Individual-Based Simulation Models of HIV Transmission: Reporting Quality and Recommendations

Background: Individual-based modeling is a growing technique in the HIV transmission and prevention literature, but insufficient attention has been paid to formally evaluate the quality of reporting in this field. We present reporting recommendations for individual-based models for HIV treatment and prevention, assess the quality of reporting in the existing literature, and comment on the contribution of this model type to HIV policy and prediction. Methods: We developed reporting recommendations for individual-based HIV transmission mathematical models, and through a systematic search, used them to evaluate the reporting in the existing literature. We identified papers that employed individual-based simulation models and were published in English prior to December 31, 2012. Articles were included if the models they employed simulated and tracked individuals, simulated HIV transmission between individuals in a particular population, and considered a particular treatment or prevention intervention. The papers were assessed with the reporting recommendations. Findings: Of 214 full text articles examined, 32 were included in the evaluation, representing 20 independent individual-based HIV treatment and prevention mathematical models. Manuscripts universally reported the objectives, context, and modeling conclusions in the context of the modeling assumptions and the model’s predictive capabilities, but the reporting of individual-based modeling methods, parameterization and calibration was variable. Six papers discussed the time step used and one discussed efforts to maintain internal validity in coding. Conclusion: Individual-based models represent detailed HIV transmission processes with the potential to contribute to inference and policy making for many different regions and populations. The rigor in reporting of assumptions, methods, and calibration of individual-based models focused on HIV transmission and prevention varies greatly. Higher standards for reporting of statistically rigorous calibration and model assumption testing need to be implemented to increase confidence in existing and future modeling results

Antiretroviral therapy to prevent HIV acquisition in serodiscordant couples in a hyperendemic community in rural South Africa

Background. Antiretroviral therapy (ART) was highly efficacious in preventing human immunodeficiency virus (HIV) transmission in stable serodiscordant couples in the HPTN-052 study, a resource-intensive randomized controlled trial with near-perfect ART adherence and mutual HIV status disclosure among all participating couples. However, minimal evidence exists of the effectiveness of ART in preventing HIV acquisition in stable serodiscordant couples in "real-life" population-based settings in hyperendemic communities of sub-Saharan Africa, where health systems are typically resource-poor and overburdened, adherence to ART is often low, and partners commonly do not disclose their HIV status to each other. Methods. Data arose from a population-based open cohort in KwaZulu-Natal, South Africa. A total of 17 016 HIV-uninfected individuals present between January 2005 and December 2013 were included. Interval-censored time-updated proportional hazards regression was used to assess how the ART status affected HIV transmission risk in stable serodiscordant relationships. Results. We observed 1619 HIV seroconversions in 17 016 individuals, over 60 349 person-years follow-up time. During the follow-up period, 1846 individuals had an HIV-uninfected and 196 had an HIV-infected stable partner HIV incidence was 3.8/100 person-years (PY) among individuals with an HIV-infected partner (95% confidence interval [CI], 2.3-5.6), 1.4/100 PY (.4-3.5) among those with HIV-infected partners receiving ART, and 5.6/100 PY (3.5-8.4) among those with HIV-infected partners not receiving ART. Use of ART was associated with a 77% decrease in HIV acquisition risk among serodiscordant couples (adjusted hazard ratio, 0.23; 95% CI,. 07-.80). Conclusions. ART initiation was associated with a very large reduction in HIV acquisition in serodiscordant couples in rural KwaZulu-Natal. However, this "real-life" effect was substantially lower than the effect observed in the HPTN-052 trial. To eliminate HIV transmission in serodiscordant couples, additional prevention interventions are probably needed

Sexual behavior, psychosocial and knowledge differences between consistent, inconsistent and non-users of condoms: a study of female bar and hotel workers in Moshi, Tanzania.

Understanding psychosocial, sexual behavior and knowledge differences between never, inconsistent and consistent condom users can improve interventions to increase condom use in resource-poor countries, but they have not been adequately studied. We examined these differences in a cohort of 961 female hotel and bar workers in Moshi, Tanzania. Forty-nine percent of women reported no condom use; 39% reported inconsistent use, and 12% reported consistent use. Women with multiple sexual partners in the past five years were less likely to be consistent rather than inconsistent users as were women who had ever exchanged sex for gifts or money. Inconsistent users had higher condom knowledge and higher perceived acceptability of condom use than did never users, but they did not differ from consistent users by these factors. There are important differences between women by level of condom use. These findings can help inform interventions to increase condom use

Impact of HAART and CNS-penetrating antiretroviral regimens on HIV encephalopathy among perinatally infected children and adolescents

Prior to antiretroviral treatment, HIV-infected children frequently developed encephalopathy, resulting in debilitating morbidity and mortality. This is the first large study to evaluate the impact of HAART and central nervous system (CNS)-penetrating antiretroviral regimens on the incidence of HIV encephalopathy and survival after diagnosis of HIV encephalopathy among perinatally infected children

Does Modality of Survey Administration Impact Data Quality: Audio Computer Assisted Self Interview (ACASI) Versus Self-Administered Pen and Paper?

BACKGROUND. In the context of a randomized controlled trial (RCT) on HIV testing in the emergency department (ED) setting, we evaluated preferences for survey modality and data quality arising from each modality. METHODS. Enrolled participants were offered the choice of answering a survey via audio computer assisted self-interview (ACASI) or pen and paper self-administered questionnaire (SAQ). We evaluated factors influencing choice of survey modality. We defined unusable data for a particular survey domain as answering fewer than 75% of the questions in the domain. We then compared ACASI and SAQ with respect to unusable data for domains that address sensitive topics. RESULTS. Of 758 enrolled ED patients, 218 (29%) chose ACASI, 343 chose SAQ (45%) and 197 (26%) opted not to complete either. Results of the log-binomial regression indicated that older (RR=1.08 per decade) and less educated participants (RR=1.25) were more likely to choose SAQ over ACASI. ACASI yielded substantially less unusable data than SAQ. CONCLUSIONS. In the ED setting there may be a tradeoff between increased participation with SAQ versus better data quality with ACASI. Future studies of novel approaches to maximize the use of ACASI in the ED setting are needed.National Institute of Mental Health (R01 MH073445, R01 MH65869

Nutritional Status and Other Baseline Predictors of Mortality among HIV-Infected Children Initiating Antiretroviral Therapy in Tanzania

BACKGROUND: We assembled a prospective cohort of 3144 children less than 15 years of age initiating antiretroviral therapy (ART) in Dar es Salaam, Tanzania. METHODS: The relationships of nutritional status and other baseline characteristics in relation to mortality were examined using Cox proportional hazards model. RESULTS: Compared with children with weight for age (WAZ) > -1, those with WAZ ≤ -2 to < -3 had a nearly double risk of death (relative risk [RR], 1.85; 95% confidence interval [CI], 1.10-3.11), and among those with WAZ ≤ -3, the risk more than tripled (RR, 3.36; 95% CI, 2.12-5.32). Other baseline risk factors for overall mortality included severe anemia (P < .001), severe immune suppression (P = .02), history of tuberculosis (P = .01), opportunistic infections (P < .001), living in the poorest district (P < .001), and advanced World Health Organization stage (P = .003). CONCLUSIONS: To sustain the obtained benefit of ART in this setting, interventions to improve nutritional status may be used as an adjunct to ART

Development, Calibration and Performance of an HIV Transmission Model Incorporating Natural History and Behavioral Patterns: Application in South Africa

Understanding HIV transmission dynamics is critical to estimating the potential population-wide impact of HIV prevention and treatment interventions. We developed an individual-based simulation model of the heterosexual HIV epidemic in South Africa and linked it to the previously published Cost-Effectiveness of Preventing AIDS Complications (CEPAC) International Model, which simulates the natural history and treatment of HIV. In this new model, the CEPAC Dynamic Model (CDM), the probability of HIV transmission per sexual encounter between short-term, long-term and commercial sex worker partners depends upon the HIV RNA and disease stage of the infected partner, condom use, and the circumcision status of the uninfected male partner. We included behavioral, demographic and biological values in the CDM and calibrated to HIV prevalence in South Africa pre-antiretroviral therapy. Using a multi-step fitting procedure based on Bayesian melding methodology, we performed 264,225 simulations of the HIV epidemic in South Africa and identified 3,750 parameter sets that created an epidemic and had behavioral characteristics representative of a South African population pre-ART. Of these parameter sets, 564 contributed 90% of the likelihood weight to the fit, and closely reproduced the UNAIDS HIV prevalence curve in South Africa from 1990–2002. The calibration was sensitive to changes in the rate of formation of short-duration partnerships and to the partnership acquisition rate among high-risk individuals, both of which impacted concurrency. Runs that closely fit to historical HIV prevalence reflect diverse ranges for individual parameter values and predict a wide range of possible steady-state prevalence in the absence of interventions, illustrating the value of the calibration procedure and utility of the model for evaluating interventions. This model, which includes detailed behavioral patterns and HIV natural history, closely fits HIV prevalence estimates

HIV Cure Strategies: How Good Must They Be to Improve on Current Antiretroviral Therapy?

Background: We examined efficacy, toxicity, relapse, cost, and quality-of-life thresholds of hypothetical HIV cure interventions that would make them cost-effective compared to life-long antiretroviral therapy (ART). Methods: We used a computer simulation model to assess three HIV cure strategies: Gene Therapy, Chemotherapy, and Stem Cell Transplantation (SCT), each compared to ART. Efficacy and cost parameters were varied widely in sensitivity analysis. Outcomes included quality-adjusted life expectancy, lifetime cost, and cost-effectiveness in dollars/quality-adjusted life year ($/QALY) gained. Strategies were deemed cost-effective with incremental cost-effectiveness ratios <$100,000/QALY. Results: For patients on ART, discounted quality-adjusted life expectancy was 16.4 years and lifetime costs were $591,400. Gene Therapy was cost-effective with efficacy of 10$54,000. Chemotherapy was cost-effective with efficacy of 88%, relapse rate 0.5%/month, and cost $12,400/month for 24 months. At$150,000/procedure, SCT was cost-effective with efficacy of 79% and relapse rate 0.5%/month. Moderate efficacy increases and cost reductions made Gene Therapy cost-saving, but substantial efficacy/cost changes were needed to make Chemotherapy or SCT cost-saving. Conclusions: Depending on efficacy, relapse rate, and cost, cure strategies could be cost-effective compared to current ART and potentially cost-saving. These results may help provide performance targets for developing cure strategies for HIV

CD4 Recovery on Antiretroviral Therapy Is Associated With Decreased Progression to Liver Disease Among Hepatitis C Virus-Infected Injecting Drug Users

Background. Human immunodeficiency virus (HIV) coinfection accelerates liver disease progression in individuals with chronic hepatitis C. We evaluated the associations of CD4, HIV RNA, and antiretroviral therapy (ART)-induced CD4 recovery with liver diagnoses in a prospective cohort of injecting drug users (IDUs). Methods. We evaluated 383 coinfected IDUs in the Boston area, prospectively observed for a median of 1.8 years. Liver disease progression included the first occurrence of hepatocellular carcinoma, variceal bleeding, ascites, encephalopathy, or death due to hepatic failure. Multivariable-adjusted extended Cox models were specified to estimate hazard ratios (HRs) for comparisons of CD4, change in CD4 (from nadir), and HIV RNA with respect to liver disease progression events. Results. Twenty-four persons experienced a liver disease progression event over 1155 person-years (2.1 per 100 person-years), including 20 deaths attributed to end-stage liver disease (1.7 per 100 person-years). CD4 at baseline and over follow-up strongly predicted liver disease progression (baseline CD4 <200 vs ≥200: HR = 5.23, 95% confidence interval [CI], 2.30–11.92; time-updated CD4 <200 vs ≥200: HR = 11.79, 95% CI, 4.47–31.07). Nadir CD4 was also a strong indicator (<100 vs ≥100: HR = 3.52, 95% CI, 1.54–8.06). A lack of CD4 recovery (failure to increase 100 cells over nadir) among ART initiators was associated with increased risk (HR = 7.69; 95% CI, 2.60–22.69). Human immunodeficiency virus RNA was not significantly associated with liver disease progression. Conclusions. Impaired immune function was highly predictive of liver disease progression in this cohort of IDUs, and a lack of CD4 recovery on ART was associated with increased risk of progression to HCV-associated liver disease

Using Observational Data to Calibrate Simulation Models

BACKGROUND: Individual-level simulation models are valuable tools for comparing the impact of clinical or public health interventions on population health and cost outcomes over time. However, a key challenge is ensuring that outcome estimates correctly reflect real-world impacts. Calibration to targets obtained from randomized trials may be insufficient if trials do not exist for populations, time periods, or interventions of interest. Observational data can provide a wider range of calibration targets but requires methods to adjust for treatment-confounder feedback. We propose the use of the parametric g-formula to estimate calibration targets and present a case-study to demonstrate its application. METHODS: We used the parametric g-formula applied to data from the HIV-CAUSAL Collaboration to estimate calibration targets for 7-y risks of AIDS and/or death (AIDS/death), as defined by the Center for Disease Control and Prevention under 3 treatment initiation strategies. We compared these targets to projections from the Cost-Effectiveness of Preventing AIDS Complications (CEPAC) model for treatment-naïve individuals presenting to care in the following year ranges: 1996 to 1999, 2000 to 2002, or 2003 onwards. RESULTS: The parametric g-formula estimated a decreased risk of AIDS/death over time and with earlier treatment. The uncalibrated CEPAC model successfully reproduced targets obtained via the g-formula for baseline 1996 to 1999, but over-estimated calibration targets in contemporary populations and failed to reproduce time trends in AIDS/death risk. Calibration to g-formula targets improved CEPAC model fit for contemporary populations. CONCLUSION: Individual-level simulation models are developed based on best available information about disease processes in one or more populations of interest, but these processes can change over time or between populations. The parametric g-formula provides a method for using observational data to obtain valid calibration targets and enables updating of simulation model inputs when randomized trials are not available