Human Immunodeficiency Virus in the State of Texas of the United States: Past Reflections, Present Shortcomings, and Future Needs of the Public Health Response.

A strategy titled "Ending the HIV Epidemic: A Plan for America" aims to reduce human immunodeficiency virus (HIV) incidence in the United States by at least 90% by 2030, using diagnosis, treatment, and prevention strategies. Texas is a Southern state that has one of the highest numbers of new HIV diagnoses and people with HIV in the country, and where HIV disproportionately impacts minorities. We retrace the historical epidemic in its largest city, Houston, to illustrate the lessons learned and milestones accomplished, which could serve as guideposts for the future. We examine the current epidemic in Texas, including the achieved levels of HIV testing, treatment continua, and pre-exposure prophylaxis prescription, and compare and contrast these with the national estimates and Plan targets. Our findings call for urgent and accelerated expansion of efforts to end HIV in Texas.

Drug resistance from preferred antiretroviral regimens for HIV infection in South Africa: A modeling study.

BACKGROUND: Tenofovir-containing regimens comprise the preferred first-line antiretroviral therapy (ART) in many countries including South Africa, where utilization of second-line regimens is limited. Considerable HIV drug resistance has occurred among persons failing tenofovir-containing first-line ART. We evaluated drug resistance at the population level using mathematical modeling. SETTING: Heterosexual HIV epidemic in KwaZulu-Natal, South Africa. METHODS: We constructed a stochastic individual-based model and simulated scenarios of ART implementation, either CD4-based (threshold < 500 cells/mL) or Fast-track (81% coverage by 2020), with consideration of major drug-associated mutations (M184V, K65R and non-nucleoside reverse transcriptase inhibitor (NNRTI)). Using base case and uncertainty analyses, we assessed (majority) drug resistance levels. RESULTS: By 2030, the median total resistance (proportion of HIV-infected persons with drug resistance) is predicted to reach 31.4% (interquartile range (IQR): 16.5%-50.2%) with CD4-based ART, decreasing to 14.5% (IQR: 7.7%-25.8%) with Fast-track implementation. In both scenarios, we find comparably high prevalence (~80%) of acquired NNRTI-associated, M184V and K65R mutations. Over 48% of individuals with acquired resistance harbor dual, 44% triple and 7% just single drug mutations. Drug-resistant HIV is predicted to comprise 40% (IQR: 27%-50%) of incident infections, while 70% of prevalent transmitted resistance is NNRTI-associated. At 2018, the projected total resistance is 15% (IQR: 7.5%-25%), with 18% (IQR: 13%-24%) of incident infections from transmitted drug-resistant HIV. CONCLUSIONS: WHO-recommended preferred first-line ART could lead to substantial drug resistance. Effective surveillance of HIV drug resistance and utilization of second-line as well as alternative first-line regimens is crucial.

Dapivirine vaginal ring for HIV prevention: modelling health outcomes, drug resistance and cost-effectiveness.

INTRODUCTION: A vaginal ring containing dapivirine is effective for HIV prevention as pre-exposure prophylaxis (PrEP). We evaluated the potential epidemiological impact and cost-effectiveness of dapivirine vaginal ring PrEP among 22- to 45-year-old women in KwaZulu-Natal, South Africa. METHODS: Using mathematical modelling, we studied dapivirine vaginal ring PrEP implementation, either unprioritized, or prioritized based on HIV incidence (≥3% per year), age (22 to 29 years) or female sex worker status, alongside the implementation of voluntary medical male circumcision and antiretroviral therapy scaled-up to UNAIDS Fast-Track targets. Outcomes over the intervention (2019 to 2030) and lifetime horizons included cumulative HIV infections, life-years lived, costs and cost-effectiveness. We assessed the incremental cost-effectiveness ratios against the revealed willingness to pay ($500) and the standard (2017 per capita gross domestic product; $6161) cost-effectiveness thresholds for South Africa. RESULTS: Compared to a reference scenario without PrEP, implementation of dapivirine vaginal ring PrEP, assuming 56% effectiveness and covering 50% of 22 to 29-year-old or high-incidence women, prevented 10% or 11% of infections by 2030 respectively. Equivalent, unprioritized coverage (30%) prevented fewer infections (7%), whereas 50% coverage of female sex workers had the least impact (4%). Drug resistance attributable to PrEP was modest (2% to 4% of people living with drug-resistant HIV). Over the lifetime horizon, dapivirine PrEP implementation among female sex workers was cost-saving, whereas incidence-based PrEP cost $1898 per life-year gained, relative to PrEP among female sex workers and $989 versus the reference scenario. In a scenario of 37% PrEP effectiveness, PrEP had less impact, but prioritization to female sex workers remained cost-saving. In uncertainty analysis, female sex worker PrEP was consistently cost-saving; and over the lifetime horizon, PrEP cost less than $6161 per life-year gained in over 99% of simulations, whereas incidence- and age-based PrEP cost below $500 per life-year gained in 61% and 49% of simulations respectively. PrEP adherence and efficacy, and the effectiveness of antiretroviral therapy for HIV prevention, were the principal drivers of uncertainty in the cost-effectiveness of PrEP. CONCLUSIONS: Dapivirine vaginal ring PrEP would be cost-saving in KwaZulu-Natal if prioritized to female sex workers. PrEP's impact on HIV prevention would be increased, with potential affordability, if prioritized to women by age or incidence.

Deciphering the Effects of Injectable Pre-exposure Prophylaxis for Combination Human Immunodeficiency Virus Prevention.

Background. A long-acting injectable formulation of rilpivirine (RPV), under investigation as antiretroviral pre-exposure prophylaxis (PrEP), may facilitate PrEP adherence. In contrast, cross-resistance between RPV and nonnucleoside reverse-transcriptase inhibitors comprising first-line antiretroviral therapy (ART) could promote human immunodeficiency virus (HIV) drug resistance and reduce PrEP's effectiveness. Methods. We use novel mathematical modeling of different RPV PrEP scale-up strategies in KwaZulu-Natal, South Africa, to investigate their effects on HIV prevention and drug resistance, compared with a reference scenario without PrEP. Results. Pre-exposure prophylaxis scale-up modestly increases the proportion of prevalent drug-resistant infections, from 33% to ≤37%. The change in the number of prevalent drug-resistant infections depends on the interplay between PrEP factors (coverage, efficacy, delivery reliability, and scale-up strategy) and the level of cross-resistance between PrEP and ART. An optimistic scenario of 70% effective RPV PrEP (90% efficacious and 80% reliable delivery), among women aged 20-29 years, prevents 17% of cumulative infections over 10 years while decreasing prevalent resistance; however, prevention decreases and resistance increases with more conservative assumptions. Uncertainty analysis assuming 40%-70% cross-resistance prevalence predicts an increase in prevalent resistance unless PrEP's effectiveness exceeds 90%. Conclusions. Prioritized scale-up of injectable PrEP among women in KwaZulu-Natal could reduce HIV infections, but suboptimal effectiveness could promote the spread of drug resistance.

Cost-effectiveness of Injectable Preexposure Prophylaxis for HIV Prevention in South Africa.

BACKGROUND: Long-acting injectable antiretrovirals such as rilpivirine (RPV) could promote adherence to preexposure prophylaxis (PrEP) for human immunodeficiency virus (HIV) prevention. However, the cost-effectiveness of injectable PrEP is unclear. METHODS: We constructed a dynamic model of the heterosexual HIV epidemic in KwaZulu-Natal, South Africa, and analyzed scenarios of RPV PrEP scale-up for combination HIV prevention in comparison with a reference scenario without PrEP. We estimated new HIV infections, life-years and costs, and incremental cost-effectiveness ratios (ICERs), over 10-year and lifetime horizons, assuming a societal perspective. RESULTS: Compared with no PrEP, unprioritized scale-up of RVP PrEP covering 2.5%-15% of adults prevented up to 9% of new infections over 10 years. HIV prevention doubled (17%) when the same coverage was prioritized to 20- to 29-year-old women, costing $10 880-$19 213 per infection prevented. Prioritization of PrEP to 80% of individuals at highest behavioral risk achieved comparable prevention (4%-8%) at <1% overall coverage, costing $298-$1242 per infection prevented. Over lifetime, PrEP scale-up among 20- to 29-year-old women was very cost-effective (<$1600 per life-year gained), dominating unprioritized PrEP, while risk prioritization was cost-saving. PrEP's 10-year impact decreased by almost 50% with increases in ICERs (up to 4.2-fold) in conservative base-case analysis. Sensitivity analysis identified PrEP's costs, efficacy, and reliability of delivery as the principal drivers of uncertainty in PrEP's cost-effectiveness, and PrEP remained cost-effective under the assumption of universal access to second-line antiretroviral therapy. CONCLUSIONS: Compared with no PrEP, prioritized scale-up of RPV PrEP in KwaZulu-Natal could be very cost-effective or cost-saving, but suboptimal PrEP would erode benefits and increase costs.

Preexposure prophylaxis will have a limited impact on HIV-1 drug resistance in sub-Saharan Africa: a comparison of mathematical models.

BACKGROUND: Preexposure prophylaxis (PrEP) with tenofovir and emtricitabine can prevent new HIV-1 infections, but there is a concern that use of PrEP could increase HIV drug resistance resulting in loss of treatment options. We compared standardized outcomes from three independent mathematical models simulating the impact of PrEP on HIV transmission and drug resistance in sub-Saharan African countries. METHODS: All models assume that people using PrEP receive an HIV test every 3-6 months. The models vary in structure and parameter choices for PrEP coverage, effectiveness of PrEP (at different adherence levels) and the rate with which HIV drug resistance emerges and is transmitted. RESULTS: The models predict that the use of PrEP in conjunction with antiretroviral therapy will result in a lower prevalence of HIV than when only antiretroviral therapy is used. With or without PrEP, all models suggest that HIV drug resistance will increase over the next 20 years due to antiretroviral therapy. PrEP will increase the absolute prevalence of drug resistance in the total population by less than 0.5% and amongst infected individuals by at most 7%. Twenty years after the introduction of PrEP, the majority of drug-resistant infections is due to antiretroviral therapy (50-63% across models), whereas 40-50% will be due to transmission of drug resistance, and less than 4% to the use of PrEP. CONCLUSION: HIV drug resistance resulting from antiretroviral therapy is predicted to far exceed that resulting from PrEP. Concern over drug resistance should not be a reason to limit the use of PrEP.

Antiretroviral therapy and pre-exposure prophylaxis: combined impact on HIV transmission and drug resistance in South Africa.

BACKGROUND: The potential impact of antiretroviral therapy (ART) and pre-exposure prophylaxis (PrEP) with overlapping and nonoverlapping antiretrovirals (ARVs) on human immunodeficiency virus (HIV) transmission and drug resistance is unknown. METHODS: A detailed mathematical model was used to simulate the epidemiological impact of ART alone, PrEP alone, and combined ART + PrEP in South Africa. RESULTS: ART alone initiated at a CD4 lymphocyte cell count <200 cells/µL (80% coverage and 96% effectiveness) prevents 20% of HIV infections over 10 years but increases drug resistance prevalence to 6.6%. PrEP alone (30% coverage and 75% effectiveness) also prevents 21% of infections but with lower resistance prevalence of 0.5%. The ratio of cumulative infections prevented to prevalent drug-resistant cases after 10 years is 7-fold higher for PrEP than for ART. Combined ART + PrEP with overlapping ARVs prevents 35% of infections but increases resistance prevalence to 8.2%, whereas ART + PrEP with nonoverlapping ARVs prevents slightly more infections (37%) and reduces resistance prevalence to 7.2%. CONCLUSIONS: Combined ART + PrEP is likely to prevent more HIV infections than either strategy alone, but with higher prevalence of drug resistance. ART is predicted to contribute more to resistance than is PrEP. Optimizing both ART and PrEP effectiveness and delivery are the keys to preventing HIV transmission and drug resistance.

Factors influencing the emergence and spread of HIV drug resistance arising from rollout of antiretroviral pre-exposure prophylaxis (PrEP).

BACKGROUND: The potential for emergence and spread of HIV drug resistance from rollout of antiretroviral (ARV) pre-exposure prophylaxis (PrEP) is an important public health concern. We investigated determinants of HIV drug resistance prevalence after PrEP implementation through mathematical modeling. METHODOLOGY: A model incorporating heterogeneity in age, gender, sexual activity, HIV infection status, stage of disease, PrEP coverage/discontinuation, and HIV drug susceptibility, was designed to simulate the impact of PrEP on HIV prevention and drug resistance in a sub-Saharan epidemic. PRINCIPAL FINDINGS: Analyses suggest that the prevalence of HIV drug resistance is influenced most by the extent and duration of inadvertent PrEP use in individuals already infected with HIV. Other key factors affecting drug resistance prevalence include the persistence time of transmitted resistance and the duration of inadvertent PrEP use in individuals who become infected on PrEP. From uncertainty analysis, the median overall prevalence of drug resistance at 10 years was predicted to be 9.2% (interquartile range 6.9%-12.2%). An optimistic scenario of 75% PrEP efficacy, 60% coverage of the susceptible population, and 5% inadvertent PrEP use predicts a rise in HIV drug resistance prevalence to only 2.5% after 10 years. By contrast, in a pessimistic scenario of 25% PrEP efficacy, 15% population coverage, and 25% inadvertent PrEP use, resistance prevalence increased to over 40%. CONCLUSIONS: Inadvertent PrEP use in previously-infected individuals is the major determinant of HIV drug resistance prevalence arising from PrEP. Both the rate and duration of inadvertent PrEP use are key factors. PrEP rollout programs should include routine monitoring of HIV infection status to limit the spread of drug resistance.

Uptake of biomedical interventions for prevention of sexually transmitted HIV.

PURPOSE OF THE REVIEW: To examine the population-level effects of introducing and/or expanding biomedical interventions for prevention of human immunodeficiency virus (HIV) sexually transmitted infections through mathematical modeling. RECENT FINDINGS: Successes of several ground-breaking clinical trials have invigorated the field of HIV prevention with new enthusiasm and opportunities for research into and application of biomedical HIV prevention. Mathematical modeling has advanced in tandem with valuable contributions to both investigative science and public health. New models provide qualitative and quantitative insights regarding the epidemiological impact of the uptake of biomedical interventions, singly and/or in combination including treatment of sexually transmitted infections, condom use, male circumcision, antiretroviral treatment and pre-exposure prophylaxis and vaccine for HIV prevention. SUMMARY: Biomedical interventions are critical for reversing the HIV pandemic. Mathematical modeling is invaluable for informed biomedical HIV prevention research, policy and practice.

Potential impact of antiretroviral chemoprophylaxis on HIV-1 transmission in resource-limited settings.

BACKGROUND: The potential impact of pre-exposure chemoprophylaxis (PrEP) on heterosexual transmission of HIV-1 infection in resource-limited settings is uncertain. METHODOLOGY/PRINCIPLE FINDINGS: A deterministic mathematical model was used to simulate the effects of antiretroviral PrEP on an HIV-1 epidemic in sub-Saharan Africa under different scenarios (optimistic, neutral and pessimistic) both with and without sexual disinhibition. Sensitivity analyses were used to evaluate the effect of uncertainty in input parameters on model output and included calculation of partial rank correlations and standardized rank regressions. In the scenario without sexual disinhibition after PrEP initiation, key parameters influencing infections prevented were effectiveness of PrEP (partial rank correlation coefficient (PRCC) = 0.94), PrEP discontinuation rate (PRCC = -0.94), level of coverage (PRCC = 0.92), and time to achieve target coverage (PRCC = -0.82). In the scenario with sexual disinhibition, PrEP effectiveness and the extent of sexual disinhibition had the greatest impact on prevention. An optimistic scenario of PrEP with 90% effectiveness and 75% coverage of the general population predicted a 74% decline in cumulative HIV-1 infections after 10 years, and a 28.8% decline with PrEP targeted to the highest risk groups (16% of the population). Even with a 100% increase in at-risk behavior from sexual disinhibition, a beneficial effect (23.4%-62.7% decrease in infections) was seen with 90% effective PrEP across a broad range of coverage (25%-75%). Similar disinhibition led to a rise in infections with lower effectiveness of PrEP (< or = 50%). CONCLUSIONS/SIGNIFICANCE: Mathematical modeling supports the potential public health benefit of PrEP. Approximately 2.7 to 3.2 million new HIV-1 infections could be averted in southern sub-Saharan Africa over 10 years by targeting PrEP (having 90% effectiveness) to those at highest behavioral risk and by preventing sexual disinhibition. This benefit could be lost, however, by sexual disinhibition and by high PrEP discontinuation, especially with lower PrEP effectiveness (< or = 50%).

Potential impact of antiretroviral therapy on HIV-1 transmission and AIDS mortality in resource-limited settings.

OBJECTIVE: To estimate the potential impact of antiretroviral therapy on the heterosexual spread of HIV-1 infection and AIDS mortality in resource-limited settings. METHODS: A mathematic model of HIV-1 disease progression and transmission was used to assess epidemiologic outcomes under different scenarios of antiretroviral therapy, including implementation of World Health Organization guidelines. RESULTS: Implementing antiretroviral therapy at 5% HIV-1 prevalence and administering it to 100% of AIDS cases are predicted to decrease new HIV-1 infections and cumulative deaths from AIDS after 10 years by 11.2% (inter-quartile range [IQR]: 1.8%-21.4%) and 33.4% (IQR: 26%-42.8%), respectively. Later implementation of therapy at endemic equilibrium (40% prevalence) is predicted to be less effective, decreasing new HIV-1 infections and cumulative deaths from AIDS by 10.5% (IQR: 2.6%-19.3%) and 27.6% (IQR: 20.8%-36.8%), respectively. Therapy is predicted to benefit the infected individual and the uninfected community by decreasing transmission and AIDS deaths. The community benefit is greater than the individual benefit after 25 years of treatment and increases with the proportion of AIDS cases treated. CONCLUSIONS: Antiretroviral therapy is predicted to have individual and public health benefits that increase with time and the proportion of infected persons treated. The impact of therapy is greater when introduced earlier in an epidemic, but the benefit can be lost by residual infectivity or disease progression on treatment and by sexual disinhibition of the general population.

Is medical informatics a mature science? A review of measurement practice in outcome studies of clinical systems.

OBJECTIVE: To determine the extent of explicit attention to formal issues of 'measurement' in studies examining outcomes of the deployment of clinical information systems. METHODS: A structured literature review identified 27 published studies reporting quantitative outcomes including attitudes, clinician behavior, quality of care, and cost of care. These studies were analyzed for types of outcome reported, evidence of 'reuse' of measurement methodology, and evidence of formal study of the reliability and validity of these measures. RESULTS: The 27 studies meeting the inclusion criteria were published between 1976 and 2002. Several of the studies addressed multiple outcome types. Nine examined clinician attitudes; 22 examined health care behaviors; 15 examined patient health status/quality of care; and four examined economic indicators. There were eight examples of reuse of measurement methods, five of which represented reuse within a single research group. Reliability indices were reported in three studies. There were no reported validity indices. CONCLUSION: Based on this sample of studies, specific attention to issues of measurement is sparse in outcome studies of deployed clinical information systems. As such, medical informatics does not appear to be on a par with more mature sciences in its approaches to measurement of key outcome variables.