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Q: HIV Drug Questions ( Answered 4 out of 5 stars,   2 Comments )
Question  
Subject: HIV Drug Questions
Category: Miscellaneous
Asked by: blucken-ga
List Price: $200.00
Posted: 17 Nov 2005 08:04 PST
Expires: 17 Dec 2005 08:04 PST
Question ID: 594174
1. What are the major HIV drugs available? 
2. Who manufacturers them?
3. How much do they cost?
4. Can they be mixed in a cocktail?  If so, how are they mixed and
what other drugs are they mixed with?
5. How often are they taken--once a day? once a week? so on.
6. How are they ingested?--orally? Injected? so on.
7. Are there any side effects of the drugs?  What are the strengths
and weaknesses of each drug?
8. Is there any information on transdermal patches being used?   We
believe that we know there is not, but why? Is there a reason they are
not used -e.g. the drugs are too large or cannot be transferred
through the skin etc.
Answer  
Subject: Re: HIV Drug Questions
Answered By: crabcakes-ga on 17 Nov 2005 20:53 PST
Rated:4 out of 5 stars
 
Hello Blucken,

    Because the answers to some of these questions overlap a bit,
don't be surprised to find answers from one question under another! I
believe I have completely answered all your questions.


1. What are the major HIV drugs available? 
===========================================

   ?The appearance in the clinic of two to three new antiretroviral
agents yearly since 1995 has permitted unprecedented advances in HIV
treatment.?

?Even drugs available for many years may have untapped potential.
Didanosine (ddI) and stavudine (d4T), once thought to be
contraindicated in combination because of their overlapping peripheral
neuropathy toxicity, have proven well tolerated and effective.
Combination therapy can increase antiviral suppression, prevent drug
resistance, optimize drug exposure and simplify dosing, but it can
also result in pharmacologic antagonism, subtherapeutic drug
concentrations and unexpected toxicities. Clinical studies have
confirmed in vitro studies showing pharmacologic antagonism for the
combination of ZDV and d4T. Combining protease inhibitors with each
other or with non-nucleoside reverse transcriptase inhibitors is
complicated by effects both classes of drugs have on drug metabolism
and clearance.?
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9632999&dopt=Citation


   The HIV drug pipeline (Clicking the folders takes you to a link
with a description of these new drugs under study):
http://www.thebody.com/tag/articles/pipeline.html


?NEW DRUGS IN THE PIPELINE
The Pharmaceutical Research and Manufacturers Association of America
lists nearly five dozen new anti-HIV drugs currently in development as
of 2003. (New Medicines in Development for HIV/AIDS 2003). They
include new protease inhibitors and more potent, less toxic RT
inhibitors, as well as other drugs that interfere with entirely
different steps in the virus? lifecycle. These new categories of drugs
include
?	Entry inhibitors?drugs that interfere with HIV?s ability to enter cells 
?	Integrase inhibitors?drugs that interfere with HIV?s ability to
insert its genes into a cell?s normal DNA
?	Assembly and budding inhibitors?drugs that interfere with the final
stage of the HIV life cycle, when new virus particles are released
into the bloodstream
?	Cellular metabolism modulators?drugs that interfere with the
cellular processes needed for HIV replication
?	Gene therapy?modified genes inserted directly into cells to suppress
HIV replication. These cells are designed to produce T cells that are
genetically resistant to HIV infection.
In addition, scientists are learning how immune modulators help boost
the immune system?s response to the virus and may make the existing
anti-HIV drugs more effective. Therapeutic vaccines are also being
evaluated for this purpose and could help reduce the number of
anti-HIV drugs needed or the duration of treatment.?
http://www.niaid.nih.gov/factsheets/treat-hiv.htm


   ?Treatment guidelines are changing constantly. First came "hit
hard, hit early", then came a more conservative approach with a
starting point somewhere between 350 and 500 CD4+ T cells/mm³. The
latest guidelines use 200 to 350 cells/mm³ as the range to consider
starting HAART. However, there remain a range of views on this subject
and ultimately the decision to commence or not to commence treatment
rests with the patient and their doctor.

Antiretroviral regimens are complex, have serious side effects, pose
difficulty with adherence, and carry serious potential consequences
from the development of viral resistance because of nonadherence to
the drug regimen or suboptimal levels of antiretroviral agents.
Patient education and involvement in therapeutic decisions are
critical. Treatment should usually be offered to all patients with
symptoms ascribed to HIV infection. Recommendations for offering
antiretroviral therapy among asymptomatic patients require analysis of
real and potential risks and benefits.?
http://en.wikipedia.org/wiki/HAART


   ?Twenty-five medications have been approved by the U.S. government
to fight HIV, with many more in development. To learn when and how
they are used, read up on the basics about HIV medications and use the
list below.?
http://www.thebody.com/treat/antivir.html



Antiretrovirals:
================

Reverse Transcriptase Inhibitors (RTIs)
---------------------------------------
   ?Reverse Transcriptase Inhibitors inhibit activity of reverse
transcriptase, a viral enzyme HIV needs to reproduce. Lack of this
enzyme prevents HIV from building DNA based on its RNA. They come in
three forms.?


Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
---------------------------------------------------------
   ?This is the third class of antiretroviral drugs that were
developed. In all cases, patents remain in force until beyond 2010.?
Nucleotide Analog Reverse Transcriptase Inhibitors (NtARTIs) or (NtRTIs)
?Normally nucleoside analogs are converted into nucleotide analogs by
the body. Taking them directly allows conversion steps to be skipped,
causing less toxicity.?

Nucleotide Analog Reverse Transcriptase Inhibitors (NtARTIs) or (NtRTIs)
------------------------------------------------------------------------
   ?Normally nucleoside analogs are converted into nucleotide analogs
by the body. Taking them directly allows conversion steps to be
skipped, causing less toxicity.?


Protease inhibitors (PIs)
--------------------------
   ?Protease inhibitors inhibit the activity of protease, an enzyme
used by HIV to cleave nascent proteins for final assembly of new HIV
virons, and so prevent viral replication. This was the second class of
antiretroviral drugs developed.?


Fusion Inhibitors
-----------------
   Fusion inhibitors inhibit fusion (entry) of HIV with the cell
membrane, preventing infection of uninfected cells.


Fixed Combinations
-------------------
Fixed Combinations are multiple drugs in a single pill


Synergistic enhancers
----------------------
   While most of these substances do not possess any antiretroviral
properties, when they are taken concurrently with antiretroviral drugs
they enhance the effect of that drug. One of these is an
over-the-counter nutritional supplement and another two of these have
been FDA approved (for other indications) and are thus readily
available for treatment use on an off-label basis.
http://en.wikipedia.org/wiki/HAART#Antiretroviral_drugs_include:




   Here is a very complete up to date (Oct. 2005) list of current HIV
drugs, from Toronto General Hospital. All are oral medications except
the last one, which is an injectable.
http://www.tthhivclinic.com/pdf/glance.pdf

From the same site, a chart of drugs, with links to patient
information sheets on each medication:
http://www.tthhivclinic.com/FactSheets/index.html

?Anti-Retroviral Drugs are used to treat infection with the Human
Immuno-deficiency Virus (HIV), the virus that causes AIDS. These
medicines cannot prevent or cure HIV infection, but they help keep the
virus in check to minimize other conditions caused by the virus, such
as opportunistic infections.

   Like other Anti-viral Drugs,Anti-retroviral Drugs do not kill
viruses, because that could also damage or kill the cells the viruses
have infected. Instead, these drugs block steps in the process through
which viruses reproduce. In this way, Anti-retroviral Drugs slow down
damage to the immune system and allow people infected with HIV to feel
better and lead more normal lives.

 However, these drugs do not eliminate HIV, and they do not completely
restore the immune system. Although people who take these drugs may
feel well most of the time, they may still get serious infections and
have other health problems. Furthermore, Anti-retroviral Drugs do not
prevent the spread of HIV from an infected person to someone else.
People taking these drugs must still observe all precautions to avoid
infecting others.

There are three main types of Anti-retroviral Drugs: 
?	Nucleoside Analogs, or Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
?	Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
?	Protease Inhibitors 
http://www.pharmaceutical-drug-manufacturers.com/pharmaceutical-drugs/anti-retroviral-drugs.html


Fusion inhibitors are the newest type of HIV drugs:
---------------------------------------------------
  Fuzeon is the frontrunner in a new class of anti-HIV drugs called
?fusion inhibitors". Unlike existing anti-HIV drugs that work inside
the cell, Fuzeon has a unique mode of action and is designed to block
HIV before entering the human immune cell. Fuzeon is active against
HIV that is resistant to the currently available classes of anti-HIV
drugs. As a result of the better than expected activity and
tolerability data, Fuzeon offers new hope to patients with limited
treatment options.

 "The incidence of drug resistant HIV among already treated patients
is increasing at a disturbing rate, with up to 78 percent of patients
in North America and Europe infected with a strain of the virus that
has developed resistance to one or more anti-HIV drugs". said Dr.
Daniel Kuritzkes, Director of AIDS Research, Brigham and Women's
Hospital, Associate Professor of Medicine, Harvard Medical School. "It
is clear that the need for new drugs such as
Fuzeon which work in completely new ways to block HIV will become ever
more urgent."
http://www.roche.com/inv-update-2002-09-17-e.pdf#page=1

http://www.roche.com/de/inv-update-2003-07-15b



   This page lists all the HIV drugs approved by the US. Each drug has
several links providing combinations that work with each drug, a
patient fact sheet, a monograph, and price comparisons.
http://www.coreynahman.com/antiHIVdrugdatabase61499.html


   ?Recommendations regarding the use of antiviral drugs in HIV are in
flux. When and what to initiate, when to change regimens, and how to
minimize the development of resistance and cross-resistance are
continually being reevaluated. Clearly, monotherapy results in
resistance and loss of efficacy as a result of the huge viral burden,
short viral half-life, and propensity to mutate.
Viral loads are critical in determining efficacy of regimens; the goal
is to make all viral loads undetectable, because high loads drive CD4
loss and ultimate immune suppression. The current recommendation is to
initiate a three-drug regimen in patients with a detectable viral load
of > 5,000 to 10,000, regardless of CD4 count. This regimen offers
sustained viral suppression over double- and single-drug regimens.

Triple combinations containing a protease inhibitor are considered the
most potent of all regimens. The difficulty with multidrug therapy is
that the patient may not fully comply because of the number of pills
and adverse effects. Even minimal noncompliance causes drug resistance
and loss of efficacy. When changing a failing regimen, two new drugs
(preferably three new drugs) should be started. All regimens must be
individualized, and occasionally when patients are unable to comply
with the rigors of three drugs, double therapy is preferable to no
therapy. The classes of anti-HIV drugs include reverse transcriptase
inhibitors (nucleoside and non-nucleoside) and protease inhibitors.?
http://www.merck.com/mrkshared/mmanual/section13/chapter154/154b.jsp


HIV vaccines seem far away, still.
?The world is inching towards a vaccine, when we should be making
strides," Reuters reported him as saying on Monday at the 15th
International Conference on AIDS in Bangkok, Thailand.
"Only a vaccine can end the epidemic."
His comments echoed those made the day before by U.N.
Secretary-General Kofi Annan, who said global efforts to reduce the
scale and the impact of the disease by next year are not following
projections made three years ago.?
http://www.cnn.com/2004/HEALTH/07/12/aids.conference/



2. Who manufacturers them?
===========================

Pfizer/Agouron
---------------
http://www.upjohn.com/pfizer/main.jsp

http://www.upjohn.com/pfizer/do/diseases/mn_hiv_infection.jsp



GlaxoSmithKline
----------------
http://www.gsk.com/index.htm

http://www.gskpoppy.com/gskinternet/publishing.nsf/Content/Ziagen

http://www.gskpoppy.com/gskinternet/publishing.nsf/Content/Combivir

http://www.gsk.com.au/gskinternet/publishing.nsf/Content/Trizivir



Boehringer Ingelheim
-------------------- 

http://us.boehringer-ingelheim.com/

http://www.boehringer-ingelheim.co.uk/Products/hiv_viramune_nevirapine.html

http://us.boehringer-ingelheim.com/about/pressreleases/062305_aptivus_approval.html

Animation of HIV replication
http://www.boehringer-ingelheim.com/hiv/art/art_videos.htm



Hoffman-LaRoche
----------------
http://www.roche.com/home.html

http://www.roche.com/inv-update-2003-05-28




Gilead Sciences
----------------

http://www.gilead.com/wt/home

http://www.gilead.com/wt/tert_uk/viread_uk

http://www.gilead.com/wt/tert_uk/truvada_uk

http://www.gilead.com/wt/tert_uk/emtriva_uk




Abbott Laboratories
--------------------
http://abbott.com/hiv/hiv.cfm


Roxanne Laboratories
--------------------
http://www.roxane.com/tpPortal/appmanager/touchpoint/rli/

https://www.roxane.com/tpPortal/appmanager/touchpoint/rli/;jsessionid=D8lWVGQyp6DLJXQLQFTn1tw0nxJRmM4Kf1bplyLSKKPYzDyyPy25!-608089189?_nfpb=true&_pageLabel=rli_common_page&attach_image=&content_id=0900975a8033fc57&page=news


Merck
------
http://www.merck.com/

http://www.merck.com/mrkshared/mmanual/section13/chapter154/154b.jsp

 
Bristol-Myers Squibb
--------------------

http://www.hivandhepatitis.com/recent/pricing/071103b.html

http://hab.hrsa.gov/tools/adap/adapSecVIChap3.htm


Cipla
------

http://www.cipla.com/

http://www.cipla.com/admin.php?mode=cat&action=disp&id=39

http://www.who.int/mediacentre/news/releases/2004/pr87/en/



Imunus Aurobindo 
-----------------
http://www.aurobindo.com/home.htm

This pharmaceutical company was given approval to manufacture liquid
oral Lamivudine.
http://www.aurobindo.com/docs/lamivudine.html



Ranbaxy Laboratories 
--------------------
http://www.ranbaxy.com/

?Ranbaxy offers a complete basket of drugs to construct several first
line HAART regimens. The current portfolio is the largest range of
bio-equivalent generics ARVs available from a single company. These
products are manufactured at one of Ranbaxy's WHO prequalified
facilities.

Besides, Ranbaxy's pipeline includes almost all major molecules being
used to treat HIV.

Treatment of HIV entails not only ARVs but also drugs for
Opportunistic infections (OIs) and continuous monitoring of the
infection to alter therapy as and when required. Ranbaxy is probably
the only company with ARVs, anti infectives for OIs, and diagnostic
solutions ranging from screening of HIV to tests for monitoring the
infection.?
http://www.aidonaids.com/antihivportfolio/anti-hiv-portfolio.htm

	?Ranbaxy?s Lamivudine Gets PEPFAR Nod: Ranbaxy Laboratories Ltd. has
become the first Indian generic drug maker to have an antiretroviral
drug approved for use in the President?s Emergency Plan for AIDS
Relief (PEPFAR). The Food and Drug Administration (FDA) has given
tentative approval for Ranbaxy?s 150 mg lamivudine tablets under an
expedited program devised for PEPFAR. Tentative approval means the
product is safe and effective but is not approved for sale in the
United States due to patent restrictions.
Indian drug makers have been leaders in providing low-cost generic
antiretrovirals to developing countries, but the $15-billion PEPFAR
initiative had declined to use them because they were not
FDA-approved. HIVMA, IDSA, and others criticized the policy for
favoring more expensive brand-name drugs. FDA developed a rapid
approval program, which approved its first tentative approval to a
generic drug in January: Aspen Pharmacare of South Africa?s
lamivudine/zidovudine fixed dose combination co-packaged with
nevirapine.
http://www.idsociety.org/Template.cfm?Section=Home&CONTENTID=13620&TEMPLATE=/ContentManagement/ContentDisplay.cfm


Asian Pharmaceutical Companies that manufacture HIV drugs:
----------------------------------------------------------
http://web.amfar.org/treatment/specialreport/Appendix1.asp



South America
--------------
   ?South America and Brazil in particular have developed capacity for
producing generic antiretroviral drugs. How has this impacted on the
epidemiology and treatment scenario for South American countries? Do
the drugs produced by the generic industry meet the quality standards
for the WHO Prequalification Project? Yes, we do have a strong generic
industry and I would say that the reason for this is that it is
largely a historical artefact. The manufacturers were making generic
drugs before antiretrovirals came on the scene. Regarding the quality
of these compounds, some of them have been approved by the WHO project
and the Ministries of Health utilize our own local FDAs to scrutinize
bioequivalence. But the quality issue is a little complicated if you
consider that we use what I call our own ?combination therapy? - that
is, we prescribe both patent and generic drugs in the same regimen, so
it could be argued that we cannot always be certain about the
individual components of the treatment. Having said that, at a
population level our results are not different from those seen in
industrialized countries with regard to the proportion of patients
that reach undetectable viral load as well as the impact on disease
progression and mortality. Not all countries use generic drugs. Chile
for example provides only brand name drugs, but then it has only a
relatively small HIV epidemic. In my hospital we have over 2,000
patients on HAART, supplied by programs from the national Ministry of
Health.

For us, the generic industry is very important, and for some countries
it has been a lifeline. Brazil has 130,000 people on HAART, so if we
are to afford good HIV treatment, the government recognizes that we
have to be pragmatic about our investment in generics. Of course, we
are also proficient in negotiating with pharmaceutical companies.
Argentina has managed to reduce its overall cost of antiretroviral
treatment by 40%, simply by asking companies to compete with each
other. In fact, I would go as far as to say that generics and brands
compete on the same market place.?
http://www.iatec.com/update.html?folder=3&page=220



Genix Pharma
-------------
I see evidence that this company makes antiretrovirals, but I found no
mention of this on their home site.

http://genixpharma.com/

http://www.trade-india.com/Indianserviceprovider-465905-245987-83-BRANDING/Market-Research/GENIX-PHARMA-LTD.html

http://www.dgroups.org/groups/hiv-aids/index.cfm?cat_id=11674&msgid=289575&op=dsp_showmsg



3. How much do they cost?
=========================


   I have found a wonderful 2005 publication from Canada that outlines
many different HIV drug regimens and their cost. (It is far too much
information to post here). Please see pages 7-27.
http://www.tthhivclinic.com/pdf/regimens05.pdf

Here is another price chart of liquid HIV drugs:
http://www.tthhivclinic.com/pdf/liq_drugs.pdf

From 1996, some prices:
http://www.thebody.com/jh/hivrept/nov96/procost.html


GlaxoSmithKline 2002 prices per day:
------------------------------------
Drug 
Cost per Day 

Trivizir 
$4.45 
Ziagen 
$2.70 
Retrovir 
$1.20 
Combivir 
$1.70 
Agenerase 
$8.50 
Epivir 
$0.41 

http://www.cptech.org/ip/health/pcuts.html


    ?Although drug prices are not going down, the good news is that
many of the pharmaceutical companies have agreed to freeze prices of
the HIV drugs. Glaxo and Pfizer have promised not to raise prices on
any of the antiretroviral products that they market for a period of
two years. The hope is that a long-term solution to find funding for
these programs will be found. Generic equivalents of branded products
used in other countries could reduce our drug bill, but they are still
years away from use in the United States because of patent protection
that these companies enforce.

At this time, each state can negotiate prices independently with each
drug company with different degrees of success. States are now banding
together to negotiate with drug companies to lower prices. This
strategy should be successful because with larger buying power, the
drug cost should come down.?
http://www.tpan.com/publications/positively_aware/jul_aug_03/medicine_chest.html



   ?Some US$1.5 billion is required yearly to contain the AIDS
epidemic in Asia, and that amount is expected to increase
significantly as more people are diagnosed with the disease, said Dr.
Peter Piot, executive director of UNAIDS.

"The cost of inaction, of not acting against AIDS, is very high," Piot
said. "The longer one waits, the higher the bill becomes."
http://www.cbsnews.com/stories/2004/06/21/health/main625106.shtml


4. Can they be mixed in a cocktail?  If so, how are they mixed and
what other drugs are they mixed with?
===============================================================================

AN anti-HIV cocktail would be a fixed combination:
?Fixed Combinations are multiple drugs in a single pill
?	Combivir® = AZT + 3TC
FDA approved Sep 26, 1997, thirteenth approved antiviral. Marketed by
GlaxoSmithKline.
?	Trizivir® = ABC + AZT + 3TC
FDA approved November 15, 2000, eighteenth approved antiretroviral
drug. Marketed by GlaxoSmithKline.
?	Kaletra® = lopinavir (for its HIV protease enzyme inhibition), with
ritonavir included to boost serum levels of lopinavir through
inhibition of CYP3A4, a liver enzyme that metabolizes many other
substances.
FDA approved Sep 15, 2000, seventeenth approved antiretroviral drug.
This is the first multi-drug capsule that contains a drug not
available individually. It has been demonstrated to be extremely
potent and is often used in 'salvage' therapy for patients with some
level of drug resistance. Some studies have suggested Kaletra is
potent enough to be used as monotherapy and is also suitable for
once-daily dosing, although neither is currently recommended. Marketed
by Abbott Laboratories. Patent will expire in the United States on
2016-06-26.
?	Epzicom® (also Kivexa®) = ABC + 3TC
FDA approved August 2, 2004 for once-a-day dosing. Marketed by GlaxoSmithKline.
?	Truvada® = emtricitabine + tenofovir
FDA approved August 2, 2004 for once-a-day dosing. Marketed by Gilead Sciences.

http://en.wikipedia.org/wiki/HAART#Fixed_Combinations


?There are many variables that impact what drug regimen your doctor
will choose for you first. Factors that affect that choice include:
?	have you been on meds before
?	do you have any resistance to medications
?	what is your current CD4 and viral load counts
?	are you able to take meds several times each day or do you need a
once per day regimen
?	are you pregnant or thinking of becoming pregnant
?	what other illnesses and conditions do you have?
These are just a few of the factors that impact your doctor's choice.
The US Department of Health and Human Services do have recommendations
for first-line regimens. They include:
?	Sustiva + (Retrovir or Viread) + (Epivir or Emtriva) or
?	Kaletra + Retrovir + (Epivir or Emtriva)
http://aids.about.com/od/themostcommonquestions/f/firstline.htm




?Combination therapy
HIV has a life span that can be as short as about 1.5 days from
assembly by an infected, effectively hijacked cell through infection
of another cell back to assembly by the newly infected cell. HIV lacks
proofreading enzymes to correct errors made when it converts its RNA
into DNA via reverse transcription. Since the life time of HIV is
short and the DNA copies are wildly diverse due to a high error rate
HIV mutates very rapidly. Most of the mutations either are inferior to
the parent virus (often lacking the ability to reproduce at all) or
convey no advantage, but some of them are superior to their parent and
can enable HIV to slip past defenses such as the human immune system
and antiretroviral drugs. The best defense against resistance is to
suppress HIV as much as possible because the more active copies there
are, the more chance that a superior one will be made. This is natural
selection in action.

Combinations of antiretrovirals work by increasing the number of
obstacles HIV has to mutate around and by reducing the chances of a
superior mutation by keeping the number of offspring low. If a
mutation arises that conveys resistance to one of the drugs being
taken, the other drugs will help suppress reproduction of that
mutation. With rare exceptions, no individual antiretroviral drug has
been demonstrated to suppress an HIV infection for long; these agents
must be taken in combinations in order to have a lasting effect. As a
result the standard of care is to use combinations of antiretroviral
drugs.?
http://en.wikipedia.org/wiki/HAART#Combination_therapy


?Combination Therapy 
Why Do I Have to Take Several Antiretrovirals? 
Shouldn't One Be Enough? 
Using a combination of antiretroviral drugs has many advantages.
First, combinations are more powerful than single-drug therapy because
reverse transcriptase inhibitors and protease inhibitors interfere
with viral reproduction in two different ways. Second, this approach
makes it possible to combat HIV in different parts of the body.
Although protease inhibitors are stronger than reverse transcriptase
inhibitors, they are unable to penetrate the brain. Fortunately, some
reverse transcriptase inhibitors, such as AZT, can reach brain cells.
Combining protease inhibitors with a drug like AZT results in a
powerful treatment that also attacks HIV in the brain.
Finally, a very important reason for using antiretrovirals in
combination is that this strategy delays the development of resistance
to any one drug. To prevent resistance, though, the drugs must be
taken on schedule.?
http://www.anemiainstitute.org/patient/anemia_and_hiv/azt_antiretroviral_treatments

?Combo drugs
Combination pills?those with two or more drugs in it?are cutting the
number of pills people take. Current combo pills on the HIV market
are: Combivir, Trizivir, Epzicom and Truvada. In the works is a new
combo pill, one that?for the first time?contains two classes of HIV
drugs. That?s the combination of Sustiva and Truvada.


Nuke backbone
Most HIV regimens contain two (sometimes more) nucleoside analogs.
This is called the ?nucleoside backbone? of the combination.


Dual PI combos
Combining two PIs can be effective in suppressing HIV, sometimes
without adding nukes or a non-nuke. The idea is to use two full-dose
PIs together, rather than just boosting one PI with a small dose of
Norvir. A powerful combination is Kaletra and saquinavir (Invirase or
Fortovase). Studies are also looking at the combination of Kaletra and
Reyataz. Kaletra and Agenerase or Lexiva should be combined with
caution, because the latter two drugs lower the blood levels of the
lopinavir component of Kaletra. Dual PI combos are generally salvage
therapies, when a person can usually no longer take simpler regimens.?
http://www.tpan.com/publications/positively_aware/jan_feb_05/combining.html



Some cocktails don?t work correctly:
   ?Gilead Sciences on Tuesday said an experimental pill combining its
HIV treatment Truvada with Bristol-Myers Squibb Co's popular Sustiva
treatment will be scrapped, but that a second version of the pill will
be developed and could be submitted to US regulators for approval by
year's end.?
?But Gilead said the first formulation of the new product created
bloodstream levels of Sustiva (efavirenz) that were lower than those
typically seen with the recommended 600 milligram dose of Sustiva used
alone.

Gilead said if the second formulation of the new product produces
satisfactory bloodstream levels of its drugs and Sustiva, the
companies could seek US approval for it by the end of the year.?
http://www.int.iol.co.za/index.php?set_id=14&click_id=117&art_id=qw1114580523303B243


Cheapest anti-HIV drug cocktail ever;
?The government (Thai) says that the cocktail, named GPO-Vir, will be
sold for just 20 baht ($0.45) per pill, meaning that a month's supply
of the drugs would fall from 5000 baht ($114) per person for the three
separate drugs, to just 1,200 baht ($27).?
http://www.newscientist.com/article.ns?id=dn2080



The Bottom Line
?Currently four different classes of HIV drugs target three different
stages of HIV?s lifecycle. Attacking HIV on multiple fronts by
combining drugs from different classes is the best way to slow or stop
HIV replication. It is also the best way to prevent the development of
drug resistance. New classes of HIV drugs?and new drugs in the classes
already available?will provide more treatment options for HIV+ people
in the future.?
http://www.thewellproject.org/Treatment_and_Trials/Anti_HIV_Meds/Lifecycle_and_ARVs.jsp




5. How often are they taken--once a day? once a week? so on. And 6.
How are they ingested?--orally? Injected? so on.
================================================================================

  HIV medications vary per patient, and are adjusted depending on the
patient's condition, and lab tests (CD4 cell count levels and viral
load titers). Some may be taken just for a few weeks/months before
they are changed.  They are taken orally, and as an injection.
Recently the FDS approved a new oral liquid form of lamivudine. (More
further along in the answer) The following charts show the recommended
dosages.

?In a small study conducted at the U.S. National Institutes of Health
(NIH), researchers have shown that it may be feasible to treat
HIV-infected patients with a simple, once-daily regimen of anti-HIV
drugs given in pre-planned, 7-day-on, 7-day-off cycles. This approach
is known formally as ?short-cycle structured intermittent
antiretroviral therapy? (SIT) or colloquially as the ?7-7? approach.


?Our data suggest that the 7-7 approach, used with well-chosen drug
regimens in settings where patient adherence is high, could be a
powerful and cost-effective tool in treating HIV-infected
individuals,? says study author Mark Dybul, M.D., of the National
Institute of Allergy and Infectious Diseases (NIAID), a component of
NIH. ?By using half as much antiretroviral medication, drug costs are
reduced and drug-related toxicities may be less in the long run.? He
adds, ?The 7-7 approach may have particular relevance to resource-poor
countries around the world.?
http://www3.niaid.nih.gov/news/newsreleases/2004/oncedaily.htm

This site lists numerous drugs, and clicking the name of each drug
links you to a page that suggests dosage.
http://aids.about.com/cs/druginformation/a/drugindex.htm

So does this page:
http://hivinsite.ucsf.edu/InSite?page=ar-drugs


?Is toxicity increased if antiretroviral treatment is delayed?
Few studies have been done in this area. In general, there seems to be
little difference in most antiretroviral side effects in patients with
lower rather than higher CD4 cell counts. Of course, in those with
comorbidities such as underlying infection with hepatitis B or C
virus, treatment delay may allow more severe liver disease. Little
prospective evidence can be cited, but most physicians who treat
patients with HIV infection agree that the hepatotoxicity of
antiretroviral drugs is increased in such cases.

A related issue is the immune reconstitution disease, which is, in a
sense, a treatment side effect. The recovery of CD4 cell counts after
antiretroviral treatment initiation may cause an apparent flare of
underlying systemic infection with, for example, tuberculosis or CMV
organ disease (15,16). This is a phenomenon seen especially in
patients with lower baseline CD4 cell counts, given their higher risk
of some of these infections. It is another reason to begin therapy, if
possible, before opportunistic infections become established (CD4 cell
count, >200 cells/microliter).?

?Essentially all regimens currently include two nucleoside reverse
transcriptase inhibitors (NRTIs). These drugs are critical to support
the NNRTI or protease inhibitor. All NRTIs have comparable, although
not precisely the same, individual potency but differ substantially in
toxicity and pharmacology.
Because each drug in the selected regimen is necessary for the
treatment's outcome, each must be chosen carefully. A complete review
of each drug or of the almost countless potential combinations of two,
three, or four drugs is beyond the scope of this article, but some
broad generalities can be provided about commonly used regimens.?
http://www.postgradmed.com/issues/2004/02_04/volberding.htm 



   ?The decision about which drugs to take, and indeed which drugs
should be made available in a particular country or area, depends on a
number of different factors. These include the availability and price
of drugs, the numbers of pills, the side-effects of the drugs, the
laboratory monitoring requirements and whether there are co-blister
packs or fixed dose combinations available.?
 
For example ?3TC is recommended for inclusion in all instances,
because it is a potent drug, and WHO considers that it has an
excellent record of efficacy, safety and tolerability. It can be taken
either once or twice daily, and it has been incorporated into a number
of fixed dose combinations.?

?Drug combinations such as AZT+3TC+NVP, and d4T+3TC+NVP are available
from a number of different manufacturers including Cipla, Imunus
Aurobindo, Ranbaxy Laboratories and Hetero Genix Pharma. The number of
different manufacturers is increasing rapidly, and there are also
rapid changes taking place in the price of these drugs.?

This site has a chart for first line and second line therapy, staging
of HIV and other useful information:
http://www.avert.org/aidstreatment.htm



7. Are there any side effects of the drugs?  What are the strengths
and weaknesses of each drug?
========================================================================
   ?This is a very difficult question to answer. Each drug has its own
side effects, and each patient responds to them differently. Some
people experience no problems with a particular drug, while others are
completely unable to tolerate it. Often, a person has no problem with
an antiretroviral alone but has new or worse side effects when it is
combined with other drugs.
 
The best way to get an idea of the side effects you may experience is
to ask your doctor. You should make it your business to know what the
negative effects of a drug may be and to use that information in
deciding whether or not you wish to take the drug.

Keep in mind, though, that no one can predict for sure exactly how you
will respond to a drug. And, even if the drug does have some side
effects, your doctor may feel the benefits may be worth it.?
http://www.anemiainstitute.org/patient/anemia_and_hiv/azt_antiretroviral_treatments
   

   ?The warnings and precautions associated with Emtriva have been
updated as of September 2004:

Lactic acidosis and severe hepatomegaly with steatosis, including
fatal cases, have been reported with the use of nucleoside analogues
alone or in combination with other antiretrovirals.

Emtriva is not indicated for the treatment of chronic hepatitis B
virus (HBV) infection and the safety and efficacy of Emtriva have not
been established in patients co-infected with HBV and HIV. Severe
acute exacerbations of hepatitis B have been reported in patients
after the discontinuation of Emtriva. Hepatic function should be
monitored closely with both clinical and laboratory follow-up for at
least several months in patients who discontinue Emtriva and are
co-infected with HBV and HIV. If appropriate, initiation of
anti-hepatitis B therapy may be warranted.?
http://www.emtriva.com/230.asp

?Firstly, the drug combinations often cause side-effects. A
side-effect is when a drug affects the body in ways other than those
that are intended. Some people only experience mild side-effects and
find them easily manageable. But for some people the side-effects are
so severe that they have to consider alternative drugs.

If it is possible to identify the drug that is causing the
side-effects then it may be possible to replace it with another drug
that does not have the same side-effects. (For example, replacing ZDV
with d4T if the side effect is anaemia, or replacing EFZ with NVP if
the side effect is central nervous system effects.) Given the limited
number of ARV combination options in resource limited settings, it is
important to try to use drug substitutions where possible so that
early switching to a completely new regimen is minimised.

Treatment Failure
The second reason for changing treatment is treatment failure. This is
when the drugs have failed to work and are not slowing down the
reproduction of the virus in the body.

What is the definition of treatment failure?
The WHO definition of treatment failure again depends on whether a CD4
test is available.

If a CD4 test is available, then treatment failure has occurred if the
CD4 count has returned to the level that is was before treatment was
started, or if there has been a fall of more than 50% of the count
whilst the person has been on therapy, unless there has been some
other infection to explain this decrease.
If a CD4 test is not available, then treatment failure is defined
firstly as the occurrence of new opportunistic infections, or a new
malignancy, signifying clinically the progression of disease. This
must however be differentiated from the immune reconstitution syndrome
which can occur in the first three months following the initiation of
ART. Treatment failure can also be indicated by the onset or
recurrence of WHO Stage III conditions.?
http://www.avert.org/aidstreatment.htm

   ?Another concern is that the combination therapy, besides being
very expensive, requires a much more complicated treatment regimen.
"Patients need to stay aware of and adhere to their dosing schedule,"
says Klein. "If not taken on a strict regimen, protease inhibitors can
result in the emergence of HIV strains that are resistant to
treatment." Numerous studies also have shown that viral load can
rapidly "rebound" to high levels if patients discontinue part or all
of the triple therapy regimen.

AIDS treatments may interact with many commonly prescribed drugs. For
example, Pfizer Inc. plans to label its impotence drug Viagra to warn
of possible interactions with certain protease inhibitors, which
appear to raise levels of Viagra in the blood.

AIDS drugs also may prompt onset of diabetes or a worsening of
existing diabetes and hyperglycemia (high blood sugar), along with
increased bleeding in people with hemophilia types A or B.

Some patients on triple therapy have experienced a type of weight
redistribution where face and limbs become thin while breasts, stomach
or neck enlarges. Some have nicknamed the appearance of fat deposits
at the back of the shoulders "buffalo hump." Fat deposits in the
midsection are sometimes called "Crix belly," after the drug Crixivan,
"although it has been seen in people taking all approved protease
inhibitors," says Klein.?
http://www.fda.gov/fdac/features/1999/499_aids.html


   Bone marrow suppression, hepatotoxicity, kidney stones, nausea,
diarrhea, weight loss, fatigue, dry mouth, rashes and elevated
cholesterol are some of the more prominent side effects of HIV drugs.
http://www.itmonline.org/arts/sfxhivdr.htm

http://aids.about.com/cs/conditions/a/sides.htm

http://aids-clinical-care.jwatch.org/cgi/content/full/2005/1108/1



?Why Are People With HIV at Special Risk for Anemia? 
There are different types of anemia, and different causes. Some types
are temporary and have fairly simple causes. One cause of anemia is a
diet that might include a shortage of certain vitamins and minerals,
such as iron, vitamin B12, and folic acid. Anemia also can be caused
by bleeding or blood loss. In fact, many women develop a mild form of
anemia during menstruation. These are considered temporary, or acute,
cases of anemia. They are relatively easy to bring under control.

In addition, certain drugs typically taken by people with HIV - like
AZT and some chemotherapy drugs - also can cause anemia. That's why
someone who is HIV+ is at a higher risk for becoming anemic. This is
called treatment-related anemia, and it cannot be corrected by itself
or through dietary supplements.
Why Do These Drugs Increase Risk for Anemia? 
A common side effect of AZT is that your bone marrow has difficulty
making red blood cells.?
http://www.anemiainstitute.org/patient/anemia_and_hiv/azt_antiretroviral_treatments



Food and HIV drugs interactions:
   ?Because nutritional status impacts the effective management of HIV
disease, the importance of optimal nutritional status can not be
overstated. Maintenance of appropriate body stores and function
becomes a central issue.45 Medication side effects increase the need
for effective nutritional therapy. Among the current problems seen in
long-term management are wasting processes, side-effects and symptoms
associated with medication therapies, altered metabolic processes, and
changes in physical attributes of the body. To address these problems
it will be essential to understand the process of nutritional
compromise and its effects on disease management.?


?Some HIV-positive people may follow harmful fad diets with the hope
of improving nutrition status. Diets such as the popular high protein
regimen are not recommended without close dietitian supervision
because they usually increase saturated fat intake, cause excessive
work for the kidney and liver, and may lead to heart disease, kidney
stones, and an increased risk for osteoporosis.114 Since stored
carbohydrate contains large amounts of water, which is eliminated when
dieters switch to a low carbohydrate diet, these regimens can also
result in the loss of both water and the weight associated with it.?
http://www.foodmedinteractions.com/hivinfo.html


The following sites chart drug interactions. All are recently updated.
I think you will agree that it?s better for you to link to each page
than attempt to duplicate a part of the information here.:

This page provides a drug interaction chart of protease inhibitors:
http://www.tthhivclinic.com/pdf/Pi-int.pdf

Drug Interactions with dual protease inhibitors:
http://www.tthhivclinic.com/pdf/DualPIs-NNRTI.pdf

Tenofovir interactions:
http://www.tthhivclinic.com/pdf/Tenofovir-INT.pdf

Non-nucleoside reverse transcriptase inhibitors
http://www.tthhivclinic.com/pdf/Nnrt-int.pdf

Nucleoside reverse transcriptase inhibitors
http://www.tthhivclinic.com/pdf/RTI-INT.pdf

 This page gives a slide show presentation on absorption and
reactivity of some HIV drugs. Click the third button from the top, on
the right hand side to advance the slides.
http://www.tthhivclinic.com/int_present/sld013.htm


Anticonvulsant-antiretroviral interactions:
http://www.tthhivclinic.com/pdf/anticonvulsant-int.pdf


Antiretroviral-methadone interactions:
http://www.tthhivclinic.com/pdf/methadone%20int.pdf


From The Center for HIV Information site, here is an interactive side effect chart:
http://hivinsite.ucsf.edu/InSite?page=md-rr-21


8. Is there any information on transdermal patches being used?   We
believe that we know there is not, but why? Is there a reason they are
not used -e.g. the drugs are too large or cannot be transferred
through the skin etc.
================================================================================

   It appears that transdermal patches may not be a good drug delivery
system for HIV meds. However, pharmaceutical companies are studying
this method, along with skin permeation enhancers to assist drugs
crossing the skin barrier, nasal sprays, suppositories, creams and
gels. Molecular size does indeed pose an impediment, but not the only
one. The sheer amount of drug needed is currently a prohibiting factor
for a transdermal delivery system.

?Many companies probably feel that it's cheaper and safer to spend
money on developing drugs that don't rely on experimental drug
delivery. However, the next leap in treating HIV disease will likely
require that researchers and drug makers think beyond the status quo.

HIV is not the only disease where people must take medicines exactly
as prescribed for long periods of time. Diabetes and tuberculosis are
two other conditions where strict drug schedules often present
challenges. Until recently, however, drug makers basically offered
only two ways to take most medicines -- as a pill or a shot.?

?Only when a compound can not make it through the digestive system
have companies considered making drugs that need a direct route to the
bloodstream. Often, such drugs weren't developed at all as companies
feared patients wouldn't use them.
People living with HIV are all too familiar with the shortcomings of
current anti-HIV drugs. All of them demand near perfect adherence.
Some cause hard-to-manage side effects like nausea, vomiting and
diarrhea because of how they affect the digestive system. Also, the
size of pills and the number that must be taken are a barrier for
many, even those who do not find these strict pill schedules
troublesome.?

?One area of intense focus is the search for needle-free devices. More
and more medicines are now delivered to the bloodstream less
intrusively, through skin patches, gels and creams, inhaled products,
nasal sprays and small patches that attach to the gums in the mouth.
In the future, consumers may be given things that look like pens, or a
sort of air gun. Both use air pressure to shoot a dose of medicine
through the skin without a needle.?

?There are currently limitations to the technologies described above,
particularly with regard to current anti-HIV drugs. Most are made of
molecules too large to pass easily through the skin or mucous
membranes. For some drugs, the quantities that must be given for each
dose are far too large to be made into patches or suppositories.
However, these obstacles may not be insurmountable.
Researchers have already found chemicals that help larger molecules
pass through the skin. Other chemicals cause drugs to stay in the body
longer or to make it into cells more easily. The substantial
improvements in treating hepatitis C with pegylated interferon is just
one example of success in this area.
While much of this research is new, it demands our attention. It's not
difficult to imagine the benefits of using anti-HIV drugs in small
doses only once a day or even once a week by a patch or inhaler.

While these treatments do not exist today, the technology to create
and test them does. Dozens of companies are developing and improving
them. These are genuinely exciting developments. They have the
potential to greatly ease the lives of people living with HIV, if not
today then certainly in the future -- as long as people living with
HIV and their advocates push for them.?
http://www.thebody.com/pinf/jul04/drug_delievery.html 


?Hydrophobic (oleic acid and lauric acid) and hydrophilic (NMP)
enhancers at concentrations of 1%, 5%, and 10% were added to
ethanol/IPM (20/80) to produce formulations F8 to F16 (Table 1). The
permeation parameters of saturated AZT in ethanol/IPM (20/80) (with
and without enhancers), across pig skin are shown in Table 5. Of the
hydrophobic enhancers (oleic acid and lauric acid), only 5% oleic acid
increased the AZT flux value, but the change was not significant when
compared with the control formulation F5. With the hydrophilic
enhancer NMP, however, a concentration of 10% NMP (F10) significantly
increased (P < .05) the AZT flux value by more than 2-fold when
compared with F5.?
http://www.aapspharmscitech.org/view.asp?art=pt050348&pdf=yes


   ?The effects of vehicles and enhancers on the skin permeation of
the dideoxynucleoside-type anti-HIV drugs Zalcitabine (DDC),
Didanosine (DDI), and Zidovudine (AZT) were studied using hairless rat
skin at 37 degrees C.?

?Although only DDC reached the target permeation rate across human
cadaver skin, these results suggest that the mutual enhancement effect
of ethanol and OA may make transdermal delivery of
dideoxynucleoside-type anti-HIV drugs feasible.?
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8683451&dopt=Abstract

   Not a antiretroviral, but a drug for HIV patients with cognitive
impairment is being studied in a transdermal patch.
?This is a three-arm study of Selegiline Transdermal Patch for HIV
infected subjects with impaired cognitive function followed by an
optional open-label treatment phase. Subjects who complete the 24-week
double-blind phase will be offered the option to participate in a
24-week open-label phase?
http://www.centerwatch.com/patient/studies/stu58842.html

?Controlled release of the medicine is one of the greatest advantages
of patches. In some cases, the active drug is mixed with another
substance that controls how quickly it?s absorbed through the skin.
Also, a thin net-like layer of material can be placed between the drug
and the skin to control absorption. This allows most patches to be
worn continually for at least 24 hours. Some can be worn for several
days.

Another form of transdermal drug delivery includes devices that use
air pressure to inject a small stream of medicine through the top
layers of the skin. Air pressure guns have been used for several years
to give vaccines to children. Small, disposable pen-like devices are
also available for diabetics who take insulin daily. Researchers
working on HIV gene therapy have experimented with this technology to
inject genetic material through the skin or into muscle.?
http://www.aegis.com/pubs/projinform/2004/PI040705.html


You can purchase an article on transdermal deliveryfor  peptide and
protein drugs, for $75 here:
http://www.ingentaconnect.com/content/apl/edd/2005/00000002/00000003/art00010



Additional Information:
=======================

  ?This is not to say that antiretrovirals have not been an advance in
HIV therapeutics. Many of us would not be here but for their
existence. But in the larger scheme of things, antiretrovirals have
not turned out to be the long-term solution to a pandemic that
threatens to destabilize governments and wreak havoc on large segments
of the world's population. For this reason many scientists, healthcare
providers, consumers, and advocates have begun searching for different
approaches to the treatment of HIV disease.

What will it take to develop new targets for therapy and new
approaches to HIV/AIDS? The short answer is that finding a different
approach may require a lot more basic understanding of the science of
HIV. Unless science serendipitously stumbles upon some solution,
researchers likely will not be able to develop new approaches to HIV
therapeutics without learning much more about how the virus works and
how our immune system functions?not just in response to the virus, but
under normal circumstances.

There have been many advances in our knowledge of viral dynamics and
pathogenesis in the past few years. Yet, despite this knowledge, to
date all our current drugs interfere only at 2 points in the viral
lifecycle: during reverse transcription and protease processing. The
research community is just now working on new targets such as
virus-cell fusion (e.g. pentafuside), coreceptor attachment (e.g. SCH
C & D), and integration (e.g. Shionogi's S-1360 and Merck's integrase
inhibitor in early development). To exploit the remaining potential
targets we must do a better job of characterizing viral and
immunological processes. We need a better understanding of
integration, replication, assembly, budding, etc. (as well as the
immune system's response to these viral activities) before we can
develop new compounds or approaches to interfere with these processes.
We need to understand virulence, infectivity, and pathogenicity to
further refine treatment and care.?
http://www.centerforaids.org/rita/0702/novel.htm


History of HIV drugs
http://www.aegis.com/pubs/atn/1993/ATN17001.html

Useful tools to chart HIV meds and lab results:
http://aidsmeds.com/

AIDS Treatment News:
http://www.aids.org/atn/i-latest.html

Medication Assistance Programs (Select your state)
http://www.atdn.org/access/states/index.html

2005 HIV Drug Guide
http://www.tpan.com/publications/drug_guide/drug_guide_2004.html

FDA review of HIV drugs
http://www.hhs.gov/news/press/2004pres/20040516a.html

Some prices in Latin America. (You?ll need MS Word or Adobe Acrobat to
open these files)
http://www.paho.org/common/Display.asp?Lang=E&RecID=5845

Interesting documents on HIV drugs in Latin America
http://www.paho.org/Project.asp?SEL=TP&LNG=ENG&ID=224&PRGRP=docs_gen




I hope this has thoroughly answered your questions. If any part of
this answer is unclear, please request an Answer Clarification, before
you rate. This will allow me to assist you further, on this question,
if possible.

Sincerely, Crabcakes


Search Terms
============
Antiretrovirals
Antiretrovirals + cost
HIV protease inhibitors
Reverse transcriptase inhibitors
Anti-retrovirals + dosage
HIV drugs + cocktail
combining HIV drugs
Antiretrovirals + side effects
Delivery systems + antiretrovirals
Transdermal patches + HIV drugs
blucken-ga rated this answer:4 out of 5 stars

Comments  
Subject: Re: HIV Drug Questions
From: doctawood-ga on 18 Nov 2005 16:02 PST
 
FYI-

there are very specific recomendations based on what we know about
resistance patterns and side effect profiles as to what to start a
newly diagnosed person with HIV on.  It also depends on that person's
pre-viral load (PVL) and CD4 count (a measure of disease activity and
how compromised the immune system is).  Any doctor who treats the
disease could have answered all of your questions and done so more
specifically to your case by knowing to check for those lab values
(some people require antibiotic coverage to prevent serious
infections) and could have done so for less than the $200 you paid
here

in fact, Medicare now reimburses doctors for answering questions by
e-mail, the bill = $20, and most insurance companies tend to to follow
what medicare does.

you could also get all of the above mentioned information plus the
regimen recommendations, lab screening recommendations, and various
other screening/treatment protocols in a format utilized by most
doctors called the Sanford Guide  www.sanfordguide.com - cost of the
HIV book = $10

...nothing substitutes for professional evaluation when it comes to
medical advice, really consider pursuing direct medical discussion.

Hope this helps.
Subject: Re: HIV Drug Questions
From: blucken-ga on 22 Nov 2005 07:34 PST
 
Thanks for your concern - this info is for a market study - thankfully
not due to my own medical condition.

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