DRUGS;ETC. -- HIV/AIDS NEWS

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Date Posted: 13:11:10 01/26/02 Sat
Author: TN_KY_CARES
Subject: DRUGS;ETC.

1. NUCLEOSIDE ANALOG REVERSE TRANSCRIPTASE INHIBITORS (NUKES)

DRUG
DAILY PILLS (Adults)
HOW TO TAKE & STORE
SIDE EFFECTS
NOTES
Abacavir (Ziagen�) 2 (300 mg: 1, 2x/day) No food restrictions. Hypersensitivity reaction in 5% of patients
AZT (Retrovir�) 6 (100 mg: 2, 3x/day) or

2 (300 mg: 1, 2x/day)
No food restrictions Anemia, nausea, vomiting, headache, fatigue, muscle aches, bone marrow toxicity Don't combine with d4T.
ddI (Videx�) 4 (100 mg: 2, 2x/day or 4, 1x/day) Chew or dissolve in water; take on empty stomach; not within 1 hour of indinavir or 2 hours of ritonavir. Diarrhea, pancreatitis, adbominal pain, neuropathy, nausea & vomiting. Don't combine with ddC.
ddC (Hivid�) 3 (0.75 mg: 1, 3x/day) Take on an empty stomach. Don't take with antacids. Peripheral neuropathy, rash, mouth ulcers, sore throat, coughing. Don't combine with ddI.
d4T (Zerit�) 2 (40 mg: 1, 2x/day) No food restrictions. Peripheral neuropathy, headache, chills & fever, diarrhea, nausea. Don't combine with AZT.
3TC (Epivir�) 2 (150 mg: 1, 2x/day) No food restrictions. Nausea, vomiting, fatigue, headaches. Can reverse resistance to AZT.
Combivir� 2 (150 mg 3TC + 300 mg AZT: 1, 2x/day) No food restrictions. See AZT and 3TC above. Combines AZT and 3TC in a single twice-daily pill.
Tenofovir� 1 (300 mg: 1, 1x/day) Take with a meal. Take 2 hours before, or one hour after ddI. Mild side effects; some nausea, vomiting, loss of appetite.
Trizivir� 2 (150 mg 3TC + 300 mg AZT + 300 mg abacavir: 1, 2x/day) No food restrictions. See AZT, 3TC and abacavir above. Combines AZT, 3TC and abacavir in a single twice-daily pill.

2. NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS (NNRTIs or NON-NUKES)

DRUG
DAILY PILLS (Adults)*
HOW TO TAKE & STORE
SIDE EFFECTS
NOTES
Nevirapine (Viramune�) 2 (200 mg: 1, 2x/day) No food restrictions. Skin rash, fever, headache, nausea. Serious interactions with many other drugs**
Delavirdine (Rescriptor�) 12 (100 mg: 4, 3x/day) No food restrictions. Can be dissolved in water. Take one hour apart from ddI or antacids. Skin rash, nausea, diarrhea, vomiting, headache, fatigue.
Efavirenz (Sustiva�) 3 (200 mg: 3, 1x/day) No food restrictions, but avoid a high-fat meal. Take before going to sleep. Rash, nausea, dizziness, diarrhea, headache and insomnia

**NNRTI's are metabolized by the liver, as are many other commonly used drugs. Drug interactions can cause large increases or decreases in the blood levels of drugs you are taking, leading to under-doses that are ineffective, or overdoses that can be fatal. Make sure your physician knows about all medications you are taking.

3. PROTEASE INHIBITORS

DRUG
DAILY PILLS (Adults)*
HOW TO TAKE & STORE
SIDE EFFECTS
NOTES
Amprenavir (Agenerase�) 16 (150 mg: 8, 2x/day) Take with or without food. Avoid high-fat foods. Don't take within 1 hour of antacids. Nausea, diarrhea, vomiting, rash, numbness around mouth, abdominal pain Serious interactions with many other drugs.**
Indinavir (Crixivan�) 8 (400 mg: 2, every 8 hours, not just 3x/day) Take with lots of water, on empty stomach or with low-fat snack. Keep cool and dry. Headache, nausea, abdominal pain, kidney stones.
Lopinavir/ritonavir (Kaletra�) 6 (133 mg lopinavir + 33 mg ritonavir: 3, 2x/day) Take with food. Keep at room temperature. Diarrhea, fatigue, nausea, headache
Nelfinavir (Viracept�) 9 (250 mg: 3, 3x/day) or 10 (5, 2x/day Take with meals or a snack. Diarrhea, nausea, gas, abdominal pain, weakness.
Ritonavir (Norvir�) 12 (100 mg: 6, 2x/day) Take with a full meal. Keep refrigerated. Take 2 hours apart from ddI. Nausea, vomiting, diarrhea, tingling & numbness around the mouth.
Saquinavir soft gel (Fortovase�) 18 (200 mg: 6, 3x/day) Take with high-fat food. Refrigerate in hot climates. Minimal nausea, diarrhea, vomiting, headache, fatigue.

*These pill counts reflect the "normal" use of each drug. However, doctors are now combining antiviral medications in new ways. Doses of each drug may be higher or lower in these new combinations.

**Protease inhibitors are metabolized by the liver, as are many other commonly used drugs. Drug interactions can cause large increases or decreases in the blood levels of drugs you are taking, leading to under-doses that are ineffective, or overdoses that can be fatal. Make sure your physician knows about all medications you are taking.

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None of these drugs can kill the HIV virus, but each class slows down the multiplication of the virus (replication) in a particular way.

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1. REVERSE TRANSCRIPTASE INHIBITORS (NUKES)

The first anti-HIV drugs. They block reverse transcription (the creation of viral DNA from RNA) by providing "decoy" building blocks that interrupt the process. Most are nucleoside analogs; tenofovir is a nucleotide analog.

Year*
Generic Name
Trade Name
Also known as:
Manufacturer
1987 Zidovudine Retrovir� AZT, ZDV GlaxoSmithKline
1991 Didanosine Videx� ddI Bristol-Myers Squibb
1992 Zalcitabine Hivid� ddC, dideoxycytidine Roche
1994 Stavudine Zerit� d4T Bristol-Myers Squibb
1995 Lamivudine Epivir� 3TC GlaxoSmithKline
1997 Zidovudine/ Lamivudine Combivir� Combines AZT and 3TC GlaxoSmithKline
1998 Abacavir Ziagen� 1592U89 GlaxoSmithKline
2000 Zidovudine/Lamivudine/Abacavir Trizivir� Combines AZT, 3TC, Abacavir GlaxoSmithKline
2001 Tenofovir Viread� bis-poc PMPA Gilead Sciences
Other nukes in human trials: Coviracil� (FTC, emtricitabine) and DAPD by Triangle Pharmaceuticals, MIV-310 by Medivir.

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2. NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS (NNRTIs or NON-NUKES)

These also interrupt reverse transcription, by binding to the reverse transcriptase enzyme and restricting its activity.

Year*
Generic Name
Trade Name
Also known as:
Manufacturer
1996 Nevirapine Viramune� NVP, BI-RG-587 Boehringer Ingelheim
1997 Delavirdine Rescriptor� DLV Agouron Pharmaceuticals
1998 Efavirenz Sustiva� EFV, DMP-266 Bristol-Myers Squibb
Other NNRTI's in human trials: +/-Calanolide A by Sarawak MediChem Pharmaceuticals, Capravirine (AG1549) by Agouron Pharmaceuticals, DPC083 by Bristol-Myers Squibb, MIV-150 by Medivir and TMC120 and TMC125 by Tibotec Virco.

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3. PROTEASE INHIBITORS

Block the action of protease, an enzyme that cuts HIV protein chains into specific proteins needed to assemble a new copy of the virus.

Year*
Generic Name
Trade Name
Also Known As:
Manufacturer
1995 Saquinavir Invirase� SQV Roche
1996 Ritonavir Norvir� RTV Abbott
1996 Indinavir Crixivan� IDV Merck
1997 Nelfinavir Viracept� NFV Agouron
1997 Saquinavir Fortovase� SQV Roche
1999 Amprenavir Agenerase� APV, 141W94 GlaxoSmithKline
2000 Lopinavir Kaletra� ABT-378/r Abbott
Other PIs in human trials: Atazanavir� (BMS 232632) by Bristol-Myers Squibb, GW433908 by GlaxoSmithKline, L-756,423 by Merck, Mozenavir (DMP-450) by Triangle Pharmaceuticals, Tipranavir� by Boehringer Ingelheim and TMC114 by Tibotec Virco.

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4. INTEGRASE INHIBITORS
Block the action of integrase, an enzyme that inserts the viral DNA into the infected cell's DNA strands. S-1360 by Shionogi Pharmaceuticals and GlaxoSmithKline is currently in Phase II human trials.

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5. ATTACHMENT AND FUSION INHIBITORS
Prevent the HIV virus from attaching to a cell. No fusion inhibitors have been approved yet. Several are in human trials: FP21399 by Fuji Pharmaceuticals, PRO 452 by Progenics Pharmaceuticals, Inc. (Phase I/II trials); SCH-C by Schering, Trimeris and Roche's T-20 (Pentafuside) (Phase III trials) and T-1249 (Phase I trials), and TNX-355 by Tanox.

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6. ANTISENSE DRUGS
These are a "mirror image" of part of the HIV genetic code that locks onto the virus to prevent it from functioning. One antisense drug, HGTV43 by Enzo Therapeutics, is in Phase I trials.

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7. IMMUNE STIMULATORS
Use the body's chemical messengers to stimulate the immune response. Interleukin 2 (Il-2, Aldesleukin�, Proleukin�) by Chiron Corporation is in Phase III trials, Multikine by Cel-Sci Corporation is in Phase I trials, and Reticulose by Advance Viral Research Corporation is in Phase III trials. Trials of Remune�, an inactivated virus preparation by Immune Response Corporation, were halted in 2001. HRG214 by Virionyx is in a Phase I trial, and resveratrol, a plant chemical, is also in a Phase I trial.

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*Year of approval in the USA.

REVERSE TRANSCRIPTASE INHIBITORS
These drugs stop HIV from multiplying by blocking the reverse transcriptase enzyme. This enzyme changes HIV's genetic material (RNA) into the form of DNA. This step has to occur before HIV's genetic code gets combined with an infected cell's own genetic codes. There are two types of reverse transcriptase inhibitors:

Nucleoside analogs (often called "nukes"). These drugs mimic the building blocks used by reverse transcriptase to make copies of the HIV genetic material. These fake building blocks disrupt the copying.
Non-nucleoside reverse transcriptase inhibitors, called NNRTIs, physically prevent the reverse transcriptase enzyme from working.

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A. NUCLEOSIDE ANALOGS (NUKES)
Nucleoside analogs (nukes) in development include DAPD, FTC and MIV-310. Tenofovir is a closely-related nucleotide analog.

DAPD (amdoxovir) by Triangle Pharmaceuticals is being studied in twice-daily doses. It appears to be effective against HIV that is resistant to other nukes and against hepatitis B. DAPD is in Phase I/II trials.

Emtricitabine (Coviracil�, formerly FTC) by Triangle Pharmaceuticals is closely related to the drug 3TC. FTC was much stronger than 3TC in the laboratory but is not stronger in humans. It is taken once a day and is in Phase III trials. Trials were halted in late 1999 due to a high rate of liver problems. It now appears these were not caused by emtricitabine. Development resumed in early 2002.

NUCLEOTIDE ANALOGS

Tenofovir (bis-poc PMPA, Viread�) by Gilead was approved by the FDA in October 2001. See fact sheet 428 for more information.

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B. NON-NUKES (NNRTIs)

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) in development include Calanolide A, Capravirine, DPC083, Emivirine, MIV-150, TMC120 and TMC125.

(+)-Calanolide A by Sarawak MediChem Pharmaceuticals was derived from a rain forest plant. It can easily cross the blood-brain barrier, and seems to stay in the bloodstream for a long time. It is in Phase I human trials. There are no recent reports on its status.

Capravirine (AG1549, formerly S-1153) by Agouron Pharmaceuticals appears to be about 10 times stronger than nevirapine or delavirdine against wild type virus. HIV needs 2 or 3 mutations to develop resistance to capravirine, compared to just one mutation for current NNRTIs. The dose will probably be two 700 mg tablets twice a day. Development was put on hold due to toxicity in dogs. The hold has reportedly been lifted but no further development plans have yet been announced.

DPC083 by Bristol-Myers Squibb is closely related to Efavirenz (Sustiva�). It has a very long half-life, so it will probably be dosed once a day. It can suppress HIV with some resistance to NNRTIs. It is in Phase I/II trials.

MIV-150 by Medivir and Chiron shows good results in the laboratory against HIV that is resistant to other NNRTIs. It takes a long time for HIV to develop resistance to MIV-150. Phase II trials are scheduled.

TMC120 and TMC125 by Tibotec Virco are active against some strains of HIV that are resistant to other NNRTIs. It takes longer for HIV to develop resistance to TMC120 or 125 than to the first NNRTI drugs. They are being studied in Phase II trials.

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DRUGS NO LONGER IN DEVELOPMENT
The following drugs are no longer being developed for use against HIV:

Nukes:

Adefovir dipivoxil (bis POM PMEA) by Gilead Sciences
dOTC (BCH-10652) by BioChem Pharma
FddA (Beta-fluoro-ddA, Lodenosine�) by US Bioscience
GW420867X by GlaxoSmithKline
Lobucavir by Bristol-Myers Squibb
NNRTIs:

Atevirdine by Upjohn
Emivirine (Coactinon) by Triangle Pharmaceuticals
Loviride by Janssen Pharmaceuticals
HBY-097 by Hoechst-Bayer
PNU142721 by Pharmacia & Upjohn

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PROTEASE INHIBITORS
These drugs block the protease enzyme. When new viral particles break off from an infected cell, protease cuts long protein strands into the parts needed to assemble a mature virus. When protease is blocked, the new viral particles cannot mature. Protease inhibitors being tested in humans include Atazanavir, GW433908, L-756,423, Mozenavir (DMP-450), Tipranavir, and TMC114. Several firms are trying to develop a new type of protease inhibitor that will not be cross-resistant with existing drugs.

Atazanavir (BMS232632) by Bristol-Myers Squibb is as strong as nelfinavir. It has few side effects and doesn't raise cholesterol like many PIs, but can cause high levels of bilirubin. It is being tested as a once daily drug in Phase III trials.

GW433908 by GlaxoSmithKline is a "prodrug" form of amprenavir. A prodrug becomes active after it is broken down in the body. GW433908 will be just 2 tablets instead of the current 8 capsules, twice daily, and will not contain Vitamin E. See Fact Sheet 445 for more information on amprenavir. GW433908 is in Phase III trials.

L-756,423 by Merck is chemically similar to indinavir. However, it stays in the blood longer and should cause fewer kidney problems. L-756,423 is being studied in combination with indinavir. The dose being studied is 5 capsules once a day with food. There have been no recent reports on its status.

Mozenavir (DMP450) by Triangle Pharmaceuticals is a very potent protease inhibitor that appears to improve the activity of several other antiviral drugs. Unfortunately, it is cross-resistant with indinavir and ritonavir. It is not broken down by the same liver enzyme as other protease inhibitors, so it is expected to have fewer interactions with other drugs. Development is on hold due to heart irregularities.

Tipranavir (PNU-140690) by Boehringer Ingelheim is a new HIV protease inhibitor. It appears to work against HIV that is already resistant to other protease inhibitors. It is being studied in twice-daily dosing combined with ritonavir and is in Phase II trials. It seems to have a high rate of side effects including diarrhea, nausea and vomiting.

TMC114 by Tibotec Virco produces very rapid drops in viral load. It is in Phase I studies.

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Revised December 22, 2001

ATTACHMENT AND FUSION INHIBITORS
This is a new class of anti-HIV drugs. They are intended to protect cells from infection by HIV by preventing the virus from attaching to a new cell and breaking through the cell membrane. Researchers hope that these drugs can prevent infection of a cell by either free virus (in the blood) or by contact with an infected cell.

Because digestive acids break them down, most of these drugs are given by injections or intravenous infusion. Fusion inhibitors in human trials include FP21399, PRO 542, Schering C, T-20 (Pentafuside), T-1249 and TNX-355.

FP21399 by Fuji Pharmaceuticals was tested for safety in a Phase I trial as a single infusion or a series of 4 weekly 1-hour intravenous infusions. The drug produced viral load decreases and CD4+ cell increases. Side effects were minor, including blue-tinted urine and temporary blue marks on the skin. There have been no recent reports on its status.

PRO 542 by Progenics Pharmaceuticals is in Phase II trials. It blocks fusion by binding to a protein on the outside of the virus.

Schering C (SCH-C) by Schering Plough blocks the CCR5 receptor on CD4 cells. It is in Phase I studies. There is some concern about heart irregularities. Schering has other, related compounds in development.

T-20 (Pentafuside) by Trimeris and Roche is currently in Phase III trials. It can lower viral load even for patients who have already used many of the approved drugs. T-20 is injected twice daily.

T-1249 by Trimeris and Roche is a new fusion inhibitor drug. It is in Phase I/II trials. T-1249 is effective against HIV that is resistant to T-20. It stays in the body longer, so it might require just one injection a day or every other day.

TNX-355 by Tanox blocks the CD4 receptor. It is a genetically engineered drug, a "monoclonal antibody." It is in Phase I trials.

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INTEGRASE INHIBITORS
After HIV's genetic code is changed from a single strand to a double strand by the reverse transcriptase enzyme, it gets inserted (integrated) into the genetic code of the infected cell. Then the HIV genetic code gets "read", producing new viruses. Scientists hope that integration will be another point in the HIV life cycle that can be targeted by drugs.

S-1360 by Shionogi and GlaxoSmithKline is currently in Phase II trials.

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ZINC FINGER INHIBITORS
The inner core of HIV is called the nucleocapsid. It is held together by structures called "zinc fingers". Zinc finger inhibitors (or zinc ejectors) are drugs that can break apart these structures and prevent the virus from functioning.

Scientists believe that the nucleocapsid core cannot mutate very easily, so a drug that works against zinc fingers might be effective for a long time. Unfortunately, zinc fingers are not only used by the HIV virus. Drugs that attack them could have serious side effects.

One zinc finger inhibitor - azodicarbonamide (ADA) - has been tested in a Phase I/II trial.

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ANTISENSE DRUGS
These are a "mirror image" of part of the HIV genetic code. The drug locks onto the virus to prevent it from functioning. One antisense drug, HGTV43 by Enzo Therapeutics, is starting Phase II trials.

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DRUGS NO LONGER IN DEVELOPMENT

AMD3100 by AnorMed

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Revised December 22, 2001

IMMUNE STIMULATORS
We can think of most antiviral drugs as "offense", attacking the virus to slow down its multiplication. Another approach to treating HIV infection is "defense", strengthening the immune response of people who are infected. This Fact Sheet describes new immune stimulators being developed.

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CYTOKINES
Some of these treatments use the body's own chemical messengers (cytokines) to increase the immune system's response to HIV. Different cytokines carry different messages to cells of the immune system. Some cytokines tell a cell to start multiplying; others can tell a cell to self-destruct.

The best-known cytokine is interleukin-2 (IL-2, Aldesleukin, Proleukin) by Chiron Corporation. It is currently in Phase III trials.

Multikine by Cel-Sci Corporation, is a mixture of several different cytokines. It is in Phase I human trials.

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VACCINE-LIKE TREATMENT
Another approach to stimulating the immune system is similar to vaccination, except that it is used in people who are already infected with HIV. HRG214 by Virionyx is a genetically engineered group of antibodies to HIV. It is called a "passive immuno-therapeutic pharmaceutical." HRG 214 is in a Phase I trial.

HIV-1 Immunogen (Remune) by Immune Response Corporation includes all of the core proteins of HIV, in an inactive form. This stimluates the immune system to respond. The development of Remune has been long and difficult. Some Phase III trials were halted in 2001 when Pfizer withdrew from a joint development agreement. Remune's future is uncertain.

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OTHER IMMUNE STIMULATORS

Ampligen by Hemispherx Biopharma is supposed to activate some of the cell's own defenses against viruses. It is in Phase II and Phase III trials.

HE2000 by Hollis-Eden Pharmaceuticals is a new drug that works on an infected person's immune system. It is designed to stregthen the "humoral" immune response which is responsible for producing antibodies. HE2000 is being tested in Phase I/II trials.

Murabutide is under study by Dr. Georges Bahr in France. It uses fragments of bacteria to stimulate the overall immune response. Murabutide is given by injection. Phase I results, reported late in 2001, were promising.

Reticulose by Advanced Viral Research Corporation is a nucleic acid that stimulates the cell-killing arm of the immune system. It is administered as a subcutaneous (beneath the skin) injection. Early clinical trials showed that patients receiving Reticulose had increases in their CD4 and CD8 cells, weight increases, and fewer opportunistic infections than patients receiving placebo. No toxic side effects have been reported yet. Reticulose is in Phase III trials.

Cell Genesys has developed an AIDS gene therapy. CD4 and CD8 cells are collected from an HIV-infected patient. The cells are genetically modified to recognize and kill HIV-infected cells. They are multiplied, and then given back to the same patient. This AIDS therapy is given along with antiviral drugs, and is in Phase II trials.

Resveratrol is a chemical found in several plants and the skin of red grapes. It protects plants against pathogens and may have other immune-boosting properties. It is being studied in a Phase I trial in people with HIV.

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Revised December 22, 2001

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