HIV MANAGEMEMNT (1)

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HIV/AIDS MANAGEMENT

• Dr. W. C. Lwabby (MMed, MD)
• Lecturer Int. Med. Dpt

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Learning Objectives

• To describe important investigations in the
  management of HIV/AIDS
• To describe the treatment of HIV/AIDS.

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BASELINE INVESTIGATIONS

• Are laboratory tests needed in HIV baseline
  evaluation.
• HIV baseline evaluation
• all important information collected during a
  persons initial visits by a health care
  provider.
• They include
• Persons health and medical history
• Physical examination
• Baseline laboratory tests

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BASELINE INVESTIGATIONS.

• The purpose of an HIV baseline evaluation is to
• Determine how far HIV infection has progressed.
• Evaluate whether the person is ready to start
  lifelong treatment with ART.
• Collect information to decide what ART to start.

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BASELINE INVESTIGATIONS

• The following lab tests are included in an HIV
  baseline evaluation
• CD4 cell count
• The normal CD4 count is over 500 cells/mm3
• Is the most useful laboratory indicator of the
  degree of immune suppression.
• It is used(together with clinical staging) in
  decisions to start prophylaxis against
  opportunistic infections.

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BASELINE INVESTIGATIONS..

• CD4 cell count..
• Is of great value in the differential diagnosis
  of clinical problems.
• Is used to monitor the effectiveness of ART.
• Should be performed every 36 months in patients
  on ART, together with measurement of the viral
  load
• ART is recommended as soon as possible for
  everyone with HIV,
• No matter what their CD4 count is

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BASELINE INVESTIGATIONS

• Viral load
• Measures how much virus is in the blood (HIV
  viral load)
• A goal of HIV treatment is to keep a viral load
  so low,
• that the virus cant be detected by a viral load
  test.
• The CD4 count and viral load test,
• are both used to monitor the effectiveness of ART.

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BASELINE INVESTIGATIONS

• Drug-resistance testing
• Identifies which ART(if any),will not be
  effective against HIV strain.
• Health care providers,
• consider drug resistance test results when
  recommending an HIV regimen.
• Other tests include
• Complete blood count (Infection, Anaemia,
  Bleeding disorders)
• Renal function tests (serum creatinine, BUN)
• Liver function tests (liver enzymes, serum
  albumin, bilirubin, etc)
• Urinalysis (UTIs, proteinuria)
• Lipid profile (serum total cholesterol,
  lipoproteins)
• Tests for co-STIs (viral hepatitis, syphilis,
  etc)

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LIFE CYCLE OF HIV
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ANTIRETROVIRAL THERAPY(ART)

• ART has transformed HIV from a progressive
  illness with a fatal outcome,
• into a chronic manageable disease with a
  near-normal life expectancy.
• The goals of ART are to
• Reduce the viral load to an undetectable level
  for as long as possible
• Improve the CD4 count to over 200 cells/mm3 so
  that severe HIV-related disease is unlikely
• Improve the quantity and quality of life without
  unacceptable drug toxicity
• Reduce HIV transmission.

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ANTIRETROVIRAL THERAPY(ART).

• The management of HIV/AIDS,
• normally includes the use of combination ARV
  drugs in an attempt to control HIV infection.
• There are six classes of ARV agents
• They act on different stages of the HIV
  life-cycle
• ART aims zero death, zero new infection and OIs
• WHO recommends offering ARVs treatment to all
  patients with HIV.

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Criteria for starting ART

• Guidelines now recommend starting ART in all
  people with confirmed HIV infection,
• irrespective of CD4 count or clinical status.
• Early initiation of ART
• has been shown to reduce morbidity and mortality
• has the additional benefit of reducing the risk
  of transmission
• In patients with major opportunistic infections,
• ART should generally be started within 2 weeks,
  with two important exceptions
• in cryptococcal meningitis,
• ART should be deferred for 5 weeks, as earlier
  initiation increases the risk of death.
• in tuberculosis,
• ART should be deferred until 8 weeks as earlier
  initiation increases the risk of the immune
  reconstitution inflammatory syndrome

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Classes of ARTs

• There are six classes of drugs,
• which are usually used in combination, to treat
  HIV infection.
• ARV drugs are broadly classified by,
• the phase of the retrovirus life-cycle that the
  drug inhibits.
• Typical combinations include
• 2 NRTIs as a "backbone,
• along with 1 NNRTI,or PIs or INSTI as a "base.

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Classes of ARTs

• 1 Entry inhibitors(or fusion inhibitors)
• Interfere with binding, fusion and entry of HIV
  to the host cell,
• by blocking one of several targets.(CD4-cell and
  its co-receptor-CCR5 or CXCR4)
• e.g Maraviroc and Enfuvirtide.
• 2 Nucleoside/nucleotide reverse transcriptase
  inhibitors
• Are nucleoside and nucleotide analogues which
  inhibit reverse transcription.
• Inhibit viral RNA-dependent DNA polymerase
  (reverse transcriptase) enzyme.

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Classes of ARTs

• Nucleoside reverse transcriptase inhibitors.
• Examples of currently used NRTIs /NtRTI include
• Zidovudine (AZT)
• Lamivudine (3TC)
• Abacavir (ABC)
• Emtricitabine (FTC)
• Tenofovir (TDF).

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Classes of ARTs

• 3Non-Nucleoside reverse transcriptase inhibitors
  (NNRTI)
• Inhibit reverse transcriptase by binding to an
  allosteric site of the enzyme
• act as non-competitive inhibitors of reverse
  transcriptase.
• They affect the handling of substrate
  (nucleotides),
• by reverse transcriptase by binding near the
  active site.
• There two subclasses
• First generation Nevirapine(NVP) and
  Efavirenz(EFV)
• available in Tz.
• Second generation etravirine and rilpivirine

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Classes of ARTs

• 4Integrase inhibitors
• Also known as integrase nuclear strand transfer
  inhibitors
• ( INSTIs)
• Inhibit the viral integrase enzyme,
• which is responsible for integration(combining)
  of viral DNA into the DNA of the infected cell
• It halts further spread of virus.
• E.g Raltegravir, elvitegravir and dolutegravir,

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Classes of ARTs

• 5Protease inhibitors. (PIs)
• Block the viral protease enzyme, necessary to
  produce mature virions.
• Competitively inhibit the HIV protease enzyme,
• whose activity is critical for the terminal
  maturation of infectious virions.
• This inhibition prevents the maturation of
  virions capable of infecting other cells.
• These drugs prevent the cleavage of gag and
  gag/pol precursor proteins.

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Classes of ARTs

• Protease Inhibitors (PIs) ,Examples are
• Lopinavir
• Indinavir
• Nelfinavir
• Amprenavir
• Ritonavir
• usually used as a booster with other PIs
• Darunavir and atazanavir(ATV)
• are currently recommended as first line therapy.
• Resistance to some protease inhibitors is high.
  

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Combination therapy

• Combinations of ARVs
• Create multiple obstacles to HIV replication to
  keep the number of virus low
• Reduce the possibility of a superior mutation
• No single ARV has been demonstrated to suppress
  an HIV infection for long
• so must be taken in combinations in order to have
  a lasting effect.
• Combinations usually consist of three drugs from
  at least two different classes.

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Classes of ARTs

• The combination treatment includes
• 2 NRTIs 1 NNRTI,
• OR
• 2 NRTIs 1 PI, OR 2NRTIs 1INSTIs, OR 3NRTIs
• With a HAART regimen
• HIV replication is inhibited.
• Viral load reduced.
• Patient survival is prolonged.

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Initiation of antiretroviral therapy

• The WHO/Tanzania preferred initial regimen for
  adults and adolescents to be
• tenofovir lamivudine
  dolutegravir(TLD)
• (TDF3TCDTG)

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First Line ARVs for Adults and Adolescent

• The drug combinations are used.
• Based on indications and contraindications,
• that govern the use of ARVs to minimize side
  effects and drug-drug interactions.
• They include
• TDF3TCDTG
• TDF3TCEFV
• TDF3TCNVP
• TDFFTCEFV
• TDFFTC NVP
• AZT 3TCEFV
• AZT3TCNVP

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Common toxicity switches for first line drugs
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Pre-exposure prophylaxis(PrEP)

• Daily use of tenofovir plus emtricitabine,
• has been shown to reduce the risk of HIV
  acquisition in people at ongoing high risk (e.g.
  from sex or injecting drug use)
• Is well tolerated.
• Regular HIV testing should be done in people on
  PrEP.

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Post-exposure prophylaxis (PEP)

• Is recommended when the risk is deemed to be
  significant,
• after a careful risk assessment(both
  occupational and non-occupational settings).
• The first dose should be given as soon as
  possible,
• preferably within 68 hours.
• There is no point in starting PEP after 72
  hours.
• Tenofovir together with emtricitabine is the most
  widely used dual NRTI combination.
• PEP should not be given if the exposed person is
  HIV-infected.
• HIV antibody testing should be performed at 3
  months after exposure.

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Changing ART

• The reasons to change ART can be grouped into
  two major categories
• Drug Adverse Events or Toxicities
• Intolerable side effects
• Drug interactions
• Treatment Failure
• Clinical failure Occurrence or persistence of
  HIV related Ois
• Immunologic failure Decrease in CD4 cell count
• Virological failure Increase in viral load

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Treatment Failure

• Virological Failure
• There is less than 10 fold drop in viral load
  after 6-8 weeks of ART.
• or
• When the viral load (VL) is persistently above
  5,000 copies/ml.
• Immunologic Failure
• 50 drop in CD4 count from peak value
• Or
• Return to pre-ART baseline CD4 count or lower
• Clinical Failure
• There are development of opportunistic
  infections, or malignancies,
• occurring three months or more after initiation
  of ART.

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ART complications

• Immune reconstitution inflammatory syndrome
  (IRIS)
• Is a common early complication of ART,
• especially in patients who start ART with CD4
  counts below 50 cells/mm3.
• Is often characterised by an exaggerated immune
  response,
• with pronounced inflammatory features
• Presents either with,
• Paradoxical deterioration of an existing
  opportunistic disease or
• The unmasking of a new infection.
• Is associated with a mortality of around 5
• Management
• To continue with ART and to ensure that the
  opportunistic disease is adequately treated.
• Symptomatic treatments are helpful
• Glucocorticoids are often used for more severe
  IRIS manifestations

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ART complications.

• Lipodystrophy
• Is due to long-term use of ART
• Is associated with changes in body fat
  distribution
• can present with
• Fat accumulation (e.g. visceral fat, buffalo
  hump) or
• Subcutaneous fat loss (lipoatrophy)
• or with both fat loss and accumulation.
• Others
• Hypersensitivity rashes, insomnia, euphoria,
  anaemia, neutropenia etc.

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REFERENCES

• Brian R, Walker N, Stuart H. Davdsons Principle
  and Practice of Medicine 23rd Edition. HIV
  Infection and AIDS , Pg 323-337.
• KASPER F,HAUSER LONGO. HARRISONS PRINCIPLES OF
  INTERNAL MEDICINE 19th Edition. Human
  Immunodeficiency Virus Disease AIDS and Related
  Disorders pg 1215-1283.

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