HIV E-book Flashcards
Initial risk groups:
o Men who have sex with men (MSM)
o Injecting drug users
o Recipients of blood products
What are HIV and AIDS?
The Human Immunodeficiency Virus (HIV) is a lentivirus (a member of the retroviridae family). As such it is an RNA virus which cannot insert itself into host DNA until it recodes itself into double-stranded DNA. To replicate, retroviruses must convert their genetic material into host genetic material through the process of reverse transcription which is accomplished by the viral enzyme reverse transcriptase.
Acquired Immune Deficiency Syndrome (AIDS) was first clinically described in late 1980 and early 1981. Initially it was observed as cases of Pneumocystis carinii - now jiroveci - (PCP) infections in homosexual men and injecting drug users.
There are two types of HIV infection
HIV-1 and HIV-2
- Both types can be transmitted by sexual contact, through blood and from mother to child. Both appear to cause clinically indistinguishable AIDS.
Which strain of HIV is responsible for the global HIV epidemic
HIV-1 Group M
HIV-2
The HIV-2 virus has five phylogenetically distinct forms which are largely concentrated in West Africa but now seem to be spreading to India. These subtypes appear to be less harmful and less transmissible in humans compared to HIV-1.
HIV-1
The HIV-1 virus is divided into four groups: M, N, O and P. These represent separate introductions from Simian Immunodeficiency Virus (SIV) into humans. Group M has nine genetic subtypes (called clades) with varying global distributions. Group M, subtype C is the most prevalent and accounts for > 55% of all HIV-1 infections.
The human body’s main defence against HIV is
skin
HIV particles are surrounded by
HIV particles are surrounded by a fatty membrane, through which protrude 72 protein spikes comprising gp41 and gp120. Within the viral core are two identical strands of RNA along with the enzymes necessary for the cell to replicate: reverse transcriptase, integrase and protease.
In order to replicate once in the body, HIV must
In order to replicate once in the body, HIV must enter a cell. The gp120 protein binds tightly to CD4 receptors on host cells. CD4 is found on the surface of T-helper cells, regulatory Tcells, monocytes, macrophages and dendritic cells. Then there is a conformational change in the gp120 which allows it to bind to a chemokine co-receptor (CCR5 on macrophages or CXCR4 on T helper cells). Drugs which act at this point in the infection process are known as entry inhibitors. Once the secondary binding occurs, the HIV gp41 interacts with the host cell fusing the HIV particle to the host cell. Once fused, the HIV RNA and the three enzymes can enter the host cell. Fusion inhibitors work at this point of the process.
Once into the cell, the
Once into the cell, the viral reverse transcriptase converts the viral RNA into viral DNA in the cytoplasm of the host cell. Nucleoside and non-nucleoside reverse transcriptase inhibitors target this conversion process. The viral DNA then moves into the host cell nucleus and becomes spliced into the host cell DNA forming a provirus using the viral integrase to facilitate the process. Integrase inhibitors target this integration of HIV DNA with host cell
DNA. Messenger RNA is then produced and the host cell’s mRNA template is utilized to produce viral proteins and enzymes. Once this translation has occurred, precursor proteins from the immature viral core are cut into smaller functional proteins by the viral protease and a viral particle is formed. This viral particle then buds off from the cell resulting in infectious virons being released into the blood stream. Protease inhibitors interfere with this final process in the HIV replication cycle
Antiretroviral drugs
- Fusion Inhibitors
- Nucleoside and nonnucleoside reverse transcriptase inhibitors (NNRTI’s & NRTI)
- Integrase inhibitors
- Protease inhibitors
HIV testing
Third generation tests
Fourth generation tests
Rapid HIV tests
Polymerase Chain Reaction (PCR) Tests.
Third generation tests
Third generation tests are an ELISA antibody test. It is inexpensive, accurate and very sensitive. If antibodies to HIV are detected then the patient is infected with HIV. The disadvantage with third generation tests is that it they only become accurate after 12 weeks, as it takes a person 6-12 weeks to raise antibodies against HIV. Third generation tests conducted before 12 weeks may result in a false negative response.
Fourth generation tests
Fourth generation tests are ELISA tests which detect antibodies and p24 antigens. As viral load increases dramatically during the first few weeks of infection, these tests will detect HIV in the great majority of individuals one month post exposure, and possibly as soon as 11
days post exposure. As a result the British association for Sexual Health and HIV (BASHH) recommends that anyone presenting for a HIV test within four weeks of exposure should be offered a fourth generation test with a follow up four weeks post exposure. This is because
a person is highly infectious within the first weeks following infection.
Self-testing kits for HIV are now available in the US, UK and France. They can be ordered online from www.test.hiv these rely on fourth generation technology, results are given to patients confidentially within a two-week timeframe due to having to post the tests to a
central laboratory.
Rapid HIV tests
Rapid HIV tests include the OraQuick HIV-1 and HIV-2 rapid test kit which works on the same principle as ELISA tests. They produce results within 20 minutes. The test uses either a blood sample or oral fluids, is easy to use, has no need for laboratory facilities and has no need for highly trained staff. All positive results from a rapid test must be followed up with a confirmatory standard ELISA test.
The Polymerase Chain Reaction (PCR)
The Polymerase Chain Reaction (PCR) test detects HIV genetic material rather than the viral antibodies. It can identify HIV in blood samples within 2-3 weeks of infection. Babies born to HIV positive mothers are usually tested with the PCR test because they retain maternal
HIV antibodies for several months after birth which would give a false positive on an ELISA test. PCR tests are not used for routine HIV detection in adults as the tests are expensive, more complicated to administer and more difficult to interpret than a standard ELISA test.
HIV disease progression
HIV attacks the immune system by destroying CD4 positive T cells (CD4 cells). These Thelper cells are involved in the co-ordination of the immune response and their destruction means that people infected with HIV are vulnerable to opportunistic infections (OIs) and other complications
There are two parameters used to monitor the progression of HIV virus:
the CD4 cell count and the viral load. The CD4 count is used as a marker for the health of an individual’s immune system.
In HIV infection a second marker, the plasma viral load (a measure of plasma HIV RNA), is also used. If the plasma viral load decreases, the CD4 count will rise.
In a healthy adult, the CD4 count is somewhere between
800 and 1500 cells/µl.
There are three clinical presentations of HIV
primary HIV infection, chronic HIV infection and AIDS.
Symptoms of primary HIV infection
Rash Fever Weight loss Persistent lymphadenopathy Diarrhoea for longer than four days Malaise Headaches
Non-specific symptoms of chronic HIV
Rapid weight loss Recurring fever Profuse night sweats Prolonged swelling of the lymph glands Immunosuppression related conditions
A diagnosis of AIDS is made when
A diagnosis of AIDS is made when a HIV infected person presents with one or more AIDS defining illnesses and a CD4 count below 200 cells/µl. AIDS defining illnesses include opportunistic infections and malignancies. These occur due to the destruction the immune system, and prevention of normal immune responses by the HIV virus.
AIDS defining illnesses
Cryptococcal meningitis Cytomegalovirus disease Mycobaterium avium complex (MAC) Pneumocystis pneumonia (PCP) Progressive multifocal leucoencephalopathy (PML) Toxoplasmosis encephalitis Tuberculosis Cervical cancer Kaposi’s sarcoma Non-Hodgkin’s lymphoma Primary cerebral lymphoma
A person presenting with an AIDS defining illness or other serious bacterial infection with a CD4 count ≤200cells/μL should
receive ART within two weeks of initiation of antibacterial chemotherapy.
Before commencing any HAART regimen a patient should be screened for the following
HIV resistance Hepatitis B and C co-infection Cardiovascular risk Diabetes Renal problems Psychiatric problems Alcohol use Recreational drug use
The BHIVA guidelines 2016 recommend three possible combinations of drugs to be used in first-line HAART regimens:
2 NRTIs + 1 boosted protease inhibitor
2 NRTIs + 1 NNRTI
2 NRTIs + an integrase inhibitor
Tenofovir-DF and Tenofovir-AF and emtricitabine
should not be given if patient CrCl <30ml/min
preferred first line NRTI backbones
Co-formulations containing a tenofovir salt and emtricitabine
Nucleoside Reverse Transcriptase Inhibitors (NRTIs) examples
Didanosine (ddi) Abacavir (ABC) Lamivudine (3TC) Emtrictabine (FTC) Tenofovir alafenamide (TAF) Tenofovir disproxil (TDF) Stavudine (d4T) Zidovudine (AZT)
Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs) examples
Rilpivirine (RPV)
Efavirenz (EFV)
Etravirine (ETV)
Nevirapine (NPV)
Protease Inhibitors
Lopinavir (LPV) Atazanavir (ATV) Darunavir (DRV) Fosamprenavir (FPV) Indinavir Ritonavir (r) Saquinavir (SQV) Tipranavir (TPV)
Integrase Inhibitors
Raltegravir (RAL)
Elvitegravir (ELV)
Dolutegravir
Fusion Inhibitors
Enfuvirtide
CCR5 antagonist
Maraviroc
Mechanism of action
NRTIs
NRTIs work by becoming incorporated into the viral DNA where they act as chain terminators in the HIV reverse transcriptase reaction. They are dideoxy-nucloside analogues which lack a second hydroxyl group which is essential for the addition of subsequent bases for DNA elongation. They inhibit HIV-1, HIV-2, human T-cell leukaemia/lymphoma virus-1 and other retroviruses.
Mechanism of action
NNRTIs
NNRTIs work by a different mechanism. They bind at a different site on reverse transcriptase and inhibit the movement of protein domains necessary for DNA synthesis and as such they are non-competitive inhibitors of reverse transcriptase.
There are two mechanisms of NRTI resistance:
- Increased drug discrimination. The active site amino acid changes leading to a decreased affinity of the enzyme for the drug.
- There is an increased rate of primer unblocking (“offloading”). A combination of amino acid changes leads to the removal of the chain terminator and replacement with a natural nucleoside. This is also known as pyrophosphorylysis (e.g. nucleoside excision mutations – NEMs).
Drug - Zidovudine Route of admin - Peak plasma conc - t1/2 - Elimination -
Drug - Zidovudine
Route of admin - Oral/IV
Peak plasma conc - 1h
t1/2 -1h
Elimination - Metabolized to inactive glucuronide in liver.
20% active form (triphosphate) excreted in urine
Drug - Didanosine Route of admin - Peak plasma conc - t1/2 - Elimination -
Drug - Didanosine
Route of admin - Oral
Peak plasma conc - 1h
t1/2 - 1.5h
Elimination - Renal clearance by glomerular filtration and
active tubular secretion. Approximately 20% of active form (triphosphate) excreted in urine
Drug - Emtricitabine Route of admin - Peak plasma conc - t1/2 - Elimination -
Drug - Emtricitabine Route of admin - Oral Peak plasma conc - 1-2h t1/2 - 10h Elimination - Excreted largely unchanged in urine (some in faeces)
Drug - Lamivudine Route of admin - Peak plasma conc - t1/2 - Elimination -
Drug - Lamivudine Route of admin - Oral Peak plasma conc - 1h t1/2 - 5-7h Elimination - Excreted mainly unchanged by active renal secretion
Drug - Stavudine Route of admin - Peak plasma conc - t1/2 - Elimination -
Drug - Stavudine Route of admin - Oral Peak plasma conc - 1h t1/2 - 1-1.5h Elimination - Renal clearance by glomerular filtration and active tubular secretion
Drug - Abacavir Route of admin - Peak plasma conc - t1/2 - Elimination -
Drug - Abacavir
Route of admin - Oral
Peak plasma conc - <1h
t1/2 - 1.5h
Elimination - Hepatic metabolism primarily by alcohol
dehydrogenase and by glucuronidation. Metabolites excreted in urine
Side effects of NRTIs
GI disturbances (nausea, vomiting, abdominal pain, flatulence, diarrhoea) Anorexia Pancreatitis Liver damage (hepatomegaly with hepatic steatosis) Lactic acidosis Dyspnoea Cough Headache Insomnia, dizziness, fatigue, Blood disorders (anaemia, neutropenia, thrombocytopenia) Myalgia, arthralgia Rash, urticaria Fever Fatal hypersensitivity (with abacavir)
Drug - Efavirenz Route of admin - Peak plasma conc - t1/2 - Elimination -
Drug - Efavirenz
Route of admin - Oral
Peak plasma conc - 3-5h
t1/2 - 52-76 hours (after single dose)
Elimination - About 14 to 34% of a dose is excreted in the
urine (less than 1% unchanged), and 16 to 61% in the faeces (mainly as unchanged drug)
Drug - Abacavir Route of admin - Peak plasma conc - t1/2 - Elimination -
Drug - Nevirapine Route of admin - Oral Peak plasma conc - 4h t1/2 - 45h (after single dose) Elimination - Excreted in urine as glucuronide conjugates of the hydroxylated metabolites
Drug - Rilpivirine Route of admin - Peak plasma conc - t1/2 - Elimination -
Drug - Rilpivirine Route of admin - Oral Peak plasma conc - 4-5h t1/2 - 45h (approx) Elimination - Primarily metabolized and eliminated in Liver. Approximately 25% in excreted unchanged in the faeces.
Side effects of NNRTIs
The most common side effect of the NNRTIs is that of a rash. This usually develops within the first two weeks of treatment (six weeks for nevirapine). The rash is more common in women with etravirine and severe hypersensitivity reactions may develop with this drug.
Potentially life-threatening hepatotoxicity (including fatal fulminant hepatitis) may occur within the first six weeks of treatment with nevirapine and so liver function must be
monitored closely these patients
Efavirenz has been associated with suicidal ideation, psychosis and severe depression and thus is now used less frequently.
Protease inhibitors
Mechanism of action
Protease inhibitors act later in the viral life cycle and so do not prevent the establishment of the proviral state. Instead they prevent the release of the mature infectious virus particle from the host cell. They competitively inhibit or reduce the activity of viral protease resulting in the production of uncleaved (inactive) viral proteins. This prevents the maturation of virions capable of infecting other cells. Protease inhibitors can be effective against HIV-1 and HIV-2.
Resistance to protease inhibitors
Resistance to all protease inhibitors has been identified. This is rarely due to a single point mutation within the virus, multiple mutations are generally required, and there is a stepwise increase in the level of resistance seen. There is extensive cross resistance between
the different protease inhibitors and resistance is widespread if protease inhibitors are used as single agents in the treatment of HIV. Therefore they are used in combination with other antiretroviral agents. Protease inhibitors are often “boosted” by being given with low doses of ritonavir (itself a protease inhibitor). The low dose of ritonavir has little intrinsic antiviral activity but it does increase the efficacy of the other protease inhibitors.
Drug - Atazanavir Route of admin - Peak plasma conc - t1/2 - Elimination -
Drug - Atazanavir Route of admin - Oral (with ritonavir) Peak plasma conc - 2 - 2.5h t1/2 - 7h Elimination - Faeces, mostly as metabolites, and to a smaller extent in the urine
Drug - Darunavir Route of admin - Peak plasma conc - t1/2 - Elimination -
Drug - Darunavir Route of admin - Oral (with ritonavir) Peak plasma conc - 2.5-4 hours t1/2 - 15h Elimination - 80% in faeces (40% unchanged), 14% in urine (8% unchanged)
Drug - Fosamprenavir (pro-drug of amprenavir) Route of admin - Peak plasma conc - t1/2 - Elimination -
Drug - Fosamprenavir (pro-drug of amprenavir)
Route of admin - Oral (with ritonavir)
Peak plasma conc - 1.5-4 hours (amprenavir)
t1/2 - 7-10 hours
Elimination - Mainly in faeces as metabolites
Drug - Indinavir Route of admin - Peak plasma conc - t1/2 - Elimination -
Drug - Indinavir Route of admin - Oral (with ritonavir) Peak plasma conc - 0.8h t1/2 - 1.8h Elimination - Mainly in faeces as metabolites
Drug - Ritonavir Route of admin - Peak plasma conc - t1/2 - Elimination -
Drug - Ritonavir Route of admin - Oral Peak plasma conc - 2.4h t1/2 - 3-5h Elimination - Mainly in faeces as metabolites
Drug - Saquinavir Route of admin - Peak plasma conc - t1/2 - Elimination -
Drug - Saquinavir Route of admin - Oral (with ritonavir) Peak plasma conc - t1/2 - 13h Elimination - Mainly in faeces
Drug - Tipranavir Route of admin - Peak plasma conc - t1/2 - Elimination -
Drug - Tipranavir Route of admin - Oral (with ritonavir) Peak plasma conc - 1-5h t1/2 - 5-6h Elimination - Metabolism minimal when given with ritonavir so majority excreted unchanged through faeces
Side effects of protease inhibitors
The list of side effects of protease inhibitors is very similar to those of NRTIs and NNRTIs. In addition, protease inhibitors are associated with hyperglycaemia and so
should be used with caution in diabetics.
protease inhibitors interactions
Protease inhibitors may be both inhibitors and inducers of cytochrome P450isoenzymes and their use in combination with ritonavir often changes the degree of inhibition/induction.
Therefore it is important to monitor their use with drugs that are affected by changes in CYP450 concentrations.
Fusion/entry inhibitors
There is only one licensed agent available – enfuvirtide. This interacts with the viral surface glycoprotein gp41 to prevent fusion of the viral and host cell membranes. Enfuvirtide is a amino acid peptide structurally very similar to a segment of gp41. It is administered by subcutaneous injection twice daily. It is only licensed to treat resistant HIV infection in combination with other antiretrovirals or for patients who are intolerant to other
antiretrovirals.
There is an impressive list of side effects associated with enfuvirtide. Patients should be told how to recognize the signs and symptoms of a hypersensitivity reaction to
enfuvirtide and they should stop treatment and seek medical attention should hypersensitivity occur.
Integrase inhibitors
Raltegravir, elvitegravir and dolutegravir are the licensed integrase inhibitors currently available in the UK. They inhibit integrase, which is the enzyme that stitches HIV DNA into the host cell’s DNA to hijack the cell’s machinery and force it to replicate the virus.
Integrase is an attractive target for therapy because there is no similar enzyme in human cells. In clinical trials of raltegravir, virus levels became undetectable in 60% of patients compared with 35% in the control group. Elvitegravir is licensed in combination with cobicistat a CYP3A inhibitor, which prolongs the half-life of metabolites such as atazanavir, darunavir and elvitegravir. As with all antiretroviral agents, the side effects of integrase inhibitors are impressive
CCR5 inhibitors
Again, there is only one licensed drug in this class – maraviroc. It is only used for CCR5- tropic HIV infections in combination with other antiretrovirals in patients who have been treated previously with antiretrovirals. It blocks the activity of the co-receptor CCR5 on macrophages and there is a need for a tropism assay to determine whether the infection is CCR5-trophic before treatment with maraviroc can be initiated.
not recommended if you have a history of depression
Efavirenz
not recommended in people with poor bone health (osteoporosis).
Tenofovir
- Older age and other factors affect bone density. Tenofovir also reduces bone density. Very thin bones increases the risk of fracture.
For people starting ART, the guidelines recommended using:
1) Tenofovir plus emtricitabine (FTC).
These two drugs come in a single pill (Truvada).
2) Plus one of the following six options: • dolutegravir • elvitegravir boosted with cobicistat • raltegravir • atazanavir boosted with ritonavir • darunavir boosted with ritonavir • rilpivirine
Abacavir plus lamivudine (3TC) are sometimes used instead of tenofovir and emtricitabine. This single pill is Kivexa.
Your choice of ART should be individualised based on:
• Your current viral load, kidney and liver health, and risk of heart disease.
• Results from a drug resistance test and a genetic test before using abacavir.
• Any history of depression, anxiety or other mental health problems.
• Personal choices including likely side effects, shift work, diet requirements.
not recommended in people with neurocognitive impairment
efavirenz
post-exposure prophylaxis following sexual exposure
1st line = truvade (emtricitabine/tenofovir disoproxil fumarate) and raltegavir for 28 days
What blood test is first line to test for HIV
4th gen (HIV antibody and p24 antigen)
pre-exposure prophylaxis
Tenfovir and emcitrabine
