Posts Tagged → #emtricitabine

HIV PEP drugs: Emtriva® (emtricitabine) reverse transcriptase inhibitor

Guid To HIV PEP Drugs - Emtriva

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

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.

HIV prevention: The Emerging Prevention Regimen from Post-exposure to Pre-exposure Prophylaxis

Like vaccinations for life-threatening diseases such as Hepatitis B and Tetanus, the HIV virus could be tackled more efficiently with the presence of a vaccination for this disease. Researchers have been successful in developing a pre-exposure prophylaxis (PrEP) for HIV which is now a leading development towards finally creating a vaccine. Pre-exposure prophylaxis is a combined treatment for the HIV retrovirus that is efficient in protecting people exposed to HIV from developing an infection. This information was very recently reported in Clinical Infectious Diseases, a scientific journal dedicated to infectious diseases.

HIV post-exposure prophylaxis (PEP) which has been in use for a long time, is given to individuals within 72 hours of an exposure to HIV. PEP is a 28-day medication that is a combination of 2-3 antiretroviral drugs. Studies have shown that patients receiving PEP are still at a higher risk of acquiring HIV. People who have a continuous exposure to HIV like injection drug users and people having multiple sexual partners are recommended to use PrEP. PrEP users are reported to have a lower risk of acquiring HIV when compared to PEP. It is, however, highly recommended to avoid the risk of exposure altogether.

The regimen for the PrEP is tenofovir-emtricitabine. This is the only combination approved by the FDA, USA, for PrEP at the moment. It is given either daily or intermittently for a longer period of time, unlike PEP.

People who have already been administering PEP and have a seronegative profile for HIV retrovirus are candidates for PrEP. According to CDC PEP guidelines, a person who has been exposed and administered with PEP can only be considered infection-free after a six-month HIV testing protocol. These candidates who have had PEP and are seronegative will benefit best with PrEP. People who continue to have high-risk exposure to HIV should be started with PrEP earlier than the 4-6 months profile for HIV.

More recently, the US Public Health Service guidelines suggest that if the HIV profile is negative in the preceding 4 weeks and the person is not having any signs and symptoms for HIV he/she can be started on PrEP.

One interesting question addressed by the report is who will be prescribing PrEP to patients. As there is no consensus to date for the specific position which should prescribe PrEP, it is currently prescribed by emergency care departments, the primary physicians and of course by HIV specialists treating the disease.

Although the side effects of PrEP and PEP are not very debilitating, PrEP should be administered with care in patients with bone diseases and renal insufficiency. The use of the tenofovir-emtricitabine combination is known to cause osteopenia, a condition in which bone mass decreases. Patients infected with Hepatitis B should be monitored closely for fulminant acute hepatic failure due to PrEP.

With PrEP, a 3-6 month screening for STI is recommended, especially for people living a high-risk sexual lifestyle.

Source:

Jain et al. The Transition From Postexposure Prophylaxis to Preexposure Prophylaxis: As Emerging Opportunity for Biobehavioural HIV Prevention. CID, 2015.

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.