Alternative medicine

Various forms of alternative medicine have been used to treat symptoms or alter the course of the disease. Acupuncture has been used to alleviate some symptoms, such peripheral neuropathy, but cannot cure the HIV infection. Several randomized clinical trials testing the effect of herbal medicines have shown that there is no evidence that these herbs have any effect on the progression of the disease, but may instead produce serious side-effects.

Some data suggest that multivitamin and mineral supplements might reduce HIV disease progression in adults, although there is no conclusive evidence on if they reduce mortality among people with good nutritional status. Vitamin A supplementation in children probably has some benefit. Daily doses of selenium can suppress HIV viral burden with an associated improvement of the CD4 count. Selenium can be used as an adjunct therapy to standard antiviral treatments, but cannot itself reduce mortality and morbidity.

Current studies indicate that that alternative medicine therapies have little effect on the mortality or morbidity of the disease, but may improve the quality of life of individuals afflicted with AIDS. The psychological benefits of these therapies are the most important use.

Retroviruses and anti-retroviral drugs

The human immunodeficiency virus (HIV) is an enveloped retrovirus which targets macrophages, T helper cells and dendritic cells of the human immune system. A retrovirus contains a single-strand of RNA as its genome, and replicates by transcribing a complementary DNA copy from its RNA genome (reverse transcription) and then uses the DNA strand to make more RNA, as a template for more copies of the viral genome or as messenger RNA to make viral proteins.

The reproductive cycle of HIV:

1. The virus attaches to the cell membrane (at CD4); upon binding the membranes of the host and the virus fuse, the viral capsid breaks down and the viral genome is able to enter the cell
2. In cell cytoplasm, the viral genome is replicated to form complementary DNA (cDNA) which is then integrated into the host’s genome – called a DNA provirus
3. When the provirus is activated, messenger RNA is produced and the host’s machinery is used to create viral proteins
4. Viral glycoproteins are inserted into the host’s plasma membrane, which, when the virus buds off, will become the viral envelope.
5. The new virus assembles itself in the cytoplasm and is released from the host via exocytosis.

Several proteins are especially vital for HIV infection and replication:

• Membrane proteins gp120 and gp41 to attach to human cells (gp = glycoprotein).
• Reverse transcriptase – catalyses the transcription of cDNA from RNA
• Integrase – catalyses the insertion of cDNA into the genome of the host
• Protease – is responsible for post-translational processing and is necessary to cleave larger initial products of translation to form individual viral proteins

Understandably, these essential proteins would be targeted by anti-retroviral drugs to inhibit infection and replication of HIV. However, scientists must take care to block only steps that are unique to the virus so that drug medications do not harm the patient. 3 general types of anti-retroviral drugs exist:

Reverse transcriptase inhibitors

If the cDNA cannot be formed, the virus’s RNA genome will be vulnerable to destruction by the host’s cellular enzymes. There are 2 types of reverse transcriptase inhibitors:

Nucleoside reverse transcriptase inhibitors – contains altered forms of deoxynucleosides, substrates in transcription and the formation of complementary DNA. These dideoxynucleoside forms have the hydroxyl group at the 3’ position replaced by an azido, hydrogen, or another group. Thus, when the HIV reverse transcriptase adds the altered substrate to the growing viral DNA chain (competitive inhibition), transcription will be inhibited as the normal 5’ to 3’ links will no longer to able to form i.e. the DNA strand will be truncated.

Non-nucleoside reverse transcriptase inhibitors – these bind to a site other than the active site of reverse transcriptase (non-competitive inhibition), causing a conformational change in the structure of the reverse transcriptase enzyme (at the active site) and therefore rendering the enzyme useless.

Protease inhibitors

These inhibitors were introduced in 1996 and work by binding competitively to the active site of the HIV protease.

HAART (Highly active anti-retroviral therapy) was developed in the late 1990s. It is similar to cancer treatment, and involves a combination of drugs that attack different parts of the life cycle of HIV. The therapy generally uses a protease inhibitor and two reverse transcriptase inhibitors (usually in the form of a pill). However, due to the lack of proofreading in HIV’s reverse transcriptase, there is a high HIV mutation rate, and unfortunately many patients who take HAART develop mutant strains that are resistant to the drug therapy. Similarly, specific genetic mutations in the protease gene may result in resistance towards to protease inhibitors. The toxic side effects of anti-retroviral drugs can be very severe e.g. diabetes, hepatitis, hypersensitivity. Scientists are continually striving to come up with new and better treatments to fight HIV.

Maria Nguyen

Sources:

Sadava et. al., Life, The Science of Biology. 8^th ed.

http://www.bmj.com/cgi/content/full/322/7299/1410

issues for patients as HIV progresses

ISSUES FOR PATIENTS AS HIV PROGRESSES (monica)

There are many complications that can occur with HIV because it is a virus that attacks the immune system directly. Effects of HIV infection include:

Neurological disease – at early stages of the disease nervous tissue can become infected. As the disease progresses AIDS dementia complex can result as well as aseptic meningitis (infection has caused meninges to become inflamed) and sensory polyneuropathy (condition in which peripheral nerves lose sensory sensation), but these conditions are becoming less frequent with the introduction of highly active anti-retroviral therapy (HAART).

Eye disease – the most serious condition is cytomegalovirus retinitis, which is a common cause of eye disease and blindness. Usually unilateral to begin with but can then progress to the other eye. Can result in floaters, loss of visual acuity, field loss and scotomata (a defect of vision in a defined area of the visual field in one or both eyes. Common symptom is shimmering film appearing as island in visual field.), orbital pain and headache.

Haematological complications – anaemia, neutropenia (abnormal fall in number of neutrophils in the blood) and thrombocytopenia (reduction in number of platelets) are all common conditions that occur as HIV advances.

Gastrointestinal effects – weight loss and diarrhoea are extremely common, and wasting is a common feature of advanced HIV, which is attributed to the effects of HIV on metabolism.

Renal complications – nephrotic syndrome can occur as a result of HIV cytopathic effects on renal tubular epithelium.

Respiratory effects – upper airway and lung damage leads to an increase in upper and lower respiratory tract infections. Sinus mucosa functions abnormally and is frequently the site of chronic inflammation.

Cardiac complications – cardiomyopathy although rare associated with HIV, may lead to congestive cardiac failure. Lymphocytic and necrotic myocarditis may also occur.

Apart from all the conditions above a major complication that occurs as HIV progresses is AIDS (acquired immune deficiency syndrome), which often leads to opportunistic infections manifesting, as the immune system is very weak or not functioning at all. Also progression to AIDS usually results in death of the patient.

Sources: Kumar and Clark,
Mosby’s Dictionary

Clinical Signs of 'full-blown' AIDS

by Rachel


Immediately after being infected with HIV, most individuals develop a brief, nonspecific “viral illness” consisting of low grade fever, rash, muscle aches, headache and/or fatigue. These symptoms usually resolve in 5-10 days, like most other viral illness.
After this time, the individual may be asymptomatic, however the HIV virus may still be active in gradually destroying their immune system. This period may range from months to several decades, until the virus has caused the patient's T cell count to fall below 200, then they are classified as having 'full-blown AIDS'. AIDS symptoms include:

# extreme fatigue
# rapid weight loss from an unknown cause
# appearance of swollen or tender glands in the neck, armpits or groin, for no apparent reason, lasting for more than four weeks
# unexplained shortness of breath, frequently accompanied by a dry cough, not due to allergies or smoking
# persistent diarrhea
# intermittent high fever or soaking night sweats of unknown origin
# a marked change in an illness pattern, either in frequency, severity, or length of sickness
# appearance of one or more purple spots on the surface of the skin, inside the mouth, anus or nasal passages
# whitish coating on the tongue, throat or vagina
# forgetfulness, confusion and other signs of mental deterioration





Due to a weakened immune system, patients with HIV/AIDS are also vulnerable to many opportunistic infections, including:

* Candidiasis (Thrush)
* Cytomegalovirus (CMV) - viral infection that causes eye disease that can lead to blindness
* Herpes simplex viruses
* Malaria
* Mycobacterium avium complex (MAC or MAI) - bacterial infection that can cause recurring fevers, general sick feelings, problems with digestion, and serious weight loss.
* Pneumocystis pneumonia (PCP) is a fungal infection that can cause a fatal pneumonia
* Toxoplasmosis (Toxo) is a protozoal infection of the brain.
* Tuberculosis (TB) is a bacterial infection that attacks the lungs, and can cause meningitis.


A patient who has been infected with HIV and also has any one of these opportunistic infections, is classified as having AIDS.




www.healthscout.com/ency/416/101/main.html
http://www.aids.org/

CD4 count and Viral Load

Viral Load, CD4 levels and HIV/AIDS
by Josh
CD4 T helper lymphocyte levels are depleted by HIV/AIDS. CD4 T helper cell depletion weakens the immune system opening it up to infections whih the body cannot combat. It also opens the body up to opportunistic infection. The normal DC4 count in a male is usually above 400 or 500 (Viral Load).
Sometimes a person can be affected with HIV and not get sypmtomes for many years. However CD4 count goes down within the first few weeks of infection. HIV targets helper T cells with the co-receptor CCR5. These cells are abundant in the intestinal mucosa. (Viral Load)
Viral load meaures the content of virus per ml of blood. This measurement indicates the severity of the virus. Obviosuly a higher viral load inidcated a more sever viral infection. In the US the FDA has approved 3 different viral load tests for HIV(viral load)
• Amplicor HIV-1 Monitor test (Hoffman-La Roche), better known as the PCR test
• NucliSens HIV-1 QT, or NASBA (bioMerieux)
• Versant/Quantiplex HIV-1 RNA, or bDNA (Chiron/Bayer)
Viral Load is how many viral particles per ML of blood
Viral Load in eq/ml Classification Remarks
below 200.000 very low below detection limit of bDNA test
200,000-1,000,000 low
1,000,000-5,000,000 medium average viral load at 3,200,000 eq/ml
5,000,000-25,000,000 high
above 25,000,000 very high

(table taken from http://www.janis7hepc.com/Viral_Loads.htmViral Load )

Recently, Logs have been used to express viral load.
log(1730000)=6.24
6.24^10 = 1730000
Bibliography
Viral Loads
http://www.janis7hepc.com/Viral_Loads.htmViral Load
http://en.wikipedia.org/wiki/Viral_load

Classes of Anti-Retroviral Drugs for Treatment of HIV

PCL 12 - Alan and Bill
Amber Hartley

Treatment of HIV/AIDS
Guidelines and aims for treating doctors are:
 Monitor plasma viral load and CD4 cell count
 Start treatment before immunodeficiency becomes evident
 Aim to reduce plasma viral concentration as much as possible for as long as possible
 Use combinations of at least three drugs
 Change to a new regimen if plasma viral concentration increases

Anti-viral drugs (in general)

Most anti-virals fall into one of the following categories:
 Nucleoside analogues that inhibit reverse transcriptase
 Non-nucleoside analogues that inhibit reverse transcriptase
 Protease inhibitors
 Inhibitors of viral DNA polymerase
 Inhibitors of viral capsule disassembly
 Inhibitors of neuraminidase that prevent viral escape from infected cells
 Immunomodulators that enhance host defences
 Immunoglobulin and related preparations that contain neutralising antibodies to various viruses.

Anti-retroviral drugs (for HIV/AIDS treatment)

Two main classes of anti-retrovirals used to treat HIV:
 Reverse transcriptase inhibitors
o May be nucleoside or non-nucleoside
o Nucleoside RTIs compete with essential substrates for viral reverse transcriptase sites
o Non-nucleoside RTIs bind to reverse transcriptase enzyme near the catalytic site and denature it
 Protease inhibitors
o Inhibit cleavage of nascent viral protein into functional and structural proteins

Because these drug types have different mechanisms of action, they are used in combination – this has dramatically improved the prognosis of the disease.

Combination treatment may take the form of HAART (highly active anti-retroviral therapy). This usually involves two nucleoside reverse transcriptase inhibitors with either a non-nucleoside reverse transcriptase inhibitor or one or two protease inhibitors. HAART can inhibit the replication of HIV, to the point of an undetectable viral load in plasma.
However, the HAART regimen is complex and has many unwanted side effects. Treatment is lifelong, because the virus is not eradicated by the therapy, but lies latent in host T cells, and will begin replication if therapy is halted.

Resistance to some anti-retrovirals has become a problem. In these cases, drugs may be changed in an effort to combat the problem, although this has limited success, and the replication of the HIV may recommence.

Treatment for pregnant/breast-feeding women
 Choice is difficult
 Main aims are to avoid damage to the foetus and prevent transmission of the disease to the newborn
 Often, zidovudine (a nucleoside reverse transcriptase inhibitor) is used alone











References:

Rang and Dale’s Pharmacology, 6e, 2007

Kumar and Clark, “Clinical Medicine”. 6e.

For explanatory videos, see http://www.youtube.com/watch?v=yYZgFndtfzc
http://www.youtube.com/watch?v=qYUnDzDO-Ic
http://www.youtube.com/watch?v=3n_MYZEfnxU
http://www.youtube.com/watch?v=2s-FKSICsz0
http://www.youtube.com/watch?v=2DzL8SQt_jo