The treatment of HIVAIDS

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The treatment of HIV/AIDS

• gjgibson2002/01

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Human Immunodeficiency Virus (HIV)
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30 Million people are HIVve, and 3 million
have AIDS most are women and children in
sub-Saharan Africa
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In many ways all anti-HIV treatment is
experimental - so perhaps the best question to
ask is not What is the best treatment for HIV? ,
but Which is the most appropriate trial to enter
my patient into?
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HIV-Infected adults and adolescents treatment...

• Treatment should be offered to all patients
• with the acute HIV syndrome
  those within six months of HIV
  seroconversion and
  all patients with symptoms
  ascribed to
• HIV infection
• Treatment require analysis of many potential
  risks and benefits
  

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Treatment should be offered to individuals with

• Fewer than 350 CD4 Tcells/mm3 or plasma HIV RNA
  levels exceeding 30 000 copies/ml (bDNA assay or
  55 000 copies /ml (RT-PCR assay)

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Recommendation to treat asymptomatic patients
based on

• Willingness and readiness of individual to begin
  therapy
• Risk of disease progression as determined by the
  CD4 T cell count and level of plasma HIV RNA
• Potential benefits and risks of initiating
  therapy
• After counseling and education, of adherence to
  the prescribed treatment regimen

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• Results of therapy are evaluated primarily with
  plasma HIV RNS levels
• Failure of therapy at 4-6 months may by ascribed
  to
  non-adherence
  inadequate potency of drugs
  suboptimal levels of
  antiretroviral agents vital resistance
  other factors
  that are poorly understood

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• Measurement of plasma HIV RNA levels (viral
  load), using quantitative methods, should be
  performed at the time of diagnosis and every 3-4
  months thereafter in the untreated patient
• CD4T cell counts should be measured at the time
  of diagnosis and generally every 3-6 months
  thereafter

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• If HIV RNA remains detectable in plasma after
  16-20 weeks of therapy, the plasma HIV RNA test
  should be repeated to confirm the result and a
  change in therapy should be considered

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Considerations of Patients with Established HIV
infection

• Two arbitrarily defined clinical categories 1.
  Asymptomatic infection
  2. Symptomatic disease
• All patients in the second category should be
  offered antiretroviral therapy

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I. VIRAL DYNAMICS IN HIV INFECTION

• HIV replicates at an extraordinarily high rate
  from the onset of infection
• The level of virus in the plasma often increases
  to values between 100 000 RNA copies/ml and
  several million RNA copies/ml within a week of
  primary infection
• This is thought to contribute significantly to
  seeding of distant tissues such as the brain,
  lymphoid tissue, thymus gland, etc.

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II GOALS OF THERAPY

• The primary goals of antiretroviral therapy are
  
• maximal and durable suppression of viral load
• restoration and/of preservation of
  immunological function
• improvement of quality of life
• reduction of HIV-related morbidity and mortality

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III CLASSES OF ANTIRETROVIRAL AGENTS AND THEIR
MECHANISMS OF ACTION

• Antiretroviral agents that are currently
  available inhibit one of two key viral enzymes
  required by HIV for intracellular viral
  replication
• 1. Agents that inhibit the enzyme reverse
  transcriptase are RTIs and act upon the early
  stages of HIV replication. RTIs that mimic the
  normal building blocks of HIV DNA are termed
  nucleoside RTIs (NRTIs) the chemically diverse
  group of drugs that directly inhibit the reverse
  transcriptase enzyme at a common site of action
  are termed non-nucleoside RTIs (NNRTIs)

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• 2. A second group of antiretroviral agents, the
  protease inhibitors (PIs), inhibit the
  functioning of an enzyme known as protease, that
  is required for the late stages of HIV replication

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Before initiating therapy...

• History and physical
• Blood count, chemistry profile
• CD4T lymphocyte count
• Plasma HIV RNA Measurement
  
  
  (RPR or VDRL, tuberculin skin test, ?toxoplasma
  IgG serology, ?gynecologic exam with Pap smear,
  chest X-ray, hepatitis C virus (HCV) serology,
  ophthalmologic exam)

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• Clinical trials data as well as observational
  data indicate that the risk of opportunistic
  disease increases markedly when the CD4T cell
  count declines to lt200 cells/mm3 , and strongly
  support the recommendation that all patients with
  a CD4 T cell count lt200 cells/mm3 or
  clinically-defined AIDS should be offered
  antiretroviral therapy

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• Antiretroviral regimens currently available that
  have the greatest potency in terms of viral
  suppression and CD4T cell preservation, are
  medically complex, are associated with a number
  of specific side effects and drug interactions,
  and pose a substantial challenge of adherence
• Optimal time to initiate antiretroviral therapy
  is not known

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Goals of Therapy

• Eradication of HIV infection cannot be achieved
  with currently available antiretroviral regimens
• HAART often leads to increases in the CD4T cell
  count of 100-200 cells/ul or more, although
  individual responses are quite variable. CD4T
  cell responses are generally related to the
  degree of viral load suppression. In turn,
  continued viral load suppression is more likely
  among those who achieve higher CD4T cell counts
  during therapy

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• Viral load is the strongest single predictor of
  long-term clinical outcomes, strong consideration
  should also be given to sustained rises in CD4T
  cell counts and partial immune restoration

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Tools to Achieve the Goals of Therapy

• 70-90 of antiretroviral drug-naïve patients
  achieve maximal viral load suppression 6-12
  months after initiation of therapy
• Sequencing of drugs for the preservation of
  future treatment options for as long as possible
• PI with 2 NRTIs/ an NNRTI with 2 NRTIs/ or a 3
  NRTI regimen
• (possible to extend the overall long-term
  effectiveness of the available therapy options)

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BENEFITS OF DELAYED THERAPY

• Avoid negative effects on quality of life
• Avoid drug-related adverse events
• Delay in development of drug resistance
• Preserve maximum number of available and future
  drug options when HIV disease risk is highest

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RISKS OF DELAYED THERAPY

• Possible risk of irreversible immune system
  depletion
• Possible greater difficulty in suppressing viral
  replication
• Possible increased risk of HIV transmission

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BENEFITS OF EARLY THERAPY

• Control of viral replication easier to achieve
  and maintain
• Delay or prevention of immune system compromise
• Lower risk of resistance with complete viral
  suppression
• Possible decreased risk of HIV transmission

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RISKS OF EARLY THERAPY

• Drug-related reduction in quality of life
• Greater cumulative drug-related adverse events
• Earlier development of drug resistance, if viral
  suppression is suboptimal
• Limitation of future antiretroviral treatment
  options

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Initiating Therapy

• Begin with a regimen thats expected to achieve
  sustained suppression of plasma HIV RNA, a
  sustained increase in CD4 T cell count, and a
  favorable clinical outcome
• Strongly recommended regimens include (either
  indinavir, nelfinavir, ritonavir) saquinavir,
  ritonavir indinavir, ritonavir lopinavir or
  efavirenz in combination with one of several 2
  NRTI combinations.

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• Clinical outcome data support the use of a PI in
  combination with 2 NRTIs
• The use of ritonavir to increase plasma
  concentrations of other protease inhibitors has
  evolved from an investigational concept to
  widespread practice
• Use of antiretroviral agents as monotherapy is
  contraindicated, except when there are no other
  options (e.g. in pregnancy or to reduce perinatal
  transmission)

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• When initiating antiretroviral therapy, all drugs
  should be started simultaneously as full dose
  with the following three exceptions
• 1. Ritonavir
• 2. Nevirapine
• 3. In some cases, ritonavir plus saquinavir
• Hydroxyurea has been used investigationally in
  combination with antiretroviral agents for
  treatment of HIV infection, however its utility
  in this setting has not been established

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Initiating Therapy in Advanced HIV Disease

• All patients diagnosed with advanced HIV disease,
  defined as any condition meeting the 1993 CDC
  definition of AIDS should be treated with
  antiretroviral agents, regardless of plasma viral
  levels.
• All patients with symptomatic HIV infection
  without AIDS, defined as the presence of thrush
  or unexplained fever, should also be treated

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• Patients who have progressed to AIDS are often
  treated with complicated combinations of drugs,
  and the potential for multiple drug interactions
  must be appreciated
• The use of rifampin to treat active tuberculosis
  is problematic in a patient receiving a protease
  inhibitor, which adversely affects the metabolism
  of rifampin (frequently needed to effectively
  suppress viral replication in these advanced
  patients)

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• Wasting and anorexia, which may prevent patient
  from adhering to the dietary requirements for
  efficient absorption of certain protease
  inhibitors
• Bone marrow suppression associated with ZDV and
  the neuropathic effects of ddC, d4T and ddI may
  combine with the direct effects of HIV to render
  the drugs intolerable

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• Hepatotoxicity associated with certain protease
  inhibitors may limit the use of these drug s,
  especially in patients with underlying liver
  dysfunction
• Absorption and half-life of certain drugs may be
  altered by antiretroviral agents, particularly
  the enzymatic pathway

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• Initiation of potent antiretroviral therapy is
  often associated with some degree of recovery of
  immune function
• Patients with advanced HIV disease and
  subclinical opportunistic infections such as MAI
  of CMV may develop a new immunologic response to
  the pathogen and thus new symptoms may develop in
  association with the heightened immunologic
  and/or inflammatory response

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...recovery of immune function...

• ...should not be interpreted as a failure of
  antiretroviral therapy
• Viral load measurement is helpful in clarifying
  this situation

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HAART-Associated Adverse Clinical Events

• 1. Lactic Acidosis / Hepatic Steatosis
• The occurrence of severe lactic acidosis and
  hepatomegaly with steatosis during use of
  nucleoside analogue reverse transcriptase
  inhibitors is rare (associated with a high
  fatality rate)
• Risk factors female gender, obesity, prolonged
  use of NRTIs

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• Clinically nonspecific gastrointestinal symptoms
  without dramatic elevation of hepatic enzymes,
  and in some cases dyspnea
• Unexplained onset and persistence of abdominal
  distention, nausea, abdominal pain, vomiting,
  diarrhea, anorexia, generalized weakness, weight
  loss and hepatomengaly, increased anion gap,
  elevated aminotransferases, CPK, LDH, liipase,
  and amylase

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• Echotomography and CT scan may demonstrate an
  enlarged fatty liver
• Treat with discontinuation of antiretroviral drug

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HAART-Associated Adverse Clinical Events

• 2. Hyperglycemia / Diabetes Mellitus
• Hyperglycemia, new onset diabetes mellitus,
  diabetic ketoacidosis, and exacerbation of
  pre-existing diabetes mellitus have been reported
• Beta cell dysfunction an peripheral insulin
  resistance appear to be causes of hyperglycemia
• Treatment continued PI therapy and initiated
  oral hypoglycemic agents or insulin

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HAART-Associated Adverse Clinical Events

• 3. Fat Maldistribution
• Changes in body fat distribution, referred to as
  lipodystrophy syndrome or pseudo-Cushings
  syndrome have been observed in 6 to 80
• Central obesity, peripheral fat wasting, and
  lipomas visceral fat accumulation,
  dorsocervical fat accumulation, wasting with
  venous prominence, facial thinning, breast
  enlargement

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3. Fat Maldistribution (cont)

• Hyperlipidemia and insulin resistance are
  frequently but not always associated with
  lipodystrophy
• Fatigue and nausea weight loss higher levels
  of lactate and alanine aminotransferase lower
  levels of albumin, cholesterol, triglycerides,
  glucose end insulin

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HAART-Associated Adverse Clinical Events

• 4. Hyperlipidemia
• All PIs have been implicated
• May be more dramatic during treatment
• Controlled studies have not yet demonstrated an
  increased risk of cardiovascular events
• Condurrent use of PIs and statins should be
  undertaken with caution due to the potential for
  enhanced statin-related toxicity

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HAART-Associated Adverse Clinical Events

• 5. Increased Bleeding Episodes in Patients with
  Hemophilia
• Increased spontaneous bleeding episodes in
  patients with hemophilia A and B have been
  observed with the use of protease inhibitors

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HAART-Associated Adverse Clinical Events

• 6. Osteopenia and Osteoporosis
• Anecdotal reports of avascular necrosis of the
  hip and compression fractures of the spine
• Risk of osteopenia and osteoporosis is
  significantly higher in patients taking PIs
• These effects are independent of PI-related
  lipodystrophy

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HAART-Associated Adverse Clinical Events

• 7. Rash
• A relatively common toxicity
• Approximately 5 of patients
• Potentially fatal cases of Stevens-Johnson
  syndrome have been reported

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INTERRUPTION OF ANTIRETROVIRAL THERAPY

• Intolerable side effects, drug interactions,
  first trimester of pregnancy when the patient so
  elects, and unavailability of drug

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CONSIDERATIONS FOR CHANGING A FAILING REGIMEN

• Recent clinical history / physical examination
• Plasma HIV RNA levels measured on two separate
  occasions
• Absolute CD4 T lymphocyte count, and changes in
  these counts
• Assessment of adherence to medications
• Remaining treatment options
• Potential resistance patterns from prior
  antiretroviral therapies
• Preparation of patient for implications of the
  new regimen.

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• Distinguish between drug failure versus drug
  toxicity

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CRITERIA FOR CHANGING THERAPY

• The goal of antiretroviral therapy (to improve
  the length and quality of the patients life) is
  likely best accomplished by maximal suppression
  of viral replication to below detectable levels
  (currently defined as lt50 copies/mL)

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Specific criteria

• Less than a 0.5-0.75 log10 reduction in plasma
  HIV RNA by 4 weeks following initiation of
  therapy, or less than a 1 log10 reduction by 8
  weeks
• Failure to suppress plasma HIV RNA to
  undetectable levels within 4-6 months of
  initiating therapy
• Repeated detection of virus in plasma after
  initial suppression to undetectable levels,
  suggesting the development of resistance

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Specific Criteria (cont)

• Any reproducible significant increase, defined as
  3-fold or greater, from the nadir of plasma HIV
  RNA
• Undetectable viremia in the patient receiving
  double nucleoside therapy
• Persistently declining CD4 T cell numbers, as
  measured on at least two separate occasions
• Clinical deterioration

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Considerations for Antiretroviral Therapy in the
HIV-Infected Pregnant Woman

• Three-part regimen of ZDV, given orally starting
  at 14 weeks gestation and continued throughout
  pregnancy
• Intravenously during labor, and to the newborn
  for the first 6 weeks of life (reduced the risk
  of perinatal transmission by 66 in a
  randomized, double-blind clinical trial, and is
  recommended for all pregnant woman)

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Considerations for Antiretroviral Therapy (cont)

• Woman who are in the first trimester of pregnancy
  and who are not receiving antiretroviral therapy
  may wish to consider delaying initiation for
  therapy until after 10 to 12 weeks gestation
• The antenatal ZDV dosing regimen used in the
  perinatal transmission prophylaxis was ZDV 100 mg
  administered five times daily
• Current standard ZDV dosing regimen for adults is
  200 mg three times daily or 300 mg twice daily

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NUCLEOSIDE ANALOG REVERSE TRANSCRIPTASE
INHIBITORS (NRTIs)
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NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS
(NNRTIs)
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PROTEASE INHIBITORS (PIs)
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RIBONUCLEOTIDE REDUCTASE INHIBITORS
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Indications for the Initiation of Antiretroviral
Therapy in the Chronically HIV-1 Infected Patient
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Recommended Antiretroviral Agents for Initial
Treatment of Established HIV Infection one
choice each from columns A and B ...

• Strongly Recommended Column A Column B
• Efavirenz Stavudine Didanosine
• Indinavir Stavudine Lamivudine Nelfinavir Z
  idovudine Didanosine Ritonavir
  Indinavir Zidovudine Lamivudine
• Ritonavir Lopinavir
• Ritonavir Saquinavir
• No Recommendation Hydroxyurea
• Not Recommended All monotherapies

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• Combivir is a fixed-dose, combination tablet of
  150 mg Epivir and 300 mg Retrovir
• Combivir is taken as a single tablet, twice a
  day
• The aim of Combivir is to reduce pill burden
  and encourage adherence
• Both Epivir and Retrovir are potent inhibitors
  of HIV reverse transcriptase
• Combivir may be administered without food
  restrictions or water requirements
• Of the currently available antiretroviral
  therapies, only Retrovir is known to penerate
  human brain tissue

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Epivir in combinations with Retrovir exhibit
synergistic or additive antiviral effects
providing a strong rationale for combining the
two agents. Cross-resistance between Epivir and
Retrovir has not been reported. The
Epivir/Retrovir combination can be used with all
the currently available NNRTIs Epivir/Retrovir
combination given throughout labour and during
and after delivery to both mother and child has
been shown to reduce transmission rates by 50
compared by placebo Epivir/Retrovir combination
is generally well tolerated
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OCCUPATIONAL EXPOSURE AND NEEDLE-STICK (?HIVve)
INJURY (Seroconversion rate 0,4 for HIV 30
for Hepatitis B - if HBeAgve) Wash well
encourage bleeding do not suck or immerse in
bleach Note name, address, and clinical
details of donor been on any anti-HIV
drugs? Store blood from both parties. If
possible, ascertain HIV and HBsAg of both.
Immunize (active and passive) against hepatitis
B at once, if needed. Counsel (HIV risk lt 0,5
if donor is HIVve) and test recipient at 3,
6, and 8 months (serovonversion may take this
long). Give 4 weeks of drugs, if possible
within 1 hour of exposure. Low risk exposure
No antiviral medication. Higher risk
Zidovudine 300 mg / 12h lamivudine 150 mg / 12
h, and, particularly for worst episodes
indinavir 800 mg / 8h, all po.
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GOLDEN RULES IN ANTI-HIV TREATMENT Aim to
stop viral replication permanently Monitor
plasma viral load and CD4 count Start
antiretroviral treatment early before
immunodeficiency sets in Use 3 antiviral drugs
(minimizes replication and cross
resistance) Change to a new combination if
plasma viral load rebounds