Optimal Treatment Strategies in the Context of 'Treatment for Prevention' against HIV-1 in Resource-Poor Settings.
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ABSTRACT:
SUBMITTER: Duwal S
PROVIDER: S-EPMC4423987 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundThe roll-out of antiretroviral treatment (ART) in developing countries concentrates on finding patients currently in need, but over time many HIV-infected individuals will be identified who will require treatment in the future. We investigated the potential influence of alternative patient management and ART initiation strategies on the impact of ART programmes in sub-Saharan Africa.Methods and findingsWe developed a stochastic mathematical model representing disease progression, diagnosis, clinical monitoring, and survival in a cohort of 1,000 hypothetical HIV-infected individuals in Africa. If individuals primarily enter ART programmes when symptomatic, the model predicts that only 25% will start treatment and, on average, 6 life-years will be saved per person treated. If individuals are recruited to programmes while still healthy and are frequently monitored, and CD4(+) cell counts are used to help decide when to initiate ART, three times as many are expected to be treated, and average life-years saved among those treated increases to 15. The impact of programmes can be improved further by performing a second CD4(+) cell count when the initial value is close to the threshold for starting treatment, maintaining high patient follow-up rates, and prioritising monitoring the oldest (> or = 35 y) and most immune-suppressed patients (CD4(+) cell count < or = 350). Initiating ART at higher CD4(+) cell counts than WHO recommends leads to more life-years saved, but disproportionately more years spent on ART.ConclusionsThe overall impact of ART programmes will be limited if rates of diagnosis are low and individuals enter care too late. Frequently monitoring individuals at all stages of HIV infection and using CD4 cell count information to determine when to start treatment can maximise the impact of ART.
| S-EPMC2265759 | biostudies-literature
Project description:Conventional HIV gene therapy approaches are based on engineering HIV target cells that are non-permissive to viral replication. However, expansion of gene-modified HIV target cells has been limited in patients. Alternative genetic strategies focus on generating gene-modified producer cells that secrete antiviral proteins (AVPs). The secreted AVPs interfere with HIV entry, and, therefore, they extend the protection against infection to unmodified HIV target cells. Since any cell type can potentially secrete AVPs, hematopoietic and non-hematopoietic cell lineages can function as producer cells. Secretion of AVPs from non-hematopoietic cells opens the possibility of using a genetic approach for HIV prevention. Another strategy aims at modifying cytotoxic T cells to selectively target and eliminate infected cells. This review provides an overview of the different genetic approaches for HIV treatment and prevention.
| S-EPMC6205348 | biostudies-literature
Project description:BackgroundCryptococcal meningitis (CM) is the most common form of meningitis in Africa. World Health Organization guidelines recommend 14-d amphotericin-based induction therapy; however, this is impractical for many resource-limited settings due to cost and intensive monitoring needs. A cost-effectiveness analysis was performed to guide stakeholders with respect to optimal CM treatment within resource limitations.Methods and findingsWe conducted a decision analysis to estimate the incremental cost-effectiveness ratio (ICER) of six CM induction regimens: fluconazole (800-1,200 mg/d) monotherapy, fluconazole + flucytosine (5FC), short-course amphotericin (7-d) + fluconazole, 14-d of amphotericin alone, amphotericin + fluconazole, and amphotericin + 5FC. We computed actual 2012 healthcare costs in Uganda for medications, supplies, and personnel, and average laboratory costs for three African countries. A systematic review of cryptococcal treatment trials in resource-limited areas summarized 10-wk survival outcomes. We modeled one-year survival based on South African, Ugandan, and Thai CM outcome data, and survival beyond one-year on Ugandan and Thai data. Quality-adjusted life years (QALYs) were determined and used to calculate the cost-effectiveness ratio and ICER. The cost of hospital care ranged from $154 for fluconazole monotherapy to $467 for 14 d of amphotericin + 5FC. Based on 18 studies investigating outcomes for HIV-infected individuals with CM in resource-limited settings, the estimated mean one-year survival was lowest for fluconazole monotherapy, at 40%. The cost-effectiveness ratio ranged from $20 to $44 per QALY. Overall, amphotericin-based regimens had higher costs but better survival. Short-course amphotericin (1 mg/kg/d for 7 d) with fluconazole (1,200 mg/d for14 d) had the best one-year survival (66%) and the most favorable cost-effectiveness ratio, at $20.24/QALY, with an ICER of $15.11 per additional QALY over fluconazole monotherapy. The main limitation of this study is the pooled nature of a systematic review, with a paucity of outcome data with direct comparisons between regimens.ConclusionsShort-course (7-d) amphotericin induction therapy coupled with high-dose (1,200 mg/d) fluconazole is "very cost effective" per World Health Organization criteria and may be a worthy investment for policy-makers seeking cost-effective clinical outcomes. More head-to-head clinical trials are needed on treatments for this neglected tropical disease. Please see later in the article for the Editors' Summary.
| S-EPMC3463510 | biostudies-literature
Project description:Reducing childhood mortality in resource-poor regions depends on effective interventions to decrease neonatal mortality from severe infection, which contributes up to a half of all neonatal deaths. There are key differences in resource-poor, compared to resource-rich, countries in terms of diagnosis, supportive care and treatment. In resource-poor settings, diagnosis is based on identifying clinical syndromes from international guidelines; microbiological investigations are restricted to a few research facilities. Low levels of staffing and equipment limit the provision of basic supportive care, and most facilities cannot provide respiratory support. Empiric antibiotic treatment guidelines are based on few aetiological and antimicrobial susceptibility data. Research on improving health care systems to provide effective supportive care, and implementation of simple pragmatic interventions, such as low-cost respiratory support, are essential, together with improved surveillance to monitor emerging drug resistance and treatment failures. Reductions in mortality will also be achieved through prevention of infection; including emerging vaccination and anti-sepsis strategies.
| S-EPMC3507620 | biostudies-other
Project description:Harmonizing measures across studies can facilitate comparisons and strengthen the science, but procedures for establishing common data elements are rarely documented. We detail a rigorous, 2-year process to harmonize measures across the Prevention And Treatment through a Comprehensive Care Continuum for HIV-affected Adolescents in Resource Constrained Settings (PATC3H) consortium, consisting of eight federally-funded studies. We created a repository of measured constructs from each study, classified and selected constructs for harmonization, and identified survey instruments. Measures were harmonized for implementation science, HIV prevention and care, demographics and sexual behavior, mental health and substance use, and economic assessment. Importantly, we present our harmonized implementation science constructs. A common set of implementation science constructs have yet to be recommended in the literature for low-to-middle-income countries despite increasing recognition of their importance to delivering and scaling up effective interventions. Drawing on RE-AIM (Reach Effectiveness Adoption Implementation Maintenance) and the Implementation Outcomes Framework, items were harmonized for staff/administrators and study participants to measure reach, adoption, implementation, maintenance, feasibility, acceptability, appropriateness, and fidelity. The process undertaken to harmonize measures and the codified set of implementation science measures developed by our consortium can inform future data harmonization efforts, critical to strengthening the replication and generalizability of findings while facilitating collaborative research-especially in resource-limited settings. We conclude with recommendations for research consortia, namely ensuring representation from all study teams and research priorities; adopting a flexible, transparent, and systematic approach; strengthening the literature on implementation science harmonization; and being responsive to life events (e.g., COVID-19).Supplementary informationThe online version contains supplementary material available at 10.1007/s43477-022-00042-7.
| S-EPMC8987520 | biostudies-literature
Project description:BackgroundMalaria incidence is in decline in many parts of SE Asia leading to a decreasing proportion of febrile illness that is attributable to malaria. However in the absence of rapid, affordable and accurate diagnostic tests, the non-malaria causes of these illnesses cannot be reliably identified. Studies on the aetiology of febrile illness have indicated that the causes are likely to vary by geographical location within countries (i.e. be spatially heterogeneous) and that national empirical treatment policies based on the aetiology measured in a single location could lead to inappropriate treatment.MethodsUsing data from Vientiane as a reference for the incidence of major febrile illnesses in the Lao People's Democratic Republic (Laos) and estimated incidences, plausible incidence in other Lao provinces were generated using a mathematical model for a range of national and local scale variations. For a range of treatment protocols, the mean number of appropriate treatments was predicted and the potential impact of a spatially explicit national empirical treatment protocol assessed.FindingsThe model predicted a negative correlation between number of appropriate treatments and the level of spatial heterogeneity. A spatially explicit national treatment protocol was predicted to increase the number of appropriate treatments by 50% for intermediate levels of spatial heterogeneity.ConclusionsThe results suggest that given even only moderate spatial variation, a spatially explicit treatment algorithm will result in a significant improvement in the outcome of undifferentiated fevers in Laos and other similar resource poor settings.
| S-EPMC3448597 | biostudies-literature
Project description:Authoritative international guidelines stipulate that for minors to participate in research, consent must be obtained from their parents or guardians. Significant numbers of mature minors, particularly in low-income settings, are currently being ruled out of research participation because their parents are unavailable or refuse to provide consent despite the possibility that they might wish to do so and that such research has the potential to be of real benefit. These populations are under-represented in all types of clinical research. We propose that, for research with a prospect of direct benefit that has been approved by relevant ethics committees, the default position should be that minors who are able to provide valid consent and meet the following criteria should be able to consent for themselves regardless of age and whether they have reached majority: the minor must be competent and mature relative to the decision; their consent must be voluntary and they must be relatively independent and used to decision making of comparable complexity. In addition, the context must be appropriate, the information related to the research must be provided in a manner accessible to the minor and the consent must be obtained by a trained consent taker in surroundings conducive for decision making by the minor. In this paper, we have argued that consent by mature minors to research participation is acceptable in some situations and should be allowed.
| S-EPMC4413844 | biostudies-literature
Project description:Predicting the population-level effects of an infectious disease intervention that incorporate multiple modes of intervention is complicated by the joint non-linear dynamics of both infection transmission and the intervention itself. In this paper, we consider the sensitivity of Dynamic Optimal Control Profiles (DOCPs) for the optimal joint investment in both a contagiousness and susceptibility-based control of HIV to bio-behavioral, economic, and programmatic assumptions. The DOCP is calculated using recently developed numerical algorithms that allow controls to be represented by a set of piecewise constant functions that maintain a constant yearly budget. Our transmission model assumes multiple stages of HIV infection corresponding to acute and chronic infection and both within- and between-individual behavioral heterogeneity. We parameterize a baseline scenario from a longitudinal study of sexual behavior in MSM and consider sensitivity of the DOCPs to deviations from that baseline scenario. In the baseline scenario, the primary determinant of the dominant control were programmatic factors, regardless of budget. In sensitivity analyses, the qualitative aspects of the optimal control policy were often robust to significant deviation in assumptions regarding transmission dynamics. In addition, we found several conditions in which long-term joint investment in both interventions was optimal. Our results suggest that modeling in the service of decision support for intervention design can improve population-level effects of a limited set of economic resources. We found that economic and programmatic factors were as important as the inherent transmission dynamics in determining population-level intervention effects. Given our finding that the DOCPs were robust to alternative biological and behavioral assumptions it may be possible to identify DOCPs even when the data are not sufficient to identify a transmission model.
| S-EPMC6193630 | biostudies-literature
Project description:BackgroundThe anticipated scale-up of antiretroviral therapy (ART) in high-prevalence, resource-constrained settings requires operational research to guide policy on the design of treatment programmes. Mathematical models can explore the potential impacts of various treatment strategies, including timing of treatment initiation and provision of laboratory monitoring facilities, to complement evidence from pilot programmes.Methods and findingsA deterministic model of HIV transmission incorporating ART and stratifying infection progression into stages was constructed. The impact of ART was evaluated for various scenarios and treatment strategies, with different levels of coverage, patient eligibility, and other parameter values. These strategies included the provision of laboratory facilities that perform CD4 counts and viral load testing, and the timing of the stage of infection at which treatment is initiated. In our analysis, unlimited ART provision initiated at late-stage infection (AIDS) increased prevalence of HIV infection. The effect of additionally treating pre-AIDS patients depended on the behaviour change of treated patients. Different coverage levels for ART do not affect benefits such as life-years gained per person-year of treatment and have minimal effect on infections averted when treating AIDS patients only. Scaling up treatment of pre-AIDS patients resulted in more infections being averted per person-year of treatment, but the absolute number of infections averted remained small. As coverage increased in the models, the emergence and risk of spread of drug resistance increased. Withdrawal of failing treatment (clinical resurgence of symptoms), immunologic (CD4 count decline), or virologic failure (viral rebound) increased the number of infected individuals who could benefit from ART, but effectiveness per person is compromised. Only withdrawal at a very early stage of treatment failure, soon after viral rebound, would have a substantial impact on emergence of drug resistance.ConclusionsOur analysis found that ART cannot be seen as a direct transmission prevention measure, regardless of the degree of coverage. Counselling of patients to promote safe sexual practices is essential and must aim to effect long-term change. The chief aims of an ART programme, such as maximised number of patients treated or optimised treatment per patient, will determine which treatment strategy is most effective.
| S-EPMC1395349 | biostudies-literature
Project description:BackgroundThis study aims to assess the most efficient combinations of vaccination and screening coverage for the prevention of cervical cancer (CC) at different levels of expenditure in Nigeria.MethodsAn optimization procedure, using a linear programming approach and requiring the use of two models (an evaluation and an optimization model), was developed. The evaluation model, a Markov model, estimated the annual number of CC cases at steady state in a population of 100,000 women for four alternative strategies: screening only; vaccination only; screening and vaccination; and no prevention. The results of the Markov model for each scenario were used as inputs to the optimization model determining the optimal proportion of the population to receive screening and/or vaccination under different scenarios. The scenarios varied by available budget, maximum screening and vaccination coverage, and overall reachable population.ResultsIn the base-case optimization model analyses, with a coverage constraint of 20% for one lifetime screening, 95% for vaccination and a budget constraint of $1 per woman per year to minimize CC incidence, the optimal mix of prevention strategies would result in a reduction of CC incidence of 31% (3-dose vaccination available) or 46% (2-dose vaccination available) compared with CC incidence pre-vaccination. With a 3-dose vaccination schedule, the optimal combination of the different strategies across the population would be 20% screening alone, 39% vaccination alone and 41% with no prevention, while with a 2-dose vaccination schedule the optimal combination would be 71% vaccination alone, and 29% with no prevention. Sensitivity analyses indicated that the results are sensitive to the constraints included in the optimization model as well as the cervical intraepithelial neoplasia (CIN) and CC treatment cost.ConclusionsThe results of the optimization model indicate that, in Nigeria, the most efficient allocation of a limited budget would be to invest in both vaccination and screening with a 3-dose vaccination schedule, and in vaccination alone before implementing a screening program with a 2-dose vaccination schedule.
| S-EPMC4057561 | biostudies-literature