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Enfuvirtide - For Drug-Resistant HIV Infection

What is Enfuvirtide? 

Enfuvirtide, also called Fuzeon® or T-20, is a drug used for antiviral therapy. It is manufactured by Roche and Trimeris. Enfuvirtide was approved recently by the FDA, March 2003.Enfuvirtide is the first "fusion inhibitor" drug. When HIV infects a cell, it attaches to the outside of the cell. Then it "fuses" or joins itself with the cell. Enfuvirtide stops this process of fusion. This means that HIV cannot infect that cell.

Fuzeon, a drug submitted by Roche and Trimeris to FDA for review in September,16, 2002 and grated a priority review (six months), is a very difficult drug to make, requiring 106 steps to produce the active substance. Fuzeon is a very expensive drug costing up to $20,000 a year. Fuzeon is targeted for patients with drug-resistant strands of the virus, and be used in combination with other drugs. Fuzeon is the first in a class known as fusion inhibitors, which are designed to block HIV from entering blood cells. It acts on the third stage of that entry process, known as fusion.

Who should take the Enfuvirtide?

Naturally, one should take the advice from one's doctor. The doctor and the patient should consider the patient's T-cell count, viral load, any symptoms the patient is having, and the patient's attitude about taking HIV medications. 

T-cells are a type of lymphocyte (white blood cell). They are an important part of the immune system. There are two main types of T-cells. T-4 cells, also called CD4+, "helper" cells. They lead the attack against infections. T-8 cells, (CD8+), are "suppressor" cells that end the immune response. CD8+ cells can also be "killer" cells that kill cancer cells and cells infected with a virus. Researchers can tell the T-cells apart by specific proteins on the cell surface. A T-4 cell is a T-cell with CD4 molecules on its surface. This is why that this type of T-cell is called "CD4 positive", or CD4+.

The viral load test measures the amount of HIV virus in your blood. There are different techniques for doing this:

Viral loads are usually reported as copies of HIV in one milliliter of blood. The tests count up to about 1.5 million copies, and are always being improved to be more sensitive. (see sensitivity definition below) The first bDNA test measured down to 10,000 copies. The second generation could detect as few as 500 copies. Now there are ultra sensitive tests that can detect less than 5 copies. Be aware of that the PCR test results are often different from the bDNA results for the same sample. 

The best viral load test result is "undetectable". This does not mean that there is no virus in your blood; it just means that there is not enough for the test to find a count. With the first generation test, "undetectable" could mean 9,999 copies. "Undetectable" depends on the sensitivity of the test used on your blood sample.

Reference for more information: http://www.aidsinfonet.org/articles.php?articleID=404  

How is the drug administered?

If Enfuvirtide is swallowed, it is destroyed by stomach acids. This means that it cannot be taken in pill form. Enfuvirtide is injected just under the skin. This is called a "subcutaneous" injection. Enfuvirtide is injected twice a day. It will most likely be used by people who have run out of choices to use antiviral medications in pill form. The adult dosage of Enfuvirtide is 90 mg per injection, twice a day. The dosage for children is based on their body weight. If one's doctor prescribes Enfuvirtide, one should be shown how to prepare such injection, and how and where to inject it.

What does drug-resistance mean?

Enfuvirtide is a new class of antiviral drug. This means that it is active against HIV that has developed resistance to any other antiviral drug. However, it cannot be used by itself. It must be combined with other antiviral drugs.

If you take Enfuvirtide with other antiviral drugs, you can reduce your viral load and increase your T-cell counts. This means possibilities of  staying healthier longer.

HIV is "resistant" to a drug if it keeps multiplying rapidly while you are taking the drug. Changes (mutations) in the virus cause resistance. The HIV virus is tricky when it makes copies of its genetic code (RNA). Many new copies of HIV are mutations: they are slightly different from the original virus. Some mutations can continue to multiply even when you are taking an antiviral drug. When this happens, the drug will stop working. This is called "developing resistance" to the drug. Not every mutation causes resistance. The "wild type" virus is the most common form of HIV. Anything different from the wild type is considered a mutation.

Resistance to Enfuvirtide can develop quickly if it is taken by itself. With combination therapy (taking more than one antiviral drug at the same time), HIV mutates much more slowly. Resistance takes longer to develop. It is very important to take antiviral medications according to instructions, on schedule, and not to skip or reduce doses.

Sometimes, if one developed resistance to one drug, one would also have resistance to other antiviral drugs. This is called "cross-resistance". Enfuvirtide has been tested and there is no known interaction with other anti-HIV medication. However, as for any new drugs, there is no complete test with all medicines, especially over-the-counter drugs or vitamins or herbal supplements. Always be sure to let one's doctor know about all medications and supplements that one is taking..

Reference for more information: http://www.aidsinfonet.org/articles.php?articleID=126

Is there any side-effects with Enfuvirtide?

A detailed discussion on side effects with anti-viral drugs can be found in the reference below. The most common side effects of Enfuvirtide are skin reactions where the drug is injected. Almost everybody who uses Enfuvirtide gets these reactions. They can be very mild, such as slight redness. They can include itching, swelling, pain, hardened skin, or hard lumps. Each reaction might last up to a week. With two injections each day, people using enfuvirtide might have reactions at several spots on their body at the same time. The most common other side effects of Enfuvirtide are headache, pain and numbness in feet or legs, dizziness, and loss of sleep.

Reference for more information on side effects: http://www.aidsinfonet.org/topic_index.php?category=550&subcategory=true

Prevention of HIV infection

Casual sexual activities, use of drugs (injection) and blood contact are the major causes of HIV infection. Babies can be born with HIV infection. With no treatment, about 25% of the babies of HIV-infected women would be born infected. The risk drops to about 2% if a woman takes AZT (Chemical Name: Azidothymidine, Generic Name: Zidovudine, Nick Name: AZT, Brand Name: Retrovir ® (Retrovis ®), Manufacturer: Glaxo-SmithKline) during pregnancy and delivery, and then her newborn is given AZT, and if the baby is delivered by Caesarian section (C-section.). Babies can get infected if they drink breast milk from an HIV-infected woman. Women with HIV should use baby formulas or breast milk from a woman who is not infected to feed their babies. The following are explanations that are helpful for understanding prevention of HIV infection.

The Human Immunodeficiency Virus (HIV) does not spread easily. You can only get HIV if you get infected blood or sexual fluids into your system. (Hence safe sex and avoiding drug are most important) You can't get it from mosquito bites, coughing or sneezing, sharing household items, or swimming in the same pool as someone with HIV. (Hence never justified to be hostile to the unfortunate HIV-infected people) 

Some people talk about "shared body fluids" being risky for HIV, but no documented cases of HIV have been caused by sweat, saliva or tears. However, even small amounts of blood in your mouth might transmit HIV during kissing or oral sex. Blood can come from flossing your teeth, or from sores caused by gum disease, or by eating very hot or sharp, pointed food.

To infect someone, the virus has to get past the body's defenses. These include skin and saliva. If your skin is not broken or cut, it protects you against infection from blood or sexual fluids. Saliva contains chemicals that can help kill HIV in your mouth.

If HIV-infected blood or sexual fluid gets inside your body, you can get infected. This can happen through an open sore or wound, during sexual activity, or if you share equipment to inject drugs.

Tests for HIV infection

If you become infected with HIV, it usually takes between three weeks and two months (About 5% of people take longer than two months to produce antibodies; a confirming test six months after exposure is a good idea) for your immune system to produce antibodies to HIV. If you think you were exposed to HIV, you should wait for two months before being tested. You can also test right away and then again after two or three months. During this "window period" an antibody test will give a negative result, but one can transmit the virus to others if one were infected.

HIV testing tells you if you are infected with the Human Immunodeficiency Virus (HIV) which causes AIDS. These tests look for "antibodies" to HIV. Antibodies are proteins produced by the immune system to fight a specific germ. Other "HIV" tests are used when people already know that they are infected with HIV. These help measure how quickly the virus is multiplying (a viral load test) or the health of your immune system (a T-cell test) as discussed above. Viral load tests detect pieces of HIV genetic material. They show up before the immune system manufactures antibodies.  In early 2002, the FDA approved "nucleic acid testing." It is similar to viral load testing. Blood banks use it to screen donated blood. Although these tests can give an early indication of HIV infection, however, they are generally not used to see if someone has been infected with HIV because they are much more expensive than an antibody test. They also have a slightly higher error rate.

Antibody test results for HIV are accurate more than 99.5% of the time. Before you get the results, the test has usually been done two or more times. The first test is called an "EIA" or "ELISA" test. Before a positive ELISA test result is reported, it is confirmed by another test called a "Western Blot".

ELISA

The ELISA is considered the best available screening because of its low cost, standardization, high reliability, and relatively quick turn-around. Numerous versions of this test have been licensed by the Food and Drug Administration since 1985. The price of each ELISA test kit is inexpensive  but the costs of performing an ELISA may vary from institution to institution.

In recent years, refinements have been made to the ELISA to prevent cross-reactions to antibodies other than HIV and to prevent other false results. Currently, most versions of the ELISA use inactivated HIV viral proteins--or HIV antigen--isolated from cell cultures. Advanced technology is being used to make synthetic HIV antigens that are even more sensitive and specific. In an early study of the ELISA, it was found to have a "sensitivity" of 99.7%. (Sensitivity refers to the rate of false negative results) In the case of the ELISA, this means that 99.7% of test samples were correctly diagnosed as positive when antibodies were present, and that 0.3% of test samples--or 3 in 1,000--were falsely diagnosed by the ELISA as negative when HIV antibodies were actually present. The test's "specificity" was 98.5%. (Specificity refers to the rate of false positive results) In the case of the ELISA, this means that 98.5% of negative test samples were correctly diagnosed as negative, and that 1.5% of the test produced positive results when antibodies were not present.

Non-reactive results can occur in someone with HIV infection when testing is done before the body has produced antibodies to HIV--a time known as the "window period"--or when a person is late in the course of AIDS, at which time the body may stop producing antibodies. In addition, some ELISAs are specific only to antibodies to HIV-1, the primary strain of HIV infection found in the United States. Another virus, HIV-2 (MWSearch expansion: HIV-2; HTLV-IV; Human Immunodeficiency Virus Type 2; Human T-Lymphotropic Virus Type IV; LAV-2; SBL-6669; human immunodeficiency virus 2; HIV-II) is found in some African countries, but very rarely in the United States. 

False positive screening results, on the rare occasions occurring, may result from biological variations in the way a blood sample responds to a test, human laboratory errors, or health conditions such as hemophilia, autoimmune disorders, and alcohol- related hepatitis. Because false positive results can occur, a supplemental test is always necessary to conclude that HIV antibodies are present and to make a diagnosis of HIV infection.

Western Blot and IFA

The Western blot is the most commonly used supplemental test. Compared to the ELISA, it is more expensive, takes longer time to perform, requires greater technical precision, and is more difficult to interpret. As a supplemental test, the overall sensitivity and specificity of the Western blot are considered to be high, at 99.3% and 91.6%, respectively, as analyzed recently by the Centers for Disease Control and Prevention (CDC).

There has been some controversy regarding interpretation of the Western blot and what are considered inconclusive readings. CDC has set specific guidelines regarding the interpretation of results. Interpretation of Western blot results involves reading several bands of reactivity that appear on a test strip. In order for a result to be considered positive, reactivity to certain bands must occur. For a result to be negative, it is necessary that no viral-specific bands show reactivity. In some cases, reactivity will occur, but not to the specific bands required for a positive reading. This result is called "indeterminate" and the overall result is called inconclusive. It is possible that this occurrence could signify early HIV infection or an early stage of seroconversion (MWSearch Expansion: HIV Seropositivity; AIDS Seroconversion; AIDS Seropositivity; Anti-HIV Positivity; HIV Antibody Positivity; HIV Seroconversion; HTLV-III Seroconversion; HTLV-III Seropositivity; SEROPOSITIVE HTLV III) or it could indicate infection with HIV-2. However, quite often when these bands appear, HIV is not present. When a result is inconclusive, a new blood sample is needed from the client. This step is required, for example, by law in California.

While the Western blot has been the most commonly used supplemental test in most parts of the country, the IFA is generally considered to be at least as reliable as the Western blot. A commercial version of the IFA received federal approval in 1992.

The IFA is less expensive and easier to perform than the Western blot. With an IFA, HIV antigens are fixed on a slide and incubated with the test sample. Another antibody is added that reacts to the first complex. Fluorescent spots will appear on the slide if HIV antibodies are present, indicating a positive result.

Other Tests

There are other methods either now available or being developed to detect HIV infection. Recently, there has been increased focus on these tests, particularly those that can be performed relatively quickly and easily outside a laboratory. In some cases, these tests are being considered as possible supplements or replacements to conventional testing methods.

With some rapid methods, test results could be available the same day blood is drawn, perhaps within an hour. However, because positive results need to be confirmed with a more complex test like the IFA or Western blot, both of which require a laboratory, clients could not receive positive results during the same visit. While tests discussed above detect infection based on the presence of antibodies--an indirect method--other tests detect the virus directly. These methods may be helpful at very early stages of infection in some situations when a Western Blot result is indeterminate. For instance, there are some ELISA-based tests that use HIV antibodies to detect HIV antigens, such as p24. This method produces very few false positive results. However, the incidence of false negative results tends to be high. Since more test methods are being developed, one should always inquire what are the differences and costs associated with different tests. Generally, the rapid tests are more expensive than the ELISA.

Mosquitoes Can Not Transmit AIDS

Often people show misconception that mosquitoes can transmit AIDS. No, They can't. The following paragraphs have been reported in the Mosquito, Not Just A Summer Nuisance on this web site. Although mosquito does transmit certain diseases but they don't transmit AIDS. We excerpt a few paragraphs here to clarify a misconception created in the early days when AIDS were discovered. 

Media releases concerning the possibility of mosquitoes transmitting AIDS (Acquired Immune Deficiency Syndrome) were common when the disease was first recognized, and the subject is still addressed by tabloids that seek captivating headlines to increase their circulation. The topic was initiated by reports from a small community in southern Florida where preliminary evidence suggested that mosquitoes may have been responsible for the higher on average incidence of AIDS in the local population. The media was quick to publicize claims that mosquitoes were involved in AIDS transmission despite findings of scientific surveys of the National Centers for Disease Control (CDC) that clearly demonstrated that mosquito transmission of AIDS in that community appeared highly unlikely. Nevertheless, media releases perpetuated the concept that mosquitoes transmitted AIDS, and many people still feel that mosquitoes may be responsible for transmission of this infection from one individual to another.

There are three theoretical mechanisms which would allow blood-sucking insects such as mosquitoes to transmit HIV.

1. In the first mechanism, a mosquito would initiate the cycle by feeding on an HIV positive carrier and ingest virus particles with the blood meal. For the virus to be passed on, it would have to survive inside the mosquito, preferably increase in numbers, and then migrate to the mosquito's salivary glands. The infected mosquito would then seek its second blood meal from an uninfected host and transfer the HIV from its salivary glands during the course of the bite. This is the mechanism used by most mosquito-borne parasites, including malaria, yellow fever, dengue, and the encephalitis viruses.

2. In the second mechanism, a mosquito would initiate the cycle by beginning to feed on an HIV carrier and be interrupted after it had successfully drawn blood. Instead of resuming the partial blood meal on its original host, the mosquito would select an AIDS-free person to complete the meal. As it penetrated the skin of the new host, the mosquito would transfer virus particles that were adhering to the mouthparts from the previous meal. This mechanism is not common in mosquito-borne infections, but equine infectious anemia is transmitted to horses by biting flies in this manner.

3. The third theoretical mechanism also involves a mosquito that is interrupted while feeding on an HIV carrier and resumes the partial blood meal on a different individual. In this scenario, however, the AIDS-free host squashes the mosquito as it attempts to feed and smears HIV contaminated blood into the wound. In theory, any of the mosquito-borne viruses could be transmitted in this manner providing the host circulated sufficient virus particles to initiate re-infection by contamination. 

Each of these mechanisms has been investigated with a variety of blood sucking insects and the results clearly show that mosquitoes cannot transmit AIDS. News reports on the findings, however, have been confusing, and media interpretation of the results has not been clear. The average person is still not convinced that mosquitoes are not involved in the transmission of a disease that appears in the blood, is passed from person to person and can be contracted by persons that share hypodermic needles. Here are just some of the reasons why the studies showed that mosquitoes cannot transmit AIDS:

Mosquitoes Digest the Virus that Causes AIDS

When a mosquito transmits a disease agent from one person to another, the infectious agent must remain alive inside the mosquito until transfer is completed. If the mosquito digests the parasite, the transmission cycle is terminated and the parasite cannot be passed on to the next host. Successful mosquito-borne parasites have a number of interesting ways to avoid being treated as food. Some are refractory to the digestive enzymes inside the mosquito's stomach; most bore their way out of the stomach as quickly as possible to avoid the powerful digestive enzymes that would quickly eliminate their existence. Malaria parasites survive inside mosquitoes for 9-12 days and actually go through a series of necessary life stages during that period. Encephalitis virus particles survive for 10-25 days inside a mosquito and replicate enormously during the incubation period. Studies with HIV clearly show that the virus responsible for the AIDS infection is regarded as food to the mosquito and is digested along with the blood meal. As a result, mosquitoes that ingest HIV-infected blood digest that blood within 1-2 days and completely destroy any virus particles that could potentially produce a new infection. Since the virus does not survive to reproduce and invade the salivary glands, the mechanism that most mosquito-borne parasites use to get from one host to the next is not possible with HIV.

Mosquitoes Do Not Ingest Enough HIV Particles to Transmit AIDS by Contamination

Insect-borne disease agents that have the ability to be transferred from one individual to the next via contaminated mouthparts must circulate at very high levels in the bloodstream of their host. Transfer by mouthpart contamination requires sufficient infectious particles to initiate a new infection. The exact number of infectious particles varies from one disease to the next. HIV circulates at very low levels in the blood--well below the levels of any of the known mosquito-borne diseases. Infected individuals rarely circulate more that 10 units of HIV, and 70 to 80% of HIV-infected persons have undetectable levels of virus particles in their blood. Calculations with mosquitoes and HIV show that a mosquito that is interrupted while feeding on an HIV carrier circulating 1000 units of HIV has a 1:10 million probability of injecting a single unit of HIV to an AIDS-free recipient. In laymen's terms, an AIDS-free individual would have to be bitten by 10 million mosquitoes that had begun feeding on an AIDS carrier to receive a single unit of HIV from contaminated mosquito mouthparts. Using the same calculations, crushing a fully engorged mosquito containing AIDS positive blood would still not begin to approach the levels needed to initiate infection. In short, mechanical transmission of AIDS by HIV-contaminated mosquitoes appears to be well beyond the limits of probability. Therefore, none of the theoretical mechanisms cited earlier appear to be possible for mosquito transmission of HIV. 

Recent Study of Enfuvirtide Treatment in North and South America

A recent study, Enfuvirtide, an HIV-1 Fusion Inhibitor, for Drug-Resistant HIV Infection in North and South America, to be published in the New England Journal of Medicine by Jacob P. Lalezari et al (16 authors) has found the following results:

A total of 501 patients underwent randomization, and 491 received at least one dose of study drug and had at least one measurement of plasma HIV-1 RNA after treatment began. The two groups were balanced in terms of the median base-line HIV-1 RNA level (5.2 log10 copies per milliliter in both groups), median CD4+ cell count (75.5 cells per cubic millimeter in the enfuvirtide group, and 87.0 cells per cubic millimeter in the control group), demographic characteristics, and previous antiretroviral therapy. At 24 weeks, the least-squares mean change from base line in the viral load (intention-to-treat, last observation carried forward) was a decrease of 1.696 log10 copies per milliliter in the enfuvirtide group, and a decrease of 0.764 log10 copies per milliliter in the control group (P<0.001). The mean increases in CD4+ cell count were 76 cells per cubic millimeter and 32 cells per cubic millimeter, respectively (P<0.001). Reactions at the site of the injections were reported by 98 percent of patients receiving enfuvirtide. There were more cases of pneumonia in the enfuvirtide group than in the control group.

The authors concluded: The addition of enfuvirtide to an optimized antiretroviral regimen provided significant antiretroviral and immunologic benefit through 24 weeks in patients who had previously received multiple antiretroviral drugs and had multidrug-resistant HIV-1 infection.

Reference for full paper: http://content.nejm.org/cgi/content/abstract/NEJMoa035026v1

Conclusions

Significant progress in testing and treatment of HIV infection has been made since the late 1980's. It is encouraging that new drugs have been shown to be effective in arresting HIV infection. However, prevention of AIDS virus is far more important as a global health issue. Since the treatment of AIDS is expensive, it is critical for countries to develop effective methods of educating and practicing prevention of HIV infection. We hope this article will serve its purpose of alerting people to the importance of prevention HIV infection.

References

http://www.aidsinfonet.org/articles.php?articleID=461
http://www.aids.org/FactSheets/451
http://www.medadvocates.org/drugs/enfuvirtidemain.html 
http://content.nejm.org/cgi/content/abstract/NEJMoa035026v1 
http://www.aidsinfonet.org/articles.php?articleID=404
http://www.aidsinfonet.org/articles.php?articleID=126
http://www.aidsinfonet.org/topic_index.php?category=550&subcategory=true
http://www.aids.wustl.edu/aids/testing.html

http://www.virusmyth.net/aids/index/azt.htm

Written by Ifay Chang, Ph.D. on March 16th, 2003

Information about the Author

Dr. Chang is the co-founder of Medical World Search which offers an intelligent medical search engine, called MWSearch. MWSearch is an independent search service without affiliation with any healthcare organization or drug companies. Medical World Search ( www.mwsearch.com ) has been offered for public use since 1996.

In early 90's, while working as a research scientist at IBM T. J. Watson Research Center, Dr. Chang led a group of researchers developing an advanced clinic information system with the purpose of supporting an efficient and reliable healthcare practice. The system has been adopted by Kaiser Permanente and other healthcare organizations.

This article is copyrighted but you may use it or reproduce it in part or in whole with proper acknowledgement made especially regarding the referenced authors. The author can be reached at ifay@mwsearch.com


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