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Basic Search

Advanced search, search techniques.

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• Utilizing Search Results
• Scenarios in PubMed
• Identifying Articles

Basic searching in PubMed   is straightforward. Enter your keyword term(s) in the search box at the top and click the Search button.

PubMed may suggest topics for you, and if you like any of them you can simply click on one. It's usually a good idea to start with a broad search, then narrow your results.

Please note, PubMed is not like Google! You cannot use full sentences. Use keywords, author names, or journal titles to begin your searching. 

An Advanced Search in PubMed allows you to narrow your search and find specific resources. By selecting "Advanced" under the search bar, you are taken to the PubMed Advanced Search Builder .  From here, you can "add terms to the query box" and search by the specified field you choose. You can search by fields such as (but not limited to): 

• Title 
• MeSH (Medical Subject Heading) 
• Field Descriptions (tags) 

There are many techniques to refine your search in PubMed, including Boolean Operators, truncation, and search filters. 

Boolean Operators are used to connect pieces of information within a search. You can use the operators AND OR and NOT to focus your search results. 

• Used to narrow your search 
• All terms connected must be present in the results 
• e.g. virus AND cell death AND influenza
• Used to broaden your search 
• Either of the terms must be present in the results 
• e.g. flu OR influenza 
• Used to exclude terms in your search 
• Ignoring terms that may typically be present in your search 
• e.g. virus NOT influenza 

Truncation in PubMed is used with an asterisk (*). It builds on the asterisked word from the right. 

• Broadens your search
• Searches for multiple variants of a word (singular/plural/conjugations etc)
• this would search for words such as: gene, genetic, genetically, etc

Often, you may want to find a particular citation in PubMed. There are a couple of quick and easy ways to do this, so that you don't have to go through a formal search.

One way is the PubMed ID (PMID) . It is a series of number and appears with each citation. If you have that, simply type (or copy and paste) it into the search box and the citation appears.

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PubMed: Find Research Articles

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Finding Comparative Effectiveness Research

Comparative effectiveness research is the conduct and synthesis of research comparing the benefits and harms of different interventions and strategies to prevent, diagnose, treat and monitor health conditions in "real world" settings.

Two specialized resources are available to inform comparative effectiveness research:

Comparative Effectiveness Research  on the PubMed Topic-Specific Queries page. Provides specialized PubMed searches of published research and research in progress to help inform investigations of comparative effectiveness.

• Medline Plus  is the world’s largest medical library, it brings you information about diseases, conditions, and wellness issues in language you can understand. MedlinePlus offers reliable, up-to-date health information, anytime, anywhere, for free.

3 Ways to Find Research Articles in PubMed

1. filter (limit) to article type.

Most citations in PubMed are for journal articles. However, you may limit your retrieval based on the type of material the article represents. Use the Filters on the Results page sidebar and look at the Article Types checklist which contains a list of frequently searched publication types.

For example, choose Randomized Controlled Trial or Clinical Trial or Meta-Analysis from the list.

2. PubMed Clinical Queries 

Enter your search terms and evidence-filtered citations will appear under Clinical Study Categories. Systematic Reviews or Medical Genetics. The Clinical Queries link is found on the PubMed home page or under the More Resources drop-down at the top of the Advanced Search page.

The resulting retrieval in PubMed Clinical Queries can be further refined using PubMed's Filters, e.g., English language, humans.

3. Limit to Articles with Structured Abstracts

Many abstracts that are added to PubMed include section labels such as BACKGROUND, OBJECTIVE, METHODS, RESULTS, and CONCLUSIONS. These 'structured' abstracts appear in many different article types such as review articles, original research, and practice guidelines and facilitate skimming of citations for relevance and specific information such as research design within the Methods section.  The presence of structured abstracts in citations are a searchable feature in PubMed.  To limit to citations containing structured abstracts, include the term hasstructuredabstract in the search box.

For example: valerian AND sleep AND hasstructuredabstract

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Literature Searching

In this guide.

• Introduction
• Steps for searching the literature in PubMed
• Step 1 - Formulate a search question
• Step 2- Identify primary concepts and gather synonyms
• Step 3 - Locate subject headings (MeSH)
• Step 4 - Combine concepts using Boolean operators
• Step 5 - Refine search terms and search in PubMed
• Step 6 - Apply limits

Steps for Searching the Literature

Searching is an iterative process and often requires re-evaluation and testing by adding or changing keywords and the ways they relate to each other. To guide your search development, you can follow the search steps below. For more information on each step, navigate to its matching tab on the right menu. 

1. Formulate a clear, well-defined, answerable search question

Generally, the basic literature search process begins with formulating a clear, well-defined research question. Asking the right research question is essential to creating an effective search. Your research question(s) must be well-defined and answerable. If the question is too broad, your search will yield more information than you can possibly look through.

2. Identify primary concepts and gather synonyms

Your research question will also help identify the primary search concepts. This will allow you to think about how you want the concepts to relate to each other. Since different authors use different terminology to refer to the same concept, you will need to gather synonyms and all the ways authors might express them. However, it is important to balance the terms so that the synonyms do not go beyond the scope of how you've defined them.

3. Locate subject headings (MeSH)

Subject databases like PubMed use 'controlled vocabularies' made up of subject headings that are preassigned to indexed articles that share a similar topic. These subject headings are organized hierarchically within a family tree of broader and narrower concepts. In PubMed and MEDLINE, the subject headings are called Medical Subject Headings (MeSH). By including MeSH terms in your search, you will not have to think about word variations, word endings, plural or singular forms, or synonyms. Some topics or concepts may even have more than one appropriate MeSH term. There are also times when a topic or concept may not have a MeSH term. 

4. Combine concepts using Boolean operators AND/OR

Once you have identified your search concepts, synonyms, and MeSH terms, you'll need to put them together using nesting and Boolean operators (e.g. AND, OR, NOT). Nesting uses parentheses to put search terms into groups. Boolean operators are used to combine similar and different concepts into one query. 

5. Refine search terms and search in PubMed

There are various database search tactics you can use, such as field tags to limit the search to certain fields, quotation marks for phrase searching, and proximity operators to search a number of spaces between terms to refine your search terms. The constructed search string is ready to be pasted into PubMed. 

6. Apply limits (optional)

If you're getting too many results, you can further refine your search results by using limits on the left box of the results page. Limits allow you to narrow your search by a number of facets such as year, journal name, article type, language, age, etc. 

Depending on the nature of the literature review, the complexity and comprehensiveness of the search strategies and the choice of databases can be different. Please contact the Lane Librarians if you have any questions. 

The type of information you gather is influenced by the type of information source or database you select to search. Bibliographic databases contain references to published literature, such as journal articles, conference abstracts, books, reports, government and legal publications, and patents. Literature reviews typically synthesis indexed, peer-reviewed articles (i.e. works that generally represent the latest original research and have undergone rigorous expert screening before publication), and gray literature (i.e. materials not formally published by commercial publishers or peer-reviewed journals). PubMed offers a breadth of health sciences literature and is a good starting point to locate journal articles.

What is PubMed?

PubMed is a free search engine accessing primarily the MEDLINE database of references and abstracts on life sciences and biomedical topics. Available to the public online since 1996, PubMed was developed and is maintained by the  National Center for Biotechnology Information (NCBI) , at the  U.S. National Library of Medicine (NLM) , located at the  National Institutes of Health (NIH) .

MEDLINE is the National Library of Medicine’s (NLM) premier bibliographic database that contains more than 27 million references to journal articles from more than 5,200 worldwide journals in life sciences with a concentration on biomedicine. The Literature Selection Technica Review Committee (LSTRC) reviews and selects journals for MEDLINE based on the research quality and impact of the journals. A distinctive feature of MEDLINE is that the records are indexed with NLM  Medical Subject Headings  (MeSH).

PubMed also contains citations for  PubMed Central (PMC)  articles. PMC is a full-text archive that includes articles from journals reviewed and selected by NLM for archiving (current and historical), as well as individual articles collected for archiving in compliance with funder policies.  PubMed allows users to search keywords in the bibliographic data, but not the full text of the PMC articles.

How to Access PubMed?

To access PubMed, go to the Lane Library homepage and click PubMed in "Top Resources" on the left. This PubMed link is coded with Find Fulltext @ Lane Library Stanford that links you to Lane's full-text articles online. 

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How to Search in Biomedical Databases

• Getting Started with your Search

PubMed Search Tips

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• Why Use PubMed?
• How to Access PubMed at NEOMED
• Before You Start Searching . . .
• Step 1: Identifying Key Search Concepts Using PICO
• Step 2: Locating Relevant MeSH Terms
• Step 3: Locating Relevant Keywords & Synonyms
• Step 4: Combining MeSH & Keywords Pt. 1
• Step 5: Combining MeSH & Keywords Pt. 2
• Step 6: Combining Search Elements Using AND
• Step 7: Applying Filters
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Contact Your Librarian for Help!

We encourage students, researchers, and faculty members throughout NEOMED's campus and at our clinical sites to use this overview of how to search in PubMed for their research and instruction needs.

Contents (click on items to jump ahead)

Overview: When should I use this database?

How to access PubMed at NEOMED

Before you start searching, keep in mind . . .

Keywords  

Automatic Term Mapping 

How to Find & Use Keywords

Controlled Vocabularies 

Medical Subject Headings (MeSH)

Explode vs. No Explode

Subheadings

Combining Searches Using Boolean Operators (OR, AND, NOT)

Applying Filters

How to Access Full Text

More Information

PubMed Tipsheet (pdf)

Overview: when should I use this database?

PubMed comprises more than 27 million citations for biomedical literature from MEDLINE, life science journals, and online books. The public database is maintained by the U.S. National Library of Medicine (NLM) and the National Center for Biotechnology Information, and this tip sheets applies to this public-facing version, not the version of Medline supported by Ovid. It offers a fairly broad overview of existing literature on a particular topic, but it should not be seen as a complete overview.

How to access PubMed at NEOMED

Please note that to access full text for articles located within PubMed, authentication with your NEOMED Library credentials  is required both  on- and  off-campus to  PubMed. The NEOMED instance of PubMed can be located from our landing page searchbox or via the following link:  PubMed . Do not simply google PubMed; it will not provide NEOMED full text links. Learn more about  how to Access Full Text  within a specific PubMed record.

Save your search in a document, citation management software (Endnote, Refworks, etc.), and/or the database

By saving your search, your strategy will be reproducible for another time and properly documented.

Explore options and instruction for citation management here , and find tips on how to export results.

To save searches in PubMed, create an NCBI account by clicking on the sign in to NCBI link in the upper-right corner of the screen (sign up for a My NCBI account by clicking here ). Once you complete a search, click on "Create an alert" underneath the search box. From here you can create a search alert or save your search strategy.

Automatic Term Mapping

PubMed uses Automatic Term Mapping (ATM) when you search with keywords. This means that the search terms you type into the search box are automatically mapped to controlled vocabulary (MeSH) terms. To see ATM in action, scroll to the "Search details" box on the left hand side of the results page. Warning: ATM is not always correct. For example, if you search for “cold AND zinc,” PubMed will include the controlled vocabulary for "cold temperatures" in the search.

Using quotes around a phrase or truncation turns off Automatic Term Mapping. The terms are instead searched as keywords.

Keywords — How to Find & Use

Keyword terms can be single words or phrases.

Use quotes around all phrases to ensure that the phrase is searched instead of each word individually. (e.g. “public health”)

For more possible search terms, visit the MeSH (Medical Subject Headings) database and look at the "entry terms" listed for each MeSH record . MeSH is NLM’s controlled vocabulary of biomedical terms used to describe the subject of each journal article in MEDLINE. The entry terms are synonyms, alternate forms, and other closely related terms generally used interchangeably with the preferred term.

Consult controlled vocabularies in other subject databases for additional help. For example, the Embase has a controlled vocabulary called Emtree . Emtree records contain synonym lists similar to the "entry terms" in a MeSH record.  The Emtree synonym list often contains European spellings/variations.

Controlled Vocabularies -- How to Find & Use

Locate controlled vocabulary (mesh).

MeSH (Medical Subject Headings) is NLM’s controlled vocabulary of biomedical terms used to describe the subject of each journal article in MEDLINE. These are a standardized set of terms that are used to bring consistency to the searching process. In total, there are approximately 26,000 terms, and they are updated annually to reflect changes in medicine and medical terminology. Using MeSH terms helps account for variations in language, acronyms, and British vs. American English.

MeSH can be searched from a NCBI interface: https://www.ncbi.nlm.nih.gov/mesh

Terms are arranged hierarchically by subject categories with more specific terms arranged beneath broader terms. MeSH terms in PubMed automatically include the more specific MeSH terms in a search.

To turn off this automatic explode feature, click on the button next to, "Do not include MeSH terms found below this term in the MeSH hierarchy" in the MeSH record or type [mh:noexp] next to the search term, e.g. neoplasms [mh:noexp]. See next page for additional information on no explode.

Once MeSH terms have been searched, terms will appear in a box labelled “Search details,” located beside the list of the results on the right side of the screen. This box will display how each term has been searched, and can be useful for editing your search. Corrections can be made directly within this box, and once corrections have been made, the search button beneath the box will re-run your search.

Difference between “Explode,” “No Explode,” and “Major Heading”

“Explode” will search with all subheadings beneath the main heading included and bring up all results listing any of these terms subject heading subheadings combinations. PubMed will default to explode any MeSH you search.

Choosing to focus (also referred to as “not exploding”) will only search for your chosen MeSH term. Terms are chosen by MeSH indexers to be the primary focus of an individual article. Command to search: [Mesh:noexp] will only find the term specified, not the terms beneath it (for example: “diarrhea”[Mesh:noexp] only finds records indexed with diarrhea, not acute diarrhea or bloody diarrhea, etc.)

Searching for “major headings” will narrow your search to only find MeSH terms listed as a major topic of an article. Command to search: [majr] (e.g. “diarrhea”[majr] will find articles with diarrhea as a major topic. Major topic MeSH terms will have an asterisks (e.g. Diarrhea*), while non-major topics will not have one.

MeSH can be made more specific by the addition of  subheadings such as "therapy" and "prevention and control"

When in the MeSH record, add subheadings by clicking on the boxes next to the desired subheadings. Then click "Add to Search Builder." Warning: Adding too many subheadings may lead to missing important articles.

MeSH/Subheading Combinations: You can manually add subheadings in the search box by using the format MeSH Term/Subheading, e.g. neoplasms/diet therapy. You can also use the two letter abbreviation for subheadings rather than typing out the full phrase, e.g. neoplasms/dh. Click here for the abbreviations of other MeSH subheadings. ( https://www.ncbi.nlm.nih.gov/books/NBK3827/table/pubmedhelp.T.mesh_subheadings/ )

For a MeSH/Subheading combination, only one Subheading at a time may be directly attached to a MeSH term. For example, a search of hypertension with the subheadings diagnosis or drug therapy will appear as hypertension/diagnosis or hypertension/drug therapy.

As with MeSH terms, PubMed search results, by default, include the more specific terms arranged beneath broader terms for the MeSH term and also includes the more specific terms arranged beneath broader  Subheadings .

Combining Searches Using Boolean Operators

A comprehensive and systematic search of PubMed includes both controlled vocabulary and keyword terms (i.e. free text, natural language, and synonyms).

Boolean operators are used to combine search terms. In PubMed, you can use the operators AND, OR, and NOT.

Go to the “Advanced Search” page to combine searches. This is where your search history is located during your search session.

Boolean operators MUST be used as upper case (AND, OR, NOT).

OR --use OR between similar keywords, like synonyms, acronyms, and variations in spelling within the same idea or concept

AND —use AND to link ideas and concepts where you want to see both ideas or concepts in your search results

NOT —used to exclude specific keywords from the search, however, you will want to use NOT with caution because you may end up missing something important.

You can use field tags to specify where the database looks for the search term. In PubMed, first type the search term and then the field tag in brackets. e.g. Cardiology [TIAB] looks for cardiology in the title and abstract.

[All Fields] or [ALL] – Untagged terms and terms tagged with [all fields] are processed using  Automatic Term Mapping . Terms enclosed in double quotes or truncated will be searched in all fields and not processed using automatic term mapping.

[Text Words] or [TW] – Includes all words and numbers in the title, abstract, other abstract, MeSH terms, MeSH Subheadings, Publication Types, Substance Names, Personal Name as Subject, Corporate Author, Secondary Source, Comment/Correction Notes, and Other Terms.

[Title/Abstract] or [TIAB] – Words and numbers included in the title, collection title, abstract, and other abstract of a citation. English language abstracts are taken directly from the published article. If an article does not have a published abstract, NLM does not create one.

NCBI explanation of Field Descriptions and Tags  

Applying Filters

On the left side of the results are options to filter your search by Article types, Publication dates, Language, Age, Gender, etc. To access the complete list of filters, click on the “Show additional filters” link.

Use the PubMed built-in limits cautiously. Limits other than date or language will limit your search to indexed records only. In most cases it is best to develop another concept to use as a limiter.

For example, if you would like to limit your results to "human studies," use the following search to exclude animal studies instead of using the "humans" limit from the search results page. Simply add this to the rest of your search strategy using the NOT Boolean operator

(animals[MeSH Terms] NOT humans[MeSH Terms])

• In PubMed you can use a * at the root of a word to find multiple endings.  For example:

arthroplast* will return arthroplasty, arthroplasties, arthroplastic, arthroplastics, etc.

mobili* will return mobility, mobilization, mobilisation, mobilize, etc.

• Note: In PubMed you cannot combine phrase searching with truncation. Either use quotes, e.g. " early childhood mobility ," or use truncation, e.g. early childhood mobili*

In PubMed, the “Northeast Ohio Medical University” icon (pictured above) will often appear within an item record. To access the full text, click the pictured icon to go to an external page listing available full-text options. If the full text is not available, you will see a heading that says, "ILLiad - Request this item through interlibrary loan." When prompted, enter your ILLiad login and password and then submit the request via the pre-filled in template. The article will be emailed to you free of charge (only available for NEOMED students, faculty, and staff).

General principles on searching in any database

PubMedTutorials

Additional tips on exploring journal table of contents, subject filters, and topic alerts

Detailed information about MeSH ( https://www.nlm.nih.gov/mesh/intro_retrieval.html )

This content was adapted from “PubMed Search Tips” by Simon Robins, which is licensed under  Creative Commons 4.0 License, CC BY , and content found on Welch Medical Library's  Nursing Resources Guide  which is licensed under  a  Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License   attributable to the Welch Medical Library

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MEDLINE content is searchable via PubMed and constitutes the primary component of PubMed, a literature database developed and maintained by the NLM National Center for Biotechnology Information (NCBI).

Last Reviewed: February 5, 2024

Reference management. Clean and simple.

The top list of academic search engines

1. Google Scholar

4. science.gov, 5. semantic scholar, 6. baidu scholar, get the most out of academic search engines, frequently asked questions about academic search engines, related articles.

Academic search engines have become the number one resource to turn to in order to find research papers and other scholarly sources. While classic academic databases like Web of Science and Scopus are locked behind paywalls, Google Scholar and others can be accessed free of charge. In order to help you get your research done fast, we have compiled the top list of free academic search engines.

Google Scholar is the clear number one when it comes to academic search engines. It's the power of Google searches applied to research papers and patents. It not only lets you find research papers for all academic disciplines for free but also often provides links to full-text PDF files.

• Coverage: approx. 200 million articles
• Abstracts: only a snippet of the abstract is available
• Related articles: ✔
• References: ✔
• Cited by: ✔
• Links to full text: ✔
• Export formats: APA, MLA, Chicago, Harvard, Vancouver, RIS, BibTeX

BASE is hosted at Bielefeld University in Germany. That is also where its name stems from (Bielefeld Academic Search Engine).

• Coverage: approx. 136 million articles (contains duplicates)
• Abstracts: ✔
• Related articles: ✘
• References: ✘
• Cited by: ✘
• Export formats: RIS, BibTeX

CORE is an academic search engine dedicated to open-access research papers. For each search result, a link to the full-text PDF or full-text web page is provided.

• Coverage: approx. 136 million articles
• Links to full text: ✔ (all articles in CORE are open access)
• Export formats: BibTeX

Science.gov is a fantastic resource as it bundles and offers free access to search results from more than 15 U.S. federal agencies. There is no need anymore to query all those resources separately!

• Coverage: approx. 200 million articles and reports
• Links to full text: ✔ (available for some databases)
• Export formats: APA, MLA, RIS, BibTeX (available for some databases)

Semantic Scholar is the new kid on the block. Its mission is to provide more relevant and impactful search results using AI-powered algorithms that find hidden connections and links between research topics.

• Coverage: approx. 40 million articles
• Export formats: APA, MLA, Chicago, BibTeX

Although Baidu Scholar's interface is in Chinese, its index contains research papers in English as well as Chinese.

• Coverage: no detailed statistics available, approx. 100 million articles
• Abstracts: only snippets of the abstract are available
• Export formats: APA, MLA, RIS, BibTeX

RefSeek searches more than one billion documents from academic and organizational websites. Its clean interface makes it especially easy to use for students and new researchers.

• Coverage: no detailed statistics available, approx. 1 billion documents
• Abstracts: only snippets of the article are available
• Export formats: not available

Consider using a reference manager like Paperpile to save, organize, and cite your references. Paperpile integrates with Google Scholar and many popular databases, so you can save references and PDFs directly to your library using the Paperpile buttons:

Google Scholar is an academic search engine, and it is the clear number one when it comes to academic search engines. It's the power of Google searches applied to research papers and patents. It not only let's you find research papers for all academic disciplines for free, but also often provides links to full text PDF file.

Semantic Scholar is a free, AI-powered research tool for scientific literature developed at the Allen Institute for AI. Sematic Scholar was publicly released in 2015 and uses advances in natural language processing to provide summaries for scholarly papers.

BASE , as its name suggest is an academic search engine. It is hosted at Bielefeld University in Germany and that's where it name stems from (Bielefeld Academic Search Engine).

CORE is an academic search engine dedicated to open access research papers. For each search result a link to the full text PDF or full text web page is provided.

Science.gov is a fantastic resource as it bundles and offers free access to search results from more than 15 U.S. federal agencies. There is no need any more to query all those resources separately!

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• 04 March 2024
• Clarification 05 March 2024

Millions of research papers at risk of disappearing from the Internet

You can also search for this author in PubMed   Google Scholar

You have full access to this article via your institution.

A study identified more than two million articles that did not appear in a major digital archive, despite having an active DOI. Credit: Anna Berkut/Alamy

More than one-quarter of scholarly articles are not being properly archived and preserved, a study of more than seven million digital publications suggests. The findings, published in the Journal of Librarianship and Scholarly Communication on 24 January 1 , indicate that systems to preserve papers online have failed to keep pace with the growth of research output.

“Our entire epistemology of science and research relies on the chain of footnotes,” explains author Martin Eve, a researcher in literature, technology and publishing at Birkbeck, University of London. “If you can’t verify what someone else has said at some other point, you’re just trusting to blind faith for artefacts that you can no longer read yourself.”

Eve, who is also involved in research and development at digital-infrastructure organization Crossref, checked whether 7,438,037 works labelled with digital object identifiers (DOIs) are held in archives. DOIs — which consist of a string of numbers, letters and symbols — are unique fingerprints used to identify and link to specific publications, such as scholarly articles and official reports. Crossref is the largest DOI registration agency, allocating the identifiers to about 20,000 members, including publishers, museums and other institutions.

The sample of DOIs included in the study was made up of a random selection of up to 1,000 registered to each member organization. Twenty-eight per cent of these works — more than two million articles — did not appear in a major digital archive, despite having an active DOI. Only 58% of the DOIs referenced works that had been stored in at least one archive. The other 14% were excluded from the study because they were published too recently, were not journal articles or did not have an identifiable source.

Preservation challenge

Eve notes that the study has limitations: namely that it tracked only articles with DOIs, and that it did not search every digital repository for articles (he did not check whether items with a DOI were stored in institutional repositories, for example).

Nevertheless, preservation specialists have welcomed the analysis. “It’s been hard to know the real extent of the digital preservation challenge faced by e-journals,” says William Kilbride, managing director of the Digital Preservation Coalition, headquartered in York, UK. The coalition publishes a handbook detailing good preservation practice.

“Many people have the blind assumption that if you have a DOI, it’s there forever,” says Mikael Laakso, who studies scholarly publishing at the Hanken School of Economics in Helsinki. “But that doesn’t mean that the link will always work.” In 2021, Laakso and his colleagues reported 2 that more than 170 open-access journals had disappeared from the Internet between 2000 and 2019.

Kate Wittenberg, managing director of the digital archiving service Portico in New York City, warns that small publishers are at higher risk of failing to preserve articles than are large ones. “It costs money to preserve content,” she says, adding that archiving involves infrastructure, technology and expertise that many smaller organizations do not have access to.

Eve’s study suggests some measures that could improve digital preservation, including stronger requirements at DOI registration agencies and better education and awareness of the issue among publishers and researchers.

“Everybody thinks of the immediate gains they might get from having a paper out somewhere, but we really should be thinking about the long-term sustainability of the research ecosystem,” Eve says. “After you’ve been dead for 100 years, are people going to be able to get access to the things you’ve worked on?”

Nature 627 , 256 (2024)

doi: https://doi.org/10.1038/d41586-024-00616-5

Updates & Corrections

Clarification 05 March 2024 : The headline of this story has been edited to reflect the fact that some of these papers have not entirely disappeared from the Internet. Rather, many papers are still accessible but have not been properly archived.

Eve, M. P. J. Libr. Sch. Commun. 12 , eP16288 (2024).

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Laakso, M., Matthias, L. & Jahn, N. J. Assoc. Inf. Sci. Technol. 72 , 1099–1112 (2021).

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• Published: 04 June 2021

Coronavirus disease (COVID-19) pandemic: an overview of systematic reviews

• Israel Júnior Borges do Nascimento 1 , 2 ,
• Dónal P. O’Mathúna 3 , 4 ,
• Thilo Caspar von Groote 5 ,
• Hebatullah Mohamed Abdulazeem 6 ,
• Ishanka Weerasekara 7 , 8 ,
• Ana Marusic 9 ,
• Livia Puljak   ORCID: orcid.org/0000-0002-8467-6061 10 ,
• Vinicius Tassoni Civile 11 ,
• Irena Zakarija-Grkovic 9 ,
• Tina Poklepovic Pericic 9 ,
• Alvaro Nagib Atallah 11 ,
• Santino Filoso 12 ,
• Nicola Luigi Bragazzi 13 &
• Milena Soriano Marcolino 1

On behalf of the International Network of Coronavirus Disease 2019 (InterNetCOVID-19)

BMC Infectious Diseases volume  21 , Article number:  525 ( 2021 ) Cite this article

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Navigating the rapidly growing body of scientific literature on the SARS-CoV-2 pandemic is challenging, and ongoing critical appraisal of this output is essential. We aimed to summarize and critically appraise systematic reviews of coronavirus disease (COVID-19) in humans that were available at the beginning of the pandemic.

Nine databases (Medline, EMBASE, Cochrane Library, CINAHL, Web of Sciences, PDQ-Evidence, WHO’s Global Research, LILACS, and Epistemonikos) were searched from December 1, 2019, to March 24, 2020. Systematic reviews analyzing primary studies of COVID-19 were included. Two authors independently undertook screening, selection, extraction (data on clinical symptoms, prevalence, pharmacological and non-pharmacological interventions, diagnostic test assessment, laboratory, and radiological findings), and quality assessment (AMSTAR 2). A meta-analysis was performed of the prevalence of clinical outcomes.

Eighteen systematic reviews were included; one was empty (did not identify any relevant study). Using AMSTAR 2, confidence in the results of all 18 reviews was rated as “critically low”. Identified symptoms of COVID-19 were (range values of point estimates): fever (82–95%), cough with or without sputum (58–72%), dyspnea (26–59%), myalgia or muscle fatigue (29–51%), sore throat (10–13%), headache (8–12%) and gastrointestinal complaints (5–9%). Severe symptoms were more common in men. Elevated C-reactive protein and lactate dehydrogenase, and slightly elevated aspartate and alanine aminotransferase, were commonly described. Thrombocytopenia and elevated levels of procalcitonin and cardiac troponin I were associated with severe disease. A frequent finding on chest imaging was uni- or bilateral multilobar ground-glass opacity. A single review investigated the impact of medication (chloroquine) but found no verifiable clinical data. All-cause mortality ranged from 0.3 to 13.9%.

Conclusions

In this overview of systematic reviews, we analyzed evidence from the first 18 systematic reviews that were published after the emergence of COVID-19. However, confidence in the results of all reviews was “critically low”. Thus, systematic reviews that were published early on in the pandemic were of questionable usefulness. Even during public health emergencies, studies and systematic reviews should adhere to established methodological standards.

Peer Review reports

The spread of the “Severe Acute Respiratory Coronavirus 2” (SARS-CoV-2), the causal agent of COVID-19, was characterized as a pandemic by the World Health Organization (WHO) in March 2020 and has triggered an international public health emergency [ 1 ]. The numbers of confirmed cases and deaths due to COVID-19 are rapidly escalating, counting in millions [ 2 ], causing massive economic strain, and escalating healthcare and public health expenses [ 3 , 4 ].

The research community has responded by publishing an impressive number of scientific reports related to COVID-19. The world was alerted to the new disease at the beginning of 2020 [ 1 ], and by mid-March 2020, more than 2000 articles had been published on COVID-19 in scholarly journals, with 25% of them containing original data [ 5 ]. The living map of COVID-19 evidence, curated by the Evidence for Policy and Practice Information and Co-ordinating Centre (EPPI-Centre), contained more than 40,000 records by February 2021 [ 6 ]. More than 100,000 records on PubMed were labeled as “SARS-CoV-2 literature, sequence, and clinical content” by February 2021 [ 7 ].

Due to publication speed, the research community has voiced concerns regarding the quality and reproducibility of evidence produced during the COVID-19 pandemic, warning of the potential damaging approach of “publish first, retract later” [ 8 ]. It appears that these concerns are not unfounded, as it has been reported that COVID-19 articles were overrepresented in the pool of retracted articles in 2020 [ 9 ]. These concerns about inadequate evidence are of major importance because they can lead to poor clinical practice and inappropriate policies [ 10 ].

Systematic reviews are a cornerstone of today’s evidence-informed decision-making. By synthesizing all relevant evidence regarding a particular topic, systematic reviews reflect the current scientific knowledge. Systematic reviews are considered to be at the highest level in the hierarchy of evidence and should be used to make informed decisions. However, with high numbers of systematic reviews of different scope and methodological quality being published, overviews of multiple systematic reviews that assess their methodological quality are essential [ 11 , 12 , 13 ]. An overview of systematic reviews helps identify and organize the literature and highlights areas of priority in decision-making.

In this overview of systematic reviews, we aimed to summarize and critically appraise systematic reviews of coronavirus disease (COVID-19) in humans that were available at the beginning of the pandemic.

Methodology

Research question.

This overview’s primary objective was to summarize and critically appraise systematic reviews that assessed any type of primary clinical data from patients infected with SARS-CoV-2. Our research question was purposefully broad because we wanted to analyze as many systematic reviews as possible that were available early following the COVID-19 outbreak.

Study design

We conducted an overview of systematic reviews. The idea for this overview originated in a protocol for a systematic review submitted to PROSPERO (CRD42020170623), which indicated a plan to conduct an overview.

Overviews of systematic reviews use explicit and systematic methods for searching and identifying multiple systematic reviews addressing related research questions in the same field to extract and analyze evidence across important outcomes. Overviews of systematic reviews are in principle similar to systematic reviews of interventions, but the unit of analysis is a systematic review [ 14 , 15 , 16 ].

We used the overview methodology instead of other evidence synthesis methods to allow us to collate and appraise multiple systematic reviews on this topic, and to extract and analyze their results across relevant topics [ 17 ]. The overview and meta-analysis of systematic reviews allowed us to investigate the methodological quality of included studies, summarize results, and identify specific areas of available or limited evidence, thereby strengthening the current understanding of this novel disease and guiding future research [ 13 ].

A reporting guideline for overviews of reviews is currently under development, i.e., Preferred Reporting Items for Overviews of Reviews (PRIOR) [ 18 ]. As the PRIOR checklist is still not published, this study was reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2009 statement [ 19 ]. The methodology used in this review was adapted from the Cochrane Handbook for Systematic Reviews of Interventions and also followed established methodological considerations for analyzing existing systematic reviews [ 14 ].

Approval of a research ethics committee was not necessary as the study analyzed only publicly available articles.

Eligibility criteria

Systematic reviews were included if they analyzed primary data from patients infected with SARS-CoV-2 as confirmed by RT-PCR or another pre-specified diagnostic technique. Eligible reviews covered all topics related to COVID-19 including, but not limited to, those that reported clinical symptoms, diagnostic methods, therapeutic interventions, laboratory findings, or radiological results. Both full manuscripts and abbreviated versions, such as letters, were eligible.

No restrictions were imposed on the design of the primary studies included within the systematic reviews, the last search date, whether the review included meta-analyses or language. Reviews related to SARS-CoV-2 and other coronaviruses were eligible, but from those reviews, we analyzed only data related to SARS-CoV-2.

No consensus definition exists for a systematic review [ 20 ], and debates continue about the defining characteristics of a systematic review [ 21 ]. Cochrane’s guidance for overviews of reviews recommends setting pre-established criteria for making decisions around inclusion [ 14 ]. That is supported by a recent scoping review about guidance for overviews of systematic reviews [ 22 ].

Thus, for this study, we defined a systematic review as a research report which searched for primary research studies on a specific topic using an explicit search strategy, had a detailed description of the methods with explicit inclusion criteria provided, and provided a summary of the included studies either in narrative or quantitative format (such as a meta-analysis). Cochrane and non-Cochrane systematic reviews were considered eligible for inclusion, with or without meta-analysis, and regardless of the study design, language restriction and methodology of the included primary studies. To be eligible for inclusion, reviews had to be clearly analyzing data related to SARS-CoV-2 (associated or not with other viruses). We excluded narrative reviews without those characteristics as these are less likely to be replicable and are more prone to bias.

Scoping reviews and rapid reviews were eligible for inclusion in this overview if they met our pre-defined inclusion criteria noted above. We included reviews that addressed SARS-CoV-2 and other coronaviruses if they reported separate data regarding SARS-CoV-2.

Information sources

Nine databases were searched for eligible records published between December 1, 2019, and March 24, 2020: Cochrane Database of Systematic Reviews via Cochrane Library, PubMed, EMBASE, CINAHL (Cumulative Index to Nursing and Allied Health Literature), Web of Sciences, LILACS (Latin American and Caribbean Health Sciences Literature), PDQ-Evidence, WHO’s Global Research on Coronavirus Disease (COVID-19), and Epistemonikos.

The comprehensive search strategy for each database is provided in Additional file 1 and was designed and conducted in collaboration with an information specialist. All retrieved records were primarily processed in EndNote, where duplicates were removed, and records were then imported into the Covidence platform [ 23 ]. In addition to database searches, we screened reference lists of reviews included after screening records retrieved via databases.

Study selection

All searches, screening of titles and abstracts, and record selection, were performed independently by two investigators using the Covidence platform [ 23 ]. Articles deemed potentially eligible were retrieved for full-text screening carried out independently by two investigators. Discrepancies at all stages were resolved by consensus. During the screening, records published in languages other than English were translated by a native/fluent speaker.

Data collection process

We custom designed a data extraction table for this study, which was piloted by two authors independently. Data extraction was performed independently by two authors. Conflicts were resolved by consensus or by consulting a third researcher.

We extracted the following data: article identification data (authors’ name and journal of publication), search period, number of databases searched, population or settings considered, main results and outcomes observed, and number of participants. From Web of Science (Clarivate Analytics, Philadelphia, PA, USA), we extracted journal rank (quartile) and Journal Impact Factor (JIF).

We categorized the following as primary outcomes: all-cause mortality, need for and length of mechanical ventilation, length of hospitalization (in days), admission to intensive care unit (yes/no), and length of stay in the intensive care unit.

The following outcomes were categorized as exploratory: diagnostic methods used for detection of the virus, male to female ratio, clinical symptoms, pharmacological and non-pharmacological interventions, laboratory findings (full blood count, liver enzymes, C-reactive protein, d-dimer, albumin, lipid profile, serum electrolytes, blood vitamin levels, glucose levels, and any other important biomarkers), and radiological findings (using radiography, computed tomography, magnetic resonance imaging or ultrasound).

We also collected data on reporting guidelines and requirements for the publication of systematic reviews and meta-analyses from journal websites where included reviews were published.

Quality assessment in individual reviews

Two researchers independently assessed the reviews’ quality using the “A MeaSurement Tool to Assess Systematic Reviews 2 (AMSTAR 2)”. We acknowledge that the AMSTAR 2 was created as “a critical appraisal tool for systematic reviews that include randomized or non-randomized studies of healthcare interventions, or both” [ 24 ]. However, since AMSTAR 2 was designed for systematic reviews of intervention trials, and we included additional types of systematic reviews, we adjusted some AMSTAR 2 ratings and reported these in Additional file 2 .

Adherence to each item was rated as follows: yes, partial yes, no, or not applicable (such as when a meta-analysis was not conducted). The overall confidence in the results of the review is rated as “critically low”, “low”, “moderate” or “high”, according to the AMSTAR 2 guidance based on seven critical domains, which are items 2, 4, 7, 9, 11, 13, 15 as defined by AMSTAR 2 authors [ 24 ]. We reported our adherence ratings for transparency of our decision with accompanying explanations, for each item, in each included review.

One of the included systematic reviews was conducted by some members of this author team [ 25 ]. This review was initially assessed independently by two authors who were not co-authors of that review to prevent the risk of bias in assessing this study.

Synthesis of results

For data synthesis, we prepared a table summarizing each systematic review. Graphs illustrating the mortality rate and clinical symptoms were created. We then prepared a narrative summary of the methods, findings, study strengths, and limitations.

For analysis of the prevalence of clinical outcomes, we extracted data on the number of events and the total number of patients to perform proportional meta-analysis using RStudio© software, with the “meta” package (version 4.9–6), using the “metaprop” function for reviews that did not perform a meta-analysis, excluding case studies because of the absence of variance. For reviews that did not perform a meta-analysis, we presented pooled results of proportions with their respective confidence intervals (95%) by the inverse variance method with a random-effects model, using the DerSimonian-Laird estimator for τ 2 . We adjusted data using Freeman-Tukey double arcosen transformation. Confidence intervals were calculated using the Clopper-Pearson method for individual studies. We created forest plots using the RStudio© software, with the “metafor” package (version 2.1–0) and “forest” function.

Managing overlapping systematic reviews

Some of the included systematic reviews that address the same or similar research questions may include the same primary studies in overviews. Including such overlapping reviews may introduce bias when outcome data from the same primary study are included in the analyses of an overview multiple times. Thus, in summaries of evidence, multiple-counting of the same outcome data will give data from some primary studies too much influence [ 14 ]. In this overview, we did not exclude overlapping systematic reviews because, according to Cochrane’s guidance, it may be appropriate to include all relevant reviews’ results if the purpose of the overview is to present and describe the current body of evidence on a topic [ 14 ]. To avoid any bias in summary estimates associated with overlapping reviews, we generated forest plots showing data from individual systematic reviews, but the results were not pooled because some primary studies were included in multiple reviews.

Our search retrieved 1063 publications, of which 175 were duplicates. Most publications were excluded after the title and abstract analysis ( n = 860). Among the 28 studies selected for full-text screening, 10 were excluded for the reasons described in Additional file 3 , and 18 were included in the final analysis (Fig. 1 ) [ 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 ]. Reference list screening did not retrieve any additional systematic reviews.

PRISMA flow diagram

Characteristics of included reviews

Summary features of 18 systematic reviews are presented in Table 1 . They were published in 14 different journals. Only four of these journals had specific requirements for systematic reviews (with or without meta-analysis): European Journal of Internal Medicine, Journal of Clinical Medicine, Ultrasound in Obstetrics and Gynecology, and Clinical Research in Cardiology . Two journals reported that they published only invited reviews ( Journal of Medical Virology and Clinica Chimica Acta ). Three systematic reviews in our study were published as letters; one was labeled as a scoping review and another as a rapid review (Table 2 ).

All reviews were published in English, in first quartile (Q1) journals, with JIF ranging from 1.692 to 6.062. One review was empty, meaning that its search did not identify any relevant studies; i.e., no primary studies were included [ 36 ]. The remaining 17 reviews included 269 unique studies; the majority ( N = 211; 78%) were included in only a single review included in our study (range: 1 to 12). Primary studies included in the reviews were published between December 2019 and March 18, 2020, and comprised case reports, case series, cohorts, and other observational studies. We found only one review that included randomized clinical trials [ 38 ]. In the included reviews, systematic literature searches were performed from 2019 (entire year) up to March 9, 2020. Ten systematic reviews included meta-analyses. The list of primary studies found in the included systematic reviews is shown in Additional file 4 , as well as the number of reviews in which each primary study was included.

Population and study designs

Most of the reviews analyzed data from patients with COVID-19 who developed pneumonia, acute respiratory distress syndrome (ARDS), or any other correlated complication. One review aimed to evaluate the effectiveness of using surgical masks on preventing transmission of the virus [ 36 ], one review was focused on pediatric patients [ 34 ], and one review investigated COVID-19 in pregnant women [ 37 ]. Most reviews assessed clinical symptoms, laboratory findings, or radiological results.

Systematic review findings

The summary of findings from individual reviews is shown in Table 2 . Overall, all-cause mortality ranged from 0.3 to 13.9% (Fig. 2 ).

A meta-analysis of the prevalence of mortality

Clinical symptoms

Seven reviews described the main clinical manifestations of COVID-19 [ 26 , 28 , 29 , 34 , 35 , 39 , 41 ]. Three of them provided only a narrative discussion of symptoms [ 26 , 34 , 35 ]. In the reviews that performed a statistical analysis of the incidence of different clinical symptoms, symptoms in patients with COVID-19 were (range values of point estimates): fever (82–95%), cough with or without sputum (58–72%), dyspnea (26–59%), myalgia or muscle fatigue (29–51%), sore throat (10–13%), headache (8–12%), gastrointestinal disorders, such as diarrhea, nausea or vomiting (5.0–9.0%), and others (including, in one study only: dizziness 12.1%) (Figs. 3 , 4 , 5 , 6 , 7 , 8 and 9 ). Three reviews assessed cough with and without sputum together; only one review assessed sputum production itself (28.5%).

A meta-analysis of the prevalence of fever

A meta-analysis of the prevalence of cough

A meta-analysis of the prevalence of dyspnea

A meta-analysis of the prevalence of fatigue or myalgia

A meta-analysis of the prevalence of headache

A meta-analysis of the prevalence of gastrointestinal disorders

A meta-analysis of the prevalence of sore throat

Diagnostic aspects

Three reviews described methodologies, protocols, and tools used for establishing the diagnosis of COVID-19 [ 26 , 34 , 38 ]. The use of respiratory swabs (nasal or pharyngeal) or blood specimens to assess the presence of SARS-CoV-2 nucleic acid using RT-PCR assays was the most commonly used diagnostic method mentioned in the included studies. These diagnostic tests have been widely used, but their precise sensitivity and specificity remain unknown. One review included a Chinese study with clinical diagnosis with no confirmation of SARS-CoV-2 infection (patients were diagnosed with COVID-19 if they presented with at least two symptoms suggestive of COVID-19, together with laboratory and chest radiography abnormalities) [ 34 ].

Therapeutic possibilities

Pharmacological and non-pharmacological interventions (supportive therapies) used in treating patients with COVID-19 were reported in five reviews [ 25 , 27 , 34 , 35 , 38 ]. Antivirals used empirically for COVID-19 treatment were reported in seven reviews [ 25 , 27 , 34 , 35 , 37 , 38 , 41 ]; most commonly used were protease inhibitors (lopinavir, ritonavir, darunavir), nucleoside reverse transcriptase inhibitor (tenofovir), nucleotide analogs (remdesivir, galidesivir, ganciclovir), and neuraminidase inhibitors (oseltamivir). Umifenovir, a membrane fusion inhibitor, was investigated in two studies [ 25 , 35 ]. Possible supportive interventions analyzed were different types of oxygen supplementation and breathing support (invasive or non-invasive ventilation) [ 25 ]. The use of antibiotics, both empirically and to treat secondary pneumonia, was reported in six studies [ 25 , 26 , 27 , 34 , 35 , 38 ]. One review specifically assessed evidence on the efficacy and safety of the anti-malaria drug chloroquine [ 27 ]. It identified 23 ongoing trials investigating the potential of chloroquine as a therapeutic option for COVID-19, but no verifiable clinical outcomes data. The use of mesenchymal stem cells, antifungals, and glucocorticoids were described in four reviews [ 25 , 34 , 35 , 38 ].

Laboratory and radiological findings

Of the 18 reviews included in this overview, eight analyzed laboratory parameters in patients with COVID-19 [ 25 , 29 , 30 , 32 , 33 , 34 , 35 , 39 ]; elevated C-reactive protein levels, associated with lymphocytopenia, elevated lactate dehydrogenase, as well as slightly elevated aspartate and alanine aminotransferase (AST, ALT) were commonly described in those eight reviews. Lippi et al. assessed cardiac troponin I (cTnI) [ 25 ], procalcitonin [ 32 ], and platelet count [ 33 ] in COVID-19 patients. Elevated levels of procalcitonin [ 32 ] and cTnI [ 30 ] were more likely to be associated with a severe disease course (requiring intensive care unit admission and intubation). Furthermore, thrombocytopenia was frequently observed in patients with complicated COVID-19 infections [ 33 ].

Chest imaging (chest radiography and/or computed tomography) features were assessed in six reviews, all of which described a frequent pattern of local or bilateral multilobar ground-glass opacity [ 25 , 34 , 35 , 39 , 40 , 41 ]. Those six reviews showed that septal thickening, bronchiectasis, pleural and cardiac effusions, halo signs, and pneumothorax were observed in patients suffering from COVID-19.

Quality of evidence in individual systematic reviews

Table 3 shows the detailed results of the quality assessment of 18 systematic reviews, including the assessment of individual items and summary assessment. A detailed explanation for each decision in each review is available in Additional file 5 .

Using AMSTAR 2 criteria, confidence in the results of all 18 reviews was rated as “critically low” (Table 3 ). Common methodological drawbacks were: omission of prospective protocol submission or publication; use of inappropriate search strategy: lack of independent and dual literature screening and data-extraction (or methodology unclear); absence of an explanation for heterogeneity among the studies included; lack of reasons for study exclusion (or rationale unclear).

Risk of bias assessment, based on a reported methodological tool, and quality of evidence appraisal, in line with the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) method, were reported only in one review [ 25 ]. Five reviews presented a table summarizing bias, using various risk of bias tools [ 25 , 29 , 39 , 40 , 41 ]. One review analyzed “study quality” [ 37 ]. One review mentioned the risk of bias assessment in the methodology but did not provide any related analysis [ 28 ].

This overview of systematic reviews analyzed the first 18 systematic reviews published after the onset of the COVID-19 pandemic, up to March 24, 2020, with primary studies involving more than 60,000 patients. Using AMSTAR-2, we judged that our confidence in all those reviews was “critically low”. Ten reviews included meta-analyses. The reviews presented data on clinical manifestations, laboratory and radiological findings, and interventions. We found no systematic reviews on the utility of diagnostic tests.

Symptoms were reported in seven reviews; most of the patients had a fever, cough, dyspnea, myalgia or muscle fatigue, and gastrointestinal disorders such as diarrhea, nausea, or vomiting. Olfactory dysfunction (anosmia or dysosmia) has been described in patients infected with COVID-19 [ 43 ]; however, this was not reported in any of the reviews included in this overview. During the SARS outbreak in 2002, there were reports of impairment of the sense of smell associated with the disease [ 44 , 45 ].

The reported mortality rates ranged from 0.3 to 14% in the included reviews. Mortality estimates are influenced by the transmissibility rate (basic reproduction number), availability of diagnostic tools, notification policies, asymptomatic presentations of the disease, resources for disease prevention and control, and treatment facilities; variability in the mortality rate fits the pattern of emerging infectious diseases [ 46 ]. Furthermore, the reported cases did not consider asymptomatic cases, mild cases where individuals have not sought medical treatment, and the fact that many countries had limited access to diagnostic tests or have implemented testing policies later than the others. Considering the lack of reviews assessing diagnostic testing (sensitivity, specificity, and predictive values of RT-PCT or immunoglobulin tests), and the preponderance of studies that assessed only symptomatic individuals, considerable imprecision around the calculated mortality rates existed in the early stage of the COVID-19 pandemic.

Few reviews included treatment data. Those reviews described studies considered to be at a very low level of evidence: usually small, retrospective studies with very heterogeneous populations. Seven reviews analyzed laboratory parameters; those reviews could have been useful for clinicians who attend patients suspected of COVID-19 in emergency services worldwide, such as assessing which patients need to be reassessed more frequently.

All systematic reviews scored poorly on the AMSTAR 2 critical appraisal tool for systematic reviews. Most of the original studies included in the reviews were case series and case reports, impacting the quality of evidence. Such evidence has major implications for clinical practice and the use of these reviews in evidence-based practice and policy. Clinicians, patients, and policymakers can only have the highest confidence in systematic review findings if high-quality systematic review methodologies are employed. The urgent need for information during a pandemic does not justify poor quality reporting.

We acknowledge that there are numerous challenges associated with analyzing COVID-19 data during a pandemic [ 47 ]. High-quality evidence syntheses are needed for decision-making, but each type of evidence syntheses is associated with its inherent challenges.

The creation of classic systematic reviews requires considerable time and effort; with massive research output, they quickly become outdated, and preparing updated versions also requires considerable time. A recent study showed that updates of non-Cochrane systematic reviews are published a median of 5 years after the publication of the previous version [ 48 ].

Authors may register a review and then abandon it [ 49 ], but the existence of a public record that is not updated may lead other authors to believe that the review is still ongoing. A quarter of Cochrane review protocols remains unpublished as completed systematic reviews 8 years after protocol publication [ 50 ].

Rapid reviews can be used to summarize the evidence, but they involve methodological sacrifices and simplifications to produce information promptly, with inconsistent methodological approaches [ 51 ]. However, rapid reviews are justified in times of public health emergencies, and even Cochrane has resorted to publishing rapid reviews in response to the COVID-19 crisis [ 52 ]. Rapid reviews were eligible for inclusion in this overview, but only one of the 18 reviews included in this study was labeled as a rapid review.

Ideally, COVID-19 evidence would be continually summarized in a series of high-quality living systematic reviews, types of evidence synthesis defined as “ a systematic review which is continually updated, incorporating relevant new evidence as it becomes available ” [ 53 ]. However, conducting living systematic reviews requires considerable resources, calling into question the sustainability of such evidence synthesis over long periods [ 54 ].

Research reports about COVID-19 will contribute to research waste if they are poorly designed, poorly reported, or simply not necessary. In principle, systematic reviews should help reduce research waste as they usually provide recommendations for further research that is needed or may advise that sufficient evidence exists on a particular topic [ 55 ]. However, systematic reviews can also contribute to growing research waste when they are not needed, or poorly conducted and reported. Our present study clearly shows that most of the systematic reviews that were published early on in the COVID-19 pandemic could be categorized as research waste, as our confidence in their results is critically low.

Our study has some limitations. One is that for AMSTAR 2 assessment we relied on information available in publications; we did not attempt to contact study authors for clarifications or additional data. In three reviews, the methodological quality appraisal was challenging because they were published as letters, or labeled as rapid communications. As a result, various details about their review process were not included, leading to AMSTAR 2 questions being answered as “not reported”, resulting in low confidence scores. Full manuscripts might have provided additional information that could have led to higher confidence in the results. In other words, low scores could reflect incomplete reporting, not necessarily low-quality review methods. To make their review available more rapidly and more concisely, the authors may have omitted methodological details. A general issue during a crisis is that speed and completeness must be balanced. However, maintaining high standards requires proper resourcing and commitment to ensure that the users of systematic reviews can have high confidence in the results.

Furthermore, we used adjusted AMSTAR 2 scoring, as the tool was designed for critical appraisal of reviews of interventions. Some reviews may have received lower scores than actually warranted in spite of these adjustments.

Another limitation of our study may be the inclusion of multiple overlapping reviews, as some included reviews included the same primary studies. According to the Cochrane Handbook, including overlapping reviews may be appropriate when the review’s aim is “ to present and describe the current body of systematic review evidence on a topic ” [ 12 ], which was our aim. To avoid bias with summarizing evidence from overlapping reviews, we presented the forest plots without summary estimates. The forest plots serve to inform readers about the effect sizes for outcomes that were reported in each review.

Several authors from this study have contributed to one of the reviews identified [ 25 ]. To reduce the risk of any bias, two authors who did not co-author the review in question initially assessed its quality and limitations.

Finally, we note that the systematic reviews included in our overview may have had issues that our analysis did not identify because we did not analyze their primary studies to verify the accuracy of the data and information they presented. We give two examples to substantiate this possibility. Lovato et al. wrote a commentary on the review of Sun et al. [ 41 ], in which they criticized the authors’ conclusion that sore throat is rare in COVID-19 patients [ 56 ]. Lovato et al. highlighted that multiple studies included in Sun et al. did not accurately describe participants’ clinical presentations, warning that only three studies clearly reported data on sore throat [ 56 ].

In another example, Leung [ 57 ] warned about the review of Li, L.Q. et al. [ 29 ]: “ it is possible that this statistic was computed using overlapped samples, therefore some patients were double counted ”. Li et al. responded to Leung that it is uncertain whether the data overlapped, as they used data from published articles and did not have access to the original data; they also reported that they requested original data and that they plan to re-do their analyses once they receive them; they also urged readers to treat the data with caution [ 58 ]. This points to the evolving nature of evidence during a crisis.

Our study’s strength is that this overview adds to the current knowledge by providing a comprehensive summary of all the evidence synthesis about COVID-19 available early after the onset of the pandemic. This overview followed strict methodological criteria, including a comprehensive and sensitive search strategy and a standard tool for methodological appraisal of systematic reviews.

In conclusion, in this overview of systematic reviews, we analyzed evidence from the first 18 systematic reviews that were published after the emergence of COVID-19. However, confidence in the results of all the reviews was “critically low”. Thus, systematic reviews that were published early on in the pandemic could be categorized as research waste. Even during public health emergencies, studies and systematic reviews should adhere to established methodological standards to provide patients, clinicians, and decision-makers trustworthy evidence.

Availability of data and materials

All data collected and analyzed within this study are available from the corresponding author on reasonable request.

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Acknowledgments

We thank Catherine Henderson DPhil from Swanscoe Communications for pro bono medical writing and editing support. We acknowledge support from the Covidence Team, specifically Anneliese Arno. We thank the whole International Network of Coronavirus Disease 2019 (InterNetCOVID-19) for their commitment and involvement. Members of the InterNetCOVID-19 are listed in Additional file 6 . We thank Pavel Cerny and Roger Crosthwaite for guiding the team supervisor (IJBN) on human resources management.

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Israel Júnior Borges do Nascimento & Milena Soriano Marcolino

Medical College of Wisconsin, Milwaukee, WI, USA

Israel Júnior Borges do Nascimento

Helene Fuld Health Trust National Institute for Evidence-based Practice in Nursing and Healthcare, College of Nursing, The Ohio State University, Columbus, OH, USA

Dónal P. O’Mathúna

School of Nursing, Psychotherapy and Community Health, Dublin City University, Dublin, Ireland

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Thilo Caspar von Groote

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Livia Puljak

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IJBN conceived the research idea and worked as a project coordinator. DPOM, TCVG, HMA, IW, AM, LP, VTC, IZG, TPP, ANA, SF, NLB and MSM were involved in data curation, formal analysis, investigation, methodology, and initial draft writing. All authors revised the manuscript critically for the content. The author(s) read and approved the final manuscript.

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Supplementary Information

Additional file 1: appendix 1..

Search strategies used in the study.

Additional file 2: Appendix 2.

Adjusted scoring of AMSTAR 2 used in this study for systematic reviews of studies that did not analyze interventions.

Additional file 3: Appendix 3.

List of excluded studies, with reasons.

Additional file 4: Appendix 4.

Table of overlapping studies, containing the list of primary studies included, their visual overlap in individual systematic reviews, and the number in how many reviews each primary study was included.

Additional file 5: Appendix 5.

A detailed explanation of AMSTAR scoring for each item in each review.

Additional file 6: Appendix 6.

List of members and affiliates of International Network of Coronavirus Disease 2019 (InterNetCOVID-19).

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Borges do Nascimento, I.J., O’Mathúna, D.P., von Groote, T.C. et al. Coronavirus disease (COVID-19) pandemic: an overview of systematic reviews. BMC Infect Dis 21 , 525 (2021). https://doi.org/10.1186/s12879-021-06214-4

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Antimicrobial resistance, mechanisms and its clinical significance

Affiliations.

• 1 Department of Clinical Laboratory Science, College of Applied Medical Sciences, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia.
• 2 Department of Clinical Laboratory Science, College of Applied Medical Sciences, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia. Electronic address: [email protected].
• 3 Department of Pharmacology & Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
• 4 Consultant, Department of Restorative Dentistry, College of Dentistry, King Saud bin Abdul Aziz University for Health Sciences, P.O Box: 22490, Riyadh 11426, Saudi Arabia.
• 5 Clinical Pharmacy Department, College of Pharmacy, King Saud University, Saudi Arabia; Pharmacology Department, Faculty of Medicine, Cairo University, Egypt.
• 6 General Dentist and Public Health Researcher, Australia.
• 7 Department of Public Health, College of Public Health, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia.
• 8 Department of Post Graduate Studies and Research in Microbiology, Gulbarga University, Gulbarga- 585106, India.
• 9 Dental Biomaterials Research Chair, Dental Health Department, College of Applied Medical Sciences, King Saud University, Riyadh 11433, Saudi Arabia.
• 10 Genome Research Chair, Department of Biochemistry, College of Science, King Saud University, Riyadh, Saudi Arabia.
• 11 CAP Research Ltd., 2nd Floor Orbis Court, 132 St Jean Road 72218 Quatre Bornes, Mauritius.
• PMID: 32201008
• DOI: 10.1016/j.disamonth.2020.100971

Antimicrobial agents play a key role in controlling and curing infectious disease. Soon after the discovery of the first antibiotic, the challenge of antibiotic resistance commenced. Antimicrobial agents use different mechanisms against bacteria to prevent their pathogenesis and they can be classified as bactericidal or bacteriostatic. Antibiotics are one of the antimicrobial agents which has several classes, each with different targets. Consequently, bacteria are endlessly using methods to overcome the effectivity of the antibiotics by using distinct types of mechanisms. Comprehending the mechanisms of resistance is vital for better understanding and to continue use of current antibiotics. Which also helps to formulate synthetic antimicrobials to overcome the current mechanism of resistance. Also, encourage in prudent use and misuse of antimicrobial agents. Thus, decline in treatment costs and in the rate of morbidity and mortality. This review will be concentrating on the mechanism of actions of several antibiotics and how bacteria develop resistance to them, as well as the method of acquiring the resistance in several bacteria and how can a strain be resistant to several types of antibiotics. This review also analyzes the prevalence, major clinical implications, clinical causes of antibiotic resistance. Further, it evaluates the global burden of antimicrobial resistance, identifies various challenges and strategies in addressing the issue. Finally, put forward certain recommendations to prevent the spread and reduce the rate of resistance growth.

Keywords: Antibiotics; Antimicrobial resistance (AMR); Mechanisms of antimicrobial action.

Copyright © 2020. Published by Elsevier Inc.

Publication types

• Anti-Bacterial Agents / pharmacokinetics*
• Anti-Bacterial Agents / therapeutic use*
• Bacterial Infections / drug therapy*
• Drug Resistance, Bacterial*
• Anti-Bacterial Agents

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HIV/AIDS epidemiology, pathogenesis, prevention, and treatment

The HIV-1 pandemic is a complex mix of diverse epidemics within and between countries and regions of the world, and is undoubtedly the defining public-health crisis of our time. Research has deepened our understanding of how the virus replicates, manipulates, and hides in an infected person. Although our understanding of pathogenesis and transmission dynamics has become more nuanced and prevention options have expanded, a cure or protective vaccine remains elusive. Antiretroviral treatment has transformed AIDS from an inevitably fatal condition to a chronic, manageable disease in some settings. This transformation has yet to be realised in those parts of the world that continue to bear a disproportionate burden of new HIV-1 infections and are most a% ected by increasing morbidity and mortality. This Seminar provides an update on epidemiology, pathogenesis, treatment, and prevention interventions pertinent to HIV-1.

HIV pandemic

An estimated 38·6 (33·4–46·0) million people live with HIV-1 worldwide, while about 25 million have died already. 1 In 2005 alone, there were 4·1 million new HIV-1 infections and 2·8 million AIDS deaths. 1 These estimates mask the dynamic nature of this evolving epidemic in relation to temporal changes, geographic distribution, magnitude, viral diversity, and mode of transmission. Today, there is no region of the world untouched by this pandemic ( figure 1 ). 2

HSex=heterosexual. MSM=Men who have sex with men. IDU=injection drug users. Based on Joint UNAIDS and WHO AIDS epidemic update December, 2005.

Heterosexual transmission remains the dominant mode of transmission and accounts for about 85% of all HIV-1 infections. Southern Africa remains the epicentre of the pandemic and continues to have high rates of new HIV-1 infections. 3 Although overall HIV-1 prevalence remains low in the emerging epidemics in China and India, the absolute numbers, which are fast approaching those seen in southern Africa, are of concern. 1 Outside of sub-Saharan Africa, a third of all HIV-1 infections are acquired through injecting drug use, most (an estimated 8·8 million) of which are in eastern Europe and central and southeast Asia. 1 The rapid spread of HIV-1 in these regions through injecting drug use is of importance, since it is a bridge for rapid establishment of more generalised epidemics.

A defining feature of the pandemic in the current decade is the increasing burden of HIV-1 infections in women, 4 which has additional implications for mother-to-child transmission. Women now make up about 42% of those infected worldwide; over 70% of whom live in sub-Saharan Africa. 1 Overall, a quarter of all new HIV-1 infections are in adults aged younger than 25 years. 1 HIV-1 infection rates are three to six times higher in female adolescents than in their male counterparts, 1 , 5 – 7 and this difference is attributed to sexual coupling patterns of young women with older men. Population prevalence of HIV-1 infection, concurrent sexual relationships, partner change, sexual practices, the presence of other sexually transmitted diseases, 8 – 11 and population mobility patterns 12 – 14 for economic and other reasons (eg, natural disasters and wars) further increase the probability of HIV-1 acquisition. 3 , 15 Emerging data accord with strong links between risk of sexual HIV-1 acquisition and episodic recreational drug or alcohol use. 16

Although sub-Saharan Africa continues to bear a disproportionate burden of HIV-1 infections, there is now an increasing number of countries reporting stabilisation or declines in prevalence (eg, Zambia, Tanzania, Kenya, Ghana, Rwanda, Burkina Faso, and Zimbabwe). 1 There is some evidence to attribute these reductions to effective changes in sexual behaviour, such as postponement of sexual debut, reduction in casual relationships, and more consistent condom use in casual relationships. 17 , 18 However, increasing morbidity and mortality rates associated with a maturing HIV-1 epidemic need to be considered when interpreting these data. 19 For example, the death of a few high-risk individuals who are key to transmission chains could exert a major effect on sexual networks and result in major reductions in infection rates. 20 Additionally, since most HIV-1 estimates are based on surveys in antenatal populations, increasing morbidity and mortality could cause the numbers of women in this group to decrease, and thus lead to underestimates of the true prevalence in these countries. 19

Although the relative contribution of cell-free virus compared with cell-associated virus in HIV-1 transmission remains unclear, there is growing evidence that viral load is predictive of transmission risk. 21 , 22 The highest levels of viraemia are seen during acute infection and advanced HIV-1 disease. 22 Further, co-infections with other sexually transmitted diseases in asymptomatic HIV-1 infected people can increase viral shedding to levels similar to those seen during acute infection. 23 Thus, sexually transmitted diseases could enhance HIV-1 transmission to rates similar to those seen during primary infection. 24 This observation could help to explain why the efficiency of HIV-1 transmission exceeds, in some settings, the earlier mathematical projections. 25 Thus, identification and treatment of recently infected people is an important means to reduce transmission. However, most people are unaware of their HIV-1 status during these crucial first months of infection. Several screening strategies based on laboratory testing and clinical algorithms are being developed and tested 26 for efficient identification of early infection before antibody development. 27 Additionally, a more aggressive management of sexually transmitted infections in settings with generalised epidemics has the potential to affect current epidemic trajectories. 24

Based on their genetic make-up, HIV-1 viruses are divided into three groups (eg, M [main], N, and O group, figure 2 ). These HIV-1 groups and HIV-2 probably result from distinct cross-species transmission events. 28 Pandemic HIV-1 has diversified into at least nine subtypes ( figures 1 and ​ and2) 2 ) and many circulating recombinant forms, 29 , 30 which encode genetic structures from two or more subtypes (eg, A/E=CRF01; A/G=CRF02). The continuously evolving HIV-1 viral diversity poses an immense challenge to the development of any preventive or therapeutic intervention. 29

The HIV-1 pandemic is largely due to viral isolates belonging to the HIV-1 M-group, with HIV-1 subtype C being the most prevalent (red). Recombinant circulating forms cluster with the M-group but have been omitted for clarity. HIV-1 M group and the contemporary SIV strains identified in wild chimpanzees in Cameroon (SIVcpzLB7/EK5 28 ) are highlighted. HIV-1 sequences cluster closely with SIV from chimpanzees (SIVcpz), whereas HIV-2 resembles SIV from macaques and sooty mangabeys (SIVmac/SIVsm).

In terms of viral diversity, subtype C viruses continue to dominate and account for 55–60% of all HIV-1 infections worldwide ( figure 1 ). 30 Non-subtype B isolates might differ in their virological characteristics from the subtype B isolates (eg, viral load, chemokine co-receptor usage, transcriptional activation in specific biological compartments). 31 – 33 However, the clinical consequences of subtype variations remain unclear.

Infection with two or more genetically distinct viruses could lead to new recombinant viruses. Recombination takes place at a higher rate than initially predicted, 30 and circulating recombinant forms account for as much as 20% of infections in some regions (eg, southeast Asia). 31 These findings are in agreement with the occurrence of co-infections with multiple distinct isolates in a close temporal context. 34 – 36 Further, superinfections in which time points of virus acquisition are months to years apart have been described, although at a much lower frequency than co-infections. 34 , 37 – 39 Collectively, these observations challenge the assumption that HIV-1 acquisition happens only once with a singular viral strain and that, thereafter, the infected individual is protected from subsequent infections. 40 This lack of immunisation has substantial implications for vaccine development. Emerging evidence suggests that clinical progression to AIDS might be more rapid in individuals with dual infections, 35 and encouraging safer sex practices in viraemic HIV-1-infected people might be appropriate to keep recurrent exposure to new viral strains to a minimum.

Pathogenesis of HIV-1

The worldwide spread of HIV-1 indicates that the virus effectively counteracts innate, adapted, and intrinsic immunity. 41 , 42 Despite its modest genome size (less than 10 kb) and its few genes ( figure 3 ), HIV-1 excels in taking advantage of cellular pathways while neutralising and hiding from the different components of the immune system. 43 – 45 Notably, our understanding of pathogenesis is often derived from studies of subtype B viruses and non-human primate studies.

(A) Envelope glycoproteins gp120/41 form the spikes on the virion’s surface. During maturation the gag protein is cleaved and Gag p24 forms the core. The viral genome, viral reverse transcriptase (RT), integrase as well as a number of host proteins are encapsidated. (B) Dir erent steps of the viral life cycle on a cellular level and the potential targets for treatment interventions. (C) HIV-1 has evolved strategies to counteract the restriction factors TRIM5α and APOBEC3G/3F. If left unchecked by HIV-1 Vif, APOBEC3G/3F is encapsidated into the egressing virion, and on infection of a target cell leads to G-to-A hypermutations in the viral genome. Rhesus TRIM5α inhibits HIV-1 replication early after infection of the target cell before the step of reverse transcription.

The HIV-1 life cycle is complex ( figure 3 ) and its duration and outcome is dependent on target cell type and cell activation. 46 In the early steps, HIV-1 gains access to cells without causing immediate lethal damages but the entry process can stimulate intracellular signal cascades, which in turn might facilitate viral replication. 47 , 48 The two molecules on the HIV-1 envelope, the external glycoprotein (gp120) and the transmembrane protein (gp41), form the spikes on the virion’s surface. 49 During the entry process, gp120 attaches to the cell membrane by first binding to the CD4+ receptor. Subsequent interactions between virus and chemokine co-receptors (eg, CCR5, CXCR4) trigger irreversible conformational changes. 49 , 50 The actual fusion event takes place within minutes by pore formation, 50 , 51 and releases the viral core into the cell cytoplasm. After the core disassembles, the viral genome is reverse transcribed into DNA by the virus’ own reverse transcriptase enzyme. 46 Related yet distinct viral variants can be generated during this process since reverse transcriptase is error prone and has no proofreading activity. 46 At the midpoint of infection, the viral protein integrase in conjunction with host DNA repair enzymes inserts the viral genome into gene-rich, transcriptionally active domains of the host’s chromosomal DNA. 52 – 54 An integrase binding host factor, LEDGF/p75 (lens epithelium-derived growth factor), facilitates integration, 55 , 56 which marks the turning point by irreversibly transforming the cell into a potential virus producer. In the late steps, production of viral particles needs host driven as well as virus driven transcription. 46 Viral proteins are transported to and assemble in proximity to the cell membrane. Virus egress from the cell is not lytic and takes advantage of the vesicular sorting pathway (ESCRT-I, II, III), which normally mediates the budding of endosomes into multivesicular bodies. 57 , 58 HIV-1 accesses this protein-sorting pathway by binding TSG101 via its late domain, a short sequence motif in p6 of Gag. 59 , 60 Cleavage of the Gag-Pol poly-protein by the viral protease produces mature infectious virions. 46 , 61

Since cytoplasmic molecules of the producer cell and components from its cell surface lipid bilayer are incorporated into the new viral particle, virions bear characteristics of the cells in which they were produced. 62 Incorporated host molecules can determine the virus’ phenotype in diverse ways (eg, shape the replicative features in the next cycle of infection or mediate immune activation of bystander cells 62 ).

Studies of the early events that happen after HIV-1 breaches the mucosal barrier suggest the existence of a window period in which viral propagation is not yet established and host defences could potentially control viral expansion. 63 The important co-receptors for HIV-1 infection are two chemokine receptors—CCR5 and CXCR4. Independently of the transmission route, most new infections are established by viral variants that rely on CCR5 usage. 64 CXCR4-tropic viruses generally appear in late stages of infection and have been associated with increased pathogenicity and disease progression. 65

Compelling evidence from non-human primate models (eg, simian immunodeficiency virus [SIV] infection of rhesus macaques) suggest that vaginal transmission results in infection of a small number of CD4+ T lymphocytes, macrophages, and dendritic cells located in the lamina propria. 63 Potential pathways for virus transmission involve endocytosis, transcytosis, and virus attachment to mannose C-type lectin receptors (eg, DC-SIGN) located on dendritic cells and macrophages. 66 The initial replication takes place in the regional lymph organs (eg, draining lymph nodes) and is composed of few viral variants, and leads to modest primary amplification. With migration of infected T lymphocytes or virions into the bloodstream, secondary amplification in the gastrointestinal tract, spleen, and bone marrow results in massive infection of susceptible cells. In close temporal relation with the resulting peak of viraemia (eg, 10 6 to 10 7 copies per mL plasma), clinical symptoms can be manifest during primary HIV-1 infection ( figure 4 ). The level of viraemia characteristic for the chronic phase of infection in an individual (viral set point) differs from the peak viraemia by one or two orders of magnitude. This reduction is largely attributed to HIV-1 specific CD8+ responses but target cell limitation could also play a part. The viral population is most homogeneous early after transmission, but as viral quasi-species diversify in distinct biological compartments, mutant viruses that are resistant to antibody neutralisation, cytotoxic T cells, or antiretroviral drugs are generated and archived in long-lived cells (ie, viral reservoirs).

Plasma viraemia (top), and dynamic changes of the CD4+ T-lymphocyte compartments (bottom). Primary infection characterised by high plasma viraemia (red line, top), low CD4 cells (green line, bottom), and absence of HIV-1 specific antibodies (orange line, bottom). Viraemia drops as cytotoxic CD8+ T-lymphocytes (CTL) develop (blue line, bottom) and an individual viral-load set point is reached during chronic infection. Viral set points dir er greatly among individuals (eg, red dotted line, top) and predict disease progression. Viral diversity increases through out the disease (closed circles, top). The risk of transmission is highest in the first weeks when viraemia peaks (closed circles, top). GALT=gut-associated lymphoid tissues.

A pronounced depletion of activated as well as memory CD4+ T cells located in the gut-associated lymphoid tissues has been seen in individuals identified early after infection. 67 The preferential depletion of the CD4+ cells in the mucosal lymphoid tissues remains despite years of antiretroviral treatment, a striking observation that contrasts with the fact that the number of CD4+ T lymphocytes in the peripheral blood can return to normal under antiretroviral treatment.

A gradual destruction of the naive and memory CD4+ T-lymphocyte populations is the hallmark of HIV-1 infection, with AIDS being the last disease stage ( figure 4 ). 68 Despite the frequent absence of symptoms during early and chronic phase, HIV-1 replication is dynamic throughout the disease. The half-life of a single virion is so short that half the entire plasma virus population is replaced in less than 30 minutes, 69 and the total number of virions produced in a chronically infected person can reach more than 10¹P particles per day. 69 , 70 The turnover rates of lymphocyte populations are upregulated many fold during HIV-1 infection, whereas cell proliferation decreases once viral replication is reduced by antiretroviral treatment. 71 , 72 Different depletion mechanisms have been proposed, with an emerging consensus favouring generalised immune activation as cause for constant depletion of the CD4+ cell reservoir. 73

Immune activation predicts disease progression 74 and, thus, seems to be a central feature of pathogenic HIV-1 infections. Recently, Nef proteins from SIV lineages that are non-pathogenic in their natural hosts (eg, African green monkeys) have proved to down-regulate CD3-T-cell receptors, resulting in reduced cell activation and apoptosis. 75 HIV-1 Nef fails to quench T-cell activation, possibly leading to the high degree of immune activation seen in infected people.

Understanding the mechanisms that lead to protection or long-lasting control of infection will guide vaccine development by providing correlates of protection. Natural resistance to HIV-1 infection is rare and varies greatly between individuals. Two groups—long-term non-progressors and highly exposed persistently seronegative individuals—have been studied widely to identify innate and acquired protective determinants ( table 1 ). 76 Host resistance factors consist of human leucocyte antigen (HLA) haplotypes, autoantibodies, mutations in the promoter regions, and coding regions of the co-receptors CCR5 and CCR2, as well as the up-regulation of chemokine production ( table 1 ). 76 , 77 Indeed, individuals encoding a truncated CCR5 version (CCR5Δ32) have slower disease progression (heterozygote) or are resistant to CCR5-using viruses (homozygote). 78 The CCL3L1 gene encodes MIP1α, a CCR5 co-receptor ligand and chemokine with antiviral activity. Recent findings show that CCL3L1 gene copies vary individually and higher numbers of gene duplications result in reduced susceptibility to infection, 77 , 79 possibly by competitive saturation of CCR5 co-receptor. Cytotoxic T-lymphocyte responses, helper T-cell functions, and humoral responses are some of the acquired factors that modulate the risk of transmission in highly exposed persistently seronegative individuals, 76 and could also contribute to spontaneous control of replication in long-term non-progressors. The putative protective role of cytotoxic T-lymphocyte activity has been suggested in seronegative sex workers and in some long-term non-progressors. 76 , 80

Some of the host factors affecting susceptibility to HIV-1 infection

HLA=human leucocyte antigen. CCR5=chemokine receptor 5. CCR2=chemokine receptor 2. CCL3L1=CC chemokine ligand like-1, APOBEC3G/3F=apolipoprotein B mRNA editing complex 3.

Mammalian cells are not welcoming micro-environments, but rather deploy a defensive web to curb endogenous and exogenous viruses. HIV-1’s ability to circumvent these defences is as impressive as its efficiency to exploit the cellular machinery. APOBEC3G/3F and TRIM5α are recently described intrinsic restriction factors that are constitutively expressed in many cells. 81 , 82 Both gene loci have been under strong selective pressure throughout primate evolution, 83 indicating an ancient need to neutralise foreign DNA and maintain genome stability that precedes the current HIV-1 pandemic.

APOBEC3 enzymes (A3) belong to the superfamily of cytidine deaminases, 84 a group of intracellular proteins with DNA/RNA editing activity. 84 , 85 Most representatives of the APOBEC3 group have some mutagenic potential and restrict endogenous retroviruses and mobile genetic elements. The deaminases A3G, A3F, and A3B have potent antiviral activity, with the first two being expressed in cells that are susceptible to HIV-1 infection (T-lymphocytes, macrophages). HIV-1 evades APOBEC3 mutagenesis by expressing Vif, which leads to APOBEC3G/3F but not A3B degradation. 42 , 86 – 90

We still need to establish how the mechanisms of DNA editing and antiviral activity are interwoven, since some antiviral activity can be maintained despite defective DNA editing. 91 The early replication block in non-stimulated CD4+ T cells has been attributed to low molecular mass complexes of APOBEC3G. 92 Hypermutated genomes in HIV-1 infected patients 93 and mutations in Vif resulting in abrogated or differential APOBEC3 neutralisation capacity have been described. 94 , 95 The degree to which APOBEC3G/3F mRNA expression predicts clinical progression remains an area of intensive investigation. 96 , 97

Several representatives of the heterogeneous family of tripartite motif proteins (TRIM) inhibit retroviruses in a species-specific manner. 81 , 98 TRIM5α from rhesus macaques and African green monkeys inhibit HIV-1 replication, whereas the human homologue is inactive against SIV and HIV-1, leading to the recorded susceptibility of human cells to both viruses. 81 Rhesus TRIM5α recognises the capsid domain of HIV-1 Gag and manipulates the kinetics of HIV-1 core disassembly within minutes after cell entry. 99 , 100 Thus, experimental approaches to render HIV-1 resistant to rhesus TRIM5α could lead to immunodeficiency viruses capable of replicating in rhesus macaques. Such a non-primate model would allow testing of antiviral treatment and vaccine interventions with HIV-1 viruses instead of SIV or SIV/HIV chimeric viruses.

Clinical management

The diagnosis of HIV-1 infection is based on the detection of specific antibodies, antigens, or both, and many commercial kits are available. Serological tests are generally used for screening. A major advance has been the availability of rapid HIV-1 antibody tests. These assays are easy to do and provide results in as little as 20 minutes, 101 enabling specimen collection and proper diagnosis at the same visit. Rapid tests are important tools for surveillance, screening, and diagnosis, and can be reliably done on plasma, serum, whole blood, or saliva by health-care providers with little laboratory expertise. The two limitations of these serological tests are detection of infection during primary infection when antibodies are absent, and in infants younger than 18 months who might bear maternal HIV-1 antibodies. In these instances direct virus detection is the only option (eg, quantification of viral RNA [standard] or p24 antigen in heat denatured serum [less expensive]).

For staging purposes, measurement of CD4+ cells and viraemia is required. Plasma viral load is widely used to monitor therapeutic success on antiretroviral treatment. Several commercially available tests provide sensitive quantification of plasma HIV-1 RNA copies. The newer versions of the Amplicor and Quantiplex (Roche, Indianapolis, IN, USA, and Bayer Diagnostics, Walpole, MA, USA, respectively) assays have overcome initial suboptimum performance for non-B subtypes. 102 While the viral load determines the rate of destruction of the immune system, the number of CD4+ cells reveals the degree of immunodeficiency and is, therefore, used to assess the stage of infection. CD4+ cell counts together with clinical manifestations (eg, occurrence of opportunistic infections) are key criteria for HIV-1 disease classification. Flow cytometry analysis is the standard method for CD4+ cells quantification.

Standard methods for quantifying viral load and CD4+ cell counts need advanced laboratory infrastructures, and assays require a specimen to be tested within a short time of collection. These requirements pose challenges for resource-constrained settings. The use of dried blood spot specimen has resolved some of the difficulties associated with transportation of samples needed for virological assessments. 103 Measurement of reverse transcriptase activity in plasma samples, simplification of gene amplification methods (eg, Taqman technology), and paper-strip quantification (dipstick assays) might provide cost-effective alternatives for the future. 104 – 106 Similarly microcapilliary flow-based systems, CD4+ chips, or total white counts (panleucocyte gating) provide alternatives for establishment of the level of immunodeficiency in resource-limited settings. 107 – 110

Drug treatment

Antiretroviral compounds.

Antiretroviral treatment is the best option for longlasting viral suppression and, subsequently, for reduction of morbidity and mortality. However, current drugs do not eradicate HIV-1 infection and lifelong treatment might be needed.

20 of the 21 antiretroviral drugs currently approved by the US Food and Drug Administration target the viral reverse transcriptase or protease ( table 2 ). Eight nucleoside/nucleotide analogues and three non-nucleoside reverse transcriptase inhibitors inhibit viral replication after cell entry but before integration. Fixed-dose combination tablets simplify treatment regimens by reducing the daily pill burden, and drugs with long half-lives allow once or twice daily dosing. Eight protease inhibitors prevent the maturation of virions resulting in production of non-infectious particles. The recently approved darunavir (June, 2006) is the first of its class that retains activity against viruses with reduced susceptibility to protease inhibitors. Enfuvirtide targets a gp41 region of the viral envelope and stops the fusion process before the cell is infected. This drug needs to be injected twice daily and its use is reserved for treatment of heavily drug-experienced patients since it can help overcome existing drug resistance. 111 , 112 Development of new antiretrovirals focuses on molecules that target entry, reverse transcription, integration, or maturation. Compounds that have been designed to inhibit resistant viruses are urgently needed since many patients treated during the past decades harbour viral strains with reduced susceptibilities to many if not all available drugs ( table 3 ).

Antiretroviral drugs currently approved by US Food and Drug Administration

Drugs belong to five drug classes and target three dir erent viral steps (entry, reverse transcription, or protease). Availability of these drugs in resource-limited countries is subject to country specific licensing agreements.

Antiretrovirals currently in phase II/III of clinical development

The goal of antiretroviral treatment is to decrease the morbidity and mortality that is generally associated with HIV-1 infection. A combination of three or more active drugs is needed to achieve this aim in most patients. Effective treatment returns to near normal the turnover rates of both CD4+ and CD8+ T-cell populations. 72 Potent but well tolerated drugs with long half-lives and simplified regimens improve the options for first-line and second-line chemotherapeutic interventions.

Combination antiretroviral treatment

High rate of viral replication, low fidelity of reverse transcription, and the ability to recombine are the viral characteristics that lead to the diversity of HIV-1 species (quasi-species) in chronically infected individuals. This high genetic variability provided the rationale for highly active antiretroviral treatments (HAART). By combination of several potent antiretroviral agents, viral replication is suppressed to such low levels that emergence of drug resistant HIV-1 variants was, if not prevented, at least delayed. By doing so, CD4+ T-lymphocyte numbers increase, leading to a degree of immune reconstitution that is sufficient to reverse clinically apparent immunodeficiency. Widespread introduction of HAART in industrialised countries resulted in a striking decrease in morbidity and mortality, putting forward the hope that HIV-1 infection can be transformed into a treatable chronic disease. 113 – 115

A set of criteria composed of plasma viraemia concentration, absolute or relative CD4+ cell counts, and clinical manifestations, is used to recommend initiation of HAART. The benefits of treatment clearly outweigh the potential side-effects in patients with clinical signs of immunodeficiency (eg, AIDS defining illnesses) or with CD4+ numbers less than 200 per μL (recommendation of US Department of Health and Human Services, October, 2005). However, the best time point to begin treatment remains controversial in asymptomatic patients with modest depletion of CD4+ T cells (eg, more than 350 per μL) and modest levels of viraemia (eg, less than 100 000 copies per mL). 116 Studies with clinical endpoints supporting the validity of early versus late interventions in asymptomatic patients are difficult to do and insufficient clinical data are currently available. Early depletion of gut CD4+ T lymphocytes, 117 increasing viral diversity, and the poor regenerative abilities of key populations of the immune system provide arguments for beginning treatment as early as possible. The wide application of this principle is restricted by long-term drug toxicities that lead to reduction of quality of life, and by treatment costs. Toxicities (eg, renal, hepato, mitochondrial), metabolic changes (eg, lipodystrophy, diabetes mellitus), and immune reconstitution disease are some of the long-term problems that complicate decade-long HAART. 118 – 121

One strategy addressing life-long daily compliance to HAART has been structured treatment interruptions. The rationale for this approach was based on the premise that the body’s own immune system could keep the virus in check if exposed to a very modest level of viral replication. If successful, this strategy could limit drug toxicity and reduce treatment costs. 122 Although preliminary findings for this strategy were mixed in terms of benefits, 123 – 125 the recent early closure of the SMART trial was based on increased morbidity and mortality in the treatment interruption arm. 126 Thus, in the absence of clinical benefits, most investigators strongly discourage treatment interruptions except as needed to address treatment intolerance.

HAART in resource-constrained settings

The transformation of AIDS into a chronic disease in industrialised countries has yet to be realised in resource-constrained settings. Access to HAART is an absolute humanitarian necessity to avert mortality in people who are central to the future survival of their countries. 127 Despite restricted health infrastructures and diverse co-morbidities in these regions, remarkable therapeutic success rates have been shown, with adherence rates at least comparable with those reported in industrialised countries. 128 – 131 WHO and UNAIDS treatment guidelines focusing on resource-limited settings suggest use of standard first-line regimen followed by a set of more expensive second-line options 132 and proposes the use of standardised decision-making steps (eg, when to start, to substitute for side-effects, to switch for virological failure). 132 , 133 In many countries, treatment options are limited not only by the costs of HAART but also by restrictive licensing policies, and current estimates suggest that 80% of people infected with HIV-1 with a clinical need for treatment do not yet have access to antiretroviral drugs. 1 Thus, efforts and strategies to further scale up treatment access are crucial, 134 – 137 since antiretroviral treatment is also an effective intervention for prevention. 138

Drug resistance

Emergence of drug resistance is the most common reason for treatment failure. Insufficient compliance, drug side-effects, or drug-drug interactions can lead to suboptimum drug concentrations, resulting in viral rebound. Viral resistance has been described to every antiretroviral drug and therefore poses a serious clinical as well as public-health problem. 139 HIV-1 subtypes differ in the sequence of mutations leading to drug resistance, and some naturally occurring polymorphisms might actually modulate resistance. 140 , 141 Drug-resistant HIV-1 is transmissible and can be detected in up to 20% of newly infected individuals in countries with broad access to antiretrovirals. 34 The prevalence of drug resistance in the untreated population remains low in regions with poor access to treatment. 142

Short-term antiretroviral-based interventions are effective in prevention of mother-to-child transmission. However, these interventions could result in drug resistant viral variants in the mother, baby, or both. 143 Around half the women who received one dose of nevirapine to prevent mother-to-child transmission harbour viruses resistant to non-nucleoside reverse transcriptase inhibitors (NNRTI). 144 , 145 These resistant viruses replicate efficiently and can be transmitted by breast milk, 146 and minor resistant populations present long after the intervention can possibly decrease the effectiveness of subsequent NNRTI-based treatment regimens. 147 The combination of short-course zidovudine, lamivudine, and nevirapine prevents peripartum transmission while reducing the risk of nevirapine resistant viruses. 148

Viral reservoirs

Viral reservoirs consist of anatomical sanctuaries and a small pool of infected long-lived memory T lymphocytes. HIV-1 latency in long-lived cell populations (eg, memory T lymphocytes, macrophages) poses an obstacle to eradication because current antiviral combination treatments fail to eliminate integrated proviruses from resting cells. Different strategies, including immune-modulatory molecules (interleukin 2, anti-CD3 mAb, interleukin 7), have been used to reactivate resting cells in the setting of HAART. Histone deacetylase-1 inhibitors, like valproic acid, release an inherent transcriptional block and by doing so facilitate viral long terminal repeat-driven expression. 149 Augmenting standard antiretroviral treatment with enfuviridine and valproic acid reduced the number of latently infected CD4+ T cells (29–84%), but to establish the relative contribution of each drug with respect to the final outcome is difficult. 150

Mother-to-child transmission

Prevention of mother-to-child transmission has seen advances in both industrialised and resource-constrained settings. 151 – 153 Intrapartum transmission has been reduced by increasing access to interventions such as one dose of nevirapine to mother and newborn baby. 154 Concerns about drug-resistant viral strains have led to several trials with combination treatments to reduce transmission during the intrapartum period. 148 , 152 , 155 In some settings, elective delivery by caesarean section can further reduce HIV-1 transmission during the intrapartum period, but the benefits of the intervention could be countered by post-partum sepsis and increasing maternal mortality. 156

Because HIV-1 can be transmitted by breastfeeding, replacement feeding is recommended in many settings. Poor access to clean running water precludes, however, the use of formula feeding under these circumstances, 157 and exclusive breastfeeding with abrupt weaning is one option for reducing transmission. 158 A potential novel intervention still being tested is the daily use of antiretrovirals during breastfeeding. More attention is starting to focus on the pregnant mother, especially initiation of antiretroviral therapy in mothers with low CD4+ counts during pregnancy and thereafter. 159 , 160 Only limited data are available regarding the health of uninfected children born to HIV-1-positive mothers. 161 In a European cohort of exposed-uninfected children, no serious clinical manifestations were apparent, at least in the short term to medium term (median follow-up 2 years). 162

Sexual transmission

Reduction of heterosexual transmission is crucial for control of the epidemic in many parts of the world. 1 , 163 Prevention is achieved through reduction in the number of discordant sexual acts or reduction of the probability of HIV-1 transmission in discordant sexual acts. The first can be achieved through abstinence and sex between concordantly seronegative individuals. Abstinence and lifelong monogamous relationships might not be adequate solutions for many people and therefore several interventions aimed at lowering the risk of transmission per discordant sexual act are in the process of clinical testing. Male and female condoms provide a proven and affordable prevention option. 164 , 165 In combination, these options are also more commonly referred to as the ABC (abstinence, be faithful, condom use) approach.

Other biomedical prevention interventions include male circumcision, antiretrovirals for prevention (eg, pre-exposure or post-exposure), chemoprophylactic treatment of herpes simplex virus-2 (HSV-2), microbicides, and vaccines. Results from one of three independent phase III male circumcision trials underway in South Africa, Kenya, and Uganda has helped to allay some of the ambivalence around the protective effect of male circumcision. 8 , 166 The findings from the South African trial show a 60% protective effect of male circumcision. 167 The possible mechanism relates to the fact that the foreskin has apocrine glands that secrete lysozymes but also Langerhans cells expressing CD4 and other receptors. 168 , 169 These skin-specific dendritic cells can uptake virus and are believed to play a part in transport of the virus to susceptible T cells. Immunofluorescence studies of foreskin mucosa suggest that these tissues might be more susceptible to HIV-1 infection than cervical mucosa. 170 Findings from this proof-of-concept trial need to be compared with evidence from the two trials still underway in Kenya and Uganda, and to acceptability data, behaviour change after circumcision, surgical complication rates, and logistics of undertaking the procedures before policy formulation and wide-scale access as a prevention strategy. 171 – 173

Since high plasma viraemia increases the risk of transmission by as much as an order of magnitude, 21 does reducing viral load in the infected partner through, for example, antiretroviral treatment reduce the risk of HIV-1 transmission in the uninfected sexual partner? A trial to explore this question is currently being run jointly by the HIV Prevention Trials Network ( www.hptn.org ) and the Adult Clinical Trials Group. Mathematical projections estimate up to 80% HIV-1 reduction, 174 , 175 but scarce observational data currently exist. 176 Post-exposure prophylaxis is recommended after occupational (eg, needle stick) 177 and non-occupational (eg, rape, sexual abuse) 178 exposure, although data for efficacy and optimum drug combinations are few. 179 Some clinical trials assessing the benefits of once daily pre-exposure chemoprophylaxis with antiretroviral compounds with long biological half-life (eg, tenofovir) have been put on hold or stopped. 175 , 180 Neither the overall idea of pre-exposure prophylaxis nor the drug itself, which is well tolerated, was at the root of the protests. Concerns were centred on clinical trials in resource-poor settings and the perceived scarcity of adequate interventions protecting these vulnerable populations.

HSV-2 might increase both the risk of transmitting and acquiring HIV-1. 181 , 182 Antivirals (eg, aciclovir, valaciclovir) are effective in reducing viral shedding 183 – 185 and HSV-2 transmission in discordant heterosexual couples. 182 The future of HSV-2 prevention might reside in the vaccine that is currently under development. 186 Whether prophylactic use of aciclovir in populations with high HSV-2 prevalence and incidence rates results in reduced HIV-1 incidence rates remains unresolved but several trials addressing this issue are underway, including HPTN039.

Gender disparities lie at the centre of women’s vulnerability. Prevention options need to be provided that can be used by women independently of their male sexual partner’s knowledge or consent. 187 Notwithstanding that redressing these disparities is a long-term challenge, several preventive interventions can be implemented in the interim on the basis of our incomplete understanding at a biological level of HIV-1 risk for women. For example, there seems to be a correlation between levels of sexual hormones (eg, progesterone) and transmission risk. 188 Observational studies also highlight the relation between abnormal vaginal flora and increased risk of HIV-1 infection. 189 , 190 The high prevalence of vaginal infections such as bacterial vaginosis (30–50%), vulvovaginal candidosis (10–13%), and trichomonas vaginalis (7–23%) in African women is associated with a substantial risk of HIV-1 acquisition. 189 In addition to increasing access to female condoms and treatment of other sexually transmitted infections, trials are underway to assess the use of other barrier methods such as cervical caps, invisible condoms, diaphragms, and diaphragms combined with micro bicides. 190 The control of vaginal infections is a potentially important method for decreasing HIV-1 acquisition that has yet to be tested. Periodic presumptive treatment for vaginal infections is being explored as an HIV-1 prevention strategy. 191

Microbicides

Microbicides are an additional important biomedical intervention technology that is covert and under women’s control. 192 These topical products potentially could be used to prevent rectal and vaginal transmission of HIV-1, but proof of concept has been elusive. Although the three phase III trial results of the first microbicidal product (nonoxynol-9) done in the mid-1980s and 1990s did not show protective effects, 193 , 194 they have informed the medical knowledge in terms of product selection, clinical testing, and safety assessments. The past 5 years have seen major advances in investment and product development. 66 , 195 , 197 Early clinical testing of multiple products including the launch of advanced clinical trials for five different products is continuing ( table 4 ). The development of antiretroviral gels increased the specificity of these third generation microbicides in relation to surfactants, vaginal enhancers, or entry inhibitors that have dominated the product pipeline so far ( figure 5 ). The first antiretroviral gel to undergo early testing is tenofovir gel, and the findings in terms of safety profile, tolerance, low systemic absorption, and slight adverse events are promising. 192 As with vaccines, a major obstacle is the absence of a surrogate marker of protection. Additional challenges are adherence to product use and the high rates of pregnancy in trial participants.

N9=nonoxonol-9. CS=cellulose sulphate.

Summary of microbicides currently undergoing advanced clinical testing

A safe, protective, and inexpensive vaccine would be the most efficient and possibly the only way to curb the HIV pandemic. 198 Despite intensive research, development of such a candidate vaccine remains elusive. Safety concerns prohibit the use of live-attenuated virus as immunogen. 199 Many different approaches with recombinant technologies have been pursued over the past two decades. Initially, efforts were focused on generating neutralising antibodies with recombinant monomeric envelope gp120 (AIDSVAX) as immunogen. 200 , 201 This vaccine did not induce neutralising antibodies and, not unexpectedly, the phase III trials failed to show protection. 202 , 203 Antibody mediated HIV-1 neutralisation is complicated by the high genetic diversity of the variable Env regions, epitopes masked by a carbohydrate shield (glycosylation), and conformational or energetic constraints. 204 Since CD8 T-cell responses control to some extent viral replication in vivo, recent vaccine development has focused on eliciting cellular immune responses. Overcoming pre-existing immunity against replication incompetent immunogenic vectors (eg, recombinant adenovirus type 5) is one of the challenges. 205 Safety and immunogenicity studies using replication defective vaccine vectors are continuing after preliminary studies in non-human primates showed some protection. 204 The immune system generally fails to spontaneously clear HIV-1 and the true correlates of protection continue to be ill defined. 198 , 206 However, the general belief is that approaches aimed at eliciting both humoral and cell mediated immunity are most promising to prevent or at least control retroviral infection. 198

Conclusions

An important gateway to both prevention and care is knowledge of HIV-1 status. 207 Fear of knowledge of status, including stigma and discrimination, has discouraged many from seeking voluntary counselling and testing services. 208 As access to antiretroviral interventions (prevention of mother-to-child transmission, antiretroviral treatment) increases, the opportunities for HIV-1 testing will grow and create opportunities for a prevention-care continuum, with the voluntary counselling and testing services as a point of entry. These changes will result in a shift in prevention efforts from a focus on individuals not infected with HIV-1 to a more effective continuum of prevention that includes uninfected, recently infected, infected, and asymptomatic people, as well as those with advancing HIV disease and on antiretroviral therapy.

HIV/AIDS is an exceptional epidemic that demands an exceptional response. Much progress has been made in a short space of time, despite many scientific and programmatic challenges ( figure 6 ). In the absence of a protective vaccine or a cure, prevention and access to antiretroviral treatments are the best options to slow down the HIV-1 pandemic. Broad implementation of these principles needs improved infrastructures in resource-constrained regions, which have been and will continue to be most affected. The fact that HIV-1 is predominantly sexually transmitted and disproportionately affects populations that are already socially or economically marginalised, or both, poses many ethical, social, economic, and political challenges.

Estimates place the cross species transmission events leading to the worldwide spread of HIV-1 to the early decades of the 20th century. Numbers circled by a hexagon identify the specific year of an event. PEPFAR=President’s Emergency Plan for AIDS Relief.

In view of the immediacy of the problem, and the fact that both research and programmes are mainly funded by the public sector, there is a greater demand from civil society for co-ownership of research and accountability for use of public funds. On the one hand, this co-ownership defines a changing role and responsibility of science in society, and on the other hand, shows a necessary synergy between activism and science. This partnership has been invaluable for antiretroviral drug development, treatment access in resource-constrained settings, and the scale-up of interventions to reduce mother-to-child transmission.

The increasing number of infected women and the disproportionate burden of infection in resource-constrained settings creates a scientific imperative to ensure research is done for people and in settings who stand to benefit most. The most affected countries face many other economic, political, and development challenges, which have raised issues in undertaking multicentre and multicountry research. Research addressing women-specific topics (such as effect of sexual hormones on transmission and disease progression, viral diversity, and antiretroviral potency) and women-specific prevention interventions including microbicides is crucial. We are probably at one of the most hopeful and optimistic points in our response to the pandemic. There is definitely more attention being directed to HIV-1, more resources ( panel ), more civil society mobilisation, more governments speaking up, more possibilities for treatment, and more evidence about what prevention and treatment strategies will work than in previous years. The unrelenting growth of the pandemic tells us that current strategies are not enough. Clearly, we need to do some things differently, while also increasing the scale and magnitude of current strategies in keeping with the pandemic.

PanelOnline resources

Epidemiology.

http://www.unaids.org/en/HIV_data/default.asp

Treatment recommendations

Centers for Disease Control and Prevention

http://www.cdc.gov/hiv/topics/treatment/index.htm

HIV-1 drug resistance

Stanford University HIV Drug Resistance Database

http://hivdb.stanford.edu/index.html

International AIDS Society–USA

http://www.iasusa.org/resistance_mutations/index.html

Microbicide

Alliance for Microbicide Development

http://www.microbicide.org

HIV Prevention Trials Network

http://www.hptn.org/index.htm

International AIDS Vaccine Initiative

http://www.iavi.org

Search strategy and selection criteria

A comprehensive literature review was undertaken by searching the PubMed database online, for English language publications between January, 2000, and June, 2006. The database search terms included keywords such as “HIV/AIDS”, “epidemiology”, “prevention”, “pathogenesis”, “HSV-2”, “male circumcision”, “PMTCT”, “scaling up treatment”, “resource constrained settings”, “antiretroviral pre-exposure prophylaxis”, “HAART”, “restriction”, “host factor”, “HIV pathogenesis”, “resistance”, “latency”. Various combinations of these words were entered. All duplicate articles were removed. A subset of relevant articles was chosen and full-text manuscripts were summarised.

Acknowledgments

We thank P D Bieniasz, W Cates, L Chakrabarti, C Cheng-Mayer, J Coovadia, H Gayle, P A Fryd, R Gray, S Abdool Karim, L Kuhn, K Mayer, P Mane, L C F Mulder, L Myer, and M Wawer for helpful discussions. M Boettiger and C Baxter assisted with literature searches. This work was supported by NIH grant RO1AI064001 (VS), by grant 1 U19AI51794 (QAK) from CAPRISA that forms part of the Comprehensive International Program of Research on AIDS (CIPRA) funded by the National Institute of Allergy and infectious Disease (NIAID), National Institutes of Health (NIH) and the US Department of Health and Human Services (DHHS) and grant D43 TW00231 (QAK) from the Columbia University-Southern African Fogarty AIDS International Training and Research Program.

Conflict of interest statement

D D Ho sits on the scientific advisory boards for Monogram, Osel, Achillion, Valiant, Oyagen, Lavipharm, and XTL. Products or work from these companies are not discussed in the review. He holds patents on vaccine candidates. The other authors declare no conflict of interest.