Drugs for HIV Infection

1
Drugs for HIV Infection

• The biggest news of the last year is that for the
  first time promising new classes of drugs and new
  combination treatments are reaching individuals.
  The number of possible combinations are
  overwhelming. Basic to HIV strategy is attacking
  the virus at various different points in its life
  cycle. See the following diagram of the life
  cycle of the HIV virus which illustrates the life
  cycle of HIV with the points at which
  pharmacologic agents may block viral maturation,
  including points for inhibition of reverse
  transcriptase, integrase, TAT transcription, and
  protease, diagram.

2

• Reverse Transcriptase Inhibitors Currently
  Available Nucleoside Analogs -- generic
  name/Trade name
• zidovudine/Retrovir (AZT, ZDV)
• didanosine/Videx (ddI) zalcitabine/HIVID (ddC)
• stavudine/Zerit (d4T) lamivudine/Epivir (3TC)
• abacavir/Ziagen (ABC)

3

• Non-Nucleoside Reverse Transcriptase Inhibitors
• nevirapine/Viramune delavirdine/Rescriptor
  efavirenz/Sustiva (DMP-266)
• Nucleotide Analog
• adefovir dipivoxil/Preveon

4

• Protease Inhibitors Currently Available(generic
  name/Trade name)
• indinavir/Crixivan ritonavir/Norvir
• saquinavir/Invirase, Fortovase
• nelfinavir/Viracept amprenavir/Agenerase

5
Combination Therapies

• In one short year, the HIV treatment environment
  has undergone huge changes. In January 1996, most
  persons in treatment for HIV in the US and Canada
  were on nucleoside analog (AZT, ddI, ddC, D4T)
  monotherapy--persons in more progressive
  practices may have added 3TC to their
  monotherapy. By fall of 1996, most persons in
  treatment were on double or triple therapy, often
  including one of the protease inhibitors approved
  during the winter of 1996 and on the market by
  spring. Later in the spring, the first two of the
  NNRTIs (non-nucleoside reverse transcriptase
  inhibitors was approved and are slowly being
  incorporated into combination therapies to
  increase the number of options individuals have
  to choose from. These classes of drugs operate on
  different targets in the life cycle of the virus
  and other targets are on the horizon for future
  clinical use--chemokines which act on surface
  receptors and integrase inhibitors.

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Nucleoside Analogs (NRTIs or "Nukes")

• The earliest class of effective AIDS
  antiretroviral medications, nucleoside reverse
  transcriptase inhibitors. . Although most early
  use of these drugs was as monotherapy (not in
  combination with other nucleoside analogs), based
  on results of ACTG 175 (announced at ICAAC in
  September 1995), a new standard of care developed
  around the use of combinations of these drugs--a
  strategy used in antibiotic therapies and cancer
  chemotherapy for many years and used
  anticipatorily by PWAs for several years while
  awaiting the results of ACTG 175. More recently,
  they have formed integral parts of combination
  regimens, containing the block-buster protease
  inhibitors which were introduced in early 1996
  and have been given credit for the 44 drop in US
  deaths from AIDS during the first half of 1997
  and the emptying of hospital wards around the
  country from opportunistic infections.

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• AZT (Retrovirreg, zidovudine, ZDV)
• ddI (Videxreg, didanosine)
• ddC (Hividreg, zalcitabine)
• d4T (Zeritreg, stavudine)
• 3TC (Epivirreg, lamivudine)
• 1592 (Abacavirreg, under development by
  Glaxo-Wellcome)

8
Non-Nucleoside Reverse Transcriptase Inhibitors
(NNRTIs)

• This class of antiretroviral drugs appeared to
  target the virus quite precisely in vitro when
  originally proposed by Belgian researchers in the
  late 1980s. You may recall the BI-RG drug
  proposed as a "magic bullet"? Soon, however,
  these drugs were found to develop resistance
  almost as soon as they entered the body. Even
  when, as proposed a couple of years later, they
  were suggested to work synergistically (much
  better than alone) in "convergent combination"
  nottherapy in conjunction with other drugs, a
  further look at the data showed flaws in the
  convergent combo theory.

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• More recently, spurred on by the unexpected
  synergism of 3TC when used in combo with AZT, we
  have been taking another look at these drugs to
  see if they merit development in combination with
  existing or new generation drugs, or as key
  elements in salvage therapies for persons who
  have failed initial protease-containing
  combination regimens.

10

• Nevirapine (BI-RG, Viramunereg), notable for
  rapid onset of resistance and for the frequent
  rashes that it causes, was licensed by the FDA in
  July of 1996. The manufacturer and distributor,
  Boeringer Ingelheim and Roxane Laboratories,
  report that Viramunereg has shown some
  synergism (enhanced effect) when used in
  combination with ddI. It tends to decrease the
  bioavailability of protease inhibitors. Studies
  show that it effectively crosses the blood-brain
  barrier.

11

• Delavirdine (U-90, BHAP, Rescriptorreg) was
  licenced by the FDA on April 4, 1997, after being
  stalled by a split vote when it went up for
  licensure in November 1996. Upjohn (January 17,
  1996) reported on surrogate marker data on
  ongoing (still-blinded) studies of Delavirdine.
  This early surrogate marker data tended to
  confirm viral load correlation with clinical
  events, while tending to show that 8-week CD4
  rises did not necessary show such a correlation
  (sustained 60-week CD4 count rises, however, was
  more reliable as an indicator of clinical
  benefit. Delavirdine tends to increase the
  bioavailability of protease inhibitors
  (saquinavir and indinavir for example) four or
  five fold.

12

• Efavirenz (DMP-266, Sustivareg) , a third NNRT
  has been studied by its sponsors Dupont-Merck for
  several years and has been put on a fast track
  for development and licensure. In early studies,
  it seems to be the best of the class--and studies
  also show that because of shared resistance
  issues, a person may have only one shot at use of
  an NNRTI in combination. Studies show that an
  NNRTI in combination may produce viral load drops
  that mimic combinations including a protease
  inhibitor.

13

• Lovirdine, a third NNRTI, has been studied
  extensively in Europe and may be a little further
  behind in development than the other drugs on
  this list.

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Protease Inhibitors

• More resources have been invested by the
  pharmaceutical industry in protease inhibitor
  research and development than all other AIDS
  drugs combined. And that research is beginning to
  pay off with some promising new treatments in a
  field remarkable for lack of good treatments.

15

• (Invirase, Hoffman-LaRoche Protease Inhibitor
  (Saquinavir Fortovasereg/Invirasereg, ).
  Current Phase III studies 1) AZT vs
  AZTsaquinavir vs AZTddC vs AZTsaquinavirddC
  in persons who are AZT naive and have CD4 counts
  between 50 and 350. 2) ddC vs saquinavir vs
  ddCsaquinavir in persons who are AZT experienced
  and have CD4 counts between 50 and 300. The main
  problem with the Hoffman-LaRoche drug is its low
  bioavailability of 4. A new formulation,
  Fortovase, increases this bioavailability to 16
  and in combination acts like a true protease
  inhibitor. Merck and Abbott products have greater
  bioavailability of about 80 (good news in terms
  of efficacy and delayed onset of resistance). The
  FDA licensed this drug in the Fall of 1995--the
  first of the protease inhibitors to be approved
  for use in HIV disease--with Merck and Abbott
  close on its heels.

16
Merck Protease Inhibitor Indinavir
(Crixivanreg, indinavir L-735,524) . Current
Phase III studies 1) AZT vs Crixivan vs
AZTCrixivan in persons who are AZT naive and
have CD4 counts between 50 and 250. 2) AZT vs
Crixivan vs AZTCrixivan in persons who are AZT
naive and have CD4 counts between 50 and 500. 3)
D4T vs Crixivan vs D4TCrixivan in persons who
are AZT experienced and have CD4 counts between
50 and 500. 4) AZT3TC vs Crixivan vs
AZT3TCCrixivan in AZT experienced persons with
CD4 counts between 50 and 400. 5) AZT3TC vs
Crixivan vs AZT3TCCrixivan in AZT experienced
persons with CD4 counts below 50. 6) Crixivan vs
placebo on a background of open-label AZT3TC
with the option to replace AZT with open-label
D4T in persons who are 3TC naive and at least
6-mo of AZT experience and who have CD4 counts
less than 200.
17
Other Antiviral Drugs for Treatment of HIV
Infection

• Zovirax (acyclovir)--much of the enthusiasm for
  this anti-herpes drug came from several studies
  done by David Cooper in Australia in the early
  90s. Many individuals with CD4 counts in all
  ranges have routinely taken acyclovir in the
  400-800 mg/day range presumptively for the
  survival benefit that Cooper's clinical research
  seemed to show. More recent studies in the US
  (ACTG 204 and others) have not yet been able to
  confirm these benefits.

18

• Hydroxyurea (Hydreareg)--new interest in this
  inexpensive anti-cancer drug was generated by
  Robert Gallo's presentation on the future course
  of drug development at the International AIDS
  Conference in Yokohama in 1994. More recently,
  the 5th Retrovirus Conference in January of 1998,
  the combination of hydroxyurea and ddI have shown
  remarkable results, presented by Franco Lori. One
  patient has dropped all drugs and has maintained
  an undetectible viral load and unculturable virus
  in peripheral blood and lymph node tissue for
  over a year. Further study is warranted.
• Bis-POM PMEA (adefovir mesylate)--the Gilead
  Science's anti-CMV drug which also has antiviral
  properties. Currently being studied in clinical
  trials in the CPCRA system. New version is called
  bis-POC PMEA.

19
Pneumocystis Carinii Pneumonia (PCP)

• The most common and, in many ways, the most
  treatable of the opportunistic infections, this
  rare lung infection is much less common among
  AIDS patients, but still remains the infection
  that first brings persons previously undiagnosed
  with HIV into hospitals.

20
Chinese Medicine and HIV Disease

• The use of acupuncture and Chinese herbal
  medications has become one of the most commonly
  used alternative therapies for AIDS. Its use has
  become so widely accepted, that two Chinese
  Medicine Clinics in San Francisco have been
  awarded contracts through the SF Health
  Department's AIDS Office to provide Chinese
  Medical treatment to people with HIV. The
  contracts are funded by Ryan White CARE Act
  allocations.

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• Most people with HIV who use acupuncture and
  Chinese herbs do so in conjunction with western
  medicine. There are, however, some who use it as
  their principal form of medical treatment. It is
  strongly suggested that it be used under the
  supervision of a licensed practitioner. The
  practice of Traditional Chinese Medicine (TCM) is
  considered a primary care medical modality in
  California, and it practitioners physicians.

22

• According to Dr. Hong-yen Hsu, in Natural Healing
  with Chinese Herbs, the systematic practice of
  Chinese Medicine dates back over two thousand
  years, making it the oldest medical system in the
  world. The first known medical book on the
  subject is The Yellow Emperor's Classic of
  Internal Medicine, which was written during the
  Han dynasty around 200 A.D. The first systematic
  compendium of collected knowledge, the Treatise
  on Febrile Diseases, appeared at approximately
  the same time.

23

• Many people erroneously view Chinese herbal
  medicine as an equivalent of taking a western
  drug for the alleviation of symptoms. But the
  differences between the two schools of thought
  are profound. Where western medicine is derived
  solely from scientific method as a means of
  treating disease, Chinese medicine is intertwined
  with a philosophy of life, and is based on a
  holistic view of supporting the mind-body's
  innate ability to maintain health and to heal
  itself should illness occur. This approach is the
  result of many thousands of years of accumulated
  experience.

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• Chinese philosophy views the universe as a living
  organism and sees the human body as a microcosm
  of that greater organism. Western medicine tends
  to view the human body as a machine and has
  evolved its practice based on this assumption.
  Rather than dealing with mechanistic components
  of the human organism, as western science
  advocates, the TCM approach is one of aligning
  the functions of the organs and systems as a
  whole, promoting the dynamic balance of energy
  polarities which maintains health and well-being.

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(ATN) DANGER Possibly Fatal Interactions Between
Ritonavir and "Ecstasy," Some Other Psychoactive
Drugs

• Abbott Laboratories has acknowledged potentially
  dangerous interactions between its protease
  inhibitor ritonavir (Norvir(R)) and certain
  recreational drugs in the aftermath of the death
  of a British person with AIDS who died after
  using MDMA, commonly known as "ecstasy," while
  taking ritonavir.