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HIV-Infected adults and adolescents

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HIV-Infected adults and adolescents Powered By Docstoc
					The treatment of
HIV/AIDS



        gjgibson2002/01
        Human Immunodeficiency
             Virus (HIV)

Trans-membranous            Spike of
glycoprotein (gp41)         envelope
                            glycoprotein
                            (gp120)
Host cell
protein


Reverse                     RNA with
transcriptase               protein
                            surround
                            (p7/p9)

Lipid layer
                            Ribonucleic
Nucleocapsid (p17)          protein (p24)
30 Million people are HIV+ve,
and 3 million have AIDS; most
  are women and children in
     sub-Saharan Africa
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?
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
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)
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
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
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
CD4+T cell counts should be measured at
 the time of diagnosis and generally every
 3-6 months thereafter
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
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
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.
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
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)
2. A second group of antiretroviral
 agents, the protease inhibitors (PI’s),
 inhibit the functioning of an enzyme
 known as protease, that is required for
 the late stages of HIV replication
Before initiating therapy...

History and physical
Blood count, chemistry profile
CD4+T 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)
Clinical trials data as well as observational data
 indicate that the risk of opportunistic disease
 increases markedly when the CD4+T cell count
 declines to <200 cells/mm3 , and strongly
 support the recommendation that all patients
 with a CD4+ T cell count <200 cells/mm3 or
 clinically-defined AIDS should be offered
 antiretroviral therapy
Antiretroviral regimens currently available
 that have the greatest potency in terms of
 viral suppression and CD4+T 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
Goals of Therapy

 Eradication of HIV infection cannot be achieved
  with currently available antiretroviral regimens
HAART often leads to increases in the CD4+T
 cell count of 100-200 cells/ul or more, although
 individual responses are quite variable. CD4+T
 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 CD4+T cell
 counts during therapy
Viral load is the strongest single predictor
 of long-term clinical outcomes, strong
 consideration should also be given to
 sustained rises in CD4+T cell counts and
 partial immune restoration
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…)
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
RISKS OF DELAYED
THERAPY

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

Begin with a regimen that’s 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.
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)
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
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
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)
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
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
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
...recovery of immune function...



...should not be interpreted as a failure of
 antiretroviral therapy
Viral load measurement is helpful in
 clarifying this situation
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 NRTI’s
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
Echotomography and CT scan may
 demonstrate an enlarged fatty liver
Treat with discontinuation of antiretroviral
 drug
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
HAART-Associated
Adverse Clinical Events

3. Fat Maldistribution
Changes in body fat distribution, referred to as
 “lipodystrophy syndrome” or “pseudo-Cushing’s
 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
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
HAART-Associated
Adverse Clinical Events

4. Hyperlipidemia
All PI’s have been implicated
May be more dramatic during treatment
Controlled studies have not yet demonstrated
 an increased risk of cardiovascular events
Condurrent use of PI’s and statins should be
 undertaken with caution due to the potential for
 enhanced statin-related toxicity
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
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 PI’s
These effects are independent of PI-
 related lipodystrophy
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
INTERRUPTION OF
ANTIRETROVIRAL THERAPY:



Intolerable side effects, drug interactions,
 first trimester of pregnancy when the
 patient so elects, and unavailability of
 drug
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.
Distinguish between drug failure versus
               drug toxicity
CRITERIA FOR CHANGING
THERAPY


The goal of antiretroviral therapy (to
 improve the length and quality of the
 patient’s life) is likely best accomplished
 by maximal suppression of viral replication
 to below detectable levels (currently
 defined as <50 copies/mL)
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
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
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)
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
NUCLEOSIDE ANALOG REVERSE
TRANSCRIPTASE INHIBITORS (NRTIs)
Zidovudine    Retrovir®   250 mb bd.      Nausea,
(AZT)                                     headache,
                                          fatigue,
                                          neutropenia,
                                          myalgia
Stavudine     Zerit®      >60kg 40mg      Peripheral
(d4T)                     bd.             neuropathy
                          <60kg 30mg
                          bd.
Didanosine    Videx®      >60kg 200mg     Peripheral
(ddl)                     bd.             neuropathy,
                          <60kg 125mg     nausea,
                          bd.             pancreatitis
                          Empty stomach
Zalcitabine   Hivid®      0.75 mg tds.    Peripheral
(ddC)                                     neuropathy,
                                          oral ulcers
Lamivudine    3TC®        150 mg bd.      Headaches,
(3TC)                                     nausea
NON-NUCLEOSIDE REVERSE
TRANSCRIPTASE INHIBITORS
(NNRTIs)

Chemical     Trade Name   Dose               Common side-
Name                                         Effects


Nevirapine   Viramune®    200 mg daily for   Rash, hepatitis.
                          two weeks, then    Liver enzyme
                          200mg twice        inducer (risk of
                          daily              drug
                                             interactions).
Efavirenz    Stocrin®     600 mg nocte.      CNS effects,
                                             dizziness and
                                             transient rash.
                                             Teratogenic.
(PI’s)
Indinavir    Crixivan®     800mg tds on      Kidney stones,
                           empty stomach     nausea, inhibits
                                             liver enzymes (risk
                                             of drug
                                             interactions)
Ritonavir    Norvir®       600mg bd (start   Diarrhea, nausea,
                           with 300mg bd).   abdominal pain.
                           Take with food    Potent liver
                                             enzyme inhibitor
                                             (risk of drug
                                             interactions)
Saquinavir   Invi-rase®    600mg tds with    Diarrhea, nausea,
                           fatty food        abdominal pain.
                           1200mg tds with   Liver enzyme
                           fatty food        inhibitor(risk of
             Forto-vase®                     drug interactions)



Nelfinavir   Vira-cept®    750mg tds with    Diarrhea
                           meals
RIBONUCLEOTIDE
REDUCTASE INHIBITORS

Chemical      Trade Name   Dose        Commons side-
Name                                   effects
Hydroxyurea   Hydrea®      500mg bd.   Bone marrow
                                       depression, hair
                                       loss,
                                       pigmentation,
                                       peripheral
                                       neuropathy
  Indications for the Initiation of Antiretroviral
  Therapy in the Chronically HIV-1 Infected
  Patient

CLINICAL CATEGORY   CD4+ T CELL COUNT   PLASMA HIV RNA   RECOMMENDATION


Symptomatic         Any value           Any value        Treat

Asymptomatic, AIDS CD4+ T cells         Any value        Treat
                   <200/ml

Asymptomatic        CD4+ T cells        Any value        Treatment should be offered
                    >200/ml                              (controversy exists)
                    but <350/ml

Asymptomatic        CD4+ T cells        >30 000(bDNA)/ Initiating therapy
                    >350/ml             >55 000(RT-PCR)

Asymptomatic        CD4+ T cells        <30 000(bDNA)/ Therapy and observe
                    >350/ml             <55 000 (RT-PCR)
  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               Zidovudine + Didanosine
                       Ritonavir + Indinavir    Zidovudine + Lamivudine
                       Ritonavir + Lopinavir
                       Ritonavir + Saquinavir

No Recommendation      Hydroxyurea

Not Recommended        All monotherapies
•   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
*   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
    OCCUPATIONAL EXPOSURE AND NEEDLE-STICK
               (?HIV+ve) INJURY

    (Seroconversion rate: 0,4% for HIV; 30% for Hepatitis B - if HBeAg+ve)
*         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 < 0,5 %
          if “donor” is HIV+ve) 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.
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

				
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