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The Principles of An by MikeJenny

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									The   Principles of Anti-Retroviral Drugs

Learning Objectives:
After working through this session, you will be able to:

•         Define what HAART is.
•         Understand the goals of HAART
•         List the different classes of ART
•         Explain how ARVs work
•         When to initiate ARVs in both adults and children.

What is HIV antiretroviral treatment?

This is the main type of treatment for HIV or AIDS. It is not a cure,
but it can stop people from becoming ill for many years. The
treatment consists of drugs that have to be taken every day for the
rest of someone's life
What is Combination Therapy, what is HAART?
For ART to be effective for a long time, it has been found that a patient would need to
take more than one ARV drug at a time. This is what is known as Combination
Therapy. The term Highly Active Antiretroviral Therapy (HAART) is used to describe
a combination of three or more anti-HIV drugs.

Goals of HAART
•      Clinical goal. Prolongation of life & improvement in quality of life.
•      Virologic goal: Greatest possible reduction in viral load (preferably to <20-50
c/Ml) for as long as possible to halt disease progression and prevent or delay
progression.
•      Immunologic goal: Immune reconstitution that is both quantitative (increase
CD4 cell count to normal range) & qualitative (pathogen-specific immune response).
•      Therapeutic goal: Rational sequencing of drugs in a fashion that achieves
clinical, virologic and immunologic goals while maintaining treatment options, limit
drug toxicity and facilitate adherence.
•      Epidemiologic goal: Reduce HIV transmission
Indications for use of ARVs
•     Treatment of HIV infected people who meet the eligibility criteria.
•     PMTCT.
•     Post-exposure prophylaxis.
•     Treatment of HIV-infected mothers identified in PMTCT programs
and to their HIV-infected family members (PMTCT-Plus).

    Tools to achieve the goals of therapy
         Maximization of adherence to ART
         Rational sequencing of drugs so as to preserve future
    treatment options
         Use resistance testing when appropriate and available
Principles of ART
Antiretroviral therapy is part of comprehensive HIV care. The guiding
principles of good ART include:

      Not to start to soon (when CD4 cell count is close to normal) or too
late (when the immune system is irreversibly damaged).
      Efficacy of the chosen drug regimens.
      Freedom from serious adverse effects.
      Ease of administration.
      Affordability and availability of drugs and drug combinations.
      Ongoing support of the patient to maintain adherence.


Available agents for ART
At present there are five different classes of ARVs present, each working at
different stages of the HIV life cycle.
   1. Nucleoside/Nucleotide Reverse Transcriptase Inhibitors

•      The first type of drug available to treat HIV infection in 1987.
NRTIs (also known as nucleoside analogues or nukes) interfere with the
action of an HIV protein called reverse transcriptase, which the virus
needs to make new copies of it’s self. NRTIs are sometimes called the
"backbone" of combination therapy because most regimens contain at
least two of these drugs.

   2. Non-Nucleoside Reverse Transcriptase Inhibitors

•     They were approved in 1997. Like the nukes, NNRTIs (also known
as non-nucleosides or non-nukes) stop HIV from replicating within cells
by inhibiting the reverse transcriptase protein directly.

   3. Protease Inhibitors

•     Approved in 1995.
•     Protease inhibitors, as the name says, inhibit protease enzyme,
which is another protein involved in the HIV replication process.
4. Fusion or Entry Inhibitors
•     T-20 (also called enfuvirtide) has been licensed both in the
US and in Europe since 2003, but only for use by people who have
already tried other treatments and failed.
•     The T-20 fusion inhibitor is given by injection (otherwise it
would be digested in the stomach).
•      Entry inhibitors prevent HIV from entering human cells.

5. Integrase Inhibitors

These interfere with the ability of the HIV DNA to insert itself into
the host DNA and thereby copy itself.

NB: Intergrase inhibitors are currently under development.
The Life Cycle of HIV type-1 & major antiviral targets.
             Nucleoside/Nucleotide Reverse Transcriptase Inhibitors
Abbreviation         Generic name       Dose                          Notes


3TC                  lamivudine         150mg bid                     Take with or without food


ABC                  abacavir           300mg bid                     Take with or without food


AZT or ZDV           zidovudine         300mg bid                     Take with or after food


d4T                  stavudine          <60KG Wt = 30mg, >60Kg Wt=    Take with or without food
                                        40mg bid

dad                  zalcitabine                                      Take with or after food


ddI                  didanosine         <60Kg Wt=125 mg bid,          Take on an empty stomach 30
                     (tablet)           >60mg=200mg bid               minutes before food


ddI                  didanosine         <60Kg Wt=125 mg bid,          Take on an empty stomach 2
                     (capsule)          >60mg=200mg bid               hours before food, with water
                                                                      only

FTC                  emtricitabine                                    Take with or without food


TDF                  tenofovir          300mg o.d                     Take with food
Combination drugs
   Combination                   Brand name                    Notes


   d4T+3TC+NVP                   Triomune                      Take with or without food



   ABC + AZT + 3TC               Trivizir3                     Take with or without food



   AZT + 3TC                     Combivir                      Take with or without food



   TDF + FTC                     Truvada                       Take with or without food



Non-Nucleoside Reverse Transcriptase Inhibitors
   Generic name                Dose                          Notes

   delavirdine                                               Take with or without food.
                                                             Licensed in US but not UK.

   efavirenz                   600mg o.d at night            Take with or without food


   nevirapine                  200mg o.d for 14 days, then   Take with or without food
                               200mg bid
Fusion inhibitors
        Code            Generic name              Brand Name             Notes



        T-20            enfuvirtide6              Fuzeon                 Intravenous injection
                                                                         into thigh, arm or
                                                                         abdomen.



Protease Inhibitors
Generic name             Brand name                        Notes
amprenavir /             Agenerase / Lexiva (US)           Take with or without food
fosamprenavir            Agenerase / Telzir (Europe)
atazanavir               Reyataz                           Take with food
indinavir                Crixivan                          Take on an empty stomach
lopinavir + ritonavir    Kaletra                           Take with food. Needs refrigeration to last
                                                           more than 6 weeks.
nelfinavir               Viracept                          Take with food
ritonavir                Norvir                            Take with food or liquid food supplement

saquinavir               Fortovase (soft gel capsule)      Take within two hours of food. Needs
                                                           refrigeration to last more than 3 months.
saquinavir               Invirase (hard gel capsule)       Take within two hours of food

tipranavir               Aptivus5                          Take with food
darunavir                Prezista                          Take with food
NB:
     Efavirenz is not given to children < 10KG bodyweight or < 3 years of age
     Efavirenz is contra-indicated in pregnant women
     Avoid initiating Nevirapine drug regimen to women with CD4 cell count > 25
cells/mm3
     Avoid initiating AZT drug regimen in patients with a hemoglobin of < 8g/dl



                        When to Initiate HAART
Before any patient is started on ART they should undergo baseline clinical assessment
to include:
      A medical history
      Physical examination
      Laboratory investigations
Counseling - at least three PRE-ART counseling sessions
     Clinical Evaluation Checklist for Patients Starting ART
Assessment

1            Level of understanding about HIV/AIDS;
                    Whether coping                    What specific education/ information/ counselling support is
             needed
2            Sexual risks:
                    Willingness to practice safer sex    Disclosure of HIV serostatus                Use of condoms

3            Household socio-economic circumstances
                   Family health                                                             What support is available

4            History of opportunistic infections & other significant illnesses e.g. TB

5            Current weight (trend) & presence of symptoms

6            Current clinical stage (WHO classification)

7            Lifestyle:
                       Whether employed & nature of work                                              Nutritional status

8            Screen for presence of:
                      STI’s, Occult TB                                        Chronic pain, Depression & Mental illness

9            Pregnancy risks:
                        Contraception options & choices
10           Functional capacity and level of disability
                       What assistance is available or required
11           History of previous ART
                       Adherence and tolerability issues
Anti retroviral therapy should not be started when patients:
•Have symptomatic liver (e.g., severe jaundice) or kidney disease
•Are on chemotherapy for non-HIV related cancers with drugs that are likely to
have an additive toxic effect with ARVs
•Are anemic (HB below 8g/dl). Use d4T instead of ZDV in the treatment regimen.

Lab tests done before starting HAART
•Confirm HIV Infection
•Hemoglobin or Haematocrit
•Full Blood Count
•CD4 Count
•+/- Chemistry:LFTs, RFTs,
•Pregnancy Test: +/- pap smear
•VDRL
•+/- serum glucose
•+/- Serum Crag if CD4 < 100
•Viral load
NB:
1 and 2 are absolute minimum tests.
3, 4, 5, 6 are basic recommended tests.
7, 8, 9 are desirable tests.
10 is optional.
Recommendations for initiating ART in adults & adolescents                                                      WHO 2006
     WHO clinical staging CD4 testing NOT available                       CD4 testing available
     1                           Do not treat
     2                           Do not treat                             Treat if CD4 is <200 cells/mm
     3                           Treat                                    Consider Treatment if CD4 count is <
                                                                          350 cells/mm & initiate ART before
     4                           Treat                                    CD4 drops below of CD4 cell count
                                                                          Treat irrespective 200 cells/mm
         Recommendation for initiating ART in HIV- infected infants & children according to clinical stage and immunolog
         markers
 WHO Paediatric stage            Availability of CD4 cell      Age-specific treatment recommendation
                                 measurement
                                                               ≤11 months                      ≥12 months

 4                                       CD4
                                         No CD4                                    Treat all

 3                                                                                             Treat all,CD4-guided in those
                                                                                               children with TB,
                                                                                               LIP,OHL,thrombocytopenia
                                                                       Treat all
                                         No CD4                                                Treat all

 2                                       CD4                   CD4-guided

                                         No CD4                TLC- guided

 1                                       CD4                   CD4-guided

                                         No CD4                Do not treat
                CD4 & TLC Criteria for severe HIV Immunodeficiency                      WHO2006



                       Age specific recommendation to initiate ART
Immunological        <11 months         12 mths- 35 mths 36 mths – 59 mths    > 5 yrs
marker
% CD4                <25%              <20%              <15%                 <15%
CD4 count            <1500cells/mm     <750cells/mm      <350 cells/mm        <200 cells/mm

TLC                  <4000 cells/mm3   <3000 cells/mm3   <2500                <2000 cells/mm3
                                                         cells/mm3
          Initiating first-line ART in relationship to starting anti-TB therapy
CD4 Cell count                  ART Recommendations             Timing of ART in relation to
                                                                start of TB Treatment

CD4<200 cells                   Recommend ART                   Between 2 to 8 wks

CD4 between 200- 350 cells/mm   Recommend ART                   After 8 wks


CD4 > 350 cells/mm              Defer ART                       Re-evaluate patient at eight wks
                                                                & at the end of TB Treatment

Not available                   Recommend ART                   Between 2 to 8 wks
 Drug regimen for 1st Line ART

 AZT or d4T                 EFV

             3TC or FTC

TDF or ABC                  NVP

WHO 2006
       NRTI Drug Combinations to avoid
•ddI + d4T (overlapping toxicities)
•AZT + d4T (proven antagonism)
•3TC + FTC (interchangeable, but should not be used together)
•TDF + 3TC + ABC and TDF + 3TC + ddI select for the K65R mutation,
associated with high incidences of virologic failure.
•TDF + ddI + any NNRTI are associated with high rates of early
virologic failure.

A triple NRTI regimen should be considered as an alternative for first-
line ART in situations where NNRTI options provide additional
complications and to preserve the PI class for second-line treatment (e.g.
in women with CD4 counts of 250-350 cells/mm3; co infection with viral
hepatitis or tuberculosis; severe adverse reactions to NVP or EFV,
infection with HIV-2). Recommended triple NRTI combinations are AZT
+ 3TC + ABC and AZT + 3TC + TDF.
                             References:

•Hoffmann – Rockstroh – Kamps, et al.(2005) HIV Medicine (s.I.:Flying
publisher)
•Ministry of Health (2003), National Antiretroviral Treatment and Care
Guidelines for Adults and Children 1st .ed. (Kampala: Earnest publishers)
•The British HIV Association (BHIVA) treatment guidelines for 2005;
2005.
•WHO, 2006. Available from: http:www.who.int/en
•John G. Bartlett, Joel E. Gallant (2005-2006) Medical Management of
HIV Infection 2005-2006 ed. (U.S.A. John Hopkins Medicine Health
Publishing Business Group)
•John Hopkins AIDS Service: http:// www.hopkins-aids.edu
•DHHS Guidelines, October 10, 2005: http//www.aidsinfo.nih.gov
•British HIV Association 2005 Draft
Guidelines(www.bhiva.org/guidelines/2005/BHIVA-
guidelines/index.html, accessed June 25,2005)

								
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