Rates of emergence of HIV drug resistance in resource-limited settings: a systematic review.
TL;DR: The emergence of drug resistance following access to ART in resource-limited settings resembles what was seen inresource-rich countries and highlights the need for virological monitoring for drug failure, drug resistance testing and alternative drug regimens that have proven beneficial in these resource-rich settings.
Abstract: BackgroundThe increasing availability of antiretroviral therapy (ART) has improved survival and quality of life for many infected with HIV, but can also engender drug resistance. This review summar...
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Rega Institute for Medical Research1, University of Barcelona2, Tufts University3, Stanford University4, University of Amsterdam5, World Health Organization6, Karolinska University Hospital7, University of Tartu8, University of Venda9, Public Health Agency of Canada10, Erasmus University Rotterdam11, Simon Fraser University12, Systems Research Institute13, Harvard University14, Paris Diderot University15, University College Dublin16, Grant Medical College and Sir Jamshedjee Jeejeebhoy Group of Hospitals17, Global Viral18, Johns Hopkins University School of Medicine19, University of Bordeaux20, Necker-Enfants Malades Hospital21, National Institutes of Health22, University of British Columbia23, Kanazawa University24, Mahidol University25, Walter Reed Army Institute of Research26, Chinese Academy of Sciences27, University of Malaya28, Indian Council of Medical Research29, Institut de recherche pour le développement30, University of Ljubljana31, University of California, San Francisco32, University of Edinburgh33, Chulalongkorn University34, University of California, San Diego35, Federal University of Rio de Janeiro36, Carlos III Health Institute37, University of Belgrade38, Universidade Federal de Goiás39, Centers for Disease Control and Prevention40
TL;DR: Most TDR strains in SSA and SSEA arose independently, suggesting that ARV regimens with a high genetic barrier to resistance combined with improved patient adherence may mitigate TDR increases by reducing the generation of new ARV-resistant strains.
Abstract: Regional and subtype-specific mutational patterns of HIV-1 transmitted drug resistance (TDR) are essential for informing first-line antiretroviral (ARV) therapy guidelines and designing diagnostic assays for use in regions where standard genotypic resistance testing is not affordable. We sought to understand the molecular epidemiology of TDR and to identify the HIV-1 drug-resistance mutations responsible for TDR in different regions and virus subtypes.We reviewed all GenBank submissions of HIV-1 reverse transcriptase sequences with or without protease and identified 287 studies published between March 1, 2000, and December 31, 2013, with more than 25 recently or chronically infected ARV-naive individuals. These studies comprised 50,870 individuals from 111 countries. Each set of study sequences was analyzed for phylogenetic clustering and the presence of 93 surveillance drug-resistance mutations (SDRMs). The median overall TDR prevalence in sub-Saharan Africa (SSA), south/southeast Asia (SSEA), upper-income Asian countries, Latin America/Caribbean, Europe, and North America was 2.8%, 2.9%, 5.6%, 7.6%, 9.4%, and 11.5%, respectively. In SSA, there was a yearly 1.09-fold (95% CI: 1.05–1.14) increase in odds of TDR since national ARV scale-up attributable to an increase in non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance. The odds of NNRTI-associated TDR also increased in Latin America/Caribbean (odds ratio [OR] = 1.16; 95% CI: 1.06–1.25), North America (OR = 1.19; 95% CI: 1.12–1.26), Europe (OR = 1.07; 95% CI: 1.01–1.13), and upper-income Asian countries (OR = 1.33; 95% CI: 1.12–1.55). In SSEA, there was no significant change in the odds of TDR since national ARV scale-up (OR = 0.97; 95% CI: 0.92–1.02). An analysis limited to sequences with mixtures at less than 0.5% of their nucleotide positions—a proxy for recent infection—yielded trends comparable to those obtained using the complete dataset. Four NNRTI SDRMs—K101E, K103N, Y181C, and G190A—accounted for >80% of NNRTI-associated TDR in all regions and subtypes. Sixteen nucleoside reverse transcriptase inhibitor (NRTI) SDRMs accounted for >69% of NRTI-associated TDR in all regions and subtypes. In SSA and SSEA, 89% of NNRTI SDRMs were associated with high-level resistance to nevirapine or efavirenz, whereas only 27% of NRTI SDRMs were associated with high-level resistance to zidovudine, lamivudine, tenofovir, or abacavir. Of 763 viruses with TDR in SSA and SSEA, 725 (95%) were genetically dissimilar; 38 (5%) formed 19 sequence pairs. Inherent limitations of this study are that some cohorts may not represent the broader regional population and that studies were heterogeneous with respect to duration of infection prior to sampling.Most TDR strains in SSA and SSEA arose independently, suggesting that ARV regimens with a high genetic barrier to resistance combined with improved patient adherence may mitigate TDR increases by reducing the generation of new ARV-resistant strains. A small number of NNRTI-resistance mutations were responsible for most cases of high-level resistance, suggesting that inexpensive point-mutation assays to detect these mutations may be useful for pre-therapy screening in regions with high levels of TDR. In the context of a public health approach to ARV therapy, a reliable point-of-care genotypic resistance test could identify which patients should receive standard first-line therapy and which should receive a protease-inhibitor-containing regimen.
206 citations
TL;DR: Molecular mechanisms that have been proposed to contribute to HIV latency are reviewed, as well as the relative roles of cis- and trans-acting mechanisms.
Abstract: Treatment with antiretroviral therapy dramatically increases the survival of HIV-infected individuals. However, treatment has to be continued for life because it does not lead to the full eradication of infection. HIV persists in resting CD4+ T cells, and possibly other cell types, and can reemerge from these cells when therapy is interrupted. Here, we review molecular mechanisms that have been proposed to contribute to HIV latency, as well as the relative roles of cis- and trans-acting mechanisms. We also discuss existing and future therapeutic opportunities regarding HIV latency that might lead to a future cure for HIV infection.
189 citations
TL;DR: Testing for human immunodeficiency virus resistance in drug-naive individuals and in patients in whom antiretroviral treatment is failing, and the appreciation of the role of testing, are crucial to the prevention and management of failure of ART.
Abstract: Background Contemporary antiretroviral therapies (ART) and management strategies have diminished both human immunodeficiency virus (HIV) treatment failure and the acquired resistance to drugs in resource-rich regions, but transmission of drug-resistant viruses has not similarly decreased. In low- and middle-income regions, ART roll-out has improved outcomes, but has resulted in increasing acquired and transmitted resistances. Our objective was to review resistance to ART drugs and methods to detect it, and to provide updated recommendations for testing and monitoring for drug resistance in HIV-infected individuals. Methods A volunteer panel of experts appointed by the International Antiviral (formerly AIDS) Society-USA reviewed relevant peer-reviewed data that were published or presented at scientific conferences. Recommendations were rated according to the strength of the recommendation and quality of the evidence, and reached by full panel consensus. Results Resistance testing remains a cornerstone of ART. It is recommended in newly-diagnosed individuals and in patients in whom ART has failed. Testing for transmitted integrase strand-transfer inhibitor resistance is currently not recommended, but this may change as more resistance emerges with widespread use. Sanger-based and next-generation sequencing approaches are each suited for genotypic testing. Testing for minority variants harboring drug resistance may only be considered if treatments depend on a first-generation nonnucleoside analogue reverse transcriptase inhibitor. Different HIV-1 subtypes do not need special considerations regarding resistance testing. Conclusions Testing for HIV drug resistance in drug-naive individuals and in patients in whom antiretroviral drugs are failing, and the appreciation of the role of testing, are crucial to the prevention and management of failure of ART.
159 citations
TL;DR: This essay will review what is known about transmitted and acquired drug resistance, multi-class drug resistant substances, resistance to newer drugs, resistance due to treatment for the prevention of mother-to-child transmission, the role of minority variants (low-frequency drug-resistance mutations), and resistance to pre-exposure prophylaxis.
Abstract: Access to combination antiretroviral treatment (ART) has improved greatly over recent years. At the end of 2011, more than eight million HIV-infected people were receiving ART in low-income and middle-income countries. ART generally works well in keeping the virus suppressed and the patient healthy. However, treatment only works as long as the virus is not resistant against the drugs used. In the last decades, HIV treatments have become better and better at slowing down the evolution of drug resistance, so that some patients are treated for many years without having any resistance problems. However, for some patients, especially in low-income countries, drug resistance is still a serious threat to their health. This essay will review what is known about transmitted and acquired drug resistance, multi-class drug resistance, resistance to newer drugs, resistance due to treatment for the prevention of mother-to-child transmission, the role of minority variants (low-frequency drug-resistance mutations), and resistance due to pre-exposure prophylaxis.
114 citations
Cites methods from "Rates of emergence of HIV drug resi..."
...For example, in a meta-analysis of studies from resource-limited settings, Stadeli and Richman (2012) find that 7% of patients who have been on ART for 6-11 months have resistance, 11 % after 12 -23 months and 21% after 36 months or more....
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...On the other hand, data reviewed by Stadeli and Richman (2012) suggest that in resourcelimited settings, multi-class drug resistance is more common and around three-quarters of patients with at least some resistance have multi-class drug resistance....
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TL;DR: Strategies to exploit miRNAs therapeutically for curbing HIV-1 infectivity, replication and latency are suggested since they hold an untapped potential that deserves further investigation.
102 citations
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TL;DR: A structured summary is provided including, as applicable, background, objectives, data sources, study eligibility criteria, participants, interventions, study appraisal and synthesis methods, results, limitations, conclusions and implications of key findings.
31,379 citations
01 Dec 2008
TL;DR: The International AIDS Society-USA (IAS-USA) Drug Resistance Mutations Group reviews new data on HIV-1 drug resistance that have been published or presented at recent scientific meetings to maintain a current list of mutations associated with antiretroviral drug resistance.
Abstract: The International AIDS Society-USA (IAS-USA) Drug Resistance Mutations Group reviews new data on HIV-1 drug resistance that have been published or presented at recent scientific meetings to maintain a current list of mutations associated with antiretroviral drug resistance.This December 2008 version of the IAS-USA drug resistance mutations figures updates those published in this journal in March/April 2008 (Johnson VA, Brun-Vezinet F, Clotet B, et al, Top HIV Med, 2008;16:62-68). The compilation includes mutations that may contribute to a reduced virologic response to HIV-1 drugs. It should not be assumed that the list presented here is exhaustive. Drugs that have been approved by the US Food and Drug Administration (US FDA) as well as any drugs available in expanded access programs are included and listed in alphabetical order by drug class. The figures are designed for practitioners to use in identifying key mutations associated with viral resistance to antiretroviral drugs and in making therapeutic decisions.
1,932 citations
01 Jan 2008
TL;DR: This report provides guidelines in key areas of antiretroviral management: when toinitiatetherapy, choice of initialimens, patient monitoring, and how best to approach treatment options, including optimal use of recently approved drugs in treatment-experienced patients.
Abstract: Context The availability of new antiretroviral drugs and formulations, including drugs in new classes, and recent data on treatment choices for antiretroviral-naive and -experienced patients warrant an update of the International AIDS Society–USA guidelines for the use of antiretroviral therapy in adult human immunodeficiency virus (HIV) infection. Objectives To summarize new data in the field and to provide current recommendations for the antiretroviral management and laboratory monitoring of HIV infection. This report provides guidelines in key areas of antiretroviral management: when toinitiatetherapy,choiceofinitialregimens,patientmonitoring,whentochangetherapy, and how best to approach treatment options, including optimal use of recently approved drugs (maraviroc, raltegravir, and etravirine) in treatment-experienced patients.
1,001 citations
World Health Organization1, Brigham and Women's Hospital2, University of Bordeaux3, Stanford University4, Centers for Disease Control and Prevention5, Brown University6, Tufts University7, Rega Institute for Medical Research8, Public Health Agency of Canada9, Erasmus University Rotterdam10, Utrecht University11, University College London12
TL;DR: This paper follows the same procedures described previously to develop an updated list of SDRMs that are likely to be useful for ongoing and future studies of transmitted drug resistance and concludes that the updated SDRM list has 93 mutations.
Abstract: Programs that monitor local, national, and regional levels of transmitted HIV-1 drug resistance inform treatment guidelines and provide feedback on the success of HIV-1 treatment and prevention programs. To accurately compare transmitted drug resistance rates across geographic regions and times, the World Health Organization has recommended the adoption of a consensus genotypic definition of transmitted HIV-1 drug resistance. In January 2007, we outlined criteria for developing a list of mutations for drug-resistance surveillance and compiled a list of 80 RT and protease mutations meeting these criteria (surveillance drug resistance mutations; SDRMs). Since January 2007, several new drugs have been approved and several new drug-resistance mutations have been identified. In this paper, we follow the same procedures described previously to develop an updated list of SDRMs that are likely to be useful for ongoing and future studies of transmitted drug resistance. The updated SDRM list has 93 mutations including 34 NRTI-resistance mutations at 15 RT positions, 19 NNRTI-resistance mutations at 10 RT positions, and 40 PI-resistance mutations at 18 protease positions.
870 citations
TL;DR: A panel of physicians and scientists with expertise in drug-resistant HIV-1, drug management, and patient care is convened to review recently published data and presentations at scientific conferences and to provide updated recommendations on resistance testing.
Abstract: Resistance to antiretroviral drugs remains an important limitation to successful human immunodeficiency virus type 1 (HIV-1) therapy. Resistance testing can improve treatment outcomes for infected individuals. The availability of new drugs from various classes, standardization of resistance assays, and the development of viral tropism tests necessitate new guidelines for resistance testing. The International AIDS Society-USA convened a panel of physicians and scientists with expertise in drug-resistant HIV-1, drug management, and patient care to review recently published data and presentations at scientific conferences and to provide updated recommendations. Whenever possible, resistance testing is recommended at the time of HIV infection diagnosis as part of the initial comprehensive patient assessment, as well as in all cases of virologic failure. Tropism testing is recommended whenever the use of chemokine receptor 5 antagonists is contemplated. As the roll out of antiretroviral therapy continues in developing countries, drug resistance monitoring for both subtype B and non-subtype B strains of HIV will become increasingly important.
570 citations