A CPPE learning@lunch programme for hospital pharmacy

bookletOctober 2009WTM 0195/11

H I V

AuthorFiona Clark, specialist pharmacist HIV and sexual health, Cardiff and Vale NHS Trust; education and training lead, HIV PharmacyAssociation (HIVPA)

Case study authorAshley Pennell, lead pharmacist, infectious diseases, Pennine Acute Hospitals NHS Trust

CPPE programme developerFionnuala McCullagh, pharmacist, learning development, CPPE

ReviewersLiz Davies, Macmillan specialist oncology pharmacist (lead pharmacist for haematology and HIV services), Central ManchesterUniversity Hospitals NHS Foundation TrustBrett Marrett*, lead pharmacist HIV and sexual health, Imperial College Healthcare NHS TrustNeal Marshall*, specialist pharmacist HIV services, Ian Charleson Centre for HIV medicine, Royal Free Hospital, London*representatives of the HIVPA committee

This programme was piloted by:North Middlesex University Hospital Trust; facilitated by Ryhanna Haniff (specialist education and training pharmacist) andChinyere Okoli (specialist HIV pharmacist) Northampton General Hospital NHS Trust; facilitated by Vijay Patel (specialist HIV pharmacist)

CPPE reviewersMatthew Shaw, deputy director, CPPEChetan Shah, regional manager, North Thames and East of England, CPPE

DisclaimerWe have developed this learning programme to support your practice in this topic area.We recommend that you use it in combinationwith other established reference sources. If you are using it significantly after the date of initial publication, then you should refer tocurrent published evidence. CPPE does not accept responsibility for any errors or omissions.

Brand namesCPPE acknowledges the following brand names and registered trademarks mentioned throughout this programme: Atripla®,Combivir®, Kaletra®, Kivexa®, Microgynon 30®, Rifater®, Rifinah®, Septrin Forte®, Trizivir® and Truvada®.

External websitesCPPE is not responsible for the content of any non-CPPE websites mentioned in this programme or for the accuracy of anyinformation to be found there.

Published in September 2009 by the Centre for Pharmacy Postgraduate Education, School of Pharmacy and PharmaceuticalSciences, University of Manchester, Oxford Road, Manchester M13 9PT http://www.cppe.ac.uk

ProductionDesigned and printed by Peacock Design and Print Ltd, Spen House, 99 Walton Road, Stockton Heath,WA4 6NR.

The learning@lunch HIV module is endorsed by the HIV Pharmacy Association

learning@lunch

Contents

Learning with CPPE 2About CPPE learning@lunch programmes 4About this learning@lunch programme on HIV 6Learning objectives 6Glossary of terms 8Reflective questions 10

Reading and practice pointsIntroduction 13The management of HIV infection 23Opportunistic infections 43Co-infections 53Pharmacy considerations with HIV-infected patients 55Post-exposure prophylaxis 58HIV and pregnancy 60

Summary 63Introductions to the case studies 64Checklist for action 72References 73Further reading 74Useful websites 75

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Learning with CPPE

The Centre for Pharmacy Postgraduate Education (CPPE) is funded by the Department ofHealth to provide continuing education for practising pharmacists and pharmacy techniciansproviding NHS services in England.We are based in the University of Manchester’s School ofPharmacy and Pharmaceutical Sciences.

<CPPE 123 icon> We recognise that people have different learning needs and not every CPPE programme is suitable for every pharmacist or pharmacy technician.We havecreated three categories of learning to cater for these differing needs:

Core learning (limited expectation of prior knowledge)

Application of knowledge (assumes prior learning)

Supporting specialties (CPPE may not be the provider and will signpost you to other appropriate learning providers).

This is a learning programme.

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Continuing professional development (CPD) - You can use this learning programmeto support your CPD. Consider what your learning needs are in this area.You may find it usefulto work with the information and activities here in a way that is compatible with the RoyalPharmaceutical Society of Great Britain’s approach to continuing professional development. Useyour CPD record sheets or go to: http://www.uptodate.org.uk/ to plan and record yourlearning.

Programme guardians - A programme guardian is a recognised expert in an area relevantto the content of a learning programme who will review the programme every six months toensure quality is maintained.We will post any alterations or further supporting materials that areneeded as an update on our website.We recommend that you refer to these updates if you areusing a programme significantly after its initial publication date.

Feedback -We hope you find this learning programme useful for your practice. Please help usto assess its value and effectiveness by visiting the My CPPE page on our website. Alternatively,please email us at: feedback@cppe.ac.uk

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About CPPE learning@lunch programmes

The CPPE learning@lunch suite has been designed as a series of short (one hour) clinical modulesto be delivered at a suitable time within your work environment.

Target audience

This learning programme is intended for:● non-specialist clinical pharmacists● post-diploma pharmacists who wish to keep up to date in this therapeutic area to inform

their continuing professional development (CPD)● specialist hospital pharmacists who work in a different area of practice and wish to keep up to

date in this therapeutic area● pharmacists who have recently moved into hospital pharmacy from community practice● registered hospital pharmacy technicians with relevant experience of clinical work and

medicines management.

The learning@lunch modules are designed to:

● be interactive and fun● update your knowledge and understanding of the topic● support your continuing professional development.

All of the printed materials for the session are contained in two booklets.

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Booklet 1

This booklet contains clinical notes for you to read through before the group session. It starts witha set of thought-provoking reflective questions to help you examine your current knowledge andstimulate you to find out more by reading the accompanying clinical notes in the module. Thequestions will also be linked to case studies. Some practice points have been included to triggerthought and action related to normal routine practice. Key clinical points are highlightedthroughout the text. There is also a glossary of the key terms and references used in this learningprogramme. Once you have read through the clinical notes, you should take some time to reflecton the introductions to the case studies, which set the scene for the second part of the programmeand are there to help you prepare for the learning@lunch event.Your facilitator will explain whichcase study/ies you will review in the session.

Booklet 2

You will work through Booklet 2 at the learning@lunch group session. Each case study is presentedin more depth in Booklet 2 and a series of questions are posed for you to work through. The casestudies are designed to help you to develop skills in interpreting guidelines, dealing withuncertainties and addressing clinically complex scenarios. Booklet 2 also contains suggestedadditional activities that you can work through after the session.

Once you have worked through the case study/ies in the group session you will be able to lookthrough our suggested answers to the reflective questions, practice points and case studies.

We have also included some suggestions for practice-based activities.

Assessment

Assess your learning, after your learning@lunch session, by working through the online e-assessment on our website: http://www.cppe.ac.uk. Further guidance on how to access theassessment is provided in Booklet 2.

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✓

About this learning@lunch programme on HIV

This CPPE learning@lunch programme deals with the topic of human immunodeficiency virus(HIV).

The purpose of this programme is to provide you with a better understanding of how HIVinfection may affect patients you encounter. It will also help you to deal with clinical and practicalissues which arise in the acute setting.

You will require access to local and national guidelines and the current edition of the BritishNational Formulary (BNF). Internet access is needed to benefit from online resources referencedin the text, and to access the online e-assessment which you can complete after the learning@lunchgroup session.

Online resources

Where we think it will be helpful we have provided the URL to take you directly to an article orspecific part of a website. However, we are also aware that web links can change (eg, Departmentof Health links) so in some cases we have provided the URL for the organisation’s home pageonly. If you have difficulty in accessing any web links, please go to the organisation’s home pageand use appropriate key words to search for the relevant item.

Note on articles: If you have difficulty locating an article on the internet, search using:http://www.google.co.uk by typing in the title, author, date and name of the journal.

Learning objectives

CPPE has linked all its learning programmes to the RPSGB competences. This will make it easierfor you to connect your professional practice to your learning needs and activities.You may beable to apply your learning to other aspects of these frameworks.We have also linked the learningto the dimensions of the NHS Knowledge and Skills Framework (KSF).

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Learning objectives

List five routes of HIV transmission.

Summarise how HIV replicates andaffects the immune system.

Explain when antiretroviral therapyshould be started and the mainparameters that should be monitored.

State the main classes andcombinations of antiretroviral therapy,and their most common side-effects.

Describe prophylaxis and treatment forthree opportunistic infections.

Explain when post-exposureprophylaxis is indicated and how toaccess it in an emergency within yourworkplace.

Briefly discuss the approach to thetreatment of HIV infection in pregnantwomen.

Apply your knowledge to two or moreHIV case studies:

• Pneumocystis jiroveci pneumonia, confidentiality

• tuberculosis• post-exposure prophylaxis.

GLF

Cluster: Problem-solvingCompetency: Knowledge -pathophysiology

Cluster: problem-solvingCompetency: Gatheringinformation - summarisesinformation

Cluster: Delivery of patient careCompetency: Monitoring drugtherapy – use of guidelines;identification of medicinesmanagement problems

Cluster: Problem-solvingCompetency: Knowledge - side-effects

Cluster: Delivery of patient careCompetency: medicinesinformation

Cluster: Problem-solvingCompetency: Analysinginformation - appraises options

Cluster: Problem-solvingCompetency: Gatheringinformation - summarisesinformation

Cluster: Delivery of patient careCompetency: Need for drug -relevant patient background;selection of drug - drug-patientinteractions

Cluster: delivery of patient careCompetency: medicinesinformation and patienteducation, identification ofmedicines management problems

Pharmacist

G1

G1

G1, G7,G8

G1, G8

G1

G1, G7,G8, G10

G1

G1, G7,G8

KSF dimensions

Health and well-beingHWB2

Health and well-beingHWB2

Health and well-beingHWB6, HWB7, HWB8

Health and well-beingHWB2

Health and well-beingHWB2, HWB3, HWB7

Health and well-beingHWB3, HWB7, HWB10

Health and well-beingHWB2, HWB3

Health and well-beingHWB2, HWB6, HWB7Information andknowledgeIK3

Pharmacytechnicians

TG7

TG7

TG7

RPSGB competences

Glossary of terms

AntibodyInfection-fighting protein molecules in blood or other bodily fluids that tag, neutralise and helpdestroy pathogenic micro-organisms, such as viruses.

AntigenA substance that is recognised by the immune system and induces a reaction.

CapsidThe protein shell of a virus that encloses the genetic material of the virus.

CD4+ T-cellWhite blood cells that orchestrate the immune response, signalling other cells in the immunesystem to perform their special functions; also known as T-helper cells, these cells are killed ordisabled during HIV infection.

Cytotoxic T-cellA type of T-lymphocyte that destroys virus-infected cells and cancerous cells.

EnzymeA protein that accelerates a specific chemical reaction without altering itself.

Host cellThe human cell in which the HIV is living.

Immune deficiencyThe inability of the immune system to work properly, resulting in susceptibility to disease.

ImmunosuppressionA reduction in the immune system’s response to infection and other foreign bodies.

IntegraseAn HIV enzyme used by the virus to integrate its genetic material into the host cell's DNA.

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Kaposi's sarcoma A type of cancer characterised by abnormal growths of blood vessels that develop into purplish orbrown lesions.

MacrophageA large immune system cell that devours invading pathogens and other foreign bodies. Itstimulates other immune system cells by presenting them with small pieces of the pathogens orforeign bodies.

MonocyteA circulating white blood cell that develops into a macrophage when it enters tissues.

Opportunistic infectionAn illness caused by an organism that usually does not cause disease in a person with a normalimmune system. People with advanced HIV infection suffer opportunistic infections of the lungs,brain, eyes and other organs.

PandemicAn epidemic so widely spread that people in other countries are affected.

PathogenesisThe production or development of a disease that may be influenced by many factors, includingthe infecting microbe and the host's immune response.

PathogenA disease-causing organism.

PhagocyteA cell that is able to engulf and digest bacteria, protozoa, cells and cell debris, and other smallparticles.

ProteaseAn HIV enzyme used to cut large HIV proteins into smaller ones, needed for the assembly of aninfectious virus particle.

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ProvirusDNA of a virus, such as HIV, that has been integrated into the genes of a host cell.

ReplicateA process by which a virus makes copies of itself.

RetrovirusHIV and other viruses that carry their genetic material in the form of RNA and that have theenzyme reverse transcriptase.

Reverse transcriptaseThe enzyme produced by HIV and other retroviruses that allows them to synthesise DNA fromtheir RNA.

VirionThe infective system of a virus, composed of the viral genome, a protein core, and a protein coatcalled a capsid, which may be naked or enclosed in a lipoprotein envelope.

Reflective questions

Consider the following questions before reading this booklet. Use them to focus your thoughtsand stimulate your learning and development. Once you have read through the booklet revisit thequestions and prepare your thoughts before you attend your learning@lunch group session, whereyou will have an opportunity to talk through the relevant points in more detail.

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1. Do you agree with the statement: ‘all prescriptions for people living with HIV should omit the patient’s name’? Explain your answer.

2. List five classes of antiretroviral agent. Give one example of each.

3. You are checking an outpatient prescription for antiretroviral medicines. Which information sources would you use to clinically check the prescription?

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4. State two side-effects that patients commonly experience when starting highly active antiretroviral therapy (HAART). Briefly suggest how the medical and pharmacy team could manage these side-effects.

5. A lady who is living with HIV infection was admitted to your ward with an acute illness but is now being discharged. She says she doesn’t really understand how her HIV medicines work, but tries her best to take them. Apart from counselling her yourself, what other resources could you direct her towards?

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Reading and practice points

1. Introduction

1.1 History

In 1981 an epidemic of the previously unknown acquired immunodeficiency syndrome (AIDS)was reported in the USA. In 1983 a virus was isolated, later named the human immunodeficiencyvirus (HIV), and this was then defined as the primary cause of AIDS. HIV destroys and impairsthe cells of the body’s immune system.

Figure 1: Structure of HIV virion

gp41 - Transmembrane Glycoproteingp120 - Docking Glycoprotein

Lipid Membrane

Viral RNA

Integrase

Capsid

Matrix

Reverse Transcriptase

Adapted with kind permission of the National Institute of Allergy and Infectious Diseases

HIV is a retrovirus. It is composed of two single strands of RNA. Enzymes needed for thedevelopment of the virion, such as reverse transcriptase, protease and integrase, are containedwithin the central capsid.

Globally, approximately 33 million people currently live with HIV, making it one of the world’smost destructive pandemics. Sub-Saharan Africa remains by far the worst-affected region, withreported incidences being as high as 28 percent of the population.1

1.2 UK prevalence

HIV infection continues to be one of the most important communicable diseases in the UK. It isan infection associated with serious morbidity, high treatment and care costs, significant mortalityand a high number of potential years of life lost. Each year, many thousands of individuals arediagnosed with HIV infection for the first time. People living with HIV frequently experiencestigma. It has a prolonged ‘silent’ period during which it often remains undiagnosed. HAART hassubstantially reduced the incidence of advanced HIV infection and deaths in the UK.

The Health Protection Agency (HPA) provides an integrated approach to protecting UK publichealth, through the provision of support and advice to the NHS, local authorities, emergencyservices, the Medicines and Healthcare products Regulatory Agency, the National Institute forHealth and Clinical Excellence (NICE) and the Department of Health. In November 2008 theHPA released its latest statistics for people living with HIV infection in the UK,2 including thefollowing:

● An estimated 77,400 people were living with HIV in the UK at the end of 2007; over a quarterof this number (28 percent) were unaware of their infection.

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● During 2007 there were 7734 new diagnoses of HIV infection, a similarly high figure to thediagnoses made in each of the previous four years.

● Almost a third (31 percent) of persons newly diagnosed with HIV infection were diagnosedlate - when the immune system had become so suppressed as to put them at high risk ofopportunistic infections.

You can check HIV infection prevalence for the area where you work on the HPA’s website:http://www.hpa.org.uk

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Practice point 1

Do you know where the nearest specialist centre for the treatment of HIV is in yourarea? Make a note of their contact details here.

1.3 Transmission routes

There are a number of well-defined ways in which someone can become infected with HIV:

● unprotected sexual intercourse with an infected partner - anal, vaginal and oral● injection or transfusion of contaminated blood or blood products; this is now rare in countries

where blood is screened for HIV● sharing unsterilised injection equipment that has been previously used by someone who is

infected● it can pass from an infected mother to baby: during pregnancy, at birth and through

breastfeeding● occupational exposure of healthcare or laboratory staff (needlestick injury, for example).

Details of transmission rates and most common routes of transmission are available on the HPAwebsite: http://www.hpa.org.uk

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1.4 HIV and the immune system

HIV infects specific host cells. It mostly targets cells carrying a molecule called CD4 on theirsurface. CD4-cells are a sub-group of lymphocytes that play an important role in strengtheningthe immune system. These cells are unusual for lymphocytes because they have no cytotoxic orphagocytic activity. Their main role is to activate and direct other immune cells, so they areparticularly important in the immune system. It is this role in influencing other immune cells thatleads to them also being known as T-helper cells.

CD4 levels in a healthy individual are in the range 500-1500 cells/microlitre. In HIV infection,CD4 cell levels begin to decrease, eventually to a level where the CD4-cell population is too smallto recognise the full range of antigens that the immune system would normally detect andrespond to. A depleted level of CD4-cells allows various pathogens to escape recognition byT-cells. This allows opportunistic infections that would normally prompt a CD4-cell response tobypass the immune system. As these opportunistic infections take hold, the core symptoms ofAIDS (now referred to as HIV infection) develop.

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1.5 HIV lifecycle

Figure 2: Replication cycle of HIV

Reverse TranscriptaseSynthesises RNAinto DNA

IntegraseIntegrates viralDNA into the cellgenome

Viral RNA leavesthe nucleus

Protease

Translation

Cuts up the protein

Integration

Transcription

Reconstruction

Virus protein

CD4 ReceptorCell membrane

HIV

Virus RNA

Double-stranded DNA

Cell Nucleus

Cytoplasm

New virus

Virus RNA

• Fusion HIV enters the CD4 cell by binding to the CD4cell receptor (and either the CCR5 or CXCR4 co-receptor)

• Reverse transcription Once fusion has occurred,the inside of the virus virion (the RNA and importantenzymes) absorbs into the infected cell. The viralenzyme, reverse transcriptase, helps translate the HIVRNA into DNA. Reverse transcriptase is error-prone andproduces mistakes every cycle. This generates manymutations which may contribute to drug resistancedeveloping.

• Integration The newly formed DNA then integrateswith the DNA from the host cell using a viral enzymecalled integrase. The DNA then replicates.

• Transcription and translation The two strandsof DNA divide and form a new strand of viral RNA calledmessenger RNA. The naturally occurring nucleosides areassembled. These are laid out in turn through thetranslation of the information contained in themessenger RNA.

• Reconstitution and viral assembly The viralproteins are cleaved by a viral protein called protease.These smaller molecules form the structure of the newHIV virion, including the enzymes and proteins andprotein membrane. Once this assembly has occurred,then the new virion buds off from the host cell and isable to infect other cells. About 109 new HIV virions areproduced every day in people with untreated HIV.

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1.6 Natural history of HIV infection

The effectiveness of the immune system declines as the circulating virus replicates, increases innumber and attacks CD4-cells. Opportunistic infections normally elicit a CD4-cell response inindividuals with a healthy immune system, so the infection can normally be fought off and no illhealth results. In HIV infection, the body is susceptible to these opportunistic infections.

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Figure 3: Natural progression of HIV infection

1200110010009008007006005004003002001000

0 3 6 9 12 1 2 3 4 5 6 7 8 9 10 11102

103

104

105

106

107

CD4

Coun

t (ce

lls/m

icrol

itre)

HIV RN

A Copies per mL Plasm

a

weeks years

PrimaryInfection

Acute HIV syndromeWide dissemination of virusSeeding of lymphoid organs

Death

ConstitutionalSymptoms

OpportunisticDiseasesClinical Latency

Adapted with kind permission of Prof Dr Giuseppe Pantaleo, 20003

Table 1: Natural progression of HIV infection

Over the last ten years or so, there have been great advances in the treatment of HIV infection. Inthe UK it is now classed as a chronic, long-term treatable disease when treated with life-longmedicines.

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1. Acute (primary) phase

Person may not know they have justbecome infected with HIV.

Antibodies may not appear in theblood for days.

Seroconversion illnessMay happen before or whileantibodies begin to appear in theblood in up to 80 percent ofinfections.Symptoms include:• prolonged fever (4-14 days) and

aching limbs• red rash over the trunk• sore throat – pharyngitis• ulceration in the mouth or

genitals• diarrhoea• severe headaches• aversion to light• symptoms similar to flu,

glandular fever, tonsillitis or asevere attack of herpes.

Symptoms may appear two to sixweeks after exposure to HIV.

Severity: from mild flu-like illness tohospitalisation.

2. Chronic (latent) phase

Damage caused by HIV may haveno clinical manifestation(s).

Asymptomatic HIV infectionmay last months to years.

May have swollen lymph nodes, ie,persistent generalisedlymphadenopathy.

3. Advanced phase

Symptomatic disease – developswith damage to the immune systemover time.

CD4 count falls; there is anincreased risk of tumours andinfections.

Opportunistic infections causedby pathogens that are around us allthe time that we can normally fightoff.When the immune system iscompromised, previouslycontrolled infections can bereactivated.

When someone is diagnosed withone of these infections or tumoursthey are said to have symptomaticHIV disease (previously referred toas AIDS) - further information isavailable via the website you aredirected to in practice point 3.

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Practice point 2

HIV patients are living longer. Therefore, as pharmacists, you are more likely to seethem in all areas of the hospital setting, eg, surgical wards, medical wards andcardiac wards. Check to see if there are any HIV patients admitted in yourspeciality.

Classification

The Centers for Disease Control and Prevention (CDC) in the United States have devised aclassification system based on clinical features, AIDS-defining illnesses and CD4 counts. Thedetails of the system can be found online at: http://www.cdc.gov

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Practice point 3

Access the following website: http://www.cdc.gov/hiv/resources/guidelines/

• Under the title Surveillance Case Definitions look through the revised guidelines.Make a note of the four stages of HIV disease, together with the clinical andlaboratory evidence for each stage.

• Look at Appendix A - AIDS Defining Conditions. See how many you recognise.Choose one condition you do not recognise. Find a definition, cause andtreatment for this condition.

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2. The management of HIV infection

In this section we will consider key issues in the management of HIV infection. However,treatment guidelines are constantly changing, so for up-to-date information please refer to theBritish HIV Association (BHIVA) website: http://www.bhiva.org/ (click on ‘publications andguidelines’ then ‘guidelines’).

2.1 Monitoring

CD4-cell counts and plasma HIV viral load are used as surrogate markers to measure diseaseprogression, as well as to evaluate the effect of antiretroviral therapy.

● CD4 countThis is a measure of the extent of damage to the immune system and the most reliableindicator of the probability of developing an opportunistic infection. Individuals with a healthyimmune system and no HIV infection have a CD4 count between 500 and 1500cells/microlitre. Please note that immunosuppressant medicines can also affect the CD4 count.

● Plasma viral load This measures the amount of virus in the peripheral blood. It is the most important parameterin monitoring response to antiretroviral treatment.Viral load assays are highly sensitive and candetect levels as low as 40-50 copies/mL, depending on the centre.Viral loads below the centre’slowest threshold level are reported as ‘undetectable’.Viral load suppression (that is, a viral loadbelow detectable levels) should be achieved within four months of starting antiretroviraltreatment.

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2.2 When to start treatment

It is now well established that untreated HIV infection is associated with both extreme morbidityand mortality as a result of disease progression.4 HAART is a combination of antiretroviralmedicines that act on different parts of the HIV lifecycle, with the aim of suppressing replicationof the virus. HAART has been a major breakthrough in HIV treatment, resulting in reduction ofviral replication, slowing of disease progression and restoration of the immune system (see page 30for further details on HAART).

The BHIVA guidelines4 recommend that therapy is started in all patients with a CD4 count of lessthan 350 cells/microlitre (confirmed on at least one consecutive blood sample).

Table 2: Recommendations for when to initiate therapy

Source: British HIV Association (BHIVA) guidelines4

Presentation

Primary HIV infection

Established HIV infectionCD4 less than 200 cells/microlitreCD4 201-350 cells/microlitreCD4 351-500 cells/microlitre

AIDS diagnosis

Guidance on starting HAART

Treatment in clinical trials

TreatTreat as soon as possible, when readyTreat in specific situations with higher risk ofclinical events

Treat (except for tuberculosis when CD4 greaterthan 350 cells/microlitre)

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HAART clearly improves both short and long-term prognosis.4 However, the benefits of startingantiretroviral drugs early in the disease need to be balanced against the risks of drug-druginteractions, overlapping toxicities and the readiness of the patient to start a life-long medicinesregime. Despite these potential disadvantages of early introduction of therapy, HAART should bestarted early in the majority of patients with opportunistic disease. For example, HAART shouldstart as soon as possible in patients who present with HIV-related lymphoma and who are alsostarting cytotoxic chemotherapy.

Patients starting HAART are at risk of immune reconstitution inflammatory syndrome(IRIS). In IRIS, it is thought that the immune system - now boosted by HAART - reacts in anexaggerated fashion to opportunistic antigens. Paradoxically, IRIS may present as a worsening ofopportunistic infection.

Poorly controlled viral load in HIV infection is also a risk factor for the development ofcardiovascular disease.

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2.3 Transmitted HIV drug resistance

Primary HIV resistance occurs when a drug-resistant virus is transmitted to another person. Thiscan limit treatment options for newly infected individuals. The BHIVA guidelines 20084

recommend that all HIV-infected patients should have a blood test prior to treatment to check forbaseline resistance (such testing is similar in principle to checking sensitivities of antibacterials inbacterial infection). A resistance test is also recommended after treatment failure.

2.4 Drug treatment of HIV infection

Classes of antiretroviral agent

Each class of antiretroviral drug inhibits the virus at different stages in its cellular life cycle. Theclasses are:

● entry/fusion inhibitors ● nucleoside reverse transcriptase inhibitors● non-nucleoside reverse transcriptase inhibitors● integrase inhibitors● protease inhibitors

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Figure 4: The mode of action of current classes of antiretroviral drugs

Fusion/entryinhibitors

Reverse transcriptaseinhibitors

Integraseinhibitors

Protease inhibitors

Attachment Uncoating Reversetranscription

Integration Transcription Translation Assemblyand release

HIV virion

CCR5 or CXCR4 co-receptor

CD4 receptor

nucleus

cellular DNA

viral mRNA

Protease

immature non-infectiousvirus particle new HIV

particles

Reversetranscriptase Integrase

viralRNA

integratedviral DNA

gag-polpolyprotein

capsidproteins andviral RNA

unintegrateddouble-stranded

viral DNA

✄✄

Table 3 note: Each drug class has differing side-effects, drug interactions and impact on co-pathologies. Individual drugs within classes may have significantly better convenience, tolerability,or side-effect profiles than others. Refer to the current edition of the BNF or individual SPCs formore information.

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Practice point 4

Look at Table 3 and choose one drug from each class. Read through the summariesof product characteristics (SPCs) for the drugs (available online at:http://www.medicines.org.uk) and list the five major side-effects for each drug inthe space provided in the table.

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Table 3: The five main classes of antiretroviral, their action on HIV infection and drugscurrently available in each class.

*Most protease inhibitors are administered with low-dose ritonavir, which is a potent inhibitor of cytochrome P450 (3A4).This increasesplasma levels of protease inhibitors.The effect is known as boosting and has the advantage of reducing dosage frequency and dietaryrestrictions.

Action

Availableagent

List fivemain side-effects forone drug ineach class

Entry/Fusioninhibitors

Interfere with thebinding, fusion andentry of the HIVvirus to a humancell. Available drugsin this class eitherhave a direct actionon the binding site,or act on co-receptors, eg, CCR5.

EnfuvirtideMaraviroc

Nucleosidereversetranscriptaseinhibitors(NRTIs)

Target the enzymereverse transcriptase,halting viral DNAsynthesis. TheNRTIs need to bephosphorylatedwithin the cell to theactive form. For thisreason measuringthe amount of drugin the blood doesnot correlate withthe clinical effect.

AbacavirDidanosineEmtricitabineLamivudineStavudineTenofovirZidovudine

Non-nucleosidereversetranscriptase inhibitors(NNRTIs)

Bind directly toreversetranscriptasecausing disruptionof the active site.

EfavirenzEtravirineNevirapine

Proteaseinhibitors(PIs)

Selectively bindand inhibit HIVprotease. Byblocking theenzyme, deformedHIV particles areformed and thesehave a reducedinfectious capacity.

Nelfinavir(the followingare boosted withlow-doseritonavir*)

AtazanavirDarunavirFosamprenavirLopinavirSaquinavirIndinavirTipranavir

Integraseinhibitors

Block the action ofintegrase, a viralenzyme that insertsthe viral geneticmaterial into theDNA of the hostcell.

Raltegravir

Highly active antiretroviral therapy (HAART)

HAART is a combination of antiretroviral medicines that act on different parts of the HIV lifecycle,with the aim of suppressing replication of the virus. The aim of such combinations is to prolong andimprove the patient’s quality of life by suppressing viral replication for as long as possible andrestoring their immune function.

HAART has dramatically improved the prognosis of people living with HIV infection. For those thathave access to this therapy, HIV infection is now regarded as a chronic manageable disease.

Drug combinations always need to be individualised for the patient to achieve maximum potency,durability, adherence and tolerability, and to avoid long-term toxicities and any likely druginteractions. Combinations should take account of the resistance test results, co-pathologies, riskfactors for diabetes and cardiovascular disease, lifestyle, and informed patient choice. Patientsnormally start with a combination of three antiretroviral medicines as described below.

The BHIVA guidelines 20084 recommend starting with either:

● two NRTIs plus an NNRTI ● two NRTIs and a ritonavir-boosted protease inhibitor.

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Table 4: Preferred regimes (a combination of three drugs, one from each group A, Band C)

Source: BHIVA guidelines, 20084

In order to decrease the tablet burden or dose frequency (or both) for patients, co-formulatedfixed-dose combinations have been produced.

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Regime

Preferred

Alternative

Specific groups

A

Efavirenz

Lopinavir/ritonavirFosamprenavir/ritonavirAtazanavir/ritonavirSaquinavir/ritonavir

Nevirapine*Atazanavir**

B

TenofovirAbacavir

DidanosineZidovudine

C

LamivudineEmtricitabine

* only when CD4 count is less than 250 cells/microlitre in female patients and less than 400 cells/microlitre in male patients

** where there are established cardiovascular disease risk factors and a protease inhibitor is required

Table 5: Available fixed-dose combinations

Certain combinations of antiretroviral agent should be avoided, or used with caution.

Some combinations to avoid:● stavudine + zidovudine - compete for the same intracellular enzyme and have an

antagonistic effect● emtricitabine + lamivudine - no additive activity

Caution with:● didanosine and stavudine - increased risk of peripheral neuropathy, lactic acidosis

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Combivir

Kivexa

Trizivir

Truvada

Atripla

Zidovudine 300 mg/lamivudine 150 mg

Abacavir 600 mg/lamivudine 300 mg

Abacavir 300 mg/lamivudine 150 mg/zidovudine 300 mg

Tenofovir 245 mg/emtricitabine 200 mg

Efavirenz 600 mg/emtricitabine 200 mg/tenofovir 245 mg

One tablet, twice daily

One tablet, once daily

One tablet, twice daily

One tablet, once daily

One tablet, once daily

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To maintain viral suppression, all antiretroviral medicines must be taken at the same time everyday and according to dietary restrictions. This means every 24 hours for a once-daily regime andevery 12 hours for a twice-daily regime.When patients do not take their medicines at the correcttimes, there will be intervals when there will be subtherapeutic drug levels in the body. This canlead to drug resistance and treatment failure. Development of cross resistance with otherantiretrovirals within the class decreases treatment options for the future.

Potential drug side-effects

As with all new medicines and relatively new conditions, not all treatment side-effects are known.In general, side-effects associated with antiretrovirals are classified as those which occur oninitiation of therapy, such as gastrointestinal intolerance or skin rashes, or those which occur afterseveral months to years of therapy, such as body shape changes (fat redistribution syndrome).

Side-effects associated with initial therapy

● Nausea and vomiting● Diarrhoea● Headache ● Abdominal bloating and flatulence● Mild to moderate rash● Severe rash (Stevens-Johnson syndrome)● Changes in liver function tests ● Alteration in sleep pattern

Side-effects are common when starting HAART; and consideration should be given to providingantiemetics and antidiarrhoeal agents for the common gastrointestinal symptoms.

Side-effects associated with long-term therapy

● Changes in renal function● Changes in bone mineral density ● Hyperlipidaemia● Hypercholesterolemia● Increased risk of cardiovascular disease● Diabetes ● Hyperglycaemia● Peripheral neuropathy ● Abnormal liver function tests and hepatotoxicity ● Acute pancreatitis● Changes in body shape, known as fat redistribution syndrome; encompassing one or

several symptoms, such as lipoatrophy (peripheral fat loss), buffalo hump, increased visceralfat, loss of fat from limbs

Refer to the current edition of the BNF or individual SPCs for side-effects of individual drugs.

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Potential drug interactions

Drug interactions are common with antiretroviral medicines. Cytochrome P450 is one of themicrosomal liver enzymes responsible for metabolism of many drugs. Therefore any agent thataffects the activity of cytochrome P450 can have an effect on the metabolism of antiretroviralmedicines. Protease inhibitors and non-nucleoside reverse transcriptase inhibitors are bothsubstrates for cytochrome P450. They can act as enzyme inducers, enzyme inhibitors or both, andcan therefore affect the clearance of other drugs the patient is taking that are metabolised by theseenzymes.

Drug interactions involving antiretrovirals can be serious. If circulating antiretroviral levels arelowered below the level needed to inhibit viral replication, viral load can increase and drugresistance may develop. The effect is all the more challenging because there are still only a limitednumber of HIV drugs. Many of them exhibit cross resistance with other agents within the samedrug class, which limits treatment options even further.

Conversely, increased plasma levels of some antiretroviral drugs and other concurrent medicationcan cause serious side-effects such as hepatotoxicity, renal failure and jaundice.

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Table 6: Common drug interactions

Drug

Midazolam and triazolam

Rifampicin

Rifabutin

Phosphodiesterase-5inhibitors

Proton pump inhibitors

H2-receptor antagonists

Methadone

Simvastatin

St John’s wort

Antiretroviral agent

All protease inhibitors andefavirenz

All protease inhibitors andnon-nucleoside reversetranscriptase inhibitors

Protease inhibitors

All protease inhibitors

Atazanavir

Saquinavir

Atazanavir

Protease inhibitors andnon-nucleoside reversetranscriptase inhibitors

All protease inhibitors

Protease inhibitors, non-nucleoside reversetranscriptase inhibitors andintegrase inhibitors

Effect

Increased sedating effect.

Complex effect oncytochrome P450.

Increase rifabutin levels.

Increase plasma levels andside-effects ofphosphodiesterase-5inhibitors.

Decrease in atazanavirlevels.Increase in saquinavirlevels.

Decrease in atazanavirlevels.

Methadone levels affected;effects vary from patientto patient.

Large increase insimvastatin levels andincreased risk of myositis.

Strong inducer ofcytochrome P450,decreases levels ofprotease inhibitors, non-nucleoside reversetranscriptase inhibitorsand integrase inhibitors.

Action

Use alternative sedative orstart with smaller dosesand observe.

Consider dose adjustmentof non-nucleoside reversetranscriptase inhibitors.Use rifabutin with proteaseinhibitors.

Decrease rifabutin to 150 mg three times perweek.

Use smallest possible dose.

Use alternative gastric acidsuppressant for atazanavir.Use with caution - monitorfor saquinavir toxicity.

H2-receptor antagonistsshould be taken two hoursafter and ten hours beforeatazanavir.

Adjust methadone dose asrequired.

Use alternative statins suchas pravastatin (care withdarunavir), fluvastatin orlow-dose atorvastatin.

Do not use.

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There have been very few studies that have examined the interactions between drugs of misuseand protease inhibitors. However, following a fatality with ecstasy (MDMA) and proteaseinhibitors, all patients should be advised to discuss recreational drug use with their HIV specialistpharmacist.

There have been no studies into the interactions between antiretroviral and herbal medicines.Potential interactions are based on the theory of pharmacology and pharmacokinetics. You shouldadvise patients to discuss herbal medicines with their HIV specialist pharmacist.

For further information about potential interactions refer to the SPCs of specific drugs or thespecialist HIV drug interaction website: http://www.hiv-druginteractions.org

Despite many patients having concerns about the confidentiality of their diagnosis outside of thehospital setting, HIV-positive individuals are strongly encouraged to disclose their HIV diagnosisto their GP and other primary care providers. This is essential when patients are taking HAARTas the GP could unknowingly prescribe contraindicated medicines, or medicines which haveclinically significant interactions with the antiretrovirals, resulting in treatment failure or drugtoxicity.

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Practice point 5

● Think of one drug in your clinical area that is commonly prescribed.● Check the current edition of the BNF and the relevant SPC to see if there

are any drug-drug interactions with antiretrovirals.● Visit the website: http://www.hiv-druginteractions.org and click on

Interaction Charts. Follow the links to check any possible interactions.

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Therapeutic drug monitoring

A fixed dose of an antiretroviral agent may not be appropriate for all patients. Measuring druglevels to determine therapeutic dose may help to promote durable suppression and decreaseresistance. Therapeutic drug monitoring (TDM) has been shown to be valuable in optimising themanagement of certain patients. Dose-response and concentration-response relationships havebeen identified for protease inhibitors and NNRTIs.

TDM may help with the management of:● vulnerable populations, for example,

● children● pregnant women● patients at extremes of body mass index

● complex clinical situations, for example,● liver impairment● treatment failure● drug interactions● malabsorption● suspected non-adherence● unlicensed once-daily regimes (eg, nevirapine).

TDM of antiretroviral medicines is highly specialised and is not available from standard hospitalbiochemistry laboratories. Testing is only available from specialist laboratories.

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HIV drug resistance

Drug resistance may be intrinsic or acquired because of mutations following use of antiretroviraldrugs. Two factors drive mutations:

● a high rate of viral replication ● error-prone reverse transcriptase.

Resistance emerges if drug levels are insufficient to inhibit viral replication but high enough toexert a positive selective pressure on these mutations. Specific mutations are associated with drugresistance.

Databases providing details of drug-specific resistance profiles are available, such as the StanfordUniversity drug resistance database, available online at: http://hivdb.stanford.edu/

Resistance testing

Genotypic assays are available to identify key mutations associated with resistance to specificantiretrovirals. In genotypic tests, mutations identified in the virus being tested can be comparedto a database in order to predict the likely susceptibility of that virus to a drug. BHIVA guidelines20084 recommend that all patients starting or switching HAART should have resistance tests toguide effective treatment choices.

Treatment influences the pattern of resistance mutations. If the initial treatment regime fails, therange of drugs available for second-line therapy is restricted. Therefore, it is important to bear inmind three aims when planning first-line treatment:

● address medicines adherence● minimise drug reactions● avoid toxicity/interactions.

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Medicines adherence

Adherence to a medicines regime is essential for successful viral suppression.When HIVreplicates, the reverse transcription stage is very prone to errors (see Figure 2, page 18). Thisproduces many mutations of the virus. These individual mutations may be resistant to theantiretrovirals currently being used. Sub-therapeutic drug levels and drug monotherapy promotereplication of these drug-resistant mutations of HIV. As their numbers increase, resistance tocertain antiretroviral agents develops. Investing in strategies that improve medicines adherence ismore cost-effective than managing the consequences of poor adherence.

Table 7: Factors influencing medicines adherence

Measures that may improve medicines adherence include programmable watches, mobile phonealarms, text messages, telephone reminders, pill diaries and charts, medicine containers, and helpfrom families and friends.

Strategies for addressing medicines adherence are provided by NICE and their quick referenceguide provides an excellent overview; visit their website at: http://www.nice.org.uk and type‘medicines adherence’ into the search box.

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Patient

● Commitment● Religious/cultural/health beliefs● Poor diet● Benefits of taking the medicine in

relation to condition/disease● Drug and alcohol use● Psychological● Presence of symptoms/side-effects● Relationship with healthcare team● Language/understanding barriers● Learning difficulties

Provider

● Provision of medicines adherence support

● Patient education● Regime● Lifestyle assessment and compliance

with type of regime● Dosing frequency, pill burden and

food requirements

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Practice point 6

Consider your daily routine. Think about what it would be (or is) like to takemedicines every day at the same time in order to maintain your health.What strategies do you think would help you to remember to take your tablets?

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3. Opportunistic infections

As HIV infection progresses and if it is left untreated, the patient is at risk of opportunisticinfections. The graph below demonstrates what happens to the immune system during the courseof infection.

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Figure 5: A representation of changes in CD4 count over time after infection with HIV

CD4

Coun

t

HIV Infection

HIV Treatment

2 - 10 yearsafter HIV infection CD4count drops a bit then

recovers

CD4 count then drops quickly ina few people, but most people

take four to seven years to dropdown to a level where HAART

needs to be started

after treatment starts CD4count should begin to rise

again

Source: adapted with kind permission from i-Base: http://www.i-base.info

The following opportunistic infections become more common when the CD4 count falls belowthe levels specified:

● below 300 cells/microlitre: diarrhoea from microsporidia and cryptosporidia infection,candida

● below 200 cells/microlitre: Pneumocystis jiroveci pneumonia (PCP) and recurrent chest infections, toxoplasmosis

● below 100 cells/microlitre: atypical mycobacterial infections ● below 50 cells/microlitre: cytomegalovirus.

In this module, we will look at the following two opportunistic infections:

● PCP● Tuberculosis

And the following HIV-related malignancy:

● non-Hodgkin’s lymphoma

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3.1 Pneumocystis jiroveci pneumonia (PCP)

Pneumocystis jiroveci is a fungus that shares biological characteristics with protozoa and can causea form of pneumonia. This pathogen was originally described as a protozoan, Pneumocystis carinii,so Pneumocystis carinii pneumonia is an alternative name still in common use.

The risk of PCP increases when the CD4 count is less than 200 cells/microlitre. In HIV-infectedindividuals, the signs and symptoms of PCP can vary greatly.

Table 8: Prophylaxis and treatment of PCP in HIV-infected individuals

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Indication

Drug

Dose

Alternativeagents

Primary prophylaxis of PCPfor all patients with CD4 count lessthan 200 cells/microlitre

Co-trimoxazole

See local/regional guidelines.A common regime is 960 mg orallydaily or three times weekly

Nebulised pentamidine Dapsone Atovaquone

Treatment of PCP

Co-trimoxazole

120 mg/kg/day in divided dosesfor 21 days (orally or viaintravenous infusion)

Clindamycin and primaquineIntravenous pentamidineDapsone and trimethoprimAtovaquone

Co-trimoxazole is associated with rare but serious side-effects, including blood dyscrasias (notablybone marrow suppression) and agranulocytosis, renal impairment, and Stevens-Johnsonsyndrome. For this reason the Committee on Safety of Medicines (now the Commission onHuman Medicines) recommends limiting its use to PCP and other bacterial infections where thereis good bacteriological evidence of sensitivity to co-trimoxazole.

Secondary prophylaxis

Following successful treatment, the same regime should be used for secondary prophylaxis as wasused for primary prevention. Careful consideration should be taken before stopping prophylaxisin patients who have had PCP, perhaps deferring interruption until complete viral suppression hasbeen achieved, as well as a sustained CD4 count that is greater than 200 cells/microlitre for sixmonths.

We will be exploring PCP in further detail in case study 1.

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Practice point 7

Check the policy for PCP prophylaxis in your hospital. Jot down some key pointsfrom it below.If your trust does not have a policy, where else would you find the information youneed?

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3.2 Tuberculosis

On a worldwide scale tuberculosis (TB) is the most important HIV-associated opportunisticinfection. Active infection can occur in HIV-infected individuals at any CD4 count. Althoughtuberculosis most typically affects the lungs, in severely immunocompromised patients, like thosewith advanced HIV infection, tuberculosis may be disseminated and infect organs such as thebone marrow, liver and central nervous system.

Empirical therapy for HIV-infected patients is with four drugs: isoniazid, rifampicin, pyrazinamideand ethambutol (rifabutin may be used as an alternative to rifampicin). For the initial phase,treatment is with the four drugs for two months then, for the continuation phase (a further fourmonths), switch to rifampicin and isoniazid depending on sensitivity results.

A total of six months’ therapy is recommended for the treatment of tuberculosis, but where centralnervous system tissue is involved, nine to twelve months’ therapy may be indicated.

If HIV treatment is started in patients who are on antituberculosis therapy, then HAART regimesmight need to be modified.

There are significant drug-drug interactions between antituberculosis and antiretroviral medicinesdue to their effects on cytochrome P450. Therefore careful choice of HAART and anti-tuberculosis drugs is essential to reduce the impact of these drug interactions.

Rifampicin is a powerful inducer of cytochrome P450 (3A4) - a particular isoenzyme within thecytochrome P450 family that is involved in the metabolism of a number of medicines. It isimportant to note, however, that rifampicin may decrease plasma and tissue levels of antiretroviralagents. Using rifabutin as an alternative may overcome some difficulties with co-administration ofrifampicin with protease inhibitors and non-nucleoside reverse transcriptase inhibitors.

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Table 9: Drug interactions with rifamycins

Pharmacists must oversee TDM in HIV-infected patients who are co-infected with tuberculosis.TDM is particularly necessary when NNRTIs or protease inhibitors are co-administered withrifabutin and rifampicin.

Case study 2 will look at the treatment of tuberculosis in a HIV-infected patient in more detail.

Multidrug-resistant tuberculosis

Multidrug-resistant tuberculosis is on the increase worldwide. Treatment should be guided bydrug sensitivities. Further information is available in the British HIV Association guidelines forTB/HIV infection, 2009, available online at: http://www.bhiva.org

Drug

Nucleoside reversetranscriptase inhibitors

Non-nucleoside reversetranscriptase inhibitors:

efavirenz

nevirapine

Protease inhibitors

Rifampicin

No major interactions

Increase dose to 800 mg if thepatient weighs more than 50 kgand monitor levels

Not recommended

Not recommended

Rifabutin

No major interactions

Increase rifabutin dose to 450 mg daily

Not recommended

Decrease rifabutin dose to 150 mg three times a week

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3.3 HIV-related malignancies

HIV infection is associated with three main types of malignancy:

● Kaposi’s sarcoma ● high-grade B-cell non-Hodgkin’s lymphoma● invasive cervical cancer.

The clinical care of patients with HIV and these malignancies requires a multidisciplinaryapproach involving input from specialists in HIV and haematology/oncology, depending on themalignancy.

Pharmacists and pharmacy technicians working in the field of haematology and oncology areincreasingly likely to see more HIV patients in their specialty.

In this module we are going to look at non-Hodgkin’s lymphoma in more detail.

For information on other HIV-related malignancies refer to the BHIVA guidelines for HIV-associated malignancies 2008, available online at: http://www.bhiva.org

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Non-Hodgkin’s lymphoma (NHL)

● NHL is the second most common tumour in individuals with HIV infection.● Optimising the immune status of patients has been shown to decrease opportunistic

infections and is associated with superior response rates and survival. Therefore, HAART should be started as soon as possible in these patients.

● Patients should receive the same treatment for their lymphomas as lymphoma patients without HIV infection.

● However, patients should be monitored for cumulative side-effects of chemotherapy and antiretroviral drugs.

Choice of chemotherapy

Treatment of lymphoma should be the same, regardless of whether the patient has HIV infection,so current local cancer network chemotherapy guidelines should be followed. However, nocomparative studies have been undertaken yet in the era of HAART, so there is no optimal ‘goldstandard’ therapy.

Choice of HAART

BHIVA guidelines should be followed in order to gain the maximum viral suppression and thebest virological response and cumulative side-effects should be considered. For example,zidovudine should be avoided if possible, because of the increased risk of anaemia andmyelosuppression, and stavudine may increase the risk of developing peripheral neuropathies.

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For those starting HAART after developing a malignancy, the recommended regimes are either:

● tenofovir/emtricitabine and efavirenz, or● abacavir/lamivudine and efavirenz (though the current BHIVA guidelines now suggest

that abacavir/lamivudine should be reserved for patients not able to take tenofovir/emtricitabine).

Although an NNRTI-based regime is preferred, this may not be possible initially if HIV resistancetest results are not available.

Prophylaxis of opportunistic infections during chemotherapy

Patients with HIV infection and non-Hodgkin’s lymphoma should receive appropriate prophylaxisfor opportunistic infections:

● PCP prophylaxis should be given to patients with a CD4 count that is less than 200 cells/microlitre

● prophylaxis for a Mycobacterium avium complex infection should be given if the CD4 count is less than 50 cells/microlitre, ie, azithromycin 1.25 g orally once a week.

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4. Co-infections

Hepatitis B and C and HIV share the same routes of transmission, therefore co-infection iscommon. Co-infection requires the multidisciplinary assessment for possible ongoing drug andalcohol use, psychiatric illness, progressive liver disease, and the degree of HIVimmunosuppression.

4.1 Hepatitis B

In the UK hepatitis B (HBV) infection is present in five to eight percent of HIV infection, butrates vary regionally. Co-infection is more common in haemophiliacs, intravenous drug users andthose from areas with a high prevalence of HIV.

When deciding on treatment of HBV/HIV co-infection the following factors should be taken intoaccount:

● for optimal management of HIV/HBV co-infection, it is vital that adequate initial assessment of both HBV and HIV status is performed to inform the decision as to whether both viruses, HBV alone or neither require treatment

● the key determinants as to whether a patient needs treatment are the HBV DNA level and the CD4 count; however, the optimal time to start treatment for HBV is still unknown

● immune depletion (ie, a declining CD4 count) has a negative effect on HBV progression,so co-infected patients with CD4 counts between 350-500 cells/microlitre should be treated with drugs active against both viruses

● in patients with CD4 counts greater than 500 cells/microlitre HBV treatment should be started using the same criteria as in an HIV-negative person.

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● the strategy used to treat HIV/HBV co-infection depends on the need for HAART therapy,guided by the CD4 count. If HAART therapy is required, drugs should be included in theregimes which have activity against both viruses. If HAART therapy is not required, thestrategy is to use agents with exclusive HBV activity and no HIV activity, so that HIVresistance is not induced. Alternatively, commence HAART earlier than usual.

For further information refer to the BHIVA guidelines on HIV and chronic hepatitis: co-infection withHIV and hepatitis B virus infection, October 2004, available online at: http://www.bhiva.org

4.2 Hepatitis C

Hepatitis C (HCV) infection is a major factor in end stage liver disease in HIV infection. HCVprevalence is much higher in people who are HIV infected than in the rest of the population (inthe UK, 5-15 percent compared with 0.4 percent respectively).5 Higher rates are found inhaemophiliacs who are infected with HIV, intravenous drug users and people who are infectedwith HIV from southern and eastern Europe.

When deciding on treatment for HCV/HIV co-infection the following factors should be taken intoaccount:

● guidelines for the management of patients with HCV mono-infection are applicable forpatients with co-infection; these recommend combined pegylated interferon and ribavirin

● if possible, HCV should be treated before there is a need for HAART; a temporary CD4 dropwhile on interferon and ribavirin may occur and there may be interactions between ribavirinand some antiretroviral medicines.

For further information refer to the BHIVA guidelines for treatment and management of HIV andhepatitis C co-infection, 2004, available online at: http://www.bhiva.org

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5. Pharmacy considerations with HIV-infected patients

5.1 Outpatient pharmacy

In all pharmacy settings it is important to have a prescription screening process in place to avoidany potentially serious drug interactions. A medication history for any patient should always beconfirmed at each visit and a clinical check of medicines made for drug-drug interactions andcontraindications.

The screening process should follow local standards and ideally include the following questions:

● Is the patient allergic to any medicines?● Is the patient taking any other medicines? ● Has the patient had the medication previously? ● Has the dose or frequency changed?

When checking for drug-drug interactions in an HIV-infected patient the following resources willbe useful:

● The electronic medicines compendium● http://www.medicines.org.uk

● Liverpool University HIV drug interactions database ● http://www.hiv-druginteractions.org

● a current edition of the BNF.

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5.2 Inpatient pharmacy

HIV infection is now classified as a chronic disease and HIV-infected patients on HAART couldhave a normal life expectancy. Along with increasing diagnoses of HIV in the UK, the number ofpatients living with HIV in the UK is increasing. It follows that there is an increased number ofHIV-positive patients admitted to hospital for non HIV-related indications. So, pharmacists andpharmacy technicians have a major role to play in maintaining HIV treatments during hospitalstays in all specialties throughout hospital.

Types of HIV-positive patients who might be admitted to hospital include:

● ‘late presenters’; people who may have opportunistic disease but have not yet been diagnosed as being HIV-positive

● ‘treatment-experienced patients’ who have no further treatment options available to them● patients who have previously refused any treatment.

There are a number of things for the pharmacy team to consider:

● the importance of patient confidentiality in a ward setting; many HIV-positive patients may nothave disclosed their HIV diagnosis to family or friends. There is still a stigma attached to HIVinfection, so patients’ confidentiality regarding their diagnoses should be respected. Careshould be taken when discussing treatments and diagnoses in an open ward or in front ofrelatives or visitors.

● the importance of medicines adherence; check that the patient’s drug charts are annotated withthe patient’s regular times of drug administration. Also:● a twice-daily dose means every 12 hours● note the importance of any food restrictions● no doses should be missed; this is particularly important if surgery is required

involving a patient being ‘nil by mouth’. Patients should take their HAART at the prescribed times, but if this is not possible then advice should be sought from a member of the HIV team.

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● continued supply of antiretrovirals; it is important that the patient does not miss any doses simply because the pharmacy has not supplied them.

● drug interactions; it is important that all co-prescribed drugs are checked for drug interactions.If in doubt consult a specialist HIV pharmacist or the medicines information department forfurther advice.

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Key point

Inpatient care of HIV-positive patients can be complex. It may involve managing multipledrug interactions and treatment-limiting toxicities, so expert advice may be needed. Makesure you have contact details available for your local referral centre where medical andpharmacy specialists will be able to offer appropriate guidance.

6. Post-exposure prophylaxis

People may be exposed to HIV infection through their occupation, as well as through high-risksexual behaviour. Although HAART may be used as post-exposure prophylaxis (PEP) followingan occupational or sexual exposure to HIV, this use is unlicensed. A case-control studyconducted by the Centers for Disease Control and Prevention has shown that zidovudine PEPgiven to people who were exposed to HIV as a result of their occupation was associated with anapproximate 80 percent decrease in infection.6

For people exposed to HIV as a result of their occupation, the Department of Health and theBritish Association of Sexual Health and HIV recommend a short 28-day course of HAART. PEPis thought to be most effective when given within 72 hours of the exposure risk. Individualsrequiring PEP should be referred immediately to the nearest sexual health service or accident andemergency department, so that the treatment course can begin as soon as possible.Where there isan occupational health department within an organisation then they can also offer support andadvice to anyone exposed to HIV through their occupation.

Guidelines from the UK Chief Medical Officer’s Expert Advisory Group for AIDS7 recommend a28-day course of:

● tenofovir 245 mg/emtricitabine 200 mg one tablet daily plus● lopinavir 200 mg/ritonavir 50 mg two tablets twice daily.

Starter packs of PEP should be readily available in acute care settings so that PEP can start assoon as possible. These packs usually consist of three to five days of PEP, dependent upon localguidelines. It is good practice for the packs to also include antidiarrhoeals and antiemetics, toalleviate the initial gastrointestinal side-effects of the antiretroviral drugs.

For further information refer to HIV-post-exposure prophylaxis: Guidance from the UK Chief MedicalOfficers’ Expert Advisory Group on AIDS, September 2008, available online at:http://www.dh.gov.uk

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Practice point 8

Do you know where PEP starter packs are kept ● in your pharmacy department?● in your hospital (on which wards)?If not, then check and find out.

7. HIV and pregnancy

HIV can be transmitted from an infected mother to her baby, during pregnancy, at birth andthrough breastfeeding, and transmission rates can be as high as 20 percent. However, withinterventions, the transmission rate can be reduced to less than two percent. These interventionsinclude:

● early diagnosis of HIV infection though national antenatal screening programmes ● antiretroviral medicines given antenatally and intrapartum, and to the neonate for the first

four weeks of life● delivery by elective caesarean section or vaginal delivery under strict criteria● avoidance of breastfeeding.

In 1999, national antenatal screening for HIV infection was introduced. All pregnant womenshould undergo HIV testing at an early stage in pregnancy, or as soon as possible if they presentfor antenatal care at a later stage. The uptake of HIV testing in antenatal clinics reached 94percent in 2007.

HAART during pregnancy

The aim of HAART during pregnancy is to decrease the mother’s plasma HIV viral load to as lowa level as possible prior to delivery. However, there is a balance between the risk of HIVtransmission and the toxicities of therapy.

Women with asymptomatic HIV infection

Current BHIVA guidelines state that women who do not require HAART for their own healthmay be treated with HAART to prevent transmission to the baby. Treatment should be started inthe second trimester, with the aim of achieving an undetectable viral load prior to delivery.

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HAART should preferably contain zidovudine and lamivudine, unless contraindicated, and aritonavir-boosted protease inhibitor. An alternative approach for women who repeatedly have alow viral load (less than 10,000 copies/mL), is to use zidovudine monotherapy, under themanagement of a specialist physician, combined with a planned caesarean section at 38 weeks.

HAART can be stopped post-delivery, although the benefits of HAART and risk of retroviralrebound should be carefully discussed.

Women with symptomatic HIV

Pregnant women who are deemed to need HAART for their own health should start treatmentin line with BHIVA guidelines as soon as possible, although it is usually possible to delaytreatment until after the first trimester. Due care and consideration should be given to theexperience and safety of the available drugs during pregnancy.

Women who conceive while on treatment

If a mother conceives while on HAART, and she has an undetectable viral load and is toleratingHAART well, then the advantages and disadvantages of continuing this regime should bediscussed with her.

Prophylaxis for the newborn

Most babies born in the UK to HIV-positive mothers will be exposed to antiretroviral agents in utero and during labour. PEP with antiretrovirals is recommended. Post-delivery prophylaxisshould be started as soon as possible after birth, and certainly within four hours, and then thenewborn should be treated for four weeks, in line with other PEP guidelines.

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Choice of neonatal PEP

The choice of which medicines to use in the case of neonatal PEP should take into account thefollowing:

● if there is a low risk of transmission, then oral zidovudine monotherapy is used● for high-risk deliveries, then triple therapy should be considered● intravenous zidovudine is available if the neonate cannot use the oral route.

It is important to liaise with a specialist paediatric pharmacist for an appropriate dose.

Paediatric HIV infection

There are separate guidelines for the treatment of children with HIV who need to be treated bypaediatricians in specialist centres. HIV infection in children is outside the scope of thislearning@lunch module, but for further information refer to the PENTA (Paediatric EuropeanNetwork for Treatment of AIDS) guidelines on the use of antiretroviral therapy in paediatric HIVinfection, 2008, available online at: http://www.pentatrials.org

You may also find additional useful information on the Children’s HIV Association website:http://www.chiva.org.uk

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Summary

HIV infection is one of the most significant communicable diseases in the UK. As HIVreplicates, the body’s CD4 cell count and immune system declines over time anddefences against opportunistic infections and malignancies are impaired.

Deeper understanding of the life cycle of HIV has led to the development ofantiretroviral medicines that suppress replication of HIV. HAART targets HIV atdifferent points in its life cycle for maximum suppression of the virus. HAART is nowthe cornerstone of treatment for HIV infection and has resulted in dramaticallyimproved prognoses, decreased mortality and reduced incidence of opportunisticinfections in the UK - so much so that HIV infection is now regarded as a long-termcondition here. Monitoring and managing sometimes serious side-effects andinteractions, adherence to medicines and minimising resistance are still majorchallenges that the pharmacy team can provide crucial advice on.

Pharmacists and pharmacy technicians working in all specialties will encounterpeople living with HIV infection.You should be aware of therapeutic issues, knowwhen and where to find the advice of an expert and also ensure that pharmacycontributes to minimising the stigma associated with HIV infection.

Introductions to the case studies

Now that you have worked through this booklet you should feel that you have updated yourknowledge on HIV infection.You will have an opportunity to apply this knowledge and debate themedicines management issues when you attend the learning@lunch session and work through oneor more of the following case studies.

We have presented introductions to three different case studies below so that you can reflect onthe scenarios before attending the group session. The clinical topics and discussion points coveredby each of the case studies are outlined in the table below.You will only have enough time in yourlearning@lunch session to discuss one or two of the case studies and your facilitator will advise youabout which case(s) you will cover.

At the learning@lunch session you will be given further questions on these case(s) to discuss withyour colleagues.

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Case study

1: Mark

2: Farida

3: Kate

Clinical topic(s)

Pneumocystis jirovecipneumonia, confidentiality

Tuberculosis

Post-exposure prophylaxis

Pharmacy technician

✓

✓

✓

Pharmacist

✓

✓

✓

Intended for

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Case study 1: Mark

Mark is a 34-year-old man who is normally fit and well. He has been admitted to the medicalevaluation unit after presenting to the accident and emergency department.

Mark is in full-time employment and goes to the gym on a regular basis. He does not take anyregular medicines but has just completed a seven-day course of clarithromycin 500 mg, twicedaily. This was prescribed by his GP for a suspected upper respiratory infection.Whenquestioned, Mark says that he has no known drug allergies.

You look at Mark’s medical notes and see the following summary written by the unit’s houseofficer:

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He is presumptively diagnosed with Pneumocystis jiroveci pneumonia (PCP).

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Medical summary

Presenting complaint

History of presentingcomplaint

Previous medical history

On examination

Weight

Fever

PO2

Chest X-ray

Intolerable shortness of breath (particularly on exertion) with atemperature of 38°C and a non-productive cough

Increasing shortness of breath over the past three weeks withaccompanying night sweats, slight weight loss and a persistentand worsening dry cough

Appendicectomy, aged nine

Bilateral mild crackles Chest discomfort on breathingIncreased respiratory rate of 17 breaths per minute with anaccompanying tachycardia of 99 beats per minute

65 kg

38°C

10 kPa

Bilateral interstitial infiltrations, areas of opacity

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Make a list of the issues you would like to discuss about Mark’s case.

Case study 2: Farida

Farida is a 29-year-old lady who has recently arrived in the UK from India and is currentlystaying with relatives.

Over the past three months she has been suffering from night sweats and a slightly productivecough. She has also lost approximately one stone in weight.

Concerned for her deteriorating health, she has visited the GP and has been referred to yourhospital for investigation. Farida has just been reviewed on your medical admissions unit by asenior house officer.

Her notes reveal the following:

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learning@lunch

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Urea & electrolytes

Sodium

Potassium

Urea

Serum creatinine

Full blood count

Haemoglobin

White cell count

Platelets

C-reactive protein (CRP)

Additional clinical observations

Heart rate

Respiratory rate

Weight

Chest X-ray

135 mmol/L (135-145 mmol/Litre)

4 mmol/L (3.5-5 mmol/Litre)

7 mmol/L (2.5-6.7 mmol/Litre)

88 micromol/L (70-150 mmol/Litre)

10 g/dL (11.5-16g/dL in women)

4.0 x 109 cells/L (4-11 x 109/Litre)

400 x 109/L (150-400 x 109/Litre)

80 (less than 10 mg/Litre)

88 beats per minute

14 breaths per minute

70 kg

Cavitation in the upper lobe of the left lung

Farida is investigated based on a presumptive diagnosis of tuberculosis.

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Write down the main pharmaceutical care issues you would consider in Farida’s case.

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Case study 3: Kate

You are on a ward round when Kate, a house officer from another team, interrupts you to discussan incident that she has just been involved in.

While taking blood from one of the patients, she has accidentally given herself a needlestick injuryon her index finger. This patient is known to be HIV positive.

She has heard of PEP after a needlestick injury, but is not sure what to do.

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Outline below how you would approach Kate’s case.

Checklist for action

Now that you have worked through Booklet 1 of this learning@lunch programme, take a momentto run through this checklist - it should help you to complete the action element of your CPDcycle.

Don’t forget to bring Booklet 1 to the learning@lunch session!

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Have you:

Read through the whole booklet?

Completed the practice points?

Looked at the introductions to the case studies andmade notes ready for your learning@lunch groupsession?

Revisited the reflective questions?

Yes, I completed this on:

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References

1. Joint United Nations Programme on HIV/AIDS. 2008 report on the global AIDS epidemic.Geneva: UNAIDS, 2008. Available online at:http://www.unaids.org/en/Knowledgecentre/HIVData/GlobalReport/2008/2008_Global_report.asp (accessed 1 March 2009).

2. Health Protection Agency. HIV in the United Kingdom: 2008 report. London: HealthProtection Agency, 2008. Available online at:http://www.hpa.org.uk/web/HPAweb&HPAwebStandard/HPAweb_C/1227515299695 (accessed 13 July 2009).

3. Pantaleo G. Mechanisms of human immunodeficiency virus (HIV) escape from the immuneresponse. Professor Dr Max Cloetta Foundation, 2000. Available online at:http://www.cloetta-stiftung.ch (accessed 26 August 2009).

4. Gazzard BG. British HIV Association guidelines for the treatment of HIV-1 infected adultswith antiretroviral therapy, 2008. HIV Medicine, 2008;9:563-608

5. British HIV Association. British HIV Association (BHIVA) guidelines for the treatment andmanagement of HIV and Hepatitis C co-infection: updated October 2004. Available online at:http://www.bhiva.org (accessed 1 March 2009).

6. Cardo DM, Culver DH, Ciesielski CA, et al. A case-control study of HIV seroconversionin health care workers after percutaneous exposure. New England Journal of Medicine,1997;337:1485-90.

7. Department of Health. HIV-post-exposure prophylaxis: guidance from the UK Chief MedicalOfficers’ Expert Advisory Group on AIDS, September 2008. London: DH, 2008. Availableonline at: http://www.dh.gov.uk/

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Further reading

Bower M, Collins S, Cottrill C et al. British HIV Association guidelines for HIV-associatedmalignancies, 2008. HIV Medicine, 2008; 9: 336-388.

British HIV Association. Guidelines on HIV and chronic hepatitis: co-infection with HIV and hepatitisB virus infection, updated October 2004. Available online at: http://www.bhiva.org

DeRuiter A, Mercey D, Anderson J, Chakraborty R et al. British HIV Association and Children’sHIV Association guidelines for the management of HIV infection in pregnant women 2008. HIVMedicine, 2008; 9: 452-502.

National Institute of Health and Clinical Excellence. Clinical guidelines: CG33 Clinical diagnosisand management of tuberculosis, and measures for its prevention and control. London: NICE, 2006.Available online at: http://www.nice.org.uk/CG033

Weston R, Portsmouth S and Benzie A. An update on HAART: Part 1. Pharmaceutical Journal,2006; 276: 631-634.

Weston R, Portsmouth S and Benzie A. An update on HAART: Part 2. Pharmaceutical Journal,2006; 276: 693-696.

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Useful websites

Organisations/guidelinesThe British HIV Association http://www.bhiva.orgChildren’s HIV Association http://www.chiva.org.uk/HIV Pharmacy Association http://www.hivpa.org

StatisticsHealth Protection Agency http://www.hpa.org.ukJoint United Nations Programme on HIV/AIDS http://www.unaids.org

Information and literatureaidsmap: information on HIV and AIDS http://www.aidsmap.com/

i-base HIV treatment information for healthcare http://www.i-base.infoprofessionals and HIV-positive people

Drug interactionsUniversity of Liverpool HIV drug interaction http://www.hiv-druginteractions.org/website

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Notes

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