Introduction to HIV
Authors:- Sharon Byrne & Lucy Hedley
Approved by: HIVPA Expert Panel
Date: June 2016
Review date: June 2018
Date: June 2016
Review date: June 2018
For the reader to be able to further develop practical and clinical skills and competencies in the HIV specialty.
At the end of this module you should:
On June 5, 1981, a short article appeared in a medical journal that described an unusual situation – five young men in Los Angeles were all suffering from pneumocystis pneumonia and other diseases found in people who have severely suppressed immune systems. All five were men who have sex with men. The article was the first published report1 in the world on the condition later named acquired immune deficiency syndrome, or AIDS, although initially it was termed GRID (Gay related immune deficiency). It’s lead author was Dr.Gottlieb and his later New England Journal paper 2 included the first description of the CD-4 T cell deficiency which is the immunologic hallmark of HIV infection.
HIV was first isolated in Paris in 1983 and belongs to the family of lentiviruses. It is a retrovirus which means it’s genetic information is encoded in RNA. It is composed of 2 single strands of RNA. The retrovirus genome needs to be reverse –transcribed into DNA by the viral reverse transcriptase enzyme before it can replicate. The enzymes needed for replication are contained within the capsid of the virus.
Diagram taken from the National Institute of Allergy and Infectious Disease
The diagram on the next slide describes step by step how the virus enters the host cell and through multiple stages uses it to replicate itself and the subsequent release of more viruses back out into the blood stream. HIV can infect numerous cells but its main target cells are lymphocytes that express the protein CD4, known as CD4 cells. Once infected the CD4 cell then dies by apoptosis, though the exact mechanism is unknown, there are theories that this is caused by the activation of DNA dependent protein kinase (a central integrator of DNA damage response) during viral integration.3
The virus replicates at a very rapid rate, which can be up to a billion new viruses a day but as it is a very error prone process millions do not survive and the viral load does not increase at the same rate.
The purpose of antiretroviral therapy (ART) is to reduce the VL to a level below the limit of detection, usually <50copies/ml. It cannot eradicate the virus from the body.
Just after infection there is a surge in viral replication and this is referred to as seroconversion. Some patients may experience a short flu-like illness that is mainly characterised by lymphadenopathy, fever, maculopapular rash and myalgia and can last a few weeks. A small minority of patients can experience a severe illness with potential CNS symptoms. However, many patients do not have any noticeable symptoms at the time of infection and will be unaware that they are carrying the virus.
Transmission risk is at its highest during this period of seroconversion as the concentration of HIV RNA is very high. At the onset of infection, the CD4 cell count can fall rapidly as initially the immune system is not ready for the viral assault, eventually it mounts a strong response and is able to bring the viral load down dramatically to less than 1% of the value at seroconversion. This then remains at a relatively steady level for several years and is referred to as a patient’s viral set point or CD4 nadir. The CD4 count will decline from a normal value (range 500-1200 cells/ mm3) at different rates for each patient. The destruction of CD4 cells impairs cell mediated immunity which increases the risk of opportunistic infections and some cancers There is a great variability between individuals with some losing CD4 cells rapidly and others retaining near normal values for many years.
This stage of clinical latency may last anything from a few months to several years where a person has no outward signs of infection. Some experience persistent swollen lymph nodes but otherwise feel well. The immune system has regained some control and the viral load has dropped from its initial peak in primary infection and is replicating at a slower rate.
In most cases the immune system will become weakened as the CD4 count declines to such an extent that serious ‘AIDS-defining’ opportunistic infections (OIs) or malignancies can occur. Signs and symptoms suggestive of a declining immune function include lymphadenopathy, oral candidiasis, herpes zoster infection, diarrhoea, fatigue, fever and blood dyscrasias. In the UK an AIDS diagnosis is confirmed if a person with HIV develops one or more of a specific number of opportunistic infections or cancers. These can be organisms, pathogens or certain cancers which would otherwise not cause problems in someone with a healthy immune system but are able to take advantage of a weakened immune system. Normally AIDS defining illnesses occur when the CD4 count has dropped below 200 cells/ mm3. It is worth noting that someone can be very unwell with HIV but not have an AIDS-defining diagnosis. Conversely, someone with an AIDS-defining diagnosis (particularly if they are established on ART and the opportunistic infections are managed) can continue to lead a full and healthy life.
On the following slides is a list of more than 20 OIs that are considered AIDS-defining conditions—the occurrence of one of the listed OIs will result in an AIDS diagnoses no matter what the CD4 count happens to be:
If the CD4 count is greater than 500 cells/mm3
In general, people with CD4 counts greater than 500 cells/mm3 are not at risk of opportunistic infections. The exception being tuberculosis which can occur in HIV positive patients with a CD4 cell count above 500 cells/mm3. For people with CD4 counts around 500, however, the daily fluctuations in CD4 cell levels can leave them vulnerable to minor infections, such as candidal vaginitis or yeast infections.
If the CD4 count is between 200 cells/mm3 and 500 cells/mm3
Some OIs can occur as the CD4 count drops towards 200cells/mm3 such as Candidiasis (Thrush) and Kaposi’s Sarcoma (KS).
Kaposi’s Sarcoma is caused by Human Herpes Virus-8. Before the introduction of antiretroviral therapy, as many as 1 in 5 patients with AIDS had KS. It can cause lesions on the body and in the mouth with distinctive brown or purple colouring. In addition, this virus can affect internal organs and disseminate to other parts of the body without any external signs.
If the CD4 Count is between 100 cells/mm3 and 200 cells/mm3
Pneumocystis Jirovecii (Carinii) Pneumonia (PCP)
PCP is classified as a fungal infection and is the most common presenting OI in patients with HIV. It is treatable with antibiotic therapy and close monitoring. Prophylaxis with co-trimoxazole is recommended for patients with low CD4 counts i:e less than 200 cells/mm3.
Histoplasmosis and Coccidioidomycosis
These are fungal infections that often present as severe, disseminated illnesses in patients with low CD4 counts.
Progressive Multifocal Leukoencephalopathy (PML) is a severe neurological condition that is caused by the JC (John Cunningham) virus and typically occurs in patients with CD4 counts below 200. While there is no definitive treatment for this disease, it has been shown to be responsive to antiretroviral therapy. In some cases, the disease resolves without any treatment.
If the CD4 count is between 50 cells/mm3 and 100 cells/mm3
Toxoplasmosis is caused by the parasite Toxoplasma gondii that can cause encephalitis and neurological disease. The parasite is carried by cats, birds, and other animals and is also found in soil contaminated by cat faeces and in meat, particularly pork. Toxoplasmosis is treatable with aggressive therapy, and prophylaxis is recommended for patients with low CD4 counts i:e: less than 200 cells/mm3. Co-trimoxazole used prophylactically will cover for toxoplasmosis as well as for PCP.
Cryptosporidiosis is a diarrhoeal disease caused by the protozoa Cryptosporidium, and it can become chronic for people with low CD4 counts. Symptoms include abdominal cramps and severe chronic diarrhoea. Infection with this parasite can occur through: swallowing water that has been contaminated with faecal material (in swimming pools, lakes, or public water supplies); eating uncooked food (like oysters) that are infected; or by person-to-person transmission, including soiled nappies or exposure to faeces during sexual contact.
If the CD4 count is between 50 cells/mm3 and 100 cells/mm3
Cryptococcal infection is caused by a fungus that typically enters the body through the lungs and can spread to the brain, causing cryptococcal meningitis. In some cases, it can also affect the skin, skeletal system, and urinary tract. This can be a very deadly infection if not caught and properly treated with antifungal medication. Although this infection is found primarily in the central nervous system, it can disseminate to other parts of the body, especially when a person has a CD4 count of less than 50 cells/mm3.
CMV is an extremely common virus that is present in all parts of the world. It is estimated that a majority of the population have had CMV by the time they are 40 years-old. CMV can be transmitted by saliva, blood, semen and other bodily fluids. It can cause mild illnesses when first contracted and many people may never have symptoms. However, it does not leave the body when someone is infected. In patients with low CD4 counts it can cause infections in the in the gastrointestinal system and in the eye which if left untreated can lead to blindness.
If the CD4 count is less than 50 Cells/mm3
Mycobacterium Avium Complex (MAC)
MAC is a mycobacterium that can be found in soil, water, and many places in the environment. The bacteria can infect the lungs or the intestines, or in some cases, can become “disseminated”. If this occurs, it can be a life threatening infection.
Some patients may develop cancers such as Kaposi’s sarcoma and non-Hodgkin’s lymphoma which are also classified as AIDS defining illnesses.
Opportunistic infections and their treatment are covered in more depth in the “British HIV Association and British Infection Association Guidelines for the Treatment of Opportunistic Infection in HIV-seropositive Individuals 2011”
which is available on www.bhiva.org and at HIVPA study days- the lectures can be accessed on eHIVe.
With the current antiretrovirals, most patients, if diagnosed before their CD4 count drops below 350mm3 go on to have a normal life expectancy.
HIV is not able to enter through most of the surface linings of the body but can be passed to another person through mucous ‘wet’ membranes or damaged tissue or directly into the blood stream. HIV is present in the blood, semen, pre-seminal fluid, vaginal and rectal fluids and breastmilk of infected people. The level of virus in some fluids, such as saliva, is too low to be infectious. There are a number of ways in which a person can become infected with HIV:
Having other sexually transmitted infections such as herpes, syphilis and gonorrhoea can increase the risk of transmission. Genital ulcers can cause breaks in the genital tract lining or skin which can be an entry point for HIV and the associated local inflammation increases the number of cells in the secretions that can be targets for the virus.
Below is a table from the BASHH (British Association of Sexual Health & HIV) guidelines detailing the risk of developing HIV following exposure from a known HIV positive person (4)
HIV antibody production begins around two weeks after transmission. HIV specific antibodies can be detected after four to six weeks in the majority of cases, and all available HIV tests are based on antigen-antibody binding. The p24 antigen, a core protein in the HIV virus, is detectable before the first occurrence of HIV-specific antibodies and its presence is representative of a recent seroconversion. The newer fourth generation tests are able to shorten the diagnostic gap by detection of the p24 antigen in addition to HIV specific antibodies and have the added advantage that they require a smaller (50 µl) venous blood sample than the older third generation tests. Although the third generation tests are less sensitive than the fourth generation tests, some are available which utilise saliva samples, offering a convenient alternative to blood sampling. When interpreting HIV diagnostic tests, consideration should be given to the fact that HIV testing immediately after a possible transmission will not detect HIV antibodies. HIV infection cannot be fully excluded until at least three months after possible transmission and a negative test result is only equivocal if there has been no further transmission risk since the original exposure.
UNAIDS factsheets 2015. Accessed June 2016 (5)
Despite the success of ART, the number of people living with HIV (PLWH) in the UK continues to rise. Public Health England estimate that by end of 2014 there were 103,700 people living with HIV in the UK with 85,489 of these accessing care and 41% of those being cared for in London. The overall HIV prevalence in the UK in 2014 was 1.9 per 1,000 people aged 15 and over. In total, almost half (48%) of all people accessing HIV care acquired their infection through heterosexual sex (Figure 1). Among heterosexuals, 60% of people were of black African ethnicity, 24% white, 4% black Caribbean, 3% other black ethnicity, 2% Indian/Pakistani/Bangladeshi, and 2% of other Asian ethnicity.
Men who have sex with men (MSM) made up 45% of people accessing HIV care in 2014 and 67% of all men. The majority of MSM were white 86%, with the next most common single ethnic group being black Caribbean 2%.
A minority of people accessing HIV care in 2014 (2%) had acquired their infection through sharing injecting drug equipment (PWID) or through mother to child transmission (2%). Worryingly 17% (18,100) of people estimated to be living with HIV were unaware of their status and therefore remain at high risk of passing on their infection to others.
There were 6,151 new diagnoses (4,611 men and 1,540 women) in 2014, a marginal increase on 2013, but consistent with other recent years. There has been a trend of declining new infections from a peak of 7,893 in 2005, with a plateau since 2010 stabilising around 6,000 per year. Almost half of all new HIV diagnoses were made in London (2,671) (7)
Figure 1: Number of adults seen for HIV care over time by key prevention groups; 2005-2014 (7)
Currently the number of infections probably acquired within the UK (almost exclusively through sexual transmission) exceeds those acquired abroad. Since the first reports of HIV in the early 1980s, MSMs have remained the group most at risk of acquiring HIV in the UK. In 2010 for the first time since 1998, the number of new HIV diagnoses in MSMs surpassed new diagnoses in heterosexuals and this trend has continued and in 2014 there were 3,360 new HIV diagnoses reported among MSM; this represents the highest number ever reported in the UK. The high number of new infections relative to the estimated size of the undiagnosed population indicates that most of the undiagnosed HIV infections in MSM were acquired very recently
Almost half (48%) of all people seen for HIV care in 2014 were aged 45 and over, up from 25% over the past decade, whilst those aged 55 or over and 65 or over now account for 15%, and 4% respectively (Figure 2). Among MSM the proportion over 55 accessing care has increased from 9% in 2005 to 17% in 2014, with similar trends amongst heterosexuals, 6% to 15% respectively7. This reflects the longer life expectancy conferred by effective antiretroviral therapy (ART), ongoing HIV transmission and steady numbers of new diagnoses.
The aging cohort of people living with HIV emphasises the importance of integrated care pathways to manage co-morbidities and other complications such as polypharmacy and the consequential potential drug interactions.
Figure 2: People seen for HIV care by age group over time; 2005-2014 (7)
On a positive note over the past decade there has been a slow but significant decline in the proportion of people diagnosed late (with a CD4 count <350 cells/mm3 within 3 months of their diagnosis) from 57% in 2004 to 40% in 2014. In tandem the median CD4 count at diagnosis has increased from 308 cells to 414 cells over the same time period. Nevertheless, the proportion of late diagnoses in the UK remains high and needs to be further reduced through increased HIV awareness and testing. People living with HIV can expect a near-normal life span if they are diagnosed promptly with their CD4 count> 350 cells/mm3, but conversely, people diagnosed late have a ten-fold increased risk of death in the year following diagnosis. In 2014, 346 people were diagnosed with AIDS for the first time and 613 people with HIV infection were reported to have died (Figure 3), most of whom were diagnosed late. (7)
Figure 3: New HIV diagnoses, AIDS and deaths over time; 1999-2014(7)
HIV specialist treatment and care in the UK remains excellent. Of all people attending for care in 2014, 91% were on ART, of whom 95% were virally suppressed and very unlikely to be infectious to others. 7This puts the UK ahead of time for two of the three ambitious UNAIDS 90/90/90 goals.
We now know a lot more about the natural progression of the virus and how to use different combinations of antiretroviral drugs to control viral replication and reduce the incidence of HIV related mortality and morbidity. Zidovudine (AZT) was the first antiretroviral to be approved for use in 1987. It was used initially as monotherapy, however, the virus quickly developed resistance to it and it was poorly tolerated due to the high doses used causing haematological toxicity. As more antiretroviral drugs were developed, it became apparent that the combined use of at least three different drugs known then as “Highly Active Antiretroviral Therapy or HAART” produced a better virological response and lower rates of resistance.
Following the introduction of HAART, now commonly called ART, in 1996 the numbers of AIDS diagnosis and deaths have dropped significantly and now remain at a steady but low level. Now that HIV infected patients are living longer, they are developing significant co-morbidities due to ageing, chronic HIV infection and the complications caused by the long term use of antiretroviral drugs. Hence the challenges in treating HIV patients have shifted from an acute fatal illness to a long term chronic one with polypharmacy as a key issue.
The decision about when to start therapy has recently changed due to overwhelming data from the “Start” study that demonstrated significant benefits in terms of long term morbidity and mortality in patients starting ART before their CD4 count drops below 500 cells/mm3. These data have been reflected in the 2015 UK BHIVA (8) and WHO (9) treatment guidelines, both of which recommend starting ART as soon as possible after diagnosis. The BHIVA guidelines also state that individuals presenting with an AIDS-defining infection, or with a serious bacterial infection and a CD4 cell count <200cells/mm3 start ART within 2 weeks of initiation of specific OI treatment.
Up until 2015 the decision to start treatment was based upon the CD4 cell count (circa 350 cells/ mm3), the CD4 percentage plus other factors such as co-infection with hepatitis B and C.
See the BHIVA guidelines for the treatment of HIV-1-positive adults with antiretroviral therapy for more specific details.
Currently there are 5 licensed classes of antiretrovirals (ARVs) and they are categorised on the basis of where they act in the HIV replication cycle. Normally drugs from two (or sometimes three) classes are combined to improve efficacy so that HIV is targeted via several different mechanisms.
The classes are:
Understanding the HIV life cycle helps us to understand how and where antiretrovirals and other drugs work. The diagram below shows where each class of antiretrovirals act.
Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
The reverse transcriptase enzyme reverse-transcribes the RNA into proviral DNA. NRTIs are analogues of naturally occurring nucleosides that are needed to synthesise the proviral DNA. Once inside the CD4 cells the NRTIs are converted into their active form- the triphosphate form by a process called phosphorylation. They then compete with natural nucleosides for incorporation into the growing viral DNA chain. Once incorporated the next nucleoside cannot form a bond resulting in chain termination. If HIV cannot convert RNA into DNA, it cannot enter the cell nucleus nor continue replication.
NRTIs are often referred to as the ‘backbone’ of a combination and nearly all patients starting therapy will have at least 2 drugs from this class in their regime.
Currently available NRTIs include:
Nucleotide Reverse transcriptase inhibitors (NtRTIs)
This class of drug works in exactly the same way as NRTIs, with the exception that an extra phosphate is attached to the drug molecule. This means that the drug is present in a more active form, as it does not have to be phosphorylated in the same way as NRTIs do. It also may be active in more types of cells within the body. At present the only antiretroviral drug available in this class is Tenofovir. The recent launch of TAF, the prodrug of tenofovir, which is preferentially taken up into the lymphoid tissue resulting in much lower blood levels of tenofovir, should result in less side effects.
Tenofovir which is available as disporoxil (Viread®) and alafenamide (TAF, the prodrug)
Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
NNRTIs work at the same site as NRTIs but are structurally different. They block reverse transcriptase by binding directly to the enzyme so are not incorporated into the viral DNA like the NRTIs. Currently available NNRTIs are:
Integrase Inhibitors (INIs)
These drugs block the action of the integrase enzyme. The HIV virus uses this enzyme to enter the cell’s nucleus. Once inside the nucleus, viral DNA is integrated into the host chromosomal DNA producing new chains of HIV proteins (mRNA). Currently available Integrase inhibitors are:
Protease Inhibitors (PIs)
Protease is the third HIV enzyme; its role is to break up the long chains of HIV proteins. Protease inhibitors prevent protease from cutting the protein chains into the shorter pieces that HIV needs to make new virus particles. Most PIs need to be boosted with a low dose of ritonavir or cobicistat that gives a more even pharmacokinetic profile (AUC) which ensures sufficient levels of drug in the body and minimises side effects. Currently available PIs are:
Cobicistat is a pharmacokinetic enhancer that does not have any antiviral effect of its own.
Entry or Fusion inhibitors work by attaching themselves to proteins on the surface of CD4 cells (entry inhibitor) or on the surface of the virus (fusion inhibitor) thereby blocking HIV from entering the cell.
The fusion inhibitor Enfuvirtide (Fuzeon®), also known as T20 is the only available drug that works by binding itself to the virus surface. T20 is manufactured as an injection only at present and is usually only used for people who have extensive drug resistance because of the inconvenience of twice daily injections.
The entry inhibitor Maraviroc (Celsentri®) is commonly called a CCR5 inhibitor and works by binding itself to the CCR5 protein on the surface of CD4 cells. These CCR5 receptors are primary entry points for HIV, particularly in early stages of infection. Not all HIV binds to a host cell via the CCR5 receptor (some use CXCR4 receptors) so it is essential to carry out a genetic test called a trofile assay (also known as a tropism test) to determine if a CCR5 inhibitor would be appropriate to use.
Click to download pdf of table
Reducing pill burden can be an important factor in improving adherence to a medication regimen. There are several tablets available that contain a combination of anti-retroviral drugs, the table below shows the individual drugs that are contained in each product and the class each drug belongs to plus the dose
Click to download pdf of table
There are several options for first line therapy and the BHIVA treatment guidelines (8) recommend that therapy-naïve patients start an ART regimen that contains:
(1) Two nucleos(t)ide reverse transcriptase inhibitors (NRTIs) with tenofovir and emtricitabine as the preferred option and abacavir and lamivudine as an acceptable alternative though it should be used with caution in patients with VL> 100,000 (though this is not applicable when it is used with dolutegravir)
(2) Plus one of the following:
As a novel ARV strategy where there is need to avoid abacavir or and tenofovir, BHIVA guidelines suggests the use of a dual based ART regimen of darunavir/r with raltegravir in treatment naïve patients with CD4 count > 200 cells/mm3 and viral load <100,000.
The exact regimen choice is patient specific and multi-factorial, including specific haematological and biochemical results such as VL, CD4 cell count, renal and hepatic function and genetic markers such as HLA status. See the table below for specific limitations with certain ARVs. The presence of hepatitis, tuberculosis, neurocognitive impairment, and cardiovascular risk or other co-morbidities plus drug-drug interactions (DDIs) with current or future medication must also be considered. Patient preference for particular medications or formulations and specific toxicity concerns will also be taken into account when choosing a regimen
Some patients may have transmitted or primary resistance, meaning that the virus has genetic mutations associated with ARV resistance despite the patient never being exposed to any treatment. The prevalence of primary drug-resistant in the UK is around 11% (7). BHIVA guidelines recommend that resistance testing is undertaken for all newly diagnosed patients as the results may affect drug choice. These patients may not be able to use one of the first line options and may require a tailor made regimen. See the table below from the BHIVA guidelines8 for preferred and alternative options in naïve patients.
BHIVA recommends that patients are assessed at baseline, within two to four weeks of starting treatment, and then, three to six monthly thereafter (unless management is problematic) (8)
The following haematological and biochemical tests should be undertaken to assess treatment response and monitor for toxicity:
Effective ART for treatment-naive patients should achieve viral suppression, demonstrated by an undetectable viral load within 12 to 24 weeks of commencing therapy. If viral decline is slow, then adherence should be checked along with other possible reasons for poor response such as drug interactions or resistance. Patients can be described as being stable on therapy when they have maintained viral suppression (<50 copies/ml) for over 6 months. Thereafter patients are usually seen by their doctors every 4-6 months and in certain clinics stable patients are able to have telephone consultations after they have had their blood results reviewed.
There is considerable variability in the severity of side effects experienced by patients receiving ARVs, ranging from the unnoticeable to the unbearable. Patients may experience side effects early in their therapy or later as a result of long-term toxicity. Common initial side effects of all antiretrovirals include rash, nausea, vomiting, headache and diarrhoea. Abnormal liver function tests, hepatotoxicity and rarely, Stevens-Johnson syndrome can also occur in the early stages of therapy. Additionally, efavirenz and dolutegravir can cause central nervous system side effects, such as dizziness, vivid dreams and morning drowsiness. Protease inhibitors are known to cause gastrointestinal disturbances, which can often be managed using appropriate medicines such as anti-emetics and loperamide. Side effects often coincide with peak drug levels in the blood and can be more intense during the first few days of treatment until a steady state is achieved. Changing the timing of doses or taking them with or without food can often help minimise effects. Long-term side effects include reduced renal function and bone mineral density, dyslipidaemia, diabetes and changes to glucose control. Toxicity issues such as peripheral neuropathy, lipodystrophy and changes to body shape are associated with the older antiretrovirals and are now rarely seen in practice. These older side effects are often the ones patients will have concerns about when they start treatment so it is important to reassure them that the newer ARVs do not cause these body shape changes.
There are ways to manage some of these longer-term toxicities. For example, metabolic syndrome (dyslipidaemia and diabetes) can be managed pharmacologically using lipid-lowering medicines and anti-diabetic treatment, and through lifestyle interventions such as smoking cessation, diet modifications and encouraging exercise.
Treatment of patients with HIV is complicated by drug interactions. As people who are infected with HIV are now living longer and there are a high proportion of patients over 50 years of age, there is a greater likelihood of them developing co–morbidities that require medication which may have interactions with the ARVs. NNRTIs and protease inhibitors have the greatest potential to interact, both with each other and with other drugs. Often dosage adjustments or sometimes regimen changes are necessary. Some of the most common interactions occur between drugs metabolised by CYP450 in particular the CYP450 3A4 enzyme. NNRTIs and PIs are both substrates for CYP3A4 and they can also act as enzyme inducers, inhibitors or both and can therefore affect the clearance of other drugs metabolised via the same pathway. Other enzymes and transport proteins such as p-glycoproteins and UGT are also involved in ARV metabolism and are also affected by ARVs. Drug interactions with ARVs can have serious consequences as low levels of ARVs can lead to resistance and high levels can result in toxicities.
As there are many possible interactions between ARVs and non ARVs, in addition to the fact that patients receive medicines from multiple sources, it is vitally important to do a thorough drug history to establish if they are taking anything that may interact with their ARVs. This includes all medicines prescribed by their GP, bought OTC medicines, inhalers, nasal sprays, creams, injections (including single dose), herbal remedies, recreational drugs and supplements. It is prudent to prompt the patient with these categories as many do not consider inhalers as a medicine and may omit it from their list.
Also due to the increased co-morbidities, there may be many different doctors and specialities involved in the patient’s care so it is important to educate the patient to inform the clinic (ideally the pharmacist) each time they are given a new medication including injections such as midazolam for procedures etc. It is unlikely that the other specialities will be aware of the drug interactions so the patient needs to be the link between them and the clinic.
Some interactions are well-documented and dosing recommendations are available. Other interactions are less easy to predict. In these cases, it is necessary to go back to first principles and use pharmacokinetic and pharmacodynamic information to understand possible mechanisms of interactions. Always consult a specialist HIV pharmacist if there are any doubts or queries regarding interactions.
These are some general points to consider:
Continued on next slide
Sources of interaction data can be found in the SPCs of the relevant drugs and on the following websites.
Commonly known as the Liverpool website: www.hiv-druginteractions.org
The Toronto HIV drug interaction websites: www.hivclinic.ca/main/drugs_interact.html
Click here for examples of recommendations from the websites.
Boosted Atazanavir & proton pump inhibitors
Coadministration of omeprazole (40 mg once daily) with atazanavir and ritonavir (300/100 mg once daily) resulted in a substantial reduction in atazanavir exposure (approximately 75% decrease in AUC, Cmax, and Cmin). Coadministration of omeprazole (20 mg once daily) with an increased dose of atazanavir and ritonavir (400/100 mg once daily) in healthy volunteers resulted in a decrease of approximately 30% in the AUC, Cmax and Cmin of atazanavir relative to atazanavir and ritonavir (300/100 mg once daily) without omeprazole.
In practice tend to avoid PPI co-administration with atazanavir.
Ritonavir-containing regimens and statins
Atorvastatin – Use with caution. The risk of myopathy including rhabdomyolysis may be increased when HIV protease inhibitors, including ritonavir, are used in combination with atorvastatin. Titrate atorvastatin dose and use the lowest possible dose with careful monitoring.
HMG-CoA reductase inhibitors which are highly dependent on CYP3A metabolism, such as lovastatin and simvastatin, are expected to have markedly increased plasma concentrations when co-administered with ritonavir dosed as an antiretroviral agent or as a pharmacokinetic enhancer. Since increased concentrations of lovastatin and simvastatin may predispose patients to myopathies, including rhabdomyolysis, the combination of these medicinal products with ritonavir is contraindicated.
The metabolism of fluvastatin and pravastatin is not dependent on CYP3A, and interactions are not expected with ritonavir. If treatment with a statin is indicated, pravastatin or fluvastatin are recommended
Not all interactions are bad: a useful interaction that is widely exploited is when ritonavir and cobicistat are dosed with some protease inhibitors. Ritonavir and cobicistat are potent inhibitors of CYP3A4 which metabolises most of the PIs; hence the beneficial interaction enables a lower dose to be used and produces a smoother pharmacokinetic profile with more consistent drug levels and fewer side effects. PI combinations involving this interaction are commonly known as ‘boosted’ PIs.
If necessary therapeutic drug monitoring (TDM) can be used to ensure adequate levels of an ARV is maintained if an interaction is suspected. TDM is commercially available for NNRTIs, PIs and INIs but not for NRTIs as their active drug is within the cell so it is more difficult to measure and this is usually only undertaken in the setting of a clinical trial.
See also HIVPA study session on drug-drug interactions which can be accessed via eHIVe.
Adherence means taking medication in accordance with the prescribed instructions. This involves the correct amount of drug at the correct time and in the correct way, taking into account food restrictions and requirements. To maintain viral suppression ARVs must be taken at the same time every day and according to the dietary restrictions. This means every 24 hours for a once daily regimen and every 12 hours for a twice daily regimen. Patients need to have an adherence rate of 95% to reduce the chance of resistance i.e. if patients are taking a once daily treatment, 95% adherence means missing no more than one dose a month. If patients are taking twice a day, 95% adherence means missing no more than two doses a month. When ARVs are not taken at the same time there will be intervals when there will be subtherapeutic drug levels in the body which can lead to drug resistance.
HIV treatment is lifelong and adhering to therapy is essential for sustaining viral suppression. Advances in drug development have led to newer medicines that are better tolerated and to regimens that are more convenient for patients. However, patients can struggle to adhere to their regimen for many reasons. These include:
Adherence can be improved by good counselling and providing support for patients around taking their medication.
For more information, consult counselling document and the BHIVA guidelines on adherence. The study day talks on adherence and counselling can be accessed on eHIVe
Also available for further reading: NICE guidelines on Medicines Adherence (CG76, Jan 2009)
The risk of drug resistance is highest when the levels of a drug in the body are low. This usually occurs when patients miss doses, take doses erratically or stop treatment.
The latter is especially important for combinations containing medicines with differing half-lives. Levels of ARVs with longer half-lives will remain in the body after those with shorter half-lives have cleared, effectively resulting in a period of monotherapy, which can lead to the development of resistance. If there is insufficient drug in the body, the virus can mutate to escape drug attack and develop resistance to the small amount of drug that is present. Thereafter the drug resistant virus replicates and becomes stronger despite the presence of full therapeutic drug levels.
Patients can also be infected with a strain of HIV that is already resistant to some or all HIV drugs. As already stated about 11% of new infections in the UK have resistance to at least one medication. For further information on resistance please see the study day on eHIVe
Often dietary restrictions can make taking some ARVs complicated. The table below indicates how some ARVs should be taken with respect to food:
Some patients may have difficulty swallowing some of the ARVs so below is a table of alternative formulations and how some may be crushed or dissolved.
It is an important role of the pharmacy team to ensure a patient is supported in taking their ARVs and other medication to enhance adherence and ensure a successful treatment outcome.
Click here to download pdf of table
Click here for pdf of Counselling Guidance
1: Morbidity and Mortality Weekly Report
2: “Pneumocystis carinii pneumonia and mucosal candidiasis in previously healthy homosexual men: evidence of a new acquired cellular immunodeficiency”. N. Engl. J. Med. 305 (24): 1425–31
3: “HIV-1 causes CD4 cell death through DNS dependent protein kinase during viral integration” Nature. 498 376-379 (20 June 2013)
4: BASHH guidelines for post exposure prophylaxis, PEP, following sexual exposure 2010
5: UNAIDS Fact sheet 2015
6: AIDS by the numbers 2015: UNAIDS
7: Public health England: HIV in the UK – Situation Report 2015, Incidence, prevalence and prevention and HIV New Diagnoses, Treatment and Care in the UK 2015 report
8: BHIVA guidelines for the treatment of HIV-1 positive adults with antiretroviral therapy 2015
9: WHO guidelines on when to start ART and on PrEP for HIV 2015
The HIV Pharmacy Association would like to acknowledge and thank the following people for their work and support in producing this learning material:
The HIV Pharmacy Association wish to acknowledge and thank individual members of their Expert Panel who reviewed and approved the learning material and the process.