HIV Human Immunodeficiency Virus
What is HIV? What is the difference between HIV & AIDS? What are Opportunistic Infections? Myths and Misperceptions about HIV HIV Transmission Understanding the Immune System Understanding Lab Tests Diagnostic Tests Understanding CD4 and CD8 Cells Immune Reconstitution Considering HIV Treatment Starting Treatment Adherence Drug Interactions Side Effects Resistance Pharmacokinetics (PK) AIDS Vaccines RIGHTS Thank You Table of contents
What is HIV? • HIV stands for Human Immunodeficiency Virus. HIV is the virus that causes AIDS (Acquired Immune Deficiency Syndrome). AIDS is the most advanced stage of HIV infection. • Many Viruses can be controlled by the immune system, However HIV targets and infects the same cells that would otherwise protect us from illness. These are a type of white blood cell called CD4 cells. • HIV takes over CD4 Cells and turns them into virus factories that can produce thousands of viral copies. • As the virus grows, it damages and kills CD4 cells, thus weakening the immune system.
What is HIV? • Please use the following Youtube link for a video on HIV. It is a good insight to how the virus actually works in the body. Some terms may be difficult, however with the information gathered throughout this presentation, perhaps come back and have another look at the end. Some of the terms used will then seem more familiar. • Targeting HIV Replication
What is the difference between HIV and AIDS? • You do not have AIDS upon infection of HIV • You can be HIV positive for years with no signs of disease, or only mild to moderate symptoms. • Without treatment, HIV will eventually wear down the immune system in most people to the point where they develop more serious Opportunistic Infections (OI’s) • The Centres for Disease Control and Prevention (CDC) defines someone as having AIDS if he or she is HIV positive and meets one or both of these conditions: • Has at least one of 21 AIDS-defining Opportunistic Infections • Has a CD4 count (T cell) of 200 or under (a ‘normal’ CD4 count is usually in the 600-1’500 range).
While many viruses can be controlled by the immune system, HIV targets and infects the same immune system cells that are supposed to protect us from illnesses. These are a type of white blood cell called CD4 cells. HIV takes over CD4 cells and turns them into virus factories that produce thousands of viral copies. As the virus grows, it damages or kills CD4 cells, weakening the immune system. When the immune system loses too many CD4 cells, you are less able to fight off infection and can develop serious illnesses, cancers, and neurological problems. These are called opportunistic infections (OIs) because they take advantage of the body's weakened defences. OIs can lead to hospitalization and disability, and are responsible for most of the deaths in people with AIDS. The Centres for Disease Control and Prevention (CDC) defines an HIV positive person with a CD4 cell count of 200 or less as having AIDS. The CDC has also developed a list of more than 20 opportunistic infections that are considered AIDS-defining conditions. If you have HIV and one or more of these OIs, you have AIDS. Even if your CD4 cell count goes back above 200 or an OI is successfully treated, you will still have a diagnosis of AIDS. This does not necessarily mean you are sick or will get sick in the future. It is just the system used by the government to count the number of people who have been diagnosed with AIDS. What are Opportunistic Infections? Basic Facts
The best way to prevent OIs is to keep your immune system as strong as possible by taking HIV drugs before your CD4 cell count falls too low (below 200). This allows the immune system to do its job of controlling infections. If your CD4 cells do fall below 200, taking appropriate medication at certain CD4 cell levels can prevent many OIs from developing. Taking medication to prevent disease is called “prophylaxis.” Effective treatment options are available in most cases if you do develop an OI. After you recover, you may still need to receive on-going maintenance treatment to prevent the OI from coming back. You may be able to stop prophylaxis or maintenance treatments if your CD4 cell count goes up. You should not discontinue any treatment without discussing it first with your doctor. What are Opportunistic Infections? Preventing and Treating OIs
What are Opportunistic Infections? • The following slides supply information on the most common OIs in HIV positive people.
Myths and Misperceptions about HIV • Many of the stories and rumours surrounding HIV are exaggerated or just made up. When dealing with HIV, it’s important to know reality from myth. • Believing myths can results in denial, fear and a change to your health • The following pages will demonstrate some myths and the reality surrounding HIV
Myth: “HIV doesn’t cause AIDS” Reality: If you don’t have HIV, you cannot get AIDS. If you have AIDS, you have HIV. 20 years of scientific proof have verified this. AIDS is not caused by party drugs, government conspiracies or anything else but a virus Myths and Misperceptions about HIV
Myth: “It’s not the AIDS that kills people, it’s the medication they take” Reality: HIV medications, known as antiretrovirals don’t cure HIV, but they can keep people healthy for many years. People died from AIDS before antiretrovirals became available. Unfortunately the drugs do have some side effects and toxicity (for some people), that can be life threatening Myths and Misperceptions about HIV
Myth: “The ‘AIDS test’ can’t be trusted” Reality: Viral Load tests measure the amount of HIV in a person’s blood. Studies have proven that people with a high viral load are much more likely to become ill or die than those with a low viral load. Myths and Misperceptions about HIV
Myth: “Viral load tests don’t really tell us anything about a person’s health” Reality: The ‘AIDS test’ measures your body’s response to HIV, called antibodies. The HIV test is one of the most reliable medical tests. According to the Centres for Disease Control and Prevention, it is more then 99% accurate. In addition, all positive tests are confirmed with another test to ensure no mistakes are made. Myths and Misperceptions about HIV
Myth: “Straight people don’t get HIV” Reality: The majority of HIV positive people on a global scale are heterosexual. Men infect women and women infect men. However: Gay men are at the most risk in western cultures. Myths and Misperceptions about HIV
Myth: “HIV can be spread through tears, sweat, mosquitoes, pools, or casual contact” Reality: HIV can only be transmitted through infected blood, semen, vaginal fluids and breast milk. The most common ways for HIV to be transmitted are through unprotected sexual contact or sharing needles with a HIV positive person. HIV can also be transmitted from mother to baby during pregnancy, birth or breast feeding. Myths and Misperceptions about HIV
Myth: “HIV can be spread through tears, sweat, mosquitoes, pools, or casual contact” Cont. Reality: The following “bodily fluids” are NOT infectious: Tears Sweat Saliva Urine Faeces Casual contact is not considered risky because it does not involve contact with blood or other infectious body fluids. Examples of casual contact include: Kissing Sharing drinks/eating utensils Swimming pools Public toilets etc Myths and Misperceptions about HIV
HIV Transmission How HIV Spreads • How HIV is spread is still misunderstood by many people. • HIV is spread through the following body fluids: • Blood (including menstrual blood) • Semen and other male sexual fluids • Vaginal fluids • Breast Milk • HIV is not spread through the following body fluids: • Sweat • Tears • Saliva
HIV Transmission Methods of transmission • In the past, HIV was spread in blood products. Many people where infected this way. The blood supply is now more strictly tested and controlled. • You cannot get HIV from donating blood – a new and clean needle is used for each donation. • Some people, primarily those working in health care are infected through ‘needle sticks’. • Today, the most common ways HIV is transmitted are: • Re-using and sharing needles • Unprotected/unsafe sex (no condoms or other barrier devices) • Mother-to-child (during pregnancy, birth or breast feeding).
HIV Transmission REMEMBER HIV is not transmitted by: • Hugs • Dancing • Sharing food or drinks • Using a shower, bath or bed used by a HIV positive person • Kissing (between people with no significant dental problems) • Sharing exercise equipment
Understanding the Immune System • The immune system is made up of cells and organs that protect your body from outside invaders such as viruses, fungi, bacteria and parasites (germs), that can cause infection, disease and death. The immune system also functions to rid the body of abnormal cancerous cells that are growing out of control. When functioning properly, it fights off infection and keeps you healthy. When in malfunctions, germs that enter the body can more easily cause infections, disease and death. Some important components of the immune system are: • Dendritic Cells • T Cells • Killer T Cells • B Cells • Neitrophilis
Dendritic cells and macrophages are the immune system’s first line of defence. Dendritic cells are found mostly in the skin and mucous membranes that protect the openings of the body (e.g. the mouth and throat). These cells capture and carry invaders to the lymph nodes or spleen. Macrophages (their name comes from Latin and means “big eaters”) protect different organs, including the intestines, lungs, liver, and brain. These two types of white blood cells are known as scavengers. They engulf foreign invaders, break them apart, and display pieces of the intruders—known as antigens—on their surfaces. They also produce chemical messengers (known as cytokines) that instruct other immune cells to go into action. Understanding the Immune System Dendritic Cells
Once antigens are processed and displayed on the surface of macrophages, they can be recognized by helper T cells (also known as CD4 cells). When CD4 cells “see” the antigens displayed, they get busy and put the word out to other immune system cells. In other words, these cells coordinate and direct the activity of other types of immune cells—such as killer T cells, B cells, and macrophages—calling them into action to fight the intruder. CD4 cells produce many different cytokines in order to communicate effectively with other immune system cells. Killer T cells directly attack and destroy cells infected by viruses as well as abnormal cancerous cells. Yet another type of T cell, called suppressor T cells, calls off the immune system attack once the invader is conquered. (This is to make sure the killer cells don’t go overboard, and relax once their job is done). Both killer T cells and suppressor T cells are also known as CD8 cells. Understanding the Immune System T Cells
B cells are another type of immune cell that is activated by CD4 cells. When a B cell recognizes an antigen, it goes into action and produces antibodies (also called immunoglobulins). Antibodies are proteins that attach to antigens like a key fits a lock. Each antibody matches a specific antigen. When an antibody matches up with an antigen, it has in essence marked the intruders for destruction by scavenger immune cells. Antibodies also activate a complex chemical chain reaction, called the complement system. This system’s purpose is to destroy bacteria, which it essentially does by punching holes in bacterial membranes. which kills them. When you are exposed to a pathogen for the first time, it usually takes awhile (several weeks to a few months) for your body to produce antibodies to fight it. But if you were exposed to a germ in the past, you will usually still have some B cells (called memory cells) lingering in your body that recognize the repeat invader. This allows the immune system to go into action right away. This also is why people get some diseases, such as chickenpox or measles, only once. And, this is the basis for how vaccines work—they cause your immune system to produce antibodies even though you have not actually had the disease. This is why the expression “vaccinated against” some disease (e.g., smallpox) is used. Understanding the Immune System B Cells
Understanding the Immune System Neitrophilis • Neutrophils are another type of white blood cell. They are made in the bone marrow. When they are needed to fight infection, they leave the marrow and travel anywhere in the body to fight it. These cells are your main defence against bacteria. They eat bacteria and produce toxic chemicals that destroy them.
The immune system has special organs, called lymph organs, that serve as a home base for all of these white blood cells. They are spread throughout the body. Lymph organs include the bone marrow and the thymus, as well as the lymph nodes, spleen, tonsils and adenoids, the appendix, and clumps of tissue in the small intestine known as Peyer's patches. (Some people would also consider the blood and vessels that carry these blood cells to and from the other structures to be lymph organs.) Lymph nodes are located along the so-called lymphatic routes. There are nodes, or clusters, in the neck, armpits, abdomen, and groin. Each lymph node contains B cells, and T cells, and other cells, ready to fight invaders. The spleen is a very important organ for a healthy immune system. It is about the size of a fist, and it is located at the upper left of the abdomen. One of its most important roles in the immune defence it to help the body weed out and discard worn-out white blood cells. It also houses various white blood cells, waiting for instruction to go out and fight infection. The lymphatic vessels carry lymph, which is a clear fluid that “bathes” the body's tissues, helping to clean out invaders or germs. The vessels carry the fluid to the lymph nodes, which can sort out the antigens in order to begin the fight against them. Understanding the Immune System Key Organs of the Immune System
In HIV positive people, the virus attacks the CD4 cells that coordinate the immune response. This causes the CD4 cells to lose the ability to communicate with the rest of the immune system. Without CD4 cells organizing the rest of the immune system, important immune cells don’t know which invaders need to be removed from the body. When this coordination breaks down, people are at risk for opportunistic infections and cancers that usually do not harm people with healthy immune systems. HIV can also infect macrophages and other immune cells. Your immune system recognizes and produces antibodies to HIV, but antibodies alone are not enough to eliminate the virus. This is partly because HIV mutates so rapidly that it can change faster than the immune system can respond to it. immune system and restore lost immune function. Other problems may result from suppression of the bone marrow, which can occur as a side effect of certain HIV drugs like AZT (Retrovir). The bone marrow is where immune cells are produced, so when it’s suppressed, you may have lower numbers of immune cells available, which again may cause you to be a little more vulnerable to infections. Effective combination HIV treatment can stop the virus from replicating (making copies of itself) and infecting more CD4 cells. Since CD4 cells are imperative to a healthy immune response, this can give your immune system a fighting chance to replenish its supply of CD4 cells and to defend itself against opportunistic infections. Researchers are also studying new HIV therapies that they hope will help repair the damaged Understanding the Immune System HIV and the Immune System
A regular part of your HIV health care involves having a sample of your blood drawn for testing in a laboratory. Laboratory tests are used to gauge your HIV disease progression and the overall health of your immune system. Common tests include viral load, CD4 cell count, complete blood count, blood chemistry tests (including liver function tests), and blood fat and sugar tests (lipid tests). When you are first diagnosed as HIV positive or when you first start taking HIV drugs (treatment), you should get “baseline” tests that give a picture of your health at that moment. Later tests can be compared against these results to see how things are going, and if they are changing. Most monitoring tests should be done every three to six months, or as often as your doctor recommends. HIV Viral Load and CD4 Cell Tests Viral load tests measure the amount of HIV in your blood. Your CD4 cell count measures how many CD4 cells are in your blood, reflecting the health of your immune system. Your doctor will usually look at the results of both these tests together, to get an idea of whether your HIV disease is progressing and whether your treatment is working. Understanding Lab Tests
Understanding Lab Tests Complete Blood Count • Blood is made up of various types of cells and liquid. The complete blood count (CBC) is an inventory of all the different cells. CBCs are important because some HIV drugs can cause low red or white blood cell counts. • Red blood cells (erythrocytes)These cells carry oxygen to all the cells of the body. Oxygen, which you take into your body through your respiratory system when you inhale, is vital for cells to live. Hematocrit and hemoglobin tests are measures of how well red blood cells carry oxygen. • White blood cells (leukocytes)These cells carry out the body’s immune responses. A normal total white blood cell count is 4,000-11,000. The “differential” reports the proportions or relative amounts of different types of white blood cells: • NeutrophilsThese white blood cells fight infections. A normal neutrophil proportion is about 50-70 percent. When your neutrophil count falls below about 500-750 cells (a condition called neutropenia), you are more likely to get bacterial infections. • LymphocytesThere are two types of lymphocytes. B cells produce antibodies and T cells target cancerous cells and cells infected with viruses. A normal lymphocyte proportion is about 20-40 percent. CD4 and CD8 cells are types of T cells that are measured separately. • Monocytes and macrophagesThese cells engulf or “eat” and destroy foreign invaders, or disease-causing organisms. They normally make up about 2-10 percent of all white blood cells. • Eosinophils and basophilsThese cells play a role in allergic reactions, and defend against parasites. They normally make up about 1-8 percent of white blood cells. • Platelets (thrombocytes) These cells are necessary for blood clotting. A normal platelet count is about 130,000-440,000. If your platelet count is low, you may bleed or bruise easily.
Understanding Lab Tests Blood Chemistry Tests • Blood chemistry tests measure important substances in the blood. They can help show how well organs like the liver and kidneys are working, and can provide useful information about drug side effects. A blood chemistry screen usually includes: Electrolytes • These particles play important roles in the healthy functioning of cells, nerves, and organs. Specific electrolytes by name include bicarbonate, calcium, chloride, magnesium, phosphorus, potassium, and sodium. Electrolyte imbalances may be caused by not getting enough nutrients (malnutrition), kidney problems, or not getting enough water into your body (dehydration, which can be caused, for example by lots of vomiting or diarrhoea). Liver function tests • These tests help measure how well your liver is working. High levels of two key liver enzymes—alanine transaminase (ALT or SGPT) and aspartate transaminase (AST or SGOT)—may be a sign of liver damage. Normal levels for women are up to about 40 for ALT and 35 for AST. Several HIV drugs can cause elevated liver enzymes, so especially if you’re taking HIV drugs, your doctor will want to monitor AST and SGOT levels in your body. High levels of bilirubin (a blood pigment) may also indicate liver problems. A normal bilirubin level is 0-1.3. Kidney function tests • These tests help measure how well your kidneys are working. They include blood urea nitrogen (BUN), creatinine, and uric acid. Kidney tests are especially important if you are taking Viread (tenofovir).
Understanding Lab Tests Blood Fat and Sugar Tests • In recent years there has been a lot of talk about elevated fat (lipid) and sugar levels in people taking HIV drugs. High blood fat levels can lead to heart disease, while high blood sugar may be a sign of diabetes or insulin resistance (when the body does not respond to insulin). Your doctor should measure your blood fats and sugar regularly if you are on HIV treatment. Exercise, changes in diet, and certain medications can help lower high blood fat and sugar levels. • Total cholesterolCholesterol is a fatty substance that circulates in the blood. A normal total cholesterol level is 120-240. The U.S. government recommends that you should try to keep your total cholesterol below 200. • Low-density lipoproteins (LDL)This is “bad” cholesterol, which can clog the arteries. You should try to keep your LDL level below 100. • High-density lipoproteins (HDL)This is “good” cholesterol, which helps reduce the risk of heart disease. You should try to get your HDL level up to at least 40. • TriglyceridesAfter eating, energy that is not needed right away is converted into a substance called triglycerides, which is stored in fat cells. A normal triglyceride level is about 45-150. Very high triglyceride levels can cause pancreatitis (inflammation of the pancreas, a serious condition).
Understanding Lab Tests The Bottom Line • Since many HIV positive people have no noticeable symptoms of health problems, it is important to get regular lab tests to monitor how you are doing. These tests are valuable tools that can indicate if something is wrong. CD4 cell counts and viral load test results can help you make decisions about starting, stopping, or switching treatments. Abnormal CBC, blood chemistry or blood fat or sugar tests can indicate other health problems that may be related to HIV or to HIV drugs that you might be taking. Regular monitoring is an important way to take charge of your health.
Diagnostic Tests • Together with having regular medical care, taking all prescribed doses of medication, and maintaining a healthy lifestyle, the following diagnostic tests can be very important in the management of HIV. Speak to your doctor about how you can use these tests to help make treatment decisions.
Diagnostic Tests CD4 Count • The CD4 count is usually the most important thing to consider when you are deciding when to start HIV treatment. You should have a baseline CD4 cell count done as soon as you know you are HIV positive. Some doctors recommend two baseline CD4 counts before starting therapy, because CD4 counts can vary widely from test to test. If two tests are done, and they are very different, a third test should be done before starting treatment. • After starting treatment, you should have a CD4 count done every three to six months.
Diagnostic Tests Viral Load • Viral load is the amount of HIV in your bloodstream. It is measured by a polymerase chain reaction or PCR test (also called a viral load test). Viral load tests are an important tool to: Monitor HIV progression: • While CD4 cell counts are your best measurement of how healthy your immune system is today, viral load tests can help you figure out if you’re at risk for more immune damage in the near future. When compared over time, results will tell you whether HIV is reproducing at a steady, fast, or slow rate. The higher your viral load, the more likely you are to lose the valuable CD4 cells Measure how well HIV drugs are working: • HIV drugs work by preventing the virus from reproducing. If the drugs are working, your viral load should go down. If there is a problem, your viral load may go up. • The goal of HIV treatment is to keep viral load as low as possible for as long as possible. With effective HIV treatment regimens, viral load can be reduced to levels that cannot be detected by lab tests. With most viral load tests this is below 50 copies.
Have a viral load test when you are first diagnosed and every three to four months when you are not on HIV therapy. Have a viral load test before starting treatment and again two to eight weeks later. If the regimen is working, your viral load should drop by 90% within two months and be undetectable (less than 50 copies) within six months of starting treatment. If these levels are achieved, viral load is usually measured every three to four months. If these levels are not achieved after starting treatment, or if your viral load has recently become detectable on stable therapy and keeps increasing, it can signal that your regimen isn’t controlling HIV as well as it should. You and your doctor should consider all possible reasons (problems with absorption, adherence, drug interactions, or drug resistance) and take steps to correct the problem, including considering changing drug treatments. Some doctors also recommend that you have a viral load test two to eight weeks after changing your treatment regimen. Diagnostic Tests When should you get the Viral Load Test?
Diagnostic Tests How to use your laboratory tests and your symptoms to decide when to start treatment • The table on the right shows how to use your CD4 count, your viral load, and your symptoms to guide your decision about when to start treatment.
Diagnostic Tests Resistance Testing • Resistance testing can be genotype or phenotype testing (see below). Resistance tests are used to determine which drugs will work best against your virus. There are several types of resistance tests available. If your HIV viral load is greater than 1000 or if you are considering changing your anti-HIV therapy, it is recommended that you have resistance testing. Genotype • Genotype tests analyse the genetic makeup of your virus. They look for changes (mutations) in HIV’s enzymes that can make it harder for drugs to work effectively. Your test result will list any mutations found. • Each drug is associated with a mutation or mutations that can make that drug less effective. Some HIV drugs don’t stop working unless several mutations are present. • We still don’t know everything about these mutations, or which combinations of them are most problematic. Because of this, it can sometimes be difficult to figure out how to make treatment decisions based on genotype results. Phenotype • The phenotype test cultures (grows) your virus in a laboratory. It is then placed in test tubes containing samples of the various HIV drugs. If a certain drug is not able to control the virus, more of that drug is added to the test tube. Depending on how much drug is needed, the lab can determine how resistant the virus is to the drug. • Phenotypic resistance results are reported as susceptible, sensitive, or less susceptible. Susceptible means that the drug will probably work well. Sensitive means that the drug will work as expected in the average person and less susceptible means the drug will probably not work very well for you. • Phenotype test results are often easier to interpret than genotype tests. Virtual Phenotype • This is a genotype test that goes one step further – it uses phenotype data from many patients to predict whether your virus will be sensitive or resistant to each of the HIV drugs.
Diagnostic Tests Bottom Line for Resistance Tests • None of the resistance tests are perfect. They cannot detect every mutation in your HIV or be used to predict exactly which drugs will work for you. However, they are quickly becoming another tool to determine treatment options in certain situations such as: • In someone who is about to start HIV therapy for the first time and whose HIV viral load is greater than 1000 • In someone who was just infected with HIV, also called acute infection (testing is used to see if the person was infected with a drug-resistant strain) • In someone who is failing his or her current regimen (testing is used to guide the choice of a new regimen) • In a pregnant woman (testing is used to determine the best regimen to prevent mother-to-child HIV transmission) • All resistance tests that are taken after you have started HIV therapy should be taken while you are still on HIV drugs (or within 4 weeks after stopping a regimen that is failing) to get the best results.
When any drug is approved, a standard dose is determined. This dose may be safe and effective for most people, but for some people, it may be more or less than needed. If people get too little of an HIV drug, it may be less effective and lead to the development of resistance. If they get too much, they may have problems with side effects. Therapeutic drug monitoring (TDM) measures levels of drugs in the bloodstream. Based on the results, doctors may be able to adjust doses as necessary in different individuals. Ideally, this should reduce side effects from too much drug in the blood stream and minimize the potential for drug resistance from too little. Drug level testing may be particularly helpful for HIV positive women. Some women have higher levels of certain drugs in their bloodstreams and experience more side effects than men. These sex (male / female) differences may be related to hormone changes that occur when women get their periods. Drug level differences also may be linked to basic biology and physiology of cells (there are differences in the cells of men and women). They may also be linked to weight differences. TDM is not approved for use with HIV drugs yet and there are still unresolved issues regarding the practical application of results. But the hope remains that TDM can lead to better-tolerated regimens and more knowledge about HIV drugs in women Diagnostic Tests Therapeutic Drug Monitoring
Understanding CD4 & CD8 Cells The Basics • CD4 and CD8 cells are white blood cells that play important roles in your body’s immune response. Tests that count your CD4 and CD8 cells provide a picture of your immune system health. Along with your viral load, your CD4 cell count can help your doctor tell whether your HIV disease is progressing or not, and how well your HIV drugs are working. • CD4 cells (sometimes called T-helper cells)These white blood cells help coordinate the various activities of your immune system. HIV targets CD4 cells more than any other kind of cell in your body. A normal CD4 cell count is about 600-1,500 cells. CD4 cell counts are often slightly higher in HIV positive women compared to HIV positive men (viral load in HIV positive women also tends to be slightly higher, relative to men, at the same stage of disease). CD4 cell counts usually fall as HIV disease progresses. • CD8 cells (T-suppressor or killer T cells)There are two main types of CD8 cells. T-suppressor cells inhibit or suppress immune responses. Killer T cells attack (“kill”) cancerous cells and cells infected with viruses. A normal CD8 cell count is about 300–1,000 cells. CD8 cell counts usually rise over time in HIV positive people, but why and how these increases relate to the health of your immune system is not well understood.