant vaccine promotion galvanised by communitarian norms, mitigating anti-gay, anti-injecting drug user and HIV-related stigma, combating discrimination in healthcare, decriminalising adult sex work and injecting drug use and providing vaccine cost subsidies - that create an enabling environment for HIV vaccine uptake among most-at-risk populations. By approaching culturally relevant social and structural interventions as integral mechanisms to the success of new HIV prevention technologies, biomedical advances may be leveraged in renewed opportunities to promote and optimise combination prevention.

Background morbidity in HIV vaccine trial participants from various geographic regions as assessed by unsolicited adverse events.

BACKGROUND: Recently, more clinical trials are being conducted in Africa and Asia, therefore, background morbidity in the respective populations is of interest. Between 2000 and 2007, the International AIDS Vaccine Initiative sponsored 19 Phase 1 or 2A preventive HIV vaccine trials in the US, Europe, Sub-Saharan Africa and India, enrolling 900 healthy HIV-1 uninfected volunteers. OBJECTIVE: To assess background morbidity as reflected by unsolicited adverse events (AEs), unrelated to study vaccine, reported in clinical trials from four continents. METHODS: All but three clinical trials were double-blind, randomized, and placebo-controlled. Study procedures and data collection methods were standardized. The frequency and severity of AEs reported during the first year of the trials were analyzed. To avoid confounding by vaccine-related events, solicited reactogenicity and other AEs occurring within 28 d after any vaccination were excluded. RESULTS: In total, 2134 AEs were reported by 76% of all participants; 73% of all events were mild. The rate of AEs did not differ between placebo and vaccine recipients. Overall, the percentage of participants with any AE was higher in Africa (83%) compared with Europe (71%), US (74%) and India (65%), while the percentage of participants with AEs of moderate or greater severity was similar in all regions except India. In all regions, the most frequently reported AEs were infectious diseases, followed by gastrointestinal disorders. CONCLUSIONS: Despite some regional differences, in these healthy participants selected for low risk of HIV infection, background morbidity posed no obstacle to clinical trial conduct and interpretation. Data from controlled clinical trials of preventive interventions can offer valuable insights into the health of the eligible population.

Use of conjoint analysis to assess HIV vaccine acceptability: feasibility of an innovation in the assessment of consumer health-care preferences.

Engaging consumers in prospectively shaping strategies for dissemination of health-care innovations may help to ensure acceptability. We examined the feasibility of using conjoint analysis to assess future HIV vaccine acceptability among three diverse communities: a multiethnic sample in Los Angeles, CA, USA (n = 143); a Thai resident sample in Los Angeles (three groups; n = 27) and an Aboriginal peoples sample in Toronto (n = 13). Efficacy had the greatest impact on acceptability for all three groups, followed by cross-clade protection, side-effects and duration of protection in the Los Angeles sample; side-effects and duration of protection in the Thai-Los Angeles sample; and number of doses and duration of protection in the Aboriginal peoples-Toronto sample. Conjoint analysis provided insights into universal and population-specific preferences among diverse end users of future HIV vaccines, with implications for evidence-informed targeting of dissemination efforts to optimize vaccine uptake.

The potential impact of an HIV vaccine with rapidly waning protection on the epidemic in Southern Africa: examining the RV144 trial results.

BACKGROUND: The prime-boost HIV vaccine regimen used in the recent RV144 trial resulted in modest efficacy of 31% over 3.5 years, but was substantially higher in the first year post-vaccination. We sought to explore the potential impact of a vaccine with rapidly waning efficacy in a South African population. METHODS: We explored two strategies using a dynamic compartmental epidemic model for heterosexual transmission of HIV: [1] vaccination of a single cohort (30%, 60% or 90% of the initial population), with exponentially waning efficacy, but booster vaccinations at 5- or 2-year intervals, and [2] continuous vaccination of the unvaccinated population at the same coverage levels (30%, 60% or 90%) but with a constant efficacy vaccine of short duration. We also examined potential changes in post-vaccination condom use. RESULTS: The single cohort vaccination strategies did not have a substantial impact on HIV prevalence, although without boosters they still prevented 2-6% of the expected infections at 20 years, depending on the population coverage. The 5-year and 2-year booster strategies prevented 8-24% and 17-45% of the expected infections, respectively. Continuous vaccination to maintain population coverage levels resulted in more substantial reductions in population HIV prevalence and greater numbers of infections prevented: HIV prevalence at 20 years was reduced from 23% to 8-14% and the number of expected infections was decreased by 34-59%, depending on the population coverage level. Moderate changes in post-vaccination condom use did not substantially affect these outcomes. CONCLUSIONS: An HIV vaccine with partial efficacy and declining protection similar to the RV144 vaccine could prevent a substantial proportion of HIV infections if booster vaccinations were effective and available. Our estimates of the population impact of vaccination would be improved by further understanding of the duration of protection, the effectiveness of booster vaccination, and whether the vaccine efficacy varies between subpopulations at higher and lower risk of exposure.

The potential impact of an HIV vaccine with limited protection on HIV incidence in Thailand: a modeling study.

BACKGROUND: The RV144 trial on the ALVAC/AIDSVAX candidate HIV vaccine, carried out in Thailand, showed short-lived protection against infection. METHODS: Using a deterministic compartmental model we explored the potential impact of this vaccine on heterosexual HIV transmission in Thailand. Both one-off vaccination strategies, as well as strategies with regular boosting, either annually or every two years, were explored. Both targeting the general adult population and prioritizing sex workers were modeled. The impact of risk compensation among high risk groups, as well as whether higher levels of safe sex in high risk groups could be an alternative to vaccination, was studied. RESULTS: One-off vaccination campaigns had only transient effects, and boosting appears to be a key component of successful vaccination campaigns. Intensive vaccination campaigns may reduce HIV incidence by up to 75% after 10 years of vaccination. Targeting only sex workers has a smaller impact but has a more favorable cost-benefit ratio. Risk compensation has the potential of undoing much of the benefits of a vaccination program and may even increase incidence. In contrast, higher levels of safe sex among sex workers would provide a viable alternative to vaccinating this group. DISCUSSION: The new vaccine holds promise for controlling HIV in Thailand and similar countries. In view of the short lived protection of the vaccine, regular boosting of immunity as well as avoidance of risk compensation are essential. Targeting sex workers would achieve the greatest reduction in incidence per vaccination and may be considered for expensive vaccines but its cost-effectiveness has to be compared to alternatives.

The potential impact of RV144-like vaccines in rural South Africa: a study using the STDSIM microsimulation model.

BACKGROUND: The only successful HIV vaccine trial to date is the RV144 trial of the ALVAC/AIDSVAX vaccine in Thailand, which showed an overall incidence reduction of 31%. Most cases were prevented in the first year, suggesting a rapidly waning efficacy. Here, we predict the population level impact and cost-effectiveness of practical implementation of such a vaccine in a setting of a generalised epidemic with high HIV prevalence and incidence. METHODS: We used STDSIM, an established individual-based microsimulation model, tailored to a rural South African area with a well-functioning HIV treatment and care programme. We estimated the impact of a single round of mass vaccination for everybody aged 15-49, as well as 5-year and 2-year re-vaccination strategies for young adults (aged 15-29). We calculated proportion of new infections prevented, cost-effectiveness indicators, and budget impact estimates of combined ART and vaccination programmes. RESULTS: A single round of mass vaccination with a RV144-like vaccine will have a limited impact, preventing only 9% or 5% of new infections after 10 years at 60% and 30% coverage levels, respectively. Revaccination strategies are highly cost-effective if vaccine prices can be kept below 150 US$/vaccine for 2-year revaccination strategies, and below 200 US$/vaccine for 5-year revaccination strategies. Net cost-savings through reduced need for HIV treatment and care occur when vaccine prices are kept below 75 US$/vaccine. These results are sensitive to alternative assumptions on the underlying sexual network, background prevention interventions, and individual's propensity and consistency to participate in the vaccination campaign. DISCUSSION: A modestly effective vaccine can be a cost-effective intervention in highly endemic settings. To predict the impact of vaccination strategies in other endemic situations, sufficient knowledge of the underlying sexual network, prevention and treatment interventions, and individual propensity and consistency to participate, is key. These issues are all best addressed in an individual-based microsimulation model.