New Integrase Inhibitors RAL, EVG and DTG improving the efficacy of ARVs in controlling HIV replication by providing personalized therapy.
Continue readingStudy: New HIV Integrase Inhibitors RAL, EVG and DTG
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New Integrase Inhibitors Better In Controlling HIV Replication than Other Antiretrovirals
Availability of new integrase inhibitors offers better opportunities to improve efficiency of cART and PEP in controlling HIV replication.
Continue readingHIV PEP drugs: Truvada® combination therapy
Truvada® is commonly used in combination with Isentress® for PEP due to the effectiveness and lack of negative interaction between the two drugs. Learn more in this detailed guide.
Continue readingHIV PEP drugs: Isentress® (Raltegravir) intergrase inhibitor
Isentress® is one of the newest classes of antiretrovirals, the intergrase inhibitors. This drug disables the HIV intergrase protein which is responsible for integrating the viral genome into the human chromosome and causing the chronic incurable infection. Developed by Merck and Co, it was approved for adult use in 2007 by the FDA and use in children as late as 2011. It has been shown to be the most highly effective anti-HIV drug in lowering viral load (numbers of virus in the blood).
Despite the drug’s effectiveness, it does have an Achilles heel. The intergrase protein is highly mutagenic and resistance can develop quickly meaning that Isentress® must be used in combination with other antiretrovirals to be effective. HIV PEP therapy at our clinic includes the use of Isentress® together with Truvada® – a pill made by Gilead Sciences containing Emtricitabine (Emtriva®) and Tenofovir (Viread®). This is currently our preferred PEP treatment combination.
Side effects
Isentress® has fairly mild side effect compared to many other antiretrovirals for most people. It is common to experience insomnia and the resulting tiredness as well as headaches, dizziness and nausea.
Less common side effects are stomach pains, depression including suicidal thoughts, hepatitis, kidney disease and weakness. Help should always be sought immediately if you are experiencing suicidal thoughts and if you start to experience the onset of hepatitis symptoms, most notably jaundice, dark urine, clay coloured stool and loss of appetite. You should be tested regularly for kidney health while taking PEP and it is important that you attend all tests as they will pick up problems before they become bigger. The rebound of hepatitis can happen when treatment stops due to the removal of suppression of HBV by Isentress®. Your doctor should be alerted if you have HBV so that your liver function can be safely monitored following cessation of treatment.
A rare and rather strange side effect of Isentress® is outbreaks of Herpes sores in those who suffer from genital herpes or cold sores and the occasional outbreak of shingles. It is not known what causes this, but is likely to be due to stress on the immune system. Inform your doctor if you suffer from herpes or cold sores or if you have had shingles in the past before starting this medication.
Like any medication, allergies are possible and can in extreme cases be life threatening. Seek emergency medical assistance should you find a rash in combination with fever, extreme tiredness, unexplained muscle or joint pains, sores in the mouth, swelling around the eyes or inside the mouth or difficulty breathing. Do not take any more of the medication if these symptoms appear until given the all clear by your doctor.
Contraindications
As with all PEP drugs, hepatitis or other liver conditions and any kidney conditions need to be closely monitored while taking Isentress®. It has not been shown one way or the other what effects it has on a growing foetus so inform your doctor if you are pregnant and Isentress® should only be taken if essential during pregnancy. There is no indication it is harmful to the baby, but not enough information to say that it isn’t. You should never breastfeed while on PEP, not only because the medication is transmitted through breastmilk but also to prevent transmission of HIV virus that has not been inactivated. PEP is not a cure for HIV, it inhibits the virus long enough for the immune system to respond and it doesn’t always catch it in time. You should behave towards others as if you were infectious until the PEP has been proven to have prevented a chronic infection.
There are indications that Isentress® can exacerbate rhabdomyolysis or myopathy as well as other conditions that increase the levels of creatine kinase in the blood. Inform your doctor if you suffer from any of these conditions and seek advice should you experience any unexplained muscle weakness or pain. As always these are not a full list of the side effects, should you experience anything that concerns you that appears to be linked to starting Isentress® speak to your doctor.
Drug interactions
There are few drugs that have a risk of negative interactions with Isentress®. One to watch for is Magnesium supplements. The magnesium or aluminium in these supplements can bind to the Isentress® and inactivate the drug. You should stop taking multi-vitamins or antacids when starting Isentress® treatment as many of these contain magnesium and/or aluminium.
There is some indication that the antibiotic rifampin may speed up the liver in clearing Isentress® from the body. You should try to ensure that you attend the same doctor while on PEP so that he or she is aware of all the medications you are taking. If you do need to see a different doctor make sure they are aware you are taking PEP. It may be that the doctor will have to change the prescribed dose of Isentress® while you are taking rifampin to ensure the levels are sufficient to inactivate any HIV virus.
Other drugs to watch for are any others that increase liver metabolism or those that raise the acidity of the blood, both may decrease the effectiveness of Isentress® and the active levels will need to be monitored while on these drugs. It will inevitably mean more blood tests, but despite the inconvenience, it is better to have a host of blood tests over the 28 days of treatment than have to have constant blood tests for the rest of your life because a HIV virus slipped past the drugs and integrated.
You should advise your doctor of any herbal remedies or supplements you are taking before starting any medication. As Isentress® is a relatively new drug it is likely there are other drugs it will react with in a negative way that are not yet known. If you feel unwell after taking another medication in combination with Isentress® inform your doctor immediately. If that medication is non-essential stop taking it immediately. If it is essential seek urgent medical advice regarding how to proceed.
Additional information
As Isentress® has only been approved for human use for less than ten years there is still a good deal to learn about how exactly it acts on the virus. Studies have shown surprising results with Isentress® notably that while the intergrase was thought to only cause integration into the human genome, blocking it resulted in viral loads falling faster with Isentress® than with the nucleoside reverse transcriptase inhibitors or the protease inhibitors. As both of these alternatives directly impact on viral replication, it would suggest that the intergrase has a more essential role in HIV replication that previously thought.
Work on other viruses, notably Hepatitis B (HBV) and Epstin-Barr virus have shown that despite being designed for HIV, Isentress® may be effective against a much wider range of viruses. Like Viread, Isentress® can cause a rebound effect in HBV sufferers as it is believed to lower HBV loads which recover when PEP treatment is stopped causing a bout of acute hepatitis. While not approved for treatment of HBV there are clinical trials currently assessing its effectiveness against HBV and it may offer hope in future for HBV sufferers.
Epstine-Barr virus (EBV) is a member of the Herpesviridae family (Lymphcrytovirus Human herpesvirus 4) and causes glandular fever (also known as infectious mononucleosis, mono or the kissing disease). It is one of the most common viruses and as well as being known for causing post-viral chronic fatigue, it is less well known as a risk factor in various cancers, notably gastric cancer and a variety of blood cancers (lymphoma) and autoimmune diseases such as lupus, rheumatoid arthritis and multiple sclerosis. Preliminary clinical trials with Isentress® suggest that the drug may be successful in reducing the severity of EBV-associated multiple sclerosis. If trials prove successful, it will lead to a very exciting possibility of treatment for this horrific disease, and perhaps many others.
It is a wonderful example of cross-discipline drug development where eagle-eyed doctors noticed a correlation between use of a drug for one purpose and followed through with their observations. The result of which is a HIV drug that not only provides hope for those with HIV, but spreads out to potentially treat cancer and autoimmune disease as well.
Watch this space, very exciting developments going on.
For more information see:
WebMD – Isentress®
http://www.webmd.com/drugs/2/drug-149324-1036/isentress-oral/raltegravir-oral/details
Isentress® product information.
https://www.isentress.com/raltegravir/isentress/consumer/hiv_medication/
Information on use of Isentress® in treatment of relapsing Multiple Sclerosis
HIV PEP Drugs: Viread® (tenofovir) nucleotide analogue reverse transcriptase inhibitor (NRTI)
Tenofovir (Viread®) was invented by Antonín Holý from at the Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic and patented in 1984, making this one of the earliest antiviral drugs. In collaboration with Gilead Sciences and the University of California, it was developed into its current form and was approved for use against HIV in 2001. It is now also being used for the Post-Exposure Prophylaxis of HIV.
Viread® is a defective nuclease that lacks the OH- group of the deoxyribose sugar. Because of this lack, when the Viread® particle is incorporated into the DNA strand, no other deoxyribose sugars can be added, terminating production. Viread® does not interact well with human DNA polymerases and so does not have a large effect on normal cell replication. It does interact with the viral reverse transcriptase that changes the viral RNA into DNA, preventing viral replication in the host cell.
Side effects
The most common side effects with Viread® are gastrointestinal upsets such as loss of appetite, stomach ache, nausea, gas, cramping, diarrhoea and vomiting. Patients can also experience a skin rash, insomnia, headaches, dizziness and depression.
Like Emtriva® it can cause lactic acidosis so patients should be on the look out for sore muscles for no reason, fatigue, chills in the limbs and irregular heartbeat or trouble breathing. Lactic acidosis can be fatal if left untreated so it is important to seek urgent medical care should you start to exhibit these symptoms. Be aware this is a rare side effect.
Liver toxicity can occur so watch for jaundice, dark urine, light stools and fatigue. Viread® has also been linked to decreases in bone mineral density so it may be wise to speak to your doctor about supplements while taking Viread®.
Contraindications
People with pre-existing liver damage should be carefully monitored while taking Viread®, particularly those with viral hepatitis.
Lactic acidosis is more commonly seen in females, people who are overweight and those who have been taking HIV medication for an extended period of time.
Alcohol can exacerbate liver conditions so it is best to avoid heavy drinking while taking Viread®. The drug has been shown to increase symptoms of hepatitis for those suffering viral hepatitis B (HBV), though the drug itself has been approved for treatment of the HBV under controlled conditions. Be sure to inform your doctor if you have HBV so that the correct dose can be administered and liver function monitored. Patients with HBV have shown a significant increase in pathological symptoms following discontinuation of Viread® so should be monitored when coming off the course.
Those with a history of osteoporosis or other bone disorders should speak to their doctor before taking Viread®.
There is no evidence to say that Viread® is dangerous during pregnancy but insufficient data to claim it is safe. As a consequence, it should be given only in the utmost need to pregnant women. Viread® is transmitted through the breast milk, as is any live HIV virus and it is advised that those women on Viread® do not breastfeed.
Drug interactions
Due to the method of clearance from the body via the kidneys it is advised that you avoid mixing Viread® with nephrotoxic (nephron=kidneys) drugs. Viread® has not been linked to kidney failure but it is still advised that kidney function is monitored. It is recommended for patients on didanosine that the didanosine is reduced or discontinued while as Viread® will increase didanosine bioavailability which can cause damage to the kidneys or pancreas.
Viread® should not be given along with HEPSERA.
Viread® is not the only drug to contain tenofovir and it is important to ensure the correct dose. Inform your doctor if you are taking any other anti-HIV medications to prevent overdosing. Often increasing the dose will not increase effectiveness against HIV but will exacerbate the side effects so it is important not to double up.
There is some evidence to show that Viread® bioavailability levels are boosted by the presence of Kaletra® in the patient’s system.
Additional information
Viread® is one of the oldest anti-HIV drugs and as it acts on the DNA itself rather than a protein, resistance is rare though it does occur. It is listed on the World Health Organisations list of essential medicines for the treatment of HIV and has proved its worth in the fight to stem the tide of AIDS.
Recent studies show that Viread® may have a larger role to play than just as an anti-HIV drug. Patients with HBV have shown a reduction in viral load when taking Viread® and some have been shown to clear the HBV virus entirely from their system when taking Viread®. Despite this FDA has not approved Viread® for treatment of co-infection with HIV and HBV, concerned about the hepatotoxicity (hepato = liver) of Viread®. The situation is very different in Britain where Viread® is the first drug of choice for treating HIV and HBV co-infection.
The jury is still out on which approach is the correct one. This older of the HIV drugs may well give hope to those who are suffering a chronic HBV infection. Hepatitis C can now be cured in up to 80% of cases with correct administration of anti-virals. It may be that a solution to HBV is on the horizon.
For more information see:
WebMD – Viread
http://www.webmd.com/drugs/2/drug-22106-6330/Viread®-oral/tenofovir-oral/details
Gilead Sciences product information sheet – Viread
http://www.gilead.com/~/media/files/pdfs/medicines/liver-disease/Viread®/Viread®_pi.pdf
HIV PEP drugs: Emtriva® (emtricitabine) reverse transcriptase inhibitor
Emtricitabine was developed as a combined effort between Dr. Dennis C. Liotta, Dr. Raymond F. Schinazi, and Dr. Woo-Baeg Choi at Emory university and was patented by Emory through Triangle Pharmaceuticals under the trade name of Emtriva® in 1996. Triangle Pharmaceuticals has been owned by Gilead Sciences since 2003.
Emtriva®™ targets the HIV protein reverse transcriptase. By inhibiting this protein, it prevents the virus from converting its viral RNA into DNA that can be read by the host cell, halting the virus replication process. This drug is now being used in both HIV treatment as well as prevention in HIV PEP therapies.
Side effects
Emtriva®™ has relatively few side effects compared to other anti-HIV drugs. Most common side effects are diarrhoea and other gastrointestinal upsets. Insomnia, fatigue and depression can be associated with Emtriva® in some patients as well as dizziness and headaches. Rashes can occur as the result of a mild allergic reaction and skin discolouration has been seen in some patients, most commonly in those with dark skin and in children. Like Kaletra®, Emtriva® can cause redistribution of body fat from the limbs to the torso.
The serious side effect of Emtriva® is the rare development of lactic acidosis where toxic lactic acid builds up in the muscles resulting in short-term muscle aches similar to those seen after exercise. This condition, if left untreated, can be fatal and you should consult your doctor if you experience unusual muscle aches along with fatigue and difficulty breathing.
Emtriva® is metabolised by the liver and can cause liver disease. Jaundice (yellowing of skin and eyes) is a sign of liver damage and you should seek medical assistance immediately if you notice any yellowing of skin or eyes. Other signs to watch for are darkening urine, going off your food, nausea, light coloured stools and abdominal pain.
Contraindications
Emtriva should not be taken by those who have shown allergies to drugs of a similar class. This drug is metabolised by the liver and so can exacerbate hepatitis. It is not approved for use in patients with Hepatitis as it may escalate prior liver damage. The same advice is given for patients with kidney disease or elderly patients as Entriva is eliminated from the body by the kidneys and may put added stress on this organ.
Alcohol use should be limited while on Entriva as the breakdown of alcohol will also stress the liver. Patients with Hepatitis should be monitored while on Entriva. While there have been case studies that show Entriva is effective against the Hepatitis B virus, others have seen a severe escalation in liver dysfunction and it is not currently approved for treatment of Hepatitis B.
Lactic acidosis is a rare side effect of Emtriva but is more likely to occur in patients that are overweight, female or who have been taking Emtriva or similar drugs for an extended period of time.
Current studies suggest that Emtriva does not harm a developing foetus and should be safe for use in pregnancy but there is not sufficient data to say it is definitely safe. As such it is suggested that Entriva is used only when absolutely necessary should the patient be pregnant. Entriva is secreted in breast milk and live HIV virus can be transmitted via breast milk even when the patient is taking antivirals. It is advised that patients taking Entriva do not breastfeed their infants.
Drug interactions
Emtriva should not be taken along with other reverse transcriptase inhibitors such as lamivudine so it is essential you inform your doctor if you are taking any other anti-HIV drugs so they can ensure the correct dose. Other drugs may interact with Emtriva, make sure you inform your doctor of any medication or supplements you are taking.
Additional information
Emtricitabine is listed as an essential medicine by the World Health Organisation (WHO). It is one of the pioneer drugs in the fight against the spread of AIDS and its relatively few side effects and high safety profile make it a drug of choice for nuclease inhibitors.
As it acts against a viral protein that is able to mutate there are strains resistant to Emtriva, notably the M184V mutation (this means that the 184th amino acid in the protein has mutated from a methionine to a valine). Resistant strains are commonly seen in those who have been taking Emtriva or the closely related lamivudine for long periods. Those with resistant strains may need to be put on a different class of nuclease inhibitor such as Retrovir or Viread.
Emtriva has shown some effectiveness in the treatment of Hepatitis B virus (HBV) and some doctors will prescribe Emtriva for patients withHBV. However, due to the exacerbations of liver illness, treatment of HBV with Emtriva can cause symptoms to worsen. It is a case of which is worse, the virus or the effects of hepatitis. Because of liver toxicity Emtriva is not recommended or approved for treatment of HBV despite possible antiviral properties.
For more information see:
WebMD – Emtriva
http://www.webmd.com/drugs/2/drug-76365/Emtriva®+oral/details#precautions
Gilead Sciences product information sheet – Emtriva
http://www.gilead.com/~/media/files/pdfs/medicines/hiv/Emtriva®/Emtriva®_pi.pdf
HIV PEP drugs: Kaletra® (lopinavir/ritonavir) viral protease inhibitors
The HIV PEP designer drug Kaletra® (LPV/r) contains the two HIV viral protease inhibitors lopinavir (LPV) and ritonavir (RTV) [Norvir®]. Developed by Abbott laboratories in 2000, it is referred to as a designer drug as it was specifically formulated based on X-ray crystallography structures to specifically target the HIV protease.
Both lopinavir and ritonavir inhibit the viral protease, but the genius behind Kaletra® is the combination dose that allows the two drugs to work in synergy. Ritonavir has toxic side effects at the levels required for it to inhibit the protease on its own while lopinavir struggles to maintain biological activity in the body. Abbott Laboratories discovered that at low dose ritonavir increases the activity of lopinavir by increasing the amount of the drug that remains biologically active and able to inhibit the HIV protease. The combination drug Kaletra® is able to produce a greater effectiveness at a lower dose for both drugs than they are able to achieve on their own.
Side effects
The lower dose in Kaletra® does reduce the side effects but does not eliminate them. Common side effects from Kaletra® include nausea, headaches, muscle pain particularly in the back, vomiting, dizziness, heartburn, redistribution of weight from limbs to the torso and itchy skin. Severe and even fatal allergic reactions have been seen with this drug and it is advised to seek emergency medical assistance should a skin rash appear on taking Kaletra®.
Contraindications
Kaletra® like many medications can stress the liver. If you have liver disease you should check with your doctor prior to taking this medication. Yellowing of the skin and eyes (jaundice) is an early warning sign of liver damage. Seek medical assistance should you notice jaundice appearing. Diabetes is another condition that needs to be monitored carefully while taking Kaletra®. Irregular heart beat may occur and patients with pre-existing heart conditions should be closely monitored.
The drug can cause an increase in sugar levels so care should be taken to monitor levels carefully in diabetics. Those who are not diabetic can start to show symptoms similar to diabetes while on this drug. Watch for increased thirst, increase in the need to urinate, fatigue, dizziness, fainting, blurred vision and fruity smelling breath. Hyperglycaemia (too much sugar in the blood) if unchecked can lead to coma and death even if the patient is not diabetic. Patients with pancreatitis, haemophilia and low potassium levels should also speak to their doctor about possible alternatives.
Pregnancy or breastfeeding should always be discussed with your doctor before starting any new medication. It is not advisable to take Kaletra if breastfeeding and a different dosing strategy is required during pregnancy.
Drug interactions
As well as complicating existing medical conditions and uncomfortable side effects, Kaletra® interacts with other drugs. Your doctor will provide you will a full list should you start taking this drug and you should advice of all drugs you are taking including herbal remedies. Kaletra® is known to interact with hormone treatments and decrease their efficiency, the pill may not work as well and extra care such as using condoms is advised as contraception while using this drug. Herbal remedies can contain strong drug compounds. It is not advisable to take St John’s wort for example while on Kaletra®. Your doctor or pharmacist can advise you on other herbal remedies that you may be taking.
Additional information
The development of Kaletra® has not been without its share of controversy. The patent held by Abbot Laboratories will not expire until 2016. The expense of the drug led the Thai government to ignore the patent and authorise the import of generic versions in 2007, reported in the Financial Times (By Amy Kazmin in Bangkok and Andrew Jack in London March 17, 2007). Abbott Laboratories responded by removing their drug from the Thai market, with resulting backlash from global NGOs. Attempts by India to follow suit left them with an inferior product (Financial Times, Andrew Jack, August 1, 2008).
The funds required to research and develop a drug such as Kaletra® are not small. Designer drugs such as Kaletra® where expensive and time-consuming studies are performed are a risky enterprise. Most designer drugs fail, either due to function or to toxicity in human trials. The patent laws are meant to ensure that the company that does the work benefits from the success of the drug. Some argue that this gives the company a monopoly and when that drug means the difference between life and death the company can in effect hold a person’s life ransom with the cost of the drug. It cannot be doubted that companies have done this in the past. From the point of view of the Thai government, they were doing what they thought necessary to save the lives of their people. From the point of view of Abbott Laboratories, they see a drug they have likely spent a decade and millions of dollars perfecting, being given to a competitor for free to profit from. The politics surrounding the global distribution of Kaletra® is a good example of the conflict between the needs of a business to be profitable and the needs of the people for treatment at a reasonable cost.
For more information see:
WebMD – Kaletra
http://www.webmd.com/drugs/2/drug-19939-542/kaletra-oral/lopinavir-ritonavir-oral/details#uses
Kaletra product information.
The World of Antiretrovirals
In the 1980’s diagnosis with HIV was a death sentence. In 1995 in the USA, it was the highest cause of death in the age range 25-44 years. Nowadays HIV is a life sentence, but a relatively painless one. Anti-retroviral therapy (ART) has ensured that the virus is kept locked away in the host DNA, never to be seen more in most cases.
From no treatment available in 1983 to more than 40 retroviral inhibitors in 2015, with more in the works, scientists are staying one step ahead of emerging resistance. The death toll from HIV continues to plummet. Anti-retrovirals consist of a wide range of drugs that target different stages of the virus lifecycle.
Stage 1: Invasion
The first thing the virus needs to do to effect a successful infection is get into the cell. This stage is thwarted by the entry inhibitors, notably maraviroc (MVC) and enfuvirtide (T-20).
Maraviroc binds to the host cell receptor that the HIV virus binds to before working its way into the cell. It is not a common treatment. The binding of Maraviroc to the cell can open up a secondary binding site, allowing the HIV to attach regardless. The drug also has liver toxicity issues. It has however been approved by the FDA for human use and is a fallback when other drugs prove ineffective.
Enfuvirtide acts on the virus rather than the host cell, binding to the gp41 protein that HIV uses to attaches to the cell, inactivating it and stopping invasion of the cell before it starts. As with Maraviroc, it is used as a ‘salvage therapy’ rather than the first port of call due to its high cost and the fact it can only be administered as an injection.
Stage 2: Transcription
HIV is a retrovirus, which means that the virus genome is made of RNA rather than DNA. In order to replicate it needs to transcribe the RNA code into the DNA used by mammalian cells for genomic content. Mammalian cells only transcribe DNA to RNA, not the other way around. The protein needed to transform the RNA into DNA has to be provided by the virus. It makes a good place for scientist to target as the fact that it is not a protein seen in humans reduces the risk of side-effects.
The Nucleoside (or Nucleotide) analogue reverse transcriptase inhibitors (NRTI). NRTIs are specialised nucleosides, the building blocks of DNA, lacking the essential hydroxy group on its 3’ end. Lack of this group prevents it from binding to another nucleoside and stops the construct of the DNA strand cold. Without this DNA strand the virus is unable to trick the host cell into replicating viral the viral genome. The NRTIs are the most effective anti-retroviral therapies and include some of the oldest anti-retroviral among their number. Examples include zidovudine (ZDV), abacavir (ABC), lamivudine (3TC), emtricitabine (FTC), and tenofovir (TDF).
Non-nucleoside analogue reverse transcriptase inhibitors (NNRTI). NNTRIs are drugs that target the viral reverse transcriptase directly rather than targeting the process. By binding the viral protein near the active site they change the structure of the active site, so it cannot bind nucleosides and catalyse the formation of DNA from the RNA viral genome. Examples include nevirapine (NVP), efavirenz (EFV), etravirine (ETR) and rilpivirine (RPV).
The virus is not able to change the building blocks of DNA so resistance to NRTIs is uncommon, however, it can change the structure of the reverse transcriptase protein. HIV-2 is naturally resistant to NNRTIs.
Stage 3: Integration
A viral infection that destroys all the cells it is able to infect does not have a long lifespan. To ensure it lives to fight another day, the virus does not destroy all the T-cells in invades. In some instead of taking over the cellular machinery to make thousands of copies with the transcribed DNA, it inserts its own DNA into the host cell genome using a viral protein known as an integrase.
In 2007, the drug raltegravir (RAL) was approved by the FDA. Raltegravir binds in preference to the native substrate, i.e. if there is any raltegravir nearby the integrase will select that before the host genome it is meant to target. In this way, it uses up all the integrase before the virus can insert into the genome. In 2014 two more integrases inhibitors were approved for use, elvitegravir (EVG) and doultegravir (DTG).
Stage 4: Virus production
Once the viral DNA has been transcribed and integrated the virus needs to then make more copies of itself. It does this by tricking the host cell to replicate the viral RNA genome and proteins in preference to its own functions, killing the cell in the process. The viral proteins are made as one long peptide (protein) chain called the gag/pol precursor and this is cut up by a viral protease (enzyme that cuts proteins) to separate the individual proteins into their active form.
The protease inhibitor antiretroviral drugs target this stage of the virus lifecycle, preventing the protease activity and activation of viral proteins. Protease inhibitors include lopinavir (LPV), indinavir (IDV), nelfinavir (NFV), amprenavir (APV) and ritonavir (RTV). Due to high mutation rates of the viral genome and high tolerance for mutation in the viral protease, this category of drugs suffers the most from emerging resistance.
The drugs are used as combinations to target multiple stages in the viral cycle and reduce the incidence of resistance. They are used in combination to target the virus at all stages of infection, commonly 2 NRTIs in combination with either a NNRTI, a protease inhibitor or an integrase inhibitor.
Different combinations are preferred for different situations. One of the earliest NRTIs Zidovudine (first approved 1989) has been shown to be incredibly effective in reducing the viral load in pregnant women to prevent transmission to the baby during birth. Use of Zidovudine has reduced transmission of HIV to the baby during birth from 30% of cases down to 2%.
The pre-exposure prophylaxis (PrEP), taken by those at high risk of encountering HIV is a combination of tenofovir and emtricitabine marketed as a one dose combination therapy under the name of Truvada® by Gilead Sciences. This drug has been shown to be safe for people ages 12 years and older and in various studies have shown that a daily dose reduces the risk of contracting HIV by up to 75% in high-risk individuals. Truvada is also recommended for post-exposure prophylaxis (PEP) though this can vary depending on doctor, socio-economic considerations and regional resistance, other combination therapies can be equally effective.
The first one dose combination therapy was developed by GlaxoSmithKline in 2007. Called Combivir® it contained a combination of lamivudine (3TC) + zidovudine (ZDV). As of February this year, eleven other single dose combination therapies had become available. This may seem a small breakthrough but it increases the likelihood that people will continue to take their medications and stay virus free, reducing the costs to the healthcare system, increasing peoples work life and reducing the risk of spreading via sexual contact. These miracle pills did what antibiotics did in the 1950’s, turned a killer into a mere inconvenience. With ongoing research this inconvenience lessens each year and with the blessing of hindsight we know how to reduce the threat of resistance. With good management, extensive education and ongoing research, AIDS may one day join smallpox and polio as a disease of interest only to historians.
New York State Department of Health AIDS Institute recently updated their HIV PEP guidelines
The New York State Department of Health AIDS Institute (NYSDHAI) recently tasked their Medical Care Criteria Committee (MCCC) to update their HIV PEP (Post-exposure Prophylaxis) guidelines. PEP refers to the treatment required and administered after exposure to HIV – a sexually transmitted disease (STD). This exposure is categorised as resulting from sexual assault, occupational exposure, and non-occupational exposure.
In 2012, the recommended medications for post-exposure treatment was the use of tenofovir [Viread®] with emtricitabine [Emtriva®] (or lamivudine [Epivir®]) and raltegravir [Isentress®] – due mainly to the higher rate of completion of the shorter 28-day course of treatment. In 2014, however, dolutegravir [Tivicay®] was added as an alternative to raltegravir [Isentress®]. Dolutegravir is an approved antiretroviral drug designed to block the action of the virus. This change was initiated to further improve the rate of completion of the course of medication based on the side-effects and dosage requirements of dolutegravir [Tivicay®] which have displayed improved tolerability.
The MCCC reported that the efficacy of the above mentioned medications may be compromised when taken alongside aluminium, calcium, iron, or magnesium. Being mindful of the presence of these minerals in food and over the counter antacids was particularly emphasised. As such it was stated that antacids should be taken a minimum of 2 hours before and 6 hours after the medication to receive the maximum benefits of the drugs.
Due to the 6 week window period during which the virus can spread undetected, the committee expressed the need to perform a laboratory blood test (HIV RNA test) even if the patient tests negative during the initial screening test. A newer fourth-generation HIV test was suggested for a more accurate result and the importance of all patients being tested was emphasised.
The recommendations stated that PEP must, as a matter of urgency, begin within 2 hours after exposure while awaiting results of the patient’s baseline tests. Baseline testing refers to the initial tests conducted and includes an immune function test (CD4 count); HIV replication test (viral load); kidney, liver, cholesterol, and blood cell tests; and tests for accompanying viruses or diseases. Baseline testing is required even in cases where PEP treatment is declined.
It was further recommended that patients receive access to psychological counselling and support in order to improve their adherence to guidelines and provide the necessary framework for the completion of treatment.
The committee later updated their recommendations to include further HIV testing at 4 weeks and 12 weeks after exposure and added that routine testing at 6 months is unnecessary in the event that the 12 week test yields a negative result for the presence of HIV. It was clarified that pre-exposure treatment should be explained and made available to individuals who display high-risk sexual activity in the case of non-occupational exposure.
In a public announcement in April 2015, the Governor of New York revealed a detailed plan to reduce new HIV infections. The Blueprint to End the AIDS Epidemic outlines the plan which requires changes to regulation, and a critical look at the state of existing medical infrastructure in order for implementation to be successful.
The uniting feature of similarity between the Governor’s announcement and the Committee’s recommendations was the emphasis on promoting education among both medical personnel and the general public. Numerous campaigns have been launched to this end including the distribution of resources to the relevant clinics and a written inventory of the resources available. The underlying factors for success in reducing HIV infections remains in the availability of resources, education, and expenses.