What antiretroviral medication is?
- Antiretroviral drugs are a class of pharmaceutical substances used for the treatment of HIV infection.
- Antiretroviral treatment cannot completely eliminate HIV from an HIV-positive person’s organism. It can, though, suppress viral replication, greatly reducing in this way its amount in one’s body.
- Antiretroviral treatment is a life-long treatment aiming at attaining and maintaining an undetectable viral load. By doing so, antiretroviral treatment protects a person’s health and dramatically reduces the possibility of HIV transmission.
As its name suggests, antiretroviral medication is a class of drugs used against retroviruses. Retroviruses are a group of viruses with one common feature: their genome is comprised of RNA molecules (in contrast to other groups of viruses or living organisms, whose genome is DNA-based). HIV is also a retrovirus (see What is HIV?).
Just like all viruses, retroviruses survive and reproduce by occupying cells of other organisms, forcing them to produce vast quantities of viral copies. Specifically, HIV preferably infects a particularly important group of cells of the human immune system, the T-helper lymphocytes or CD4+ cells (see How HIV affects the immune system?). If not treated properly, HIV gradually debilitates the infected person’s immune system, rendering him or her more and more vulnerable to a series of other infections and diseases, leading, finally, to the development of the Acquired Immune Deficiency Syndrome or AIDS (see The stages of HIV infection).
The antiretroviral drugs used to treat HIV infection aim at constantly suppressing the virus’s replication within the cells of the human host, this way preventing further weakening of the immune system and the development of AIDS. This is achieved by the drugs interfering in various stages of the virus’s life cycle and blocking its replication mechanisms . Several classes of antiretroviral drugs can be distinguished, each one of which interferes in a distinct stage of the virus’s replication cycle (see HIV life cycle and the effect of antiretroviral drugs). However, HIV has the ability to develop resistance to all antiretroviral drugs at some point, if these are administered separately. Therefore, in the last two decades, the treatment of choice has included the administration of (most commonly) three different antiretroviral drugs simultaneously (see HIV resistance to antiretroviral drugs and HAART). This combinational form of treatment is known as HAART (Highly Active Antiretroviral Treatment) or ART (Antiretroviral Treatment) [1,2]. If ART is received on a regular basis and according to the prescribed instructions, viral replication can be suppressed, without running the risk of HIV developing resistant strains (see Taking antiretroviral drugs the right way).
Antiretroviral medication can stop HIV from multiplying and spreading across the cells of an HIV-positive individual. It is also known that most tissues in our body are renewed on a more or less regular basis (old or damaged cells die off and are replaced by new ones). Thus, it would seem reasonable to expect that, after a sufficient amount of time on antiretroviral treatment, the virus should be entirely removed from an infected individual’s organism. Unfortunately, when it comes to HIV, this is not the case. Antiretroviral drugs can greatly reduce the amount of virus in one’s organism, but cannot completely eliminate it.
The reason for this is that HIV infects, amongst others, a group of immature and latent immune cells of the human body, which may stay in this inactive state for many years, thus hiding the virus inside them . In other words, HIV creates for itself a secret viral ‘reservoir’, as it is usually called, whose detection and elimination has not been possible to this day. If, for any reason, the HIV-positive individual discontinues his or her treatment, these latently infected cells will mature and activate, allowing the virus to start actively multiplying and spreading again.
Consequently, for the virus to remain constantly suppressed and not replicate, it is necessary to maintain sufficient levels of the drugs’ active substances in the blood of an HIV-positive individual. This means that HIV treatment is necessarily a lifelong treatment. Once started, one must take his or her drugs following a strict daily timetable for the rest of his or her life (see Taking antiretroviral drugs the right way).
Eventually, antiretroviral treatment aims at reducing and stabilizing the amount of virus in an HIV-positive individual’s body to a very low level – so low that HIV RNA in the blood serum (viral load, as it is usually referred to) cannot even be traced by the commonly used laboratory tests (see Viral load). Spe cifically, when the amount of HIV RNA is less than 50 copies per ml of blood (50 c/ml), the viral load is called “undetectable” .
Although this doesn’t mean that the virus has been completely eliminated (a small amount still hides in the so-called ‘reservoir’), maintaining an undetectable viral load is of utmost importance, since:
- HIV doesn’t cause any damage to the immune system and doesn’t pose any significant health risk, and
- the chance of the virus being passed on to another individual is greatly reduced.
Indeed, the development of ART during the last two decades has been one of the most astonishing achievements in the field of medical science, having changed the lives of millions of people across the whole world (see 1995 and after: the era of HAART). Due to antiretroviral medication, most people living today with HIV and receiving proper treatment will never develop AIDS . Due to antiretroviral medication, the once dreaded and incident to death illness became a chronic but manageable and not life-threatening disease. By adhering to their treatment and by generally taking care of their health, people living with HIV can expect to have a long, healthy and satisfying life, as all people do [5,6] (see HIV infection and life expectancy).
HIV life cycle and the effect of antiretroviral drugs
- HIV replication, from the point of its entrance into a target cell to the formation of new, mature viral particles, is a complex procedure that can be distinguished into 4 stages.
- Various classes of antiretroviral drugs can block the mechanisms involved in each stage of HIV replication, thus completely suppressing its reproduction.
HIV is a retrovirus, that is, its genome is made up from RNA (while the genome of other viruses or mammals, like humans, is DNA-based). The HIV genetic material (RNA) together with a few enzymes, essential for the virus’s reproduction, are located within a protective membrane (capsid), while a second outer membrane (envelope) encircles the virus particle (see What is HIV?) [2,3].
Figure 1. Illustration of the HIV structure
As all viruses do, HIV has one and only purpose: to replicate. HIV multiplies by invading certain cells of the human body (mainly cells of the immune system, like T-helper lymphocytes, macrophages and dendritic cells) and forcing them to produce vast quantities of new viral copies. The newly formed viral particles will, in turn, invade more and more cells and so, as this circle is repeated billions of times, the virus rapidly multiplies and spreads across the organism of the infected person (see How HIV affects the immune system?). The replication process of a single HIV virion, from its entrance into a cell until the formation of a new, mature and infectious viral particle, can be divided in 5 stages . These are described in more detail below. Accordingly, antiretroviral drugs can block the virus’s biological mechanisms involved in these stages, thus suppressing its replication and largely confining its spreading (see above What antiretroviral treatment is?).
Stage 1 – HIV enters a cell
HIV’s replication starts with the virus binding to a new target cell. In particular, HIV can only attach to human cells that carry two specific proteins on their outer surface (receptors). The first one is the CD4+ protein, which acts as an entrance gate for HIV, since the virus carries on its own outer surface another protein, called gp120, which fits to CD4+ like a key to a lock. The second receptor is either CCR5 or CXCR4, depending on the HIV strain, to which gp120 also needs to bind in order to gain access inside the cell. Therefore, all cells that carry these particular protein receptors on their surface are potential targets for HIV. These are mainly found on T-helper lymphocytes (also called CD4+ cells), as well as on certain cell types of the human immune and nervous system.
Once binding has been completed, another protein (called gp41), also located on HIV’s outer layer, comes into play. Gp41 merges the virus and the cell outer membranes (fusion), which results in the HIV RNA and other enzymes being released inside the cell body.
Respectively, antiretroviral drugs that intervene at the HIV’s entrance stage are the CCR5 antagonist maraviroc, which prevents the gp120 protein from binding to the CCR5 receptor, and the fusion inhibitor enfuvirtide, which blocks the gp41 protein and prevents the fusion of the viral and the cellular membrane.
Stage 2 – Transcription of viral RNA to DNA
HIV genetic material is made up from RNA, that is, it is incompatible with the DNA-based human genome. The next stage, then, in HIV’s replication is the transformation of the virus’s RNA-based genetic code into a DNA-based one. This complex process, called transcription, is performed by a unique viral enzyme, the reverse transcriptase. Reverse transcriptase is released into the infected cell’s body together with the viral RNA, during the fusion of the two membranes.
Antiretroviral drugs that suppress the transcription of the viral RNA to DNA by blocking reverse transcriptase are called [nucleoside and non-nucleoside] reverse transcriptase inhibitors (e.g. tenofovir, emtricitabine, efavirenz, nevirapine, etc.)
Stage 3 – Viral DNA is integrated to the cell genome
The HIV genetic code, having been transcribed to DNA (provirus), enters the host cell’s core, where it is integrated into the cell DNA. This process is performed by another important viral enzyme, called integrase.
Antiretroviral drugs that block integrase and stop the integration of the viral DNA to host cell genome are called integrase inhibitors (e.g. raltegravir).
Stage 4 – Viral replication
DNA can be found in almost all cells of the human body and acts as a code, a set of instructions, for the cells to produce all the substances necessary for their life-maintaining functions. This process is called translation. HIV takes advantage of these very same mechanisms. As the infected cell normally translates its own DNA into necessary cellular proteins, it also translates the integrated viral DNA into the virus’s structural components. These scattered viral elements will form new viral particles (virions) not very long after.
No drug can interfere at this point, as it is a process that normally and continuously takes places in all the cells of our body.
Stage 5 – New viral particles assemble and mature
The newly copied HIV’s various components, its RNA and the accompanying enzymes and proteins, are finally assembled near the host cell outer membrane. As they exit the cell, they clip off certain proteins from its membrane. These are used to form the envelope of a new virion. At this stage, the core (capsid) of the young virions hasn’t been formed yet, so they are considered to be immature and non-infectious.
The HIV replication cycle ends with the maturation of the new virus particles, as a result of another essential viral enzyme’s action, called protease. Protease sets apart and allocates accordingly the different virus’s components, forming its capsid. The virus particles (now called virions) have ultimately reached their final form and are now able to occupy other cells in the body of the infected individual.
Antiretroviral drugs that interfere at this last stage of HIV replication, by blocking protease and hindering the virus’s maturation, are called protease inhibitors (e.g. ritonavir, darunavir, etc.).
Figure 2. Illustration of the HIV life/reproduction cycle
HIV resistance to antiretroviral drugs and HAART
- HIV treatment is particularly complicated by the virus’s ability to mutate and develop strains that are resistant to antiretroviral drugs.
- If HIV develops resistance to one or more antiretroviral drugs, these drugs are no longer able to suppress viral replication. In this case, it is necessary to administer a different medication scheme, which may involve more daily doses and more intense side-effects.
- To avoid resistance development, it is critical for the person on antiretroviral treatment to strictly adhere to his or her treatment instructions.
For many reasons, dealing with the HIV/AIDS pandemic, counting over three decades now, has proved to be quite a complicated venture, presenting a series of challenges for the scientific community to overcome. One of these is the fact that HIV is characterized by a very high mutation rate. To put it simply, HIV has the ability to take different forms, creating small variations of itself (‘strains’ is the commonly used term), each of which slightly differs from the others in terms of structure and function. This happens to a much smaller extent in all living organisms, but is most frequently observed in viruses and, especially, retroviruses (RNA-based viruses), like HIV. It is estimated that HIV presents mutations in its genome at a one million times more frequent rate compared to the mammalian DNA-based genome .
The reason for HIV’s high mutation rate is, firstly, the fact that its replication mechanism is not particularly accurate, resulting in random mistakes often occurring during its reproduction process (these are called mutations). So, in a few instances, some parts of the virus may not be accurately copied, presenting small changes in their structure and function . In particular, it has been calculated that about 1 in every 10,000 copying operation goes wrong, that is, a subtle mutation occurs. Moreover, in contrast to the DNA-based organisms, retroviruses like HIV do not possess any repairing mechanisms for their genetic material, so the variations that occur tend to stick.
Such a small mutation may have no impact at all, may render the mutated strain non-infectious, but may also make it resistant to a certain antiretroviral drug. This means that the drug’s active substance can no longer attach to the mutated part of the virus and inactivate it, since its structure has altered (see above HIV life cycle and the effect of antiretroviral drugs). In this way, the particular drug becomes useless, as it can have no effect on the new viral strain. Respectively, the mutated strain of the virus is considered to be ‘resistant’ to this particular drug.
The second reason for HIV’s high mutation rate is that it multiplies extremely fast. In an HIV-positive individual that receives no treatment at all a few billion copies of the virus can be produced in just a single day. Having in mind that about 1 in 10,000 copying operations results in a random mutation and that hundreds of such mutations do occur each day, the chance of one of them making the virus resistant to a certain drug is not low at all, let alone in the long-term.
In fact, the possibility of resistant viral strains’ development is quite high and this is exactly the reason why the first treatment attempts, during the late 80s, failed. The treatment strategy followed back then was based on the daily administration of a single antiretroviral regimen (monotherapy), like azidothymidine (AZT). However, after a relatively short period of impressive improvement, these first HIV/AIDS patients quickly showed the virus bouncing back, their health deteriorating and the drug being no longer of any use. What was happening is that HIV was developing ‘resistance’ to those particular drugs, creating resistant viral strains that were able to keep on multiplying uncontrollably.
From 1995 and on, when HIV’s ability to mutate had been more fully understood and more antiretroviral regimens had been made available (see 1995 and after: the era of HAART), the treatment strategy was adjusted accordingly [8,9]. It may be relatively easy for HIV to become resistant to a single antiretroviral drug, when this is administered individually, but it is almost impossible to become resistant to more antiretroviral regimens, if these are administered simultaneously. Since 1995, monotherapy was replaced by the so-called ‘combination treatment’, which involves the simultaneous administration of – usually – three different antiretroviral regimens . This treatment strategy for HIV infection and AIDS became widely known as Highly Active Antiretroviral Treatment or HAART.
What is more, a series of specialized laboratory tests have been made available during the last years, which can detect the presence of resistant viral strains in an HIV-positive individual (HIV-drug resistance testing). This examination is typically performed upon diagnosis with HIV and certainly before initiating treatment with antiretrovirals and guides the attending physician’s choice of the most suitable medication scheme .
Combination treatment can fully suppress HIV reproduction in the body of an HIV-positive individual and greatly reduces the chance of resistance development, as the virus cannot replicate and mutate (see above What antiretroviral treatment is?). Nevertheless, the success of HIV treatment directly depends on the person’s strict adherence to the physician’s instructions regarding proper administration. This means that the person must take his or her medication every day, at certain times each day and always according to the attending physician’s instructions (see below Taking antiretroviral drugs the right way). This way it is ensured that the concentration of the drugs’ active substances in the blood circulation is consistently adequate to continuously suppress viral replication.
If treatment adherence is poor (e.g. if doses are skipped or taken irregularly), HIV is given the chance, even for short time periods, to reproduce, mutate and develop strains that are resistant to the medication the individual is already receiving. If this happens, the viral load will start rising again and the individual’s immune system will gradually weaken. In such a case, it is very likely that the person will have to change his or her medication. This could mean that he or she will receive an older drug treatment, which may involve a more complex administration scheme (i.e. more daily doses) and may have more negative side-effects, making treatment adherence even harder. Besides, the available antiretroviral drugs are not countless. Exhausting one’s treatment options could mean that he or she is putting his or her health at risk.
Superinfection is another reason for HIV resistance to antiretroviral drugs. The term ‘superinfection’ refers to the reinfection of an already HIV-positive individual with a different HIV strain, e.g. by having condomless sex with another HIV-positive person. If this newly transmitted strain of HIV is resistant to the medication the superinfected individual is already receiving, it can multiply uncontrollably and result in an increase in viral load and, finally, in necessary treatment changes.
Important medical tests
- Viral load is the amount of HIV in the various body fluids, especially in the blood serum. It is measured in HIV RNA copies per blood ml (c/ml).
- Viral load is one of the most important tests for monitoring an HIV-positive person’s health and treatment progress. The higher the viral load, the higher the virus’s replication rate and the bigger the damage to the immune system.
- Antiretroviral treatment aims at attaining and maintaining an undetectable viral load, that is, below 50 c/ml.
- Most frequently, having an undetectable viral load in the blood serum corresponds to an undetectable viral load in other body fluids as well. However, this is not always the case.
Viral load is the term used to refer to the amount of HIV (in particular, the amount of HIV genetic material: HIV RNA) in the various body fluids and tissues of a person living with HIV. Viral load is most commonly measured in the blood serum, which is considered indicative of the virus’s concentration in the whole body. Viral load is one of the most important medical examinations for monitoring the health and the treatment progress of an HIV positive person and is therefore performed at the time of diagnosis, as well as at regular periods of time thereafter (once every 3 or 6 months according to most recent guidelines) .
For those who haven’t started antiretroviral treatment yet, viral load shows the rate at which HIV infection is progressing – the higher the viral load, the faster the reduction of CD4+ cells and, therefore, the higher the possibility of an opportunistic infection to occur (see The stages of HIV infection). For those who are on treatment, viral load shows how effective treatment has been.
Viral load is typically measured with a specialized blood test and its value is expressed as copies of HIV RNA per milliliter of blood (c/ml). For example, a viral load value above 100,000 c/ml is generally considered to be high, suggesting that the virus is rapidly multiplying and is causing a respective decrease of CD4+ cells. On the other hand, a viral load value below 10,000 c/ml is considered relatively low .
All the available viral load tests for HIV have a detection threshold, below which viral RNA cannot be detected and measured. For the most widely used tests, this threshold is at 40 or 50 HIV RNA copies per milliliter of blood. So, a viral load below 50 c/ml is generally called undetectable. This doesn’t mean that the virus has been completely removed from one’s body, but only that its amount is so low that it can’t be detected and measured by conventional laboratory tests.
Reducing and sustaining viral load at an undetectable level is the main aim of antiretroviral treatment (see above What antiretroviral treatment is? and HIV life cycle and the effect of antiretroviral drugs). Having an undetectable viral load means that one’s immune system can recover and protect his or her health, as well as that the possibility of the virus being passed on to another person is greatly reduced.
Viral load is measured more frequently during the first months after starting antiretroviral treatment, as it is the most significant indicator of the treatment effectiveness. Within 3 to 6 months after initiating treatment and with proper adherence to treatment instructions (see below Taking antiretroviral drugs the right way), viral load is normally expected to become undetectable. If this is not the case, the attending physician will investigate the possible causes of treatment failure (e.g. poor adherence, resistance, interactions of ART with other medication) and may proceed to changes in the prescribed medication, if necessary.
Many people that regularly and properly receive their antiretroviral medication and have sustained an undetectable viral load for a long time may present, at some points, transient small increases in their viral load (these are usually called blips). That is, their viral load slightly increases, becoming detectable (usually reaching values not higher than 500 – 1,000 c/ml), and then, within 1 or 2 months, returns back to an undetectable level. The reasons for such variations are not yet understood. It seems, though, that under certain circumstances viral load may be affected by vaccinations or by the presence of other infectious diseases (e.g. influenza). These blips do not necessarily suggest treatment failure but certainly need careful monitoring, especially if they happen often or if viral load does not return back to being undetectable within a reasonable period of time .
Viral load in the blood serum correlates to viral load in other body fluids, like sperm and vagginal or rectal fluids. That is, if viral load is undetectable in the blood, it is most likely undetectable in other body fluids as well. However, this is not always the case. Research shows that a sufficient percentage of men (ranging from 4 to 10%) who are on antiretroviral treatment and have undetectable viral load in their blood, do have a detectable, although low, viral load in their sperm [19,20,21]. The same is true for women’s genital secretions, most likely at a more frequent rate than men [22,23,24]. Besides, viral load in women’s vaginal fluids may present small deviations, in accordance with their menstrual cycle. The highest values are typically observed during the first days of menstruation and the lowest just before ovulation [25,26]. Finally, quite a few studies have examined the relation between viral load in the blood serum and rectal fluids, so that no safe conclusion can be reached.
- CD4 cells count per blood mm3 is indicative of our immune system’s efficiency and is, therefore, one of the most important medical examinations for monitoring an HIV-positive person’s health. The higher the CD4 count, the healthier the immune system.
- CD4 count normally ranges from 500 to 1500 CD4/mm3. If CD4 count is below 350 CD4/mm3 and especially if lower than 200 CD4/mm3, there is an increased risk of developing a series of severe conditions. If this is the case, it is considered urgent to initiate antiretroviral treatment.
CD4 cells (or T-helper lymphocytes) are a particularly important group of immune cells, necessary for our immune system’s effective function and the protection of our health. These are also the cells that HIV preferably invades and infects (see How does HIV affects the immune system?). Unless a person living with HIV regularly takes antiretroviral treatment (see above What antiretroviral treatment is?), the virus gradually depletes his or her immune system CD4 cells, eventually leading to severe immunodeficiency and the development of the acquired immune deficiency syndrome or AIDS (see The stages of HIV infection). CD4 cells have been named after the CD4+ protein attached to their exterior surface, which acts as a receptor for HIV (see above HIV life cycle and the effect of antiretroviral drugs) .
CD4 cells count is one of the most important medical tests for monitoring the health of a person living with HIV, since it is an excellent indicator of our immune system efficiency, that is, its ability to fight off infections and other diseases. The CD4 cells count test is performed on a blood sample and its value is expressed as the total number of CD4 cells per mm3 of blood (e.g. 800 CD4/mm3) or as the percentage of CD4 cells to the sum of all lymphocytes (e.g. CD4% > 40).
CD4 cells normally range from 500 to 1,500 per mm3 of blood (or from 30 to 60% of the total number of lymphocytes). A person with a CD4 count above 500 can generally expect to have a good health. An HIV-positive person with a CD4 count below 200 (or CD4% <14) is considered to have AIDS and is running a serious risk for developing life-threatening diseases (see What is AIDS?) . In this case, starting antiretroviral treatment is considered immediately necessary.
A CD4 cells count test is recommended every 3 or 6 months, while people living with HIV that regularly and properly receive antiretroviral medication and consistently have a CD4 count above 350 may be screened annually .
Up until a few of years ago, CD4 cells count was the main factor for deciding when an HIV positive individual should start antiretroviral treatment (see Starting antiretroviral medication). However, in view of recent research findings , the most recent guidelines by the World Health Organization , the Hellenic Centre for Disease Control and Prevention  and respective organizations in many other countries  recommend starting treatment for all people diagnosed with HIV, that is, irrespectively of their CD4 cells count. The lower the CD4 cells count (especially if lower than 350 or 200), the more urgent the need for starting antiretroviral treatment.
After the initiation of antiretroviral treatment and the reduction of viral load, a gradual increase of CD4 cells is typically observed. This means that the immune system strengthens and is in better position to protect one’s health. Most commonly, CD4 cells count increases relatively fast during the first months of treatment, while their numbers continue to increase at a much slower rate thereafter . However, this can vary to a large extend amongst people living with HIV. To this day, it is not possible to predict the degree to which the immune system of any individual person will recover. It is neither possible to predict whether CD4 cells keep on increasing for as long as treatment continues, or they plateau at a certain level after a few years . Various factors seem to influence this process, such as age (the lower the age, the greater the CD4 cells’ replenishment is expected to be)  and the CD4 cells count at treatment initiation (the higher the CD4 cells count, the greater their expected replenishment) .
Finally, it should be noted that the CD4 cells count test is not a particularly accurate one, due to both its technical features and the high variation in the number of each individual’s CD4 cells from time to time. CD4 cells count can actually be affected by many factors, including other active infections, leukopenia, taking steroids or the other immuno-suppressive drugs, intense physical exercise and fatigue, surgery, pregnancy, sleep deprivation, smoking, even the time of the day (the number of CD4 cells tends to be lower at noon and higher early in the evening) . In such cases, it is important to inform the personnel performing the test (they may consider postponing the examination).
For the above reasons, the general trend of the CD4 cells count, as outlined from test to test over time, is often much more informative than the result of a single examination. If, however, the result of a single CD4 test is much different than expected, it is likely that the attending physician will consider repeating it, in order to rule out confounding effects.
Other medical examinations
- Besides the immune system, HIV itself, as well as antiretroviral treatment may affect other systems of the human body. This is why regular monitoring of an HIV-positive person’s general health is considered essential.
- Typically, people living with HIV have a general health check-up on a regular basis (e.g. annually). This usually includes a full blood count, assessment of cardiovascular, liver, kidneys and bone health, checking for the presence of other sexually transmitted infections and preventive screening for various types of cancer.
The health care of a person living with HIV is not limited to just taking antiretroviral drugs or monitoring CD4 cells and viral load. HIV itself as well as certain antiretroviral drugs can affect other systems and organs of our body, besides the immune system, while treatment progress may be influenced (and may require adjustment) by the presence of other illnesses. Therefore, it is considered critical to systematically check a person’s living with HIV general health through additional medical examinations. Some of these tests are routinely performed on a regular basis (e.g. once every 3 or 6 moths), while others only if the attending physician considers them necessary. The most important medical examinations for people living with HIV are the following:
Full blood count
Full blood count is a broadly used screening test for examining the various parts that consist our blood (e.g. red and white blood cells) and certain blood-related features (e.g. hematocrit). This provides very important information for one’s health and may indicate the presence of other illnesses and their progress. It is normally performed as part of the routine check once a year or more frequently, if the attending physician considers it necessary [17,38].
People living with HIV have an increased risk for developing cardiovascular diseases compared to the general population, so monitoring their cardiovascular function is considered essential [31,32]. Doctors take into account various factors when estimating cardiovascular risk, the most important of which are blood pressure, glucose and lipids amount in the blood and smoking. A cardiovascular check-up is recommended once every 2 years for all men living with HIV above 40 years and for all women living with HIV above 50 years [17,38].
Antiretroviral medication may have negative effects on the liver, especially if additional risk factors for liver disease are present [33,34], such as frequent use of alcohol or other addictive substances, hepatitis B or C, obesity, diabetes, insulin resistance, increased levels of lipids in the blood and taking other hepatotoxic drugs. Checking liver function and estimating the risk for diseases of the liver is recommended once a year for all people living with HIV that are on antiretroviral treatment. The attending physician may recommend more frequent or more specialized testing for people with additional risk factors [17,38].
Some antiretroviral drugs (e.g. tenofovir, atazanavir) may negatively impact the kidneys, so it is necessary to regularly check renal function through special blood and urine tests, especially during the first months after treatment initiation . Checking renal function and estimating the risk for diseases of the kidneys is recommended once a year for all people living with HIV that are on antiretroviral treatment. The attending physician may recommend more frequent or more specialized testing for people with additional risk factors, such as high blood pressure, diabetes, cardiovascular disease, family history of renal disease, African origin, hepatitis B or C, low CD4 cells count, smoking, increased age and taking additional nephrotoxic drugs [17,38].
HIV itself as well as certain antiretroviral drugs may affect metabolism in the bone cells and cause loss of bone mass and decreased bone density [36,37]. Bone health is monitored with certain blood tests and the estimation of the so-called FRAX score (bone fracture risk). This screening is recommended once every 2 years for all people living with HIV that are 40 years or older [17,38]. More frequent and specialized tests (e.g. DEXA) may be ordered for people with additional risk factors, including increased age, female gender, hypogonadism, family history of hip fracture, low body mass index, lack of vitamin D, smoking, lack of physical exercise, history of mild fractures, alcohol abuse and use of steroids.
Other infectious diseases
The presence of additional sexually transmitted (e.g. syphilis, hepatitis B or C) or other infectious (e.g. tuberculosis and other bacterial or viral infections) diseases is routinely checked upon diagnosis with HIV. Screening for these conditions is usually repeated once every year or even more frequently, especially if a person is involved in high-risk behaviors and taking into account his or her general health . Some infectious diseases can be prevented by vaccination.
Cancer screening tests
The incidence of certain types of cancer is higher in people living with HIV, so that regular screening is considered essential for prompt diagnosis and treatment. In particular, according to the most recent guidelines of the European AIDS Clinical Society (EACS, 2016)  and the Hellenic Centre for Disease Control and Prevention (KEELPNO, 2017) , recommended screening includes:
- Regarding anal cancer, many specialists (although not unanimously) recommend a digital rectal exam and an anal Pap test every 1 to 3 years to all men who have sex with men.
- Regarding breast cancer, a mammography (also called mastography) is recommended every 1 to 3 years to all women between 50 and 70 years old.
- Regarding cervical cancer, a Pap test is recommended every 1 to 3 years to all sexually active women.
- Regarding colorectal cancer, a fecal occult blood test is recommended every 1 to 3 years to all men and women between 50 and 75 years old.
- Regarding liver cancer, an ultrasound exam is recommended every 6 months to people at high risk (such as Asian origin, family history of liver cancer, cirrhosis, non-alcoholic fatty liver disease, chronic viral hepatitis).
- Regarding prostate cancer, a digital rectal exam and a PSA blood test is recommended every 1 to 3 years to all men above 50 years.
Starting antiretroviral medication
- Until recently, starting antiretroviral treatment was recommended to people living with HIV that had a CD4 count below 500 or 350 CD4/mm3. However, recent research findings have shown that immediate treatment initiation, irrespective of CD4 count, is much more beneficiary compared to late treatment initiation.
- Revised treatment guidelines in many countries, including Greece, recommend immediate antiretroviral treatment initiation for all people living with HIV, irrespective of CD4 count.
- Antiretroviral treatment is a rigorous life-long treatment. Each person that is about to start treatment should be appropriately prepared for it.
The first-generation antiretroviral drugs used for treating people with HIV/AIDS back in the 90s were far from tolerable for most of the people receiving them. The large number of daily doses, the frequently severe side-effects, the fear for possible toxic effects on other body organs, low compliance to treatment and the subsequent risk for resistance development, all these made both people living with HIV/AIDS and their doctors reluctant to starting antiretroviral treatment – which, once started, should be continued throughout one’s whole life. So, doctors usually preferred to hold off treatment until the virus had started to seriously damage their patients’ immune system and there was no room for any further delay. Up till the mid-2000s, most people started antiretroviral medication with 200-270 CD4/mm3 on average  (see above Important medical tests). The 2004 guidelines of the Hellenic Centre for Disease Control and Prevention recommended treatment for people with less than 200 CD4/mm3 and, under certain conditions only, less than 350 CD4/mm3 .
During the next years, new generation antiretroviral drugs were made available, with far fewer daily doses, as well as less frequent and less severe side-effects. As a result, adherence was greatly improved and treatment became more effective in restraining the virus. A trend towards earlier treatment initiation soon followed. In 2007-8, guidelines in most developed countries recommended treatment for all HIV-positive people with less than 350 CD4/mm3 and, a few years later, less than 500 CD4/mm3 . The 2014 guidelines of the Hellenic Centre for Disease Control and Prevention recommended treatment for people with less than 350 CD4/mm3 and, under certain conditions, less than 500 CD4/mm3 .
This common – until recently – practice, which essentially based treatment initiation mainly on the number of CD4 cells, was drastically changed in the spring of 2015, after the expedited publication of the START (Strategic Timing of AntiRetroviral Treatment) study’s results [14,15]. START was a large-scale randomized clinical trial that looked into possible benefits of early treatment initiation (that is, regardless of CD4 cells count) compared to its delay. 4,685 men and women living with HIV from 35 countries took part in this study, all with a CD4 count above 500 at their enrollment. Half of those started antiretroviral treatment immediately (with >500 CD4/mm3) and the other half only until the number of their T lymphocytes had dropped below 350 CD4/mm3. Results showed beyond any doubt that immediate treatment initiation reduces at a far more great extend (57% difference compared to delayed treatment) the possibility of developing AIDS and a series of other conditions (e.g. cardiovascular, renal or liver diseases), decreases overall mortality, as well as increases quality of life.
The results of the START study, as well as of other studies with similar findings, had an international impact. In September 2015 the World Health Organization published its revised treatment guidelines, recommending immediate treatment initiation for all people diagnosed with HIV, regardless of their CD4 cells count . Soon, treatment guidelines were accordingly adjusted in many other countries, such as the United States, the United Kingdom and the European AIDS Clinical Society .
The same principle has been applied in Greece as well. The revised guidelines of the Hellenic Centre for Disease Control and Prevention, published in May 2017, state that: “Antiretroviral treatment (ART) is recommended to all patients with a chronic HIV infection irrespective of the number of their CD4 lymphocytes”. It is additionally specified that: “the lower the number of CD4 cells, the more urgent the need for immediate initiation of antiretroviral treatment” (p. 13) .
Nevertheless, every person that is about to start antiretroviral treatment should, at first, appropriately prepare him or herself for that. Antiretroviral treatment is a lifelong treatment and a demanding one as well, in terms of adherence to its prescribed instructions. Once started, treatment must go on for the rest of one’s life, involving daily doses that must be taken at specific hours and always in compliance with the attending physician’s instructions. This means that the person may have to make certain adjustments, so that treatment is orderly integrated into his or her daily program (see below Taking antiretroviral drugs the right way). Eating or sleeping habits may have to be regulated or a stable daily routine to be scheduled, possibly taking into account where one works or lives, so that treatment adherence is simplified and facilitated. Planning ahead for these changes may be quite helpful.
Taking antiretroviral drugs the right way
What does adherence mean?
- Proper treatment adherence means that antiretroviral drugs are received every day, at the same hour(s) each day, according to the dietary instructions given by the attending physician and with caution to possible interactions with other medications.
- Antiretroviral treatment requires a high degree of compliance, of at least 95%. If treatment involves 1 dose per day, 95% compliance means that no more than one dose per month is omitted.
A necessary condition for the effectiveness of antiretroviral treatment is taking it the right way. This is usually referred to as adherence to treatment instructions, as prescribed by the attending physician. To put it simply, adherence to antiretroviral treatment means that:
- drugs are taken every day (no doses are skipped)
- drugs are taken at specific times (neither sooner nor later)
- drugs are taken in compliance with the dietary instructions given by the attending physician (e.g. some drugs are better absorbed with an empty and others with a full stomach)
- drugs must not be taken together with other medication or substances (legal or illegal) that may interact with antiretrovirals.
Many studies show that full or almost full adherence to antiretroviral treatment is the most important predictor of its success (that is, achieving and sustaining an undetectable viral load). On the other hand, low adherence to antiretroviral treatment is the most important predictor of its failure (that is, the viral load remaining in detectable levels) .
Specifically, effective antiretroviral treatment prerequisites a pretty high compliance rate of at least 95% [40,41]. This means that in at least 95 out of 100 treatment days drugs are taken indeed and are taken at the right hours and according to the prescribed dietary instructions. If a person skips on average 5 out of 100 doses and takes sooner or later than scheduled another 10 of them, his or her compliance rate is 85%. As far as antiretroviral treatment is concerned, this is considered low and involves serious risks (see below). If treatment involves 2 doses per day (every 12 hours), 95% compliance means that no more than 3 doses per month can be omitted. If treatment involves 1 dose per day (every 24 hours), 95% compliance means that no more than 1 dose per month can be omitted.
Furthermore, a person on antiretroviral treatment must inform his or her doctor about any other medication prescribed by another physician, before receiving it. The same applies to the use of parapharmaceutical products, as well as of addictive substances. Some of these substances could interact with antiretroviral medication, affecting its blood concentration.
Why is adherence to antiretroviral treatment necessary?
- Poor adherence to antiretroviral treatment may lead to the development of viral strains that are resistant to the drugs an individual is receiving.
- If resistance to one or more antiretrovirals is developed, these are no longer effective in suppressing viral replication. This leads to the gradual weakening of the immune system and an increased risk of HIV transmission.
- In such a case, it is very likely that different drugs will have to be prescribed, which may involve more daily doses and more intense side-effects.
In many chronic conditions (and lifelong treatments) low compliance is often not considered a matter of such essential importance. For example, if a man with hypertension forgets to take his medication every now and then, his blood pressure will probably increase temporarily and return to normal with the next dose, usually not causing any particular problem. This is not the case with HIV infection.
Antiretroviral treatment is a treatment to which one should fully or almost fully adhere, otherwise not take it at all (until he or she is able to fully comply) . The reason is that poor adherence to antiretroviral treatment (and, subsequently, partial viral suppression) is just the right condition for the development of viral strains that are resistant to the antiretroviral drugs one is receiving. Indicative is the finding of a US study showing that the risk for resistance is equally reduced if one has either very good (above 90-95%) or very bad (below 69%) compliance, while moderate adherence (70-89%) is related to higher risk of resistance development .
Antiretroviral drugs do not completely eliminate the virus from the body of an HIV-positive individual. However, they do suppress the virus’s reproduction and, therefore, the spreading of the infection to other cells (see above What antiretroviral treatment is? and HIV life cycle and the effect of antiretroviral drugs). This requires a constantly sufficient concentration of the drugs’ active substances in the blood of the person receiving them. If doses are omitted or if taken sooner or later than scheduled or if the administration instructions are not kept, the drugs’ concentration in the blood may not suffice to suppress HIV replication for some time. Within this timespan allowed, HIV is given the chance to multiply, mutate and possibly develop resistant strains (see above HIV resistance to antiretroviral drugs and HAART).
If resistance to certain drugs does develop, this means that these drugs are no longer able to suppress viral replication. Therefore, viral load is expected to increase within time, also increasing the possibility of passing the virus (resistant viral strains in particular) on to another person. Similarly, the number of CD4 cells will gradually fall, weakening the person’s immune system.
In such a case, it is very likely that the person will have to change medication, switching to older drugs that may involve more daily doses and more severe side-effects (thus making adherence even more difficult). Besides, available antiretroviral drugs are not endless. Exhausting one’s treatment options might mean that he or she is putting his or her health at risk.
Rigorous compliance is especially required during the first months after treatment initiation, as long as viral load is not fully suppressed to an undetectable level. Poor adherence during this time is more likely to result in resistance development .
What can complicate adherence to antiretroviral medication?
- Adherence to antiretroviral treatment may be affected by various factors related to either the person on treatment (e.g. drug use, negligence), or the doctor-patient relationship (e.g. insufficient information and support), or the characteristics of the medication itself (e.g. side-effects, high number of daily doses), or the context in which health services are provided (e.g. drugs shortage, access difficulties), or to wider social factors (e.g. fear of stigmatization).
Antiretroviral treatment is admittedly a relatively demanding type of treatment with a small margin for negligence. The high level of precision, caution and diligence it requires may cause various practical difficulties to some people. This is why timely preparation and continuous support could be very helpful in such cases.
Research has identified a series of factors that may complicate adherence to antiretroviral treatment [44,45], the most important of which are:
- complex medication schemes and large number of daily doses
- negative side-effects
- issues of availability or access to antiretroviral treatment
- lack of support by the medical staff
- disbelief at the antiretroviral treatment’s effectiveness or necessity
- low self-efficacy regarding one’s ability to rigorously follow treatment instructions
- general psychological distress
- use of addictive substances
- low quality of life
- negligence, forgetting, falling asleep
- lack of family or social support network
- fear of possible disclosure to others
- work or family responsibilities
On the other hand, factors that seem to facilitate adherence include:
- positive self-image
- acceptance of being HIV-positive
- understanding the need for full treatment adherence
- perceived positive treatment effects
- simple medication scheme (small number of daily doses)
- use of reminders
Tips for better adherence to antiretroviral treatment
Learn about how HIV works, how antiretroviral drugs deal with the virus and why treatment adherence is essential.
Give yourself time to carefully organize a daily time schedule for taking your drugs, also considering your doctor’s instructions and your daily activities. This schedule must remain stable, so that you do take your medication at the same hour (or hours) each day. You may have to adjust your daily program in order to facilitate adherence. If you take your medication every 24 hours (1 dose per day), think about which time would be more convenient for you. Try to think ahead of any difficulties that may come up. If you take your medication every 12 hours (2 doses per day), your options are necessarily more limited.
If you already have a stable daily routine (e.g. if you go to sleep or wake up at a certain time, if you have a fixed work shift), you might try to fit taking your medication into that. For example, you could take your drugs right after brushing your teeth or after your meal (as long as these are done at the same time each day, even the non-working days). If you do not have a stable routine, you could try planning one.
You could try using some sort of reminder aid, like your mobile or alarm clock. Many people find helpful the use of a pill box. You can find a variety of such products in pharmacies or e-shops.
You might also try using a diary, where you can right down the time you take your drugs each day. This would also help you have a clear picture of how well you adhere to your treatment.
If you wish, you could ask other persons that know your HIV status and with whom you spend time together (e.g. colleagues, relatives, friends, partners) to remind you of taking your drugs.
Not all antiretroviral drugs are equally demanding in terms of precision to the time of their administration. Some antiretrovirals are metabolized relatively quickly and others more slowly. Resistance is more likely to develop to some antiretrovirals and less likely to others. Ask your doctor about the degree of time precision required from you, considering your own medication scheme. In some cases, taking your drugs a bit earlier or later (e.g. ±30 mins) is not considered a problem.
If you completely forget to take one dose, you do not need to panic. If this happens only rarely (no more than once in a month), there is almost no risk at all. If it does happen more frequently though, you certainly have to discuss it with your doctor and find ways of improving your treatment adherence.
Ask your doctor what you should do in case you remember to take your drugs later than scheduled. Instructions may differ depending on the exact medication you are receiving. In some cases it is advised to take the late dose anyway, in others to skip the delayed dose and take the next one on time. Never take a double dose to compensate for the forgotten one!
Talk to your doctor about any side-effects you are experiencing that may be caused by the antiretrovirals you are receiving (especially if they are persistent). He or she may be able to prescribe other drugs to alleviate these symptoms. In some cases, your doctor may consider it necessary to modify your medication.
If you are taking or are going to take any other medication, talk to your HIV specialist first. Some regimens can interact with antiretrovirals, affecting their blood concentration. The same applies to other parapharmaceutical products (e.g. herbs, supplements).
If you are using psychoactive/addictive substances (even occasionally), do inform your doctor. They may interact with your antiretroviral drugs, affecting their blood concentration.
If you need to change the time you take your drugs, talk to your doctor about how this can be done without missing a dose.
Be honest to your doctor about how well you comply with your treatment instructions. This may determine important decisions about your treatment and health.
If you are going on a trip, make sure you take with you an adequate surplus of drugs, in case you have to stay longer than expected. Ask your doctor if you need to transfer your medication in some sort of protective package (e.g. a heat-resistant case).
Ask for help from the medical staff of your HIV clinic or from other organizations supporting people living with HIV, like the Centre for Life, if you are faced with psychosocial problems that interfere with your treatment (e.g. mental health issues, financial strains, addiction, intra-family violence etc.).
Possible side-effects of antiretroviral treatment
Just like most drugs, antiretroviral medication can cause side-effects. These can vary considerably among people, depending on the particular drug combination one is receiving. The first-generation antiretrovirals (used until two decades ago) caused severe side-effects to many people taking them, making proper treatment adherence an especially hard undertaking . Things have greatly improved since then. Modern antiretroviral drugs normally cause only mild, temporary and tolerable reactions, if any at all . In quite rare cases, side-effects can be more severe and treatment modification may be considered.
Not everyone who is on antiretroviral treatment will experience side-effects and not everyone will experience the same kind of side-effects. Apart from the particular medication one is receiving, drug reactions depend on a wide range of factors, like a person’s genetic predisposition to allergic reactions to certain substances, comorbid conditions and concurrent use of other medication, use of alcohol or other addictive substances, mental health issues, dietary habits, smoking, gender, age, race, etc. All these factors are carefully examined by the HIV specialist before treatment initiation, so that the drug combination with the least possible unwanted reactions is chosen.
In any case, if someone is experiencing unpleasant drug reactions while on antiretroviral treatment, he or she should certainly talk to his or her doctor before doing anything case. It is possible that symptoms are caused by other drugs or another condition. If symptoms are side-effects of antiretroviral medication indeed, they can be effectively dealt with in most cases. Under no condition should someone disrupt his or her treatment or omit doses to avoid unpleasant symptoms without consulting his or her doctor first. This could lead to the virus developing resistance to these particular drugs.
According to their time of presentation, side-effects can be distinguished into short-term and long-term.
Short-term side effects are usually presented within the first days after treatment initiation, as the organism adjusts to the medication. Most commonly, symptoms are mild and lessen or completely go away after a few weeks on treatment. Less frequently, symptoms can be more intense or persist for a longer time period . In any case, the HIV specialist needs to be informed about any symptoms experienced, so that he or she can identify their cause and do what is necessary to alleviate them. Most frequent short-term side-effects of antiretroviral treatment are:
Emotional and sleep disorders
Certain antiretroviral drugs may cause serious allergic reactions to some people during the first weeks of treatment. Allergic reactions are most frequently related to abacavir (Ziagen, Kivexa, Triumeq, Trizivir) and nevirapine (Viramune, Nevirapine) and rarely to atazanavir (Reyataz), etravirine (Intelence), efavirenz (Stocrin, Efavirenz, Atripla), darunavir (Prezista, Rezolsta), fosamprenavir (Telzir), maraviroc (Celsentri) and raltegravir (Isentress) . The HIV specialist will assess the possibility for a certain individual to present an allergic reaction to a certain drug before prescribing it. He or she will also inform the patient about what to look for during the first weeks of treatment. One should immediately consult his or her HIV clinic if he or she presents:
a skin rash or
at least one symptom from two of the symptom groups below:
Group 1: fever
Group 2: breathlessness, swollen throat, cough
Group 3: nausea, feeling sick, diarrhea, abdominal pain
Group 4: fatigue, muscle pain, weakness
Long-term side-effects may be presented after many months or even years on antiretroviral treatment. This is why all people living with HIV need to regularly have a full medical check-up (see Important medical tests), so that symptoms can be promptly identified and accordingly dealt with. The most important possible long-term side-effects of antiretroviral medication include:
Certain antiretroviral drugs that are metabolized by the kidneys, such as tenofovir (Truvada, Striblid, Eviplera, Atripla, Argiodin) and atazanavir (Reyataz) can have harmful effects on the kidneys, especially if additional risk factors are present . These include high blood pressure, diabetes, cardiovascular disease, family history of renal disease, African origin, hepatitis B or C, low CD4 cells count, smoking, increased age and taking additional nephrotoxic drugs. It is recommended to assess renal function once every year in all HIV-positive people who are on antiretroviral treatment [17,38].
Some antiretroviral drugs (protease inhibitors in particular) may increase levels of blood lipids (LDL cholesterol, triglycerides) and blood sugar, which increases the risk for cardiovascular diseases, such as arteriosclerosis, heart attack and stroke [31,32]. Additional risk factors include smoking, high blood pressure, family history of cardiovascular disease, lack of physical exercise, age above 45 years for men and above 55 for women, diabetes, increased fatty food consumption, use of alcohol or stimulant addictive substances and obesity. Blood lipids and sugar levels are regularly monitored with a full blood count. It is also recommended to assess risk for cardiovascular disease once every 2 years in all HIV-positive men above 40 years and women above 50 years who are on antiretroviral treatment [17,38].
Antiretroviral drugs can negatively affect the liver, especially if additional risk factors are present [33,34]. These include frequent alcohol consumption or use of other addictive substances, hepatitis B or C coinfection, obesity, diabetes, insulin resistance, increased levels of blood lipids and use of other hepatotoxic drugs. Liver function is assessed once every year in all people with HIV that are on antiretroviral treatment [17,38].
Some antiretroviral drugs may affect metabolism in the bone cells and result in loss of bone mass and decreased bone density [36,37], especially if other risk factors are present. These include increased age, female gender, hypogonadism, family history of hip fracture, low body mass index, lack of vitamin D, smoking, lack of physical exercise, history of mild fractures, alcohol abuse and use of steroids. Bone health is recommended to be evaluated once every 2 years in all people living with HIV above 40 years old [17,38].
Lipodystrophy is a syndrome in which lipid tissue distribution across the body is significantly altered (e.g. loss of lipid tissue from the face or the limbs and increased lipid concentration in the abdomen or the neck) and results in considerable changes in a person’s physical appearance. Lipodystrophy is a possible side-effect of older generation antiretroviral drugs, which are now only rarely used. It is extremely uncommon for modern antiretrovirals to affect lipid tissue distribution [1,11].
It should be pointed out that the side-effects of antiretroviral treatment described above are possible, not necessary. All HIV-positive people that adhere to their treatment (see above Taking antiretroviral drugs the right way) and consistently attend their medical appointments (see above Important medical tests) can expect to live a long and healthy life, just like everyone else (see HIV infection and life expectancy). If serious side-effects do occur, there is almost always something that can be done to effectively deal with them.
On the other hand, HIV infection itself and the lifelong use of antiretroviral treatment still is a potentially harmful factor for a person’s health. This is why it is essential for people living with HIV to avoid further burdening their health. Treatment of HIV is not confined to just taking a few pills every day. There are lots of other things that can be done to take care of one’s health.
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