scholarly journals Challenging conventional wisdom on the evolution of resistance to multi-drug HIV treatment: Lessons from data and modeling

2019 ◽  
Author(s):  
Alison Feder ◽  
Kristin Harper ◽  
Pleuni S. Pennings
Keyword(s):  
Drug Resistance ◽  
Standard Of Care ◽  
Compartment Model ◽  
Antiretroviral Drugs ◽  
Hiv Treatment ◽  
Current Standard ◽  
Hiv Drug Resistance ◽  
Resistance Evolution ◽  
Single Drug ◽  
Evolution Of Resistance

AbstractUnder the current standard of care, individuals with HIV take three antiretroviral drugs simultaneously. Triple-drug combination therapies limit HIV drug resistance evolution, because viruses resistant to a subset of the cocktail are suppressed by the remainder of the drugs and should not complete replication and spread. Despite this, reanalysis of HIV genetic data shortly after triple drug therapies became available (1990s and 2000s) reveals ongoing drug resistance in patients on three-drug therapies. In disagreement with expected patterns of evolution in three-drug therapy-treated HIV populations, resistance usually evolves one mutation at a time in a semi-predictable order. We argue here that these surprising observations can be explained using a model that divides the human body into compartments (for example, the gut, lymph nodes and brain). If one drug reaches a compartment that the other two drugs cannot, this creates a single-drug compartment that can select for single-drug resistant viruses. Such viruses can potentially become resistant to additional drugs, if they migrate to another compartment where a second drug is present, and so on. In addition to a compartment model, for some drug combinations, an alternative model of time-heterogeneity due to short half-lives combined with sub-optimal adherence could also explain the observations. We discuss how these lessons from HIV drug resistance evolution may be useful for other systems.

Pre-treatment and acquired HIV drug resistance in Dar es Salaam, Tanzania in the era of tenofovir and routine viral load monitoring

2019 ◽  
Vol 74 (10) ◽  
pp. 3016-3020 ◽  
Author(s):  
Godfrey Barabona ◽  
Macdonald Mahiti ◽  
Salim Masoud ◽  
Peter Mbelele ◽  
Amina Shaban Mgunya ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Progressive Increase ◽  
Dar Es Salaam ◽  
Antiretroviral Drugs ◽  
Hiv Treatment ◽  
Resistance Mutations ◽  
Genetic Barrier ◽  
Hiv Drug Resistance ◽  
Pre Treatment ◽  
Treat All

Abstract Objectives We investigated the prevalence and patterns of pre-treatment and acquired HIV drug resistance mutations (DRMs) in Tanzania as a ‘treat all’ strategy, virological monitoring and the progressive increase in usage of tenofovir are being implemented in HIV treatment programmes. Methods Viral RNA was isolated from plasma of 60 ART-naive and 166 treated-but-viraemic (>400 copies/mL) HIV-1-infected adults attending a care and treatment clinic at Muhimbili National Hospital, Dar es Salaam, Tanzania, between June and October 2017. Viral genes encoding protease and reverse transcriptase were amplified by PCR and directly sequenced. Results Viral genotyping of successfully amplified samples revealed pre-treatment DRMs in 14/47 (29.8%) ART-naive subjects. Of these, 7/47 (14.9%) harboured mutations that confer high-level resistance to at least one drug of the default first-line regimen. In treated-but-viraemic subjects, DRMs were found in 100/111 (90%), where DRMs against NNRTI, NRTI and PI were observed in 95/100 (95%), 92/100 (92%) and 13/100 (13%), respectively. Tenofovir-resistance mutations K65R and K70G/E or ≥3 thymidine analogue resistance mutations including M41L and L210W were found in 18/36 (50%) subjects on a tenofovir-containing regimen at failure. Four patients harboured multiple DRMs, which can confer resistance to all available ART regimens in Tanzania. Conclusions Taken together, pre-treatment and acquired DRMs were highly prevalent, which represents a major risk for the efficacy of ART programmes in Tanzania. Availability of a newer generation of antiretroviral drugs with a higher genetic barrier to resistance and robust treatment monitoring is warranted for effective and sustainable HIV treatment.

scholarly journals Immune selection suppresses the emergence of drug resistance in malaria parasites but facilitates its spread

2021 ◽  
Vol 17 (7) ◽  
pp. e1008577
Author(s):  
Alexander O. B. Whitlock ◽  
Jonathan J. Juliano ◽  
Nicole Mideo
Keyword(s):  
Drug Resistance ◽  
Immune Selection ◽  
Global Pattern ◽  
Agent Based ◽  
Low Transmission ◽  
Resistance Evolution ◽  
High Transmission ◽  
Population Immunity ◽  
Evolution Of Resistance ◽  
Selection For

Although drug resistance in Plasmodium falciparum typically evolves in regions of low transmission, resistance spreads readily following introduction to regions with a heavier disease burden. This suggests that the origin and the spread of resistance are governed by different processes, and that high transmission intensity specifically impedes the origin. Factors associated with high transmission, such as highly immune hosts and competition within genetically diverse infections, are associated with suppression of resistant lineages within hosts. However, interactions between these factors have rarely been investigated and the specific relationship between adaptive immunity and selection for resistance has not been explored. Here, we developed a multiscale, agent-based model of Plasmodium parasites, hosts, and vectors to examine how host and parasite dynamics shape the evolution of resistance in populations with different transmission intensities. We found that selection for antigenic novelty (“immune selection”) suppressed the evolution of resistance in high transmission settings. We show that high levels of population immunity increased the strength of immune selection relative to selection for resistance. As a result, immune selection delayed the evolution of resistance in high transmission populations by allowing novel, sensitive lineages to remain in circulation at the expense of the spread of a resistant lineage. In contrast, in low transmission settings, we observed that resistant strains were able to sweep to high population prevalence without interference. Additionally, we found that the relationship between immune selection and resistance changed when resistance was widespread. Once resistance was common enough to be found on many antigenic backgrounds, immune selection stably maintained resistant parasites in the population by allowing them to proliferate, even in untreated hosts, when resistance was linked to a novel epitope. Our results suggest that immune selection plays a role in the global pattern of resistance evolution.

scholarly journals Superinfection and the evolution of resistance to antimalarial drugs

2012 ◽  
Vol 279 (1743) ◽  
pp. 3834-3842 ◽  
Author(s):  
Eili Y. Klein ◽  
David L. Smith ◽  
Ramanan Laxminarayan ◽  
Simon Levin
Keyword(s):  
Drug Resistance ◽  
Plasmodium Falciparum ◽  
General Theory ◽  
Mathematical Models ◽  
Random Sampling ◽  
Transmission Rate ◽  
Drug Resistant ◽  
Antimalarial Drug Resistance ◽  
Resistance Evolution ◽  
Evolution Of Resistance

A major issue in the control of malaria is the evolution of drug resistance. Ecological theory has demonstrated that pathogen superinfection and the resulting within-host competition influences the evolution of specific traits. Individuals infected with Plasmodium falciparum are consistently infected by multiple parasites; however, while this probably alters the dynamics of resistance evolution, there are few robust mathematical models examining this issue. We developed a general theory for modelling the evolution of resistance with host superinfection and examine: (i) the effect of transmission intensity on the rate of resistance evolution; (ii) the importance of different biological costs of resistance; and (iii) the best measure of the frequency of resistance. We find that within-host competition retards the ability and slows the rate at which drug-resistant parasites invade, particularly as the transmission rate increases. We also find that biological costs of resistance that reduce transmission are less important than reductions in the duration of drug-resistant infections. Lastly, we find that random sampling of the population for resistant parasites is likely to significantly underestimate the frequency of resistance. Considering superinfection in mathematical models of antimalarial drug resistance may thus be important for generating accurate predictions of interventions to contain resistance.

scholarly journals Oral Antiretroviral Drugs as Public Health Tools for HIV Prevention: Global Implications for Adherence, Drug Resistance, and the Success of HIV Treatment Programs

2013 ◽  
Vol 207 (suppl_2) ◽  
pp. S101-S106 ◽  
Author(s):  
Ravindra K. Gupta ◽  
Mark A. Wainberg ◽  
Francoise Brun-Vezinet ◽  
Jose M. Gatell ◽  
Jan Albert ◽  
...  
Keyword(s):  
Public Health ◽  
Drug Resistance ◽  
Hiv Prevention ◽  
Antiretroviral Drugs ◽  
Hiv Treatment ◽  
Treatment Programs

scholarly journals Immune selection suppresses the emergence of drug resistance in malaria parasites but facilitates its spread

2020 ◽  
Author(s):  
Alexander O B Whitlock ◽  
Jonathan J Juliano ◽  
Nicole Mideo
Keyword(s):  
Drug Resistance ◽  
Immune Selection ◽  
Agent Based ◽  
Low Transmission ◽  
Resistance Evolution ◽  
High Transmission ◽  
Population Immunity ◽  
Evolution Of Resistance ◽  
Selection For ◽  
The Relationship

Although drug resistance in Plasmodium falciparum  typically evolves in regions of low transmission, resistance spreads readily following introduction to regions with a heavier disease burden. This suggests that the origin and the spread of resistance are governed by different processes, and that high transmission intensity specifically impedes the origin. Factors associated with high transmission, such as highly immune hosts and competition within genetically diverse infections, are associated with suppression of resistant lineages within hosts. However, interactions between these factors have rarely been investigated and the specific relationship between adaptive immunity and selection for resistance has not been explored. Here, we developed a multiscale, agent-based model of Plasmodium  parasites, hosts, and vectors to examine how host and parasite dynamics shape the evolution of resistance in populations with different transmission intensities. We found that selection for antigenic novelty (“immune selection”) and within-host competition both suppressed the evolution of resistance in high transmission settings.  We show that high levels of population immunity increased the strength of immune selection relative to selection for resistance. As a result, immune selection delayed the evolution of resistance in high transmission populations by allowing novel, sensitive lineages to remain in circulation at the expense of common, resistant lineages. In contrast, in low transmission populations, we observed that common, resistant strains were able to sweep to high population prevalence without interference. Additionally, we found that the relationship between immune selection and resistance changed when resistance was widespread in the population. Once resistance was common enough to be found on many antigenic backgrounds, immune selection stably maintained resistance in the population because resistance was able to proliferate, even in untreated hosts, when it was linked to a novel epitope. The results of our simulations demonstrate that immune selection plays a major role in observed dynamics of resistance evolution.

scholarly journals The clarifying role of time series data in the population genetics of HIV

2018 ◽  
Author(s):  
Alison F Feder ◽  
Pleuni S Pennings ◽  
Dmitri A Petrov
Keyword(s):  
Time Series ◽  
Drug Resistance ◽  
Population Genetics ◽  
Time Series Data ◽  
Hiv Treatment ◽  
Series Data ◽  
Adaptive Landscape ◽  
Resistance Evolution ◽  
Hiv Drugs ◽  
Traditional Population

HIV can evolve remarkably quickly in response to anti-retroviral therapies and the immune system. This evolution stymies treatment effectiveness and prevents the development of an HIV vaccine. Consequently, there has been great interest in using population genetics to disentangle the forces that govern the HIV adaptive landscape (selection, drift, mutation, recombination). Traditional population genetics approaches look at the current state of genetic variation and infer the processes that can generate them. However, because HIV evolves rapidly, we can also sample populations repeatedly over time and watch evolution in action. In this paper, we demonstrate how time series data can bound evolutionary parameters in a way that complements and informs traditional population genetic approaches. Specifically, we focus on our recent paper (Feder et al. 2016), in which we show that, as improved HIV drugs have led to fewer patients failing therapy due to resistance evolution, less genetic diversity has been maintained following the fixation of drug resistance mutations. We interpret this as evidence that resistance to early HIV drugs that failed quickly and predictably was driven by soft sweeps while evolution of resistance to better drugs is both less frequent and when it takes place it is associated with harder sweeps due to an effectively lower HIV population mutation rate (θ). Recently, Harris et al. 2018 have proposed an alternative interpretation: the signal could be due to an increase in the selective benefit of mutations conferring resistance to better drugs. Therefore, better drugs lead to faster sweeps with less opportunity for recombination to rescue diversity. In this paper, we use time series data to show that drug resistance evolution during ineffective treatment is very fast, providing new evidence that soft sweeps drove early HIV treatment failure.

We need to use the best antiretroviral drugs worldwide to prevent HIV drug resistance

AIDS ◽  
2016 ◽  
Vol 30 (17) ◽  
pp. 2725-2727 ◽  
Author(s):  
Bluma Brenner ◽  
Mark A. Wainberg
Keyword(s):  
Drug Resistance ◽  
Antiretroviral Drugs ◽  
Hiv Drug Resistance

scholarly journals Therapeutic targeting of FLT3 and associated drug resistance in acute myeloid leukemia

2020 ◽  
Vol 13 (1) ◽  
Author(s):  
Melat T. Gebru ◽  
Hong-Gang Wang
Keyword(s):  
Drug Resistance ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Molecular Mechanisms ◽  
Gene Mutations ◽  
Standard Of Care ◽  
Cell Transplant ◽  
Current Standard ◽  
Hematopoietic Stem ◽  
Acute Myeloid

AbstractAcute myeloid leukemia (AML) is a heterogeneous disease caused by several gene mutations and cytogenetic abnormalities affecting differentiation and proliferation of myeloid lineage cells. FLT3 is a receptor tyrosine kinase commonly overexpressed or mutated, and its mutations are associated with poor prognosis in AML. Although aggressive chemotherapy often followed by hematopoietic stem cell transplant is the current standard of care, the recent approval of FLT3-targeted drugs is revolutionizing AML treatment that had remained unchanged since the 1970s. However, despite the dramatic clinical response to targeted agents, such as FLT3 inhibitors, remission is almost invariably short-lived and ensued by relapse and drug resistance. Hence, there is an urgent need to understand the molecular mechanisms driving drug resistance in order to prevent relapse. In this review, we discuss FLT3 as a target and highlight current understanding of FLT3 inhibitor resistance.

scholarly journals HIV DRUG RESISTANCE EARLY WARNING INDICATORS AND THEIR ASSESSMENT IN SOME REGIONS OF RUSSIA

2019 ◽  
Vol 10 (4) ◽  
pp. 67-75 ◽  
Author(s):  
N. N. Lebedeva ◽  
S. Ya. Zverev ◽  
V. V. Kulagin ◽  
N. V. Kurina ◽  
A. Yu. Pronin ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Early Warning ◽  
Retention Rate ◽  
Antiretroviral Drugs ◽  
Hiv Drug Resistance ◽  
Saint Petersburg ◽  
Limited Experience ◽  
Early Warning Indicators ◽  
Warning Indicators ◽  
Regions Of Russia

The article describes the first limited experience of early warning indicators (EWIs) of HIV drug resistance recommended by WHO; information on their content and order of use is given. The results of EWIs survey performed in 2016 in nine Russian cities: Blagoveshchensk, Vladivostok, Yekaterinburg, Izhevsk, Krasnodar, Perm, Saint-Petersburg, Khanty-Mansiysk, and the Moscow Region — are presented. The on-time pill pick up indicators were optimal, >90% in four centers (44,4%), all others showed intermediate resulеs (80–90%). The retention rate was over 85% in six of the nine regions (66,6%). Two of the nine regions (22,2%) reported the existence of stock-outs in the supply of antiretroviral drugs. Bi-and monotherapy with antiretroviral drugs was administered to patients in three regions (33,3%). Suppression of viral load to values less than 1000 copies RNA/ml in more than 85% of patients was achieved only in three regions (33,3%). The conclusion was made concerning the necessity to implement the monitoring of HIV drug resistance in Russia as soon as possible, including an analysis of the EWIs and other types of monitoring studies.

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