Evolution of HIV virulence in response to disease-modifying vaccines: A modeling study.

Pathogens face a tradeoff with respect to virulence; while more virulent strains often have higher per-contact transmission rates, they are also more likely to kill their hosts earlier. Because virulence is a heritable trait, there is concern that a disease-modifying vaccine, which reduces the disease severity of an infected vaccinee without changing the underlying pathogen genotype, may result in the evolution of higher pathogen virulence. We explored the potential for such virulence evolution with a disease-modifying HIV-1 vaccine in an agent-based stochastic epidemic model of HIV in United States men who have sex with men (MSM). In the model, vaccinated agents received no protection against infection, but experienced lower viral loads and slower disease progression. We compared the genotypic set point viral load (SPVL), a measure of HIV virulence, in populations given vaccines that varied in the degree of SPVL reduction they induce. Sensitivity analyses were conducted under varying vaccine coverage scenarios. With continual vaccination rollout under ideal circumstances of 90 % coverage over thirty years, the genotypic SPVL of vaccinated individuals evolved to become greater than the genotypic SPVL of unvaccinated individuals. This virulence evolution in turn diminished the public health benefit of the vaccine, and in some scenarios resulted in an accelerated epidemic. These findings demonstrate the complexity of viral evolution and have important implications for the design and development of HIV vaccines.

Population-level impact of expanding PrEP coverage by offering long-acting injectable PrEP to MSM in three high-resource settings: a model comparison analysis.

INTRODUCTION: Long-acting injectable cabotegravir (CAB-LA) demonstrated superiority to daily tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) for HIV pre-exposure prophylaxis (PrEP) in the HPTN 083/084 trials. We compared the potential impact of expanding PrEP coverage by offering CAB-LA to men who have sex with men (MSM) in Atlanta (US), Montreal (Canada) and the Netherlands, settings with different HIV epidemics. METHODS: Three risk-stratified HIV transmission models were independently parameterized and calibrated to local data. In Atlanta, Montreal and the Netherlands, the models, respectively, estimated mean TDF/FTC coverage starting at 29%, 7% and 4% in 2022, and projected HIV incidence per 100 person-years (PY), respectively, decreasing from 2.06 to 1.62, 0.08 to 0.03 and 0.07 to 0.001 by 2042. Expansion of PrEP coverage was simulated by recruiting new CAB-LA users and by switching different proportions of TDF/FTC users to CAB-LA. Population effectiveness and efficiency of PrEP expansions were evaluated over 20 years in comparison to baseline scenarios with TDF/FTC only. RESULTS: Increasing PrEP coverage by 11 percentage points (pp) from 29% to 40% by 2032 was expected to avert a median 36% of new HIV acquisitions in Atlanta. Substantially larger increases (by 33 or 26 pp) in PrEP coverage (to 40% or 30%) were needed to achieve comparable reductions in Montreal and the Netherlands, respectively. A median 17 additional PYs on PrEP were needed to prevent one acquisition in Atlanta with 40% PrEP coverage, compared to 1000+ in Montreal and 4000+ in the Netherlands. Reaching 50% PrEP coverage by 2032 by recruiting CAB-LA users among PrEP-eligible MSM could avert >45% of new HIV acquisitions in all settings. Achieving targeted coverage 5 years earlier increased the impact by 5-10 pp. In the Atlanta model, PrEP expansions achieving 40% and 50% coverage reduced differences in PrEP access between PrEP-indicated White and Black MSM from 23 to 9 pp and 4 pp, respectively. CONCLUSIONS: Achieving high PrEP coverage by offering CAB-LA can impact the HIV epidemic substantially if rolled out without delays. These PrEP expansions may be efficient in settings with high HIV incidence (like Atlanta) but not in settings with low HIV incidence (like Montreal and the Netherlands).

Estimating benefits of using on-demand oral prep by MSM: A comparative modeling study of the US and Thailand.

Background: Daily and on-demand pre-exposure prophylaxis (PrEP) are effective at preventing HIV acquisition among men who have sex with men (MSM), but only daily PrEP is approved in the US. On-demand PrEP may improve uptake and adherence. We identify sub-groups of MSM who would benefit from on-demand PrEP and determine effectiveness achieved if individuals used their optimal regimens. Methods: Using data from the HPTN 067 study (study period 2012-2014), we created an individual-based stochastic model of HIV risk in two synthetic MSM populations with parameters separately estimated using data from Harlem, US, and Bangkok, Thailand. Agents were assigned daily and on-demand PrEP for six months each. Two personalized PrEP assignments: optimal, based on improved predicted effectiveness and reduced pill burden, and adherence-based, using daily PrEP adherence, were simulated for another six months. Findings: Simulated on-demand PrEP was optimal for approximately one-third of MSM. It was assigned mainly to those with low daily PrEP adherence (88% (Harlem), 95% (Bangkok) of MSM with daily PrEP adherence <40%). Mean effectiveness was slightly higher in the full synthetic population with optimal PrEP assignment compared to universal daily PrEP. Among MSM for whom on-demand PrEP was optimal, mean effectiveness improved by 18 (Harlem) and 7 percentage points (Bangkok). Comparable predicted effectiveness was achieved if on-demand PrEP was assigned to the population with daily PrEP adherence <50%. There was no advantage in assigning on-demand PrEP by sex act frequency. Interpretation: On-demand PrEP could benefit many MSM by increasing effectiveness or decreasing pill burden with similar effectiveness. On-demand PrEP may be an effective alternative to daily PrEP for individuals with difficulty taking daily PrEP consistently. Results were similar for Harlem and Bangkok, indicating that these conclusions were robust in populations with different overall adherence levels and may inform future public-health policies. Funding: US NIH grant UM1 AI068617.

Why does age at HIV infection correlate with set point viral load? An evolutionary hypothesis.

BACKGROUND: Set-point viral load (SPVL) correlates with the age at which people acquire HIV. Although immunosenescence may seem like a parsimonious explanation for this, it does not easily explain the observation that the relationship between age and SPVL attenuates when accounting for source partner SPVL. Here we propose an alternative explanation that encompasses this latter finding: that decreasing risk of acquisition with older age generates a selection bottleneck that selects for more virulent strains with age. METHODS: We adapted a previously published model of HIV transmission and evolution (EvoNetHIV), parameterized here for men who have sex with men (MSM). We conducted a series of simulation experiments that vary seven behavioral or clinical parameters that affect exposure risk as people age. We conducted regressions to determine the mean increase in SPVL per 10-year increase in seroconversion age, with and without source SPVL in the model. RESULTS: All runs generated significant relationships between seroconversion age and SPVL when not including source SPVL. All saw attenuated relationships, most to near 0, with source SPVL included. Four of our behavioral measures (relational duration, age-related homophily, coital frequency, and mean age at relationship formation) had clear effects on this relationship, all in the hypothesized direction. Combining multiple forms of behavioral heterogeneity yielded an increase of 0.056 log10 copies/mL SPVL per 10-year increase in seroconversion age, nearly as large as that seen in two empirical studies of age-SPVL correlations in MSM. CONCLUSION: The higher virulence of HIV among those infected later in life may be partly explained by a combination of selective bottlenecks and behavioral heterogeneity by age. Variation in the strength of this effect across populations may be in part due to different behavioral, epidemiological and clinical conditions, and not require assumptions about differences in patterns of immunosenescence among populations.

Test-and-treat coverage and HIV virulence evolution among men who have sex with men.

HIV set point viral load (SPVL), the viral load established shortly after initial infection, is a proxy for HIV virulence: higher SPVLs lead to higher risk of transmission and faster disease progression. Three models of test-and-treat scenarios, mainly in heterosexual populations, found that increasing treatment coverage selected for more virulent viruses. We modeled virulence evolution in a population of men who have sex with men (MSM) with increasing test-and-treat coverage. We extended a stochastic, dynamic network model (EvoNetHIV). We varied relationship patterns (MSM vs. heterosexual), HIV transmission models (increasing vs. plateauing probability of transmission at very high viral loads), and treatment roll-out (with explicit testing or fixed intervals between infection and treatment). In scenarios most similar to previous models (longer relational durations and the plateauing transmission function), we replicated trends previously found: increasing treatment coverage led to increased virulence (0.12 log10 increase in mean population SPVL between 20% and 100% treatment coverage). In scenarios reflecting MSM behavioral data using the increasing transmission function, increasing treatment coverage selected for viruses with lower virulence (0.16 log10 decrease in mean population SPVL between 20% and 100% treatment coverage). These findings emphasize the impact of sexual network conditions and transmission function details on predicted epidemiological and evolutionary outcomes. Varying these features creates very different evolutionary environments, which in turn lead to opposite effects in mean population SPVL evolution. Our results suggest that, under some realistic conditions, effective test-and-treat strategies may not face the previously reported tradeoff in which increasing coverage leads to evolution of greater virulence. This suggests instead that a virtuous cycle of increasing treatment coverage and diminishing virulence is possible.

Large benefits to youth-focused HIV treatment-as-prevention efforts in generalized heterosexual populations: An agent-based simulation model.

Predominantly heterosexual HIV-1 epidemics like those in sub-Saharan Africa continue to have high HIV incidence in young people. We used a stochastic, agent-based model for age-disparate networks to test the hypothesis that focusing uptake and retention of ART among youth could enhance the efficiency of treatment as prevention (TasP) campaigns. We used the model to identify strategies that reduce incidence to negligible levels (i.e., < 0.1 cases/100 person-years) 20-25 years after initiation of a targeted TasP campaign. The model was parameterized using behavioral, demographic, and clinical data from published papers and national reports. To keep a focus on the underlying age effects we model a generalized heterosexual population with average risks (i.e., no MSM, no PWIDs, no sex workers) and no entry of HIV+ people from other regions. The model assumes that most people (default 95%, range in variant simulations 60-95%) are "linkable"; i.e., could get linked to effective care given sufficient resources. To simplify the accounting, we assume a rapid jump in the number of people receiving treatment at the start of the TasP campaign, followed by a 2% annual increase that continues until all linkable HIV+ people have been treated. Under historical scenarios of CD4-based targeted ART allocation and current policies of untargeted (random) ART allocation, our model predicts that viral replication would need to be suppressed in 60-85% of infected people at the start of the TasP campaign to drive incidence to negligible levels. Under age-based strategies, by contrast, this percentage dropped by 18-54%, depending on the strength of the epidemic and the age target. For our baseline model, targeting those under age 30 halved the number of people who need to be treated. Age-based targeting also minimized total and time-discounted AIDS deaths over 25 years. Age-based targeting yielded benefits without being highly exclusive; in a model in which 60% of infected people were treated, ~87% and ~58% of those initiating therapy during a campaign targeting those <25 and <30 years, respectively, fell outside the target group. Sensitivity analyses revealed that youth-focused TasP is beneficial due to age-related risk factors (e.g. shorter relationship durations), and an age-specific herd immunity (ASHI) effect that protects uninfected adolescents entering the sexually active population. As testing rates increase in response to UNAIDS 90-90-90 goals, efforts to link all young people to care and treatment could contribute enormously to ending the HIV epidemic.

Models to predict the public health impact of vaccine resistance: A systematic review.

Pathogen evolution is a potential threat to the long-term benefits provided by public health vaccination campaigns. Mathematical modeling can be a powerful tool to examine the forces responsible for the development of vaccine resistance and to predict its public health implications. We conducted a systematic review of existing literature to understand the construction and application of vaccine resistance models. We identified 26 studies that modeled the public health impact of vaccine resistance for 12 different pathogens. Most models predicted that vaccines would reduce overall disease burden in spite of evolution of vaccine resistance. Relatively few pathogens and populations for which vaccine resistance may be problematic were covered in the reviewed studies, with low- and middle-income countries particularly under-represented. We discuss the key components of model design, as well as patterns of model predictions.

Sexual role and HIV-1 set point viral load among men who have sex with men.

BACKGROUND: HIV-1 set point viral load (SPVL) is a highly variable trait that influences disease progression and transmission risk. Men who are exclusively insertive (EI) during anal intercourse require more sexual contacts to become infected than exclusively receptive (ER) men. Thus, we hypothesize that EIs are more likely to acquire their viruses from highly infectious partners (i.e., with high SPVLs) and to have higher SPVLs than infected ERs. METHODS: We used a one-generation Bernoulli model, a dynamic network model, and data from the Multicenter AIDS Cohort Study (MACS) to examine whether and under what circumstances MSM differ in SPVL by sexual role. RESULTS: Both models predicted higher SPVLs in EIs than role versatile (RV) or ER men, but only in scenarios where longer-term relationships predominated. ER and RV men displayed similar SPVLs. EI men remained far less likely than ER men to become infected, however. When the MACS data were limited by some estimates of lower sex partner counts (a proxy for longer relationships), EI men had higher SPVLs; these differences were clinically relevant (>0.3 log10 copies/mL) and statistically significant (p < 0.05). CONCLUSIONS: Mode of acquisition may be an important aspect of SPVL evolution in MSM, with clinical implications.

Relational concurrency, stages of infection, and the evolution of HIV set point viral load.

HIV viral load (VL) predicts both transmission potential and rate of disease progression. For reasons that are still not fully understood, the set point viral load (SPVL) established after acute infection varies across individuals and populations. Previous studies have suggested that population mean SPVL (MSPVL) has evolved near an optimum that reflects a trade-off between transmissibility and host survival. Sexual network structures affect rates of potential exposure during different within-host phases of infection marked by different transmission probabilities, and thus affect the number and timing of transmission events. These structures include relational concurrency, which has been argued to explain key differences in HIV burden across populations. We hypothesize that concurrency will alter the fitness landscape for SPVL in ways that differ from other network features whose impacts accrue at other times during infection. To quantitatively test this hypothesis, we developed a dynamic, stochastic, data-driven network model of HIV transmission, and evolution to assess the impact of key sexual network phenomena on MSPVL evolution. Experiments were repeated in sensitivity runs that made different assumptions about transmissibility during acute infection, SPVL heritability, and the functional form of the relationship between VL and transmissibility. For our main transmission model, scenarios yielded MSPVLs ranging from 4.4 to 4.75 log10 copies/ml, covering much of the observed empirical range. MSPVL evolved to be higher in populations with high concurrency and shorter relational durations, with values varying over a clinically significant range. In linear regression analyses on these and other predictors, main effects were significant (P < 0.05), as were interaction terms, indicating that effects are interdependent. We also noted a strong correlation between two key emergent properties measured at the end of the simulations-MSPVL and HIV prevalence-most clearly for phenomena that affect transmission networks early in infection. Controlling for prevalence, high concurrency yielded higher MSPVL than other network phenomena. Interestingly, we observed lower prevalence in runs in which SPVL heritability was zero, indicating the potential for viral evolution to exacerbate disease burden over time. Future efforts to understand empirical variation in MSPVL should consider local HIV burden and basic sexual behavioral and network structure.

Sources of racial disparities in HIV prevalence in men who have sex with men in Atlanta, GA, USA: a modelling study.

BACKGROUND: In the USA, men who have sex men (MSM) are at high risk for HIV, and black MSM have a substantially higher prevalence of infection than white MSM. We created a simulation model to assess the strength of existing hypotheses and data that account for these disparities. METHODS: We built a dynamic, stochastic, agent-based network model of black and white MSM aged 18-39 years in Atlanta, GA, USA, that incorporated race-specific individual and dyadic-level prevention and risk behaviours, network attributes, and care patterns. We estimated parameters from two Atlanta-based studies in this population (n=1117), supplemented by other published work. We modelled the ability for racial assortativity to generate or sustain disparities in the prevalence of HIV infection, alone or in conjunction with scenarios of observed racial patterns in behavioural, care, and susceptibility parameters. FINDINGS: Race-assortative mixing alone could not sustain a pre-existing disparity in prevalence of HIV between black and white MSM. Differences in care cascade, stigma-related behaviours, and CCR5 genotype each contributed substantially to the disparity (explaining 10·0%, 12·7%, and 19·1% of the disparity, respectively), but nearly half (44·5%) could not be explained by the factors investigated. A scenario assessing race-specific reporting differences in risk behaviour was the only one to yield a prevalence in black MSM (44·1%) similar to that observed (43·4%). INTERPRETATION: Racial assortativity is an inadequate explanation for observed disparities. Work to close the gap in the care cascade by race is imperative, as are efforts to increase serodiscussion and strengthen relationships among black MSM particularly. Further work is urgently needed to identify other sources of, and pathways for, this disparity, to integrate concomitant epidemics into models, and to understand reasons for racial differences in behavioural reporting. FUNDING: The Eunice Kennedy Shriver National Institute of Child Health and Development, the National Institute of Allergy and Infectious Diseases, the National Institute of Minority Health and Health Disparities, and the National Institute of Mental Health.