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ARV Mx of HIV

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					      HIV – 25 Years Later

• Diversity of HIV
• Epidemiology
• Management Options
  – when to start HAART
  – reinventing old drugs
  – simplifying therapy
  – new therapeutic choices
  – drug interactions
Assessing the Impact of HIV

           Pitfalls
                                HIV Surveillance - Pitfalls
                                  National vs Regional
                                                                                                                        27

                                                                                                            24.8   25
                     25
                                                                                              22.8   22.4


                     20
HIV prevalence (%)




                                                                                         17

                     15                                                    14.2


                                                                  10.4
                     10
                                                          7.6


                     5                            4

                                1.7   2.1
                          0.7
                     0
                          90    91    92         93       94       95       96       97       98     99     00     01   02

                                            Source: Department of Health, South Africa
Trends in median HIV prevalence among women
attending antenatal care clinics in southern Africa,
data from the same clinics, by country, 1997-2002




                       40
  HIV prevalence (%)




                       30
                       20
                       10
                       0
                      Median HIV prevalence in pregnant women
                   attending antenatal clinics in sub-Saharan Africa,
                                    1997/98-2003
        Southern Africa                                                                                        Eastern Africa

                   40                                                                   Botswana                           40

                                                                                 South Africa
                   30                                                                                                      30
% HIV prevalence




                                                                                                        % HIV prevalence
                   20                                                                                                      20
                                                                                       Mozambique                                                                          Ethiopia
                   10                                                                                                      10
                                                                                                                                                                           Kenya
                                                                                                                                                                  Uganda
                   0                                                                                                       0
                        1997-1998   1999-2000                   2001            2002           2003                             1997-1998      1999-2000   2001   2002      2003


                                                         West Africa

                                                                     40

                                                                     30
                                                  % HIV prevalence




                                                                     20

                                                                     10                                                              Cote d'Ivoire
                                                                                                             Nigeria
                                                                                Ghana
                                                                     0                                                               Senegal
                                                                          1997-1998      1999-2000    2001                       2002           2003




    Source: Adapted from Asamoah-Odei, et al., (2004). Data from consistently reporting antenatal clinics.
       Ca
M          rle
  uta          to
                  nv
     sa               ille
        Di
            str
                           ,R                           HIV-infected %
                ic t          SA
                    ,Z            ,1
                        im           99
                           ba           8




                                                        10
                                                        20
                                                        30
                                                        40
                                                        50
                                                        60




                                                         0
            Ki                             (u
               su             bw              rb
                   m              e,             an
                                                    )
                      u,             19
                          Ke            98
             Nd              ny              (ru
                 o la            a,              ra
    Ya                 ,Z           19             l)
       ou                  am          98
          nd                               (u
              e,              b ia            rb
                   Ca             ,1             an
      Fo               m             99             )
         rt P             er            7
                            oo             (u
              or                n,            rb
                  tal                            an
                      ,U            19
                                      97            )
                          ga              (U
                             nd               rb
                                 a,              an
                                    19
                                       95           )
                                           (u
                                              rb
                                                 an
                                                    )
                                                                           National vs Regional
                                                                         HIV Surveillance - Pitfalls




                 Women 20-24
                 Women 15-19
     Percentage of households that are female-headed
    and households with orphans that are female-headed,
           nine southern African countries, 2003

                                         % of all households with children        % of households with orphans
                                         that are female-headed                   that are female-headed

         100



          75



   %      50



          25



            0
                  Botswana           Lesotho         Malawi Mozambique Namibia   South    Swaziland   Zambia     Zimbabwe
                                                                                 Africa




Source: Africa’s Orphaned Generations, UNICEF/UNAIDS, 2003

AIDS epidemic update, December 2004. Fig. 5.
                                       Percentage of 15-19 girls
                              who do not know that an HIV-infected person
                                     may look healthy, 1994-1999
                             100
Percentage who do not know



                             90
                             80
                             70
                             60
                             50
                             40
                             30
                             20
                             10
                              0




                                   Source: UNICEF, DHS surveys and other nationwide surveys, 1994-99.
   Percentage of women who are mothers
   or pregnant by the end of their teens,
                 1990-1998
             80

             60
Percentage
 of women




             40

             20

             0




    Source: Demographic and Health Surveys, various countries
       Reduction in life expectancy compared to the
    'no AIDS' scenario in selected countries: 2000-2005

       Botswana
      Zimbabwe
      Swaziland
    South Africa
          Kenya
   Mozambique
   Côte d'Ivoire
      Cameroon
   Burkina Faso
           Haiti
         Guyana
        Bahamas
      Cambodia
 Dominican Rep.
          Angola
       Myanmar
        Thailand

                    0           5          10         15         20          25           30   35   40
                                                       Number of years

Source: UN Department of Economic and Social Affairs (2002) World Population Prospects,
the 2000 Revision
    Predicted loss in life expectancy
due to HIV/AIDS in children born in 2000

                   Predicted life expectancy            Loss in life expectancy due to HIV/AIDS

Botswana
Zimbabwe
South Africa
Kenya
Zambia
Côte d'Ivoire
Rwanda
Mozambique
Haiti
Cambodia
               0          10           20        30       40        50      60        70
                                        Life expectancy at birth (years)



         Source: U.S. Census Bureau, 2000
         Percentage of workforce lost to AIDS
    by 2005 and 2020 in selected African countries

     50
                         2005          2020
     40

     30
%
     20

     10

       0
           Botswana                   Côte d’Ivoire              Mozambique                    Togo
                  Cameroon                      Ethiopia                 Nigeria                      UR Tanzania
                                CAR                    Guinea-Bissau                South Africa             Zimbabwe




    Sources: ILO (2000) POPILO population and labour force projection; UN Department of
    Economic and Social Affairs, Population Division (1998)
    World Population Prospects: the 1998 Revision
HIV – The Virus
       Anatomy of the Virus

• Lentiviridae:     retrovirus
  – Reverse transcription: RNA  DNA
• Two types, with  40-60% amino acid
  homology
• HIV-1: Majority of HIV infection
  worldwide
• HIV-2: West Africa
Spread of Major HIV Types & Groups




             HIV-2
              (1940)
HIV-1 O/N
                       HIV-1 M
                        (1930)
        Classification of HIV-1
                            F1
• Groups
                            F2
   – M, N, O
• Subtypes                  K
                            B
   – A,B,C,D,F,G,H,J,K
                            D          GROUP M
• Sub-subtypes              C
   – A-A2,F1-F2,B-D         H
                            A
• Circulating Recombinant   CRF02-AG
  Forms (CRFs)              CRF01-AE

   – CRF01 to CRF15         G
• (Unique Recombinants)     J

                            SIVcpzUS GROUP N
                            SIVcpzGAB
                                      GROUP O
                            SIVcpzANT
Classification of HIV-1
 •    A     •   CRF01_AE
 •    B     •   CRF02_AG*
            •   CRF03_AB
•    C*     •   CRF04_cpx
 •    D     •   CRF05_DF
•    „E‟    •   CRF06_cpx
            •   CRF07_BC
 •    F     •   CRF08_BC
•     G     •   CRF09_cpx
 •    H     •   CRF10_CD
            •   CRF11_AGJ
 •    „I‟   •   CRF12_BF
 •    J     •   CRF13_cpx
 •    K     •   CRF14_BG
            •   CRF15_01B


                  Predominant strains in Africa
                HIV-1 Group N
• Very few cases
  documented (<10)
   – only in Cameroon
• Among HIV-1 strains               HIV-1 Group M
  most closely related to
  SIVcpz
   – isolated from naturally
     infected chimpanzees
                               Chimpanzee from
• Recombinant virus            West Central Africa
  between Group M and               HIV-1 Group N
  SIVcpz
                                    HIV-1 Group O
                               Chimpanzee from
                               East Africa
       Classification of HIV-2
• 8 subtypes              G       D
• Each represents a
  zoonotic transmission
  from sooty mangabey
• A - Senegal, Guinea
  Bissau                                  C
• B- Ghana
• C, D - Sierra-Leone,                A
  Liberia
                              B
• E, F - Sierra-Leone E   F
• H identified in 2004
     HIV & Genetic Diversity

• A result of inherent mutability
• Implications for:
  – Viral diagnostics
  – Vaccine development
  – Possible differences in clinical progression
• Epidemiologic variation
  – 1st epidemic in RSA = B
  – Current predominant clade = C
HIV - The Virus
          CORE
          • 2 X ssRNA
          • Gag
               – p24 (capsid)
               – p17 (matrix)
               – p7 (internal structural protein
                 = nucleocapsid)
               – P55 (gag-pol precursor)
          • Pol
               – p66/p51 (reverse
                 transcriptase)
               – p31
                 (endonuclease/integrase)

    LIPID BILAYER(derived from host/infected cell)
    • env glycoproteins
        • gp120 (outer env)
        • gp 41 (transmembrane)
   Cellular Receptors for HIV

• HIV infects cells expressing CD4+
   –   T-helpers
   –   Monocytes
   –   Macrophages
   –   Glial cells (CNS)
   –   Chromaffin cells (intestine)
   –   Langerhans cells (mucous membranes)
• ?other cellular targets
   – Neurones not expressing CD4+
   Cellular Receptors for HIV
• Human cell surface proteins crucial for entry
  – CCR5*
      • Monocytes & T-lymphocytes
      • Entry for NSI, monocytotropic strains of HIV-1
  – CXCR4 (fusin)*
      • T-lymphocytes
      • Entry for SI, T-cell tropic strains of HIV-1
  *Normally function as receptors for chemoattractant
    cytokines (chemokines)
• Chemokines produced by CD8+ T-cells
  – RANTES (regulated upon activation, normally T-cell expressed & secreted)
  – MIP-1 & MIP-1 (macrophage inflammatory proteins)
  These bind to CCR-5, blocking entry, inhibiting infection in vitro
    with monocytotropic, but not T-lymphotropic strains of HIV
 Natural Resistance to HIV Infection

• Co-receptors
  – 32-base pair deletion in CCR-5 gene
    • Caucasians
       – 10% heterozygous (?slower rate of progression)
       – 1% homozygous (appear to be resistant)

• CTL responses
  – Kenyan Commercial Sex Workers
• Other mechanisms
   Initial Infection at Mucosa

• Oropharynyx, rectum, genitalia
  – Langerhans cells (FDCs)
  – Lymphoid tissue beneath mucosa
  – Regional lymphoid tissues
  – Dissemination
• Net result is primary viraemia
• Spread to lymphoid tissues throughout
              Primary Viraemia

• Peripheral blood
   –    numbers infected cells
   –   High titres infectious virus ( 107 c/ml)
   –   Wide dissemination of virus
   –   Individuals are highly infectious
• Then
   – Rapid decline in virus titres prior to Ab
   – HIV-specific CTLs and Ab-dependent cellular
     cytotoxicity (ADCC) prior to Ab
   – FDC network traps extracellular HIV particles
• Resultant low levels circulating virus
    HIV Production & Clearance
•   FDC trapping  virus replication in LN
•    0.1-10 billion virions produced daily
•    50% of circulating virus is replaced daily
•   Rate of clearance similar in all individuals
•   Rate of production determines serum VL
•   HIV production is coupled to CD4 destruction
•   1-2 billion new CD4 cells produced daily
    – T1/2 of infected CD4 cells =  1.2 days
    – T1/2 of mØ and latently infected CD4 cells =  14/7
• T1/2 of resting CD4s =  5-6 months
• T1/2 of cells with defective virus =  3-6/12
         HIV Dynamics In Vivo

             Productively infected
              CD4 lymphocytes                                         Latently infected
                                                                      CD4 lymphocytes
                                                <1%

                                         >99%


                        t1/2 ~ 10 mins                                      Uninfected
± 10 hours                                                                CD4 lymphocytes
    per
generation                                      HIV-1   <1%

                                                                  CD4 lymphocytes infected
                                                                    with defective virus


                                                        Long-lived cell
                   Uninfected, activated
                                                        populations
                    CD4 lymphocytes

                                                                          Adapted from David Ho
       Advanced HIV Infection

•   HIV accumulation in FDC network
•   Destruction of LN architecture
•   Release of virus and other organisms
•   CD4 cells infected and destroyed faster
•   Failure of regenerative capacity
    – Infection of precursor stem cells
    – Failure of CD4 programming in thymus
• Hence failure to mount immune response
The Life Cycle of HIV-1

          1 Binding – CD4 recognition,
          V3 of gp120
     2 Membrane fusion & Entry, gp41, CCR5
   3 Reverse transcription (RNA  DNA)
 4 Integration  proviral DNA
 5 Proviral Transcription  mRNA
 6 Cytoplasmic expression, rev determines RNAs
 to encode Tat, Rev and Nef, new viral genomes
   and essential viral proteins – Gag, Pol, Env
    7 Translation into new HIV-1 particles
       8 Assembly at host-cell surface
          9 Budding and maturation, protease
                  cleaving Gag & Gag-Pol
                                             Natural History of HIV-1
                                               Sero-
                                                     Infection
                                             conversion


1200
                                                                                                          107
            CD4+ T Lymphocytes (cells/cmm)




                                                                                                                HIV-1RNA copies/ml plasma
                                                                      Constitutional                      106
CD4 Count




                                                                       Symptoms

                                                                                                          105



                                                                                          Opportunistic
                                                                                                          104
                                                                                            Diseases

 200
                                                                                                          103



                  0     WEEKS                             12   1                  YEARS            10
               Primary
              Infection
                      Symptomatic                                  Asymptomatic                   AIDS
        HIV-1 and Laboratory Testing
                                                Sero-
                                              conversion


1200                                         Detectable Virus (p24 Antigen, PCR)
                                                                                                                    107
            CD4+ T Lymphocytes (cells/cmm)




                                                                                                                          HIV-1RNA copies/ml plasma
                                                                                Constitutional                      106
CD4 Count




                                                                                 Symptoms

                                                                                                                    105



                                                                                                    Opportunistic
                                                                                                                    104
                                                                                                      Diseases

 200
                                                                                                                    103
                                                     Detectable Virus Antibody (ELISA, Western Blott)
                  0     WEEKS                                 12         1                  YEARS            10
               Primary
              Infection
                      Symptomatic                                            Asymptomatic                   AIDS
            Basic Test Principles
                            DISEASE
               Present              Absent
              TRUE               FALSE
            POSITIVES           POSITIVES

                                                                     _a_
 Positive               a                    b                 +PV = a+b



TEST
              FALSE               TRUE
            NEGATIVES           NEGATIVES

                                                                     _d_
Negative                c                   d                  -PV = c+d



                                                                _a+c_
                                                    Prevalence =
                 SENSITIVITY          SPECIFICITY              a+b+c+d
                        _a_                 _d_                 _a+d_
                        a+c                 b+d     Accuracy =
                                                               a+b+c+d
                                 Basic Test Principles
                                                 DISEASE                         Example
                                    Present               Absent             Sensitivity = 99.8%
                                   TRUE                FALSE                 Specificity = 99.6%
                                 POSITIVES            POSITIVES
Population = 1,000
Prevalence = 25%




                                                                                           _a_
                      Positive               a                     b                 +PV = a+b


                                   249                  3
                     TEST
                                   FALSE                TRUE
                                 NEGATIVES            NEGATIVES

                                                                                           _d_
                     Negative                c                    d                  -PV = c+d

                                    1                   747
                                                                                      _a+c_
                                                                          Prevalence =
                                        SENSITIVITY         SPECIFICITY              a+b+c+d
                                             _a_                  _d_                 _a+d_
                                             a+c                  b+d     Accuracy =
                                                                                     a+b+c+d
                                 Basic Test Principles
                                                 DISEASE                         Example
                                    Present               Absent             Sensitivity = 99.8%
                                   TRUE                FALSE                 Specificity = 99.6%
                                 POSITIVES            POSITIVES
Population = 1,000
 Prevalence = 1%




                                                                                           _a_
                      Positive               a                     b                 +PV = a+b


                                   249                  3
                                   10                   4
                     TEST
                                   FALSE                TRUE
                                 NEGATIVES            NEGATIVES

                                                                                           _d_
                     Negative                c                    d                  -PV = c+d

                                    1                   747
                                    0                   986
                                                                                      _a+c_
                                                                          Prevalence =
                                        SENSITIVITY         SPECIFICITY              a+b+c+d
                                             _a_                  _d_                 _a+d_
                                             a+c                  b+d     Accuracy =
                                                                                     a+b+c+d
                                 Basic Test Principles
                                                 DISEASE                        Example
                                    Present              Absent              Sensitivity = 93%
                                   TRUE               FALSE                  Specificity = 97%
                                 POSITIVES           POSITIVES
Population = 1,000
Prevalence = 25%




                                                                                          _a_
                      Positive               a                    b                 +PV = a+b


                                   249                 3
                                   232                 23
                     TEST
                                   FALSE               TRUE
                                 NEGATIVES           NEGATIVES

                                                                                          _d_
                     Negative                c                   d                  -PV = c+d

                                    1                  747
                                    18                 727
                                                                                     _a+c_
                                                                         Prevalence =
                                      SENSITIVITY          SPECIFICITY              a+b+c+d
                                             _a_                 _d_                 _a+d_
                                             a+c                 b+d     Accuracy =
                                                                                    a+b+c+d
         Clinical Assessment
               First Encounter
•   Stage the HIV infection
•   Dx associated conditions
•   Review counseling, education, support
•   Plan follow-up, immunizations
•   Consider ARV
•   Consider prophylaxis
       Clinical Assessment
           Physical Examination
• Comprehensive
• NB:
  – Skin, oropharynx, lymph nodes
  – Anogenital regions
    • Especially other STIs
  – Ophthalmic
  – CNS/PNS
       Clinical Assessment
                Laboratory Dx
• Pre- and post-test counseling
• Detection of:
  – Antibodies
  – p24 antigen
  – Viral nucleic acid (PCR)
  – Virus by isolation from cell culture
• Typically ELISA (diagnosis)
• Western Blott, PCR (confirmation)
         Clinical Assessment
          Window Period and Testing
                                        Days to
             Assay
                                      Positivity (±)
1st generation ELISA (Lysate)              42
3rd generation ELISA (sandwich             23
recombinant and synthetic peptides)

p24 antigen assays                         16
DNA PCR (proviral DNA)                     16
RNA PCR (HIV-1 RNA)                        11
           Clinical Assessment
     Clinical Features Suggestive of HIV
Signs and Symptoms
•Acute Retroviral Syndrome
Monospot negative mononucleosis
Syndromes with maculopapular rash
Aseptic meningitis
•Constitutional complaints
Fatigue
Malaise
Fever
Night sweats
Weight loss
•Generalized lymphadenopathy
               Clinical Assessment
      Clinical Features Suggestive of HIV
Signs and Symptoms
•Dermatological manifestations
Seborrhoea
Psoriasis
Folliculitis
Pruritic eruptions
Herpes zoster
Superficial dermatophytosis
Molluscum contagiosum
Warts
Xerosis
            Clinical Assessment
     Clinical Features Suggestive of HIV
Signs and Symptoms
•Mucous membranes
Thrush
Aphthous stomatitis
Oral hairy leukoplakia
Necrotizing gingivitis
Severe/recurrent oro-labial herpes simplex
Genital candidiasis
Severe/recurrent genital herpes simplex
Condylomata acuminata
Cervical intraepithelial neoplasia
       Clinical Assessment
            Screening Diagnosis
• Clinical suspicion
• ELISA
  – Confirmatory tests
  – 4 generations
     • 1st included human HLA antigens ( specificity)
     • 2nd used recombinant Ag from transfected
       organisms
     • 3rd = chemically synthesized peptides
     • 4th includes detection of p24 itself
         Clinical Assessment
             Confirmatory Testing
• High prevalence vs low prevalence
• Clinical situation vs insurance testing
• Western Blott
   – Any 2 envelope bands (gp41, gp120, gp160)
   – +PV >99%
• Rapid tests
   – Reserve for screening
   – Saliva and urine – reserve for epidemiology
• Special considerations in newborn
   – PCR (DNA)
   – ELISA > 18/12 of life
         Clinical Assessment
               Confirmatory Testing
• p24
   – Window period
   – Not for MTCT
      • „neutralization‟ results in false negative results
• Viral nucleic acid (DNA or RNA)
   – RNA assays for window period (blood bank)
   – DNA assays for established infection
   – NB, these have lower sensitivity than ELISAs
• HIV cell culture
       Clinical Assessment
     Supportive Tests for Diagnosis
• CD4+ T lymphocyte count
  – Different ranges for adults and children
  – Percentages important, esp in children
• FBC & Chemistry
• STIs
  – Esp, HBV, HCV, syphilis
• Others
  – p24, neopterin, 2-mcg (not routine Mx)
 The Role of Laboratory Markers

• Viral load and CD4+ cell count are essential
  for optimum Mx
• CD4+ > 500 cells/cmm with VL < 10,000 c/ml
  = low risk for progression
• HIV RNA > 30,000 c/ml =  risk for
  progression
• Viral load indicates risk for progression
• CD4+ count indicates degree of immune
  compromise and risk for other infections
        The CD4+ Cell Count

• Indicative of risk for OIs
• Independent risk factor for AIDS/death
• Determinant for initiation of ARV
• Not predictive for future immunological
  damage
• Increases rapidly in response to ARV
    – Redistribution of memory cells (CD45RO+)
    – Naïve CD4+ cells = new production
            The Viral Load

• VL = powerful independent risk factor for
  progression
• VL > 100,000 c/ml within 6/12 of
  seroconversion = 10 X  risk of AIDS within 5
  years
• CD4+ cell count and VL can become
  discordant
  – Thus may have rapid progression from high CD4+
    cell count despite low VL
                               Loss of CD4+ Cells/Year
                                                 HIV-1 RNA (c/ml)
                                   <500       501-3,000    3,001-10,000 10,001-30,000   >30,000
                              0
Loss per year of CD4 cells




                             -10
                             -20
                             -30
                                      -36.1
                             -40
                                                   -44.9
                             -50
                                                                  -55.2
                             -60
                                                                                -65.1
                             -70
                             -80                                                            -76.8

                             -90
 HIV Viral Load Measurement

• Expressed as an absolute number
  (copies/ml)
  – Or as a logarithm (log10)
• Logarithms are important in assaying
  the change in viral load
  – < 0.5 log10 variation
  – 0.5 log10  threefold difference
     Comparison of VL Assays
   Assay          RT-PCR           bDNA         NASBA
  Manufacturer       Roche           Bayer        Organon

Range (c/ml)     •400-750,000   50-500,000    40 to 10 million
                 •40-75,000
Comparison       2X bDNA        0.5X RT-PCR    RT-PCR

Specimen         •0.2ml         10l to 1ml   10l to 2ml
Volume           •0.5ml
Specimen         EDTA           EDTA          EDTA, heparin,
Collection                                    whole blood,
                                              other body
                                              fluids
      Frequency of Testing

• At initial assessment
• Four-monthly thereafter
  – Can omit VL if ARV not yet indicated
• Prior to commencing ARV
  – Four-monthly thereafter
• Repeat analysis within 2-4/52 if routine
  test gives unusual result
• Non-routine tests if clinically indicated
 Testing and the Goal of ARV

• A  in VL of  1 log from pre-Rx levels
  by 6-8/52 on ARV
• A  in VL to < 5,000 c/ml by 12/52

• A VL < 50 c/ml has the greatest
  durability
 What Influences ARV Choice?
•Side Effects
•Drug Interactions                                  •QOL
•Drug Toxicities                                        •wellness vs ADE
    •rash                                           •Decreased cost
    •liver                                              •hospital/medical
    •lipodystrophies                                    •productivity
                                                    •Therapeutic Drug
                                                    Monitoring

               RISK                         BENEFIT
•QOL
    •ADE vs wellness                               •Newer therapies
•Resistance                                           •ntRTIs (TDF)
                           •Newer therapies           •fusion inhibitors
    •primary & secondary      •ntRTIs (TDF)
    •adherence                                        •vaccines
                              •fusion inhibitors
    •NB: suboptimal          •vaccines
•‘Herd’ behaviour
                           A Significant Number of
                            Initial Regimens Fail
   • High rate of                                              • Causes vary and are
     modification and                                            seldom possible to
                                                                 predict in advance
     discontinuation of
                                                                      – nonadherence
     HAART regimens                                                      • side effects
     (single clinic data)                                                • complex regimens
               60                                                        • lifestyle conflicts
               50                                   n=247
                                                                      – pharmacologic variations
Patients (%)




               40           Modification
               30                                   n=148             – ARV-resistant HIV-1
               20
               10                          Discontinuation

                    0       3       6       9     12      15     18
                        Months after starting potent ARV therapy
                                                                           Mocroft A et al. AIDS, 2001
                          Duration of Initial HAART
                          100
Patients without change



                           80
     in therapy (%)




                           60

                           40

                           20

                           0
                                0   120   240   360        480          600          720
                                                Days
197 patients, Cologne 1997–1999
                                                       Fätkenheuer G et al. 8th ECCATH, 2001
How, Why, What for 1st-line Rx?
How, Why, What for 1st-line Rx?

• 30-year-old male
• Combivir® for two years
• Pre-therapy:
  – CD4 = 200 cells/cmm
  – VL = 80,000 c/ml
• Current results:
  – CD4 = 176
  – VL = 3,000 c/ml
How, Why, What for 2nd-line Rx?
Drug                    Primary Mutation Secondary Mutation
Amprenavir (Agenerase®)
ABT-378/r (Kaletra®)
Indinavir (Crixivan®)
Nelfinavir (Viracept®)
Ritonavir (Norvir®)
Saquinavir (Invirase®)

AZT (Retrovir®)                         D67N, K70R, K219Q     20
Lamivudine (3TC®)           M184V
FTC (Coactinon®)            M184V
ddI (Videx®)                            M184V, D67N           <4
d4T (Zerit®)                            M184V, D67N, A98G     <6
ddC (Hivid®)                            M184V, D67N           16
ABC (Ziagen®)                           M184V, K70R, K219Q    <4

Delavirdine (Rescriptor®)               A98G                  <4
Efavirenz (Stocrin®)                    A98G                  <6
Nevirapine (Viramune®)                  A98G                  12
  Optimizing First Regimen is
            Crucial
• Resistance to ARV agents is one of the
  major challenges to successful therapy
• Chances of long-term viral suppression
  are greatly reduced once drug
  resistance has developed
• Prevention of resistance to our first
  choice regimen is crucial to the future
  morbidity and mortality of our patients
 Reduced ARV Susceptibility (>10-fold) in
  Untreated, Recently Infected Patients
                           9 North American cities, n=389

               16
               14
               12                                                              NRTI
Patients (%)




               10                                                              NNRTI
                8                                                              PI
                6
                4
                2
                0
                    1996   1997    1998   1999     2000
                                   Year

                                                 Little SJ et al. N Engl J Med, 2002
First-line Treatment Regimens
 Are Not All Destined to Fail
• Potent HAART regimens are available
  – can achieve long-term viral suppression
  – can restore immune function
• Concerns
  – development of resistance
  – tolerability and toxicity
• Alternative treatment strategies
    Potential ARV Regimens

• Some 16 ARV compounds have been
  licensed
• Theoretically 560 triple combinations
  can be made
• Due to cross-resistance and cross-
  toxicity only 2–4 different regimens are
  applicable for an individual patient
       Availability of ARVs
             Evolution of Usage
• 80‟s – early 90‟s
  – Monotherapy
• Early 90‟s – mid 90‟s
  – Mono- & Dual-therapy
Advent of Viral Load technology
  Understanding of suboptimal therapy
• Mid 90‟s – present
  •  3 drug therapy
                Availability of ARVs
                         FDA Approval Dates
 Date      Abbreviation             Ge ne ric Nam e                       Trade Nam e
 1982     First FDA IND Submission for Rx of AIDS
Mar-87    AZT (ZDV)     Zidovudine                           Retrovir/Aspen-Zidovudine
Oct-91    ddI           Didanosine                           Videx/Aspen-Didanosine
Jun-92    ddC           Zalcitabine                          Hivid
Jun-94    d4T           Stavudine                            Zerit/Aspen-Stavudine
Nov-95    3TC           Lamivudine                           3TC/Aspen-Lamivudine
Dec-95    SQChgc        Saquinavir-sgc                       Invirase
Mar-96    RTV           Ritonavir                            Norvir
Mar-96    IDV           Indinavir                            Crixivan
Jun-96    NVP           Nevirapine                           Viramune/Aspen-Nevirapine
Jun-96    RT-PCR/bDNA/NASBA - Viral Load Assays
Mar-97    NFV           Nelf inavir                          Viracept
Apr-97    DLV           Delavirdine                          Rescriptor
Sep-97    COM           Zidovudine + Lamivudine              Combivir/Aspen-Lamzid
Nov-97    SQVsgc        Saquinavir-hgc                       Fortovase
Sep-98    EFV           Ef avirenz                           Stocrin
Feb-99    ABC           Abacavir                             Ziagen
Apr-99    APV           Amprenavir                           Agenerase
Sep-00    LPV/r         Lopinavir/ritonavir                  Kaletra
Nov-00    TZV           Zidovudine + Lamivudine + Abacavir   Trizivir
Oct-01    TDF           Tenof ovir DF                        Viread
Mar-03    T20           Enf uvirtide                         Fuzeon
Jun-03    ATV           Atazanavir                           Reyataz
 Jul-03   FTC           Emtricitabine                        Emtriva
Nov-03    FPV           Fosamprenavir                        Lexiva
           Antiretroviral Agents

•    Three main classes of ARV agents
    1. Nucleoside reverse transcriptase inhibitors
       –   NRTIs
    2. Non-nucleoside reverse transcriptase inhibitors
       –   NNRTIs
    3. Protease inhibitors
       –   PIs
•    Two additional drug classes
    4. Nucleotide reverse transcriptase inhibitors
       –   NtRTIs
    5. Fusion inhibitors
        Antiretroviral Therapy

     NRTI’s        NNRTI’s               PI’s
Zidovudine AZT Nevirapine NVP     Indinavir      IDV
Lamivudine 3TC Efavirenz  EFV     Nelfinavir     NFV
Didanosine ddI                    Ritonavir      RTV
Stavudine   d4T                   Saquinavir     SQV
Abacavir    ABC                   Lopinavir/r   LPV/r


2X   NRTI + 1X       NNRTI
2X   NRTI +             PI
                             = HAART
              1-2X
 Nucleoside Reverse Transcriptase Inhibitors
                  NRTIs

• Nucleoside analogs
• Phosphorylated by cellular enzymes
  – Compete with nucleosides wrt HIV RT
• Inhibit HIV DNA elongation
• Penetrate blood brain barrier
  – ABC > AZT > d4T
• Minimal drug-drug interactions
• Renal excretion
• Mitochondrial toxicity
  – Inhibit DNA polymerase
Codon structure


             Mutations
                       NRTIs
             Zidovudine – AZT (ZDV)
• Thymidine analog
• 250-300mg BID PO
• S/E
  – Nausea, headache, myalgia
     • Usually transient
  – Anaemia, neutropaenia
     • Usually need to change drug
  – Macrocytosis
  – Lactic acidosis and hepatic steatosis
     • Moderate potential
• CANNOT combine with d4T
                          NRTIs
                    Didanosine - ddI
• Adenosine analog
• >60kg 400mg OD PO (or 200mg BID PO)
• <60kg 250mg OD PO
       • Empty stomach
       • Minimum of 2 tablets in one dose
• S/E
  –   Nausea, vomiting, dyspepsia
  –   Pancreatitis
  –   Peripheral neuropathy (12%)
  –   Lactic acidosis and hepatic steatosis
       • HIGH potential
                          NRTIs
                   Zalcitabine - ddC
•   Cytosine analog
•   0.75mg TID PO (not BID)
•   Less potent
•   S/E
    – Peripheral neuropathy (31%)
       • >d4T (15%) > ddI (12%)
    – GIT ulceration (esp aphthous ulcers)
    – Lactic acidosis and hepatic steatosis
       • HIGH potential
• Seldom used because of S/E & dosage
                        NRTIs
                  Lamivudine – 3TC
• Cytosine analog
• 150mg BID PO or 300mg OD PO
• S/E
  – Well tolerated
  – Rarely
     • Bone marrow toxicity
     • Pancreatitis in children
  – Lactic acidosis and hepatic steatosis
     • Low potential
                          NRTIs
                    Stavudine – d4T
•   Thymidine analog
•   >60kg 40mg BID PO
•   <60kg 30mg BID PO
•   S/E
    – Peripheral neuropathy (15%)
       • ddC (31%) > d4T > ddI (12%)
    – Lipoatrophy
    – Lactic acidosis and hepatic steatosis
       • HIGH potential
• CANNOT combine with AZT
                        NRTIs
                     Abacavir - ABC
• Guanosine analog
• 300mg BID PO
• S/E
  – Hypersensitivity in 1-5%
     •   Median time to onset = 11 days
     •   Serious
     •   Rash common, with fever, myalgia, abdominal pain
     •   Never rechallenge
  – Lactic acidosis and hepatic steatosis
     • Low potential
   Non-Nucleoside Reverse Transcriptase Inhibitors
                              NNRTIs

• Structurally distinct from NRTIs
• Bind directly to RT enzyme
  – Near catalytic site
• Potent and rapid reduction in VL
• High level resistance in suboptimal regimens
  – K103N
  – Cross-class resistance
      • „Lose one lose all‟
  – But no cross-resistance to NRTIs or PIs
  Non-Nucleoside Reverse Transcriptase Inhibitors
                     NNRTIs

• Good CNS penetration
•  frequency hypersensitivity/rash
• Frequent drug-drug interactions
  – Inducers of CYP450
• No antiviral effect on HIV-2
                     NNRTIs
                  Nevirapine - NVP
• 200mg OD PO X 2/52, then 200mg BID PO
• Safe in pregnancy
• S/E
   – Hypersensitivity rash – 17% (Most by week 3)
      • 7% discontinue
      • Stevens-Johnson syndrome
   – Subclinical hepatitis
• Contraindicated ( risk of hepatitis)
   – Women with CD4+ > 250 cells/cmm
   – ? Men with CD4+ > 400 cells/cmm
• Induces CYP450
                     NNRTIs
                 Nevirapine - NVP
Hypersensitivity Mx
• Discontinue drug if
  – Systemic symptoms, hepatitis, mucosal
    involvement
     • Do not reintroduce
• Treat through
  – Antihistamines
  – Delay dose escalation till reaction settled
     • Most cases
• Do not switch to EFV
  –  50% chance of hypersensitivity cross-reaction
                      NNRTIs
                   Efavirenz - EFV
• 600mg NOCTE PO
• Teratogenic in simian studies
  – Contraindicated in women of child-bearing
    potential
• S/E
  – CNS
     • Dysphoria, euphoria, dizziness, headache
     • Insomnia, nightmares
        – Lessen after first few weeks
• Hypersensitivity rashes less severe
  – 10% risk (only 2% discontinue)
• Induces and inhibits CYP450
          Protease Inhibitors
                          PIs
• Potent inhibitors of HIV replication
   – In vitro and in vivo
   – At all stages of HIV disease
• Poor CNS penetration
• CYP450 inhibition
   Drug-drug interactions common
   Use RTV to boost other PIs
• S/E
   • GIT intolerance common
   • Dyslipidaemias and lipodystrophies
                          PIs
                  Saquinavir - SQV
• Poor oral bioavailability
   – hgc = 4%                sgc = 12%
• Boost with RTV
   –  bioavailability to  40%
   – Preferable to always use boosted SQV
      • Use hgc – less GIT S/E
• 400mg BID PO + RTV 400mg BID PO
   – Or 1000mg BID PO + RTV 100mg BID PO
   – Or 1600mg OD PO + RTV 100mg OD PO
• S/E
   – Moderate to low potential for metabolic disorders
                       PIs
                 Ritonavir - RTV
• Good bioavailability
• 600mg BID PO
  – But VERY poorly tolerated
  Recommended for PK boosting only
• S/E
  • Moderate to high potential for metabolic disorders
• Must be refrigerated until use, then kept
  below 25°C
                            PIs
                      Indinavir - IDV
• Good bioavailability
• 800mg 8 hourly PO, on empty stomach
• Preferable:
  – 800mg BID PO + RTV 100mg BID PO
       • No meal restrictions
• S/E
  –   Nephrotoxic
  –   Hair loss, dry skin, ingrown toenails
  –   Hyperbilirubinaemia
  –   Moderate potential for metabolic disorders
                        PIs
                  Nelfinavir - NFV
• 750mg TID PO or 1250mg BID PO
  – Preferable with fatty meal
• Minimal interaction with RTV
  – No clinical benefit of boosting
• Safe in pregnancy
• S/E
  – 30% may have ongoing diarrhoea
  – Moderate potential for metabolic disorders
• Reduced potency compared to others
                    PIs
          Lopinavir/ritonavir – LPV/r

• Fixed dose combination
• 400/100mg (3 caps) BID PO
• Virologic suppression of other PI-
  resistant strains of HIV-1
• S/E
  – Moderate potential for metabolic disorders
  – Low incidence of diarrhoea
    Initial ARV Regimens for the Naïve Patient

                      Clinician experience
                      Communication skills

                           Clinician
                                                        Potency
Replication rate
                                                Pharmacokinetics
 (Viral load)
Mutation rate      Virus                 Drug     (dosage schedule)
                                                      Tolerability
 (Resistance)                                            Toxicity
Latent reservoirs                                   Convenience
                           Patient                   Resistance


                           Adherence
                         Access to care
                      Access to medication
                          Life situation
                         Disease stage
                          Initial ARV Regimens for the
                                   Naïve Patient
                                                                                                          Impact of Treatment Experience
                                                                                                           on Virologic Response (MACS)
                         100                                                                                     ARV-naïve (n=91)
                                                                                                    100
virologic failure* (%)




                                                                                                                 ARV-experienced (n=73)
                         80




                                                                            Patients with HIV RNA
    Patients with




                                                                             <400 copies/mL (%)
                                                                                                    80

                         60
                                                                                                    60

                         40
                                                                                                    40

                         20                                                                         20

                          0                                                                          0
                               >95   90–95     80–90 70–80       <70
                                                                                                             <200      200–400     >400
                                     Adherence (%)
                                                                                                                CD4 count (cells/mm3)
               P<0.001, r=–0.554
               *Virologic failure defined as
               HIV RNA >400 copies/mL at
               last study visit                    Paterson DL et al. Ann                                                     Yamashita TE et al.
                                                        Intern Med, 2000                                                            AIDS, 2001
     Initial ARV Regimens for the
              Naïve Patient


                                        Highly-
                    Experienced
 Naïve patient                        experienced
                      patient
                                        patient




Success Failure   Success Failure   Success   Failure
      Initial ARV Regimens for the
               Naïve Patient
                               HIV Infection



ADE or CD4<200                              CD4>200


    Treat        CD4 200-350               CD4 200-350           CD4>350


                 VL>100,000    Symptomatic        Asymptomatic    Delay


                    Treat          Treat                 Delay
       Initial ARV Regimens for the
                Naïve Patient
      NRTI’s                   NNRTI’s           PI’s
 Zidovudine#           AZT Nevirapine NVP Indinavir                            IDV
 Stavudine#            d4T Efavirenz  EFV Nelfinavir                           NFV
 Didanosine            ddI                Ritonavir                            RTV
 Lamivudine            3TC                Saquinavir                           SQV
 Abacavir              ABC                Lopinavir/r                         LPV/r
                               #d4T
             2X   NRTI     =        + 1 other         +      EFV* or NVP
                                 or
                                       NRTI
       OR 2X      NRTI     =   #AZT +                 +      LPV/r or PI/r
#Thymidine analogs, AZT and d4T cannot be used together – use either one or the other
(and add an other second NRTI)
*EFV should be avoided in WOCBP - teratogenic
              When Do You
             Choose To Treat?
• Acute HIV (<6/12 after seroconversion)
  – Treat all [clinical trials]
• Symptomatic (ADE, unexplained fever, oral
  thrush, recurrent vulvo-vaginal thrush, oral
  hairy leucoplakia, recurrent zoster)
  – Treat all
• CD4  200 cells/cmm
  – Treat all
• CD4  350 cells/cmm AND VL > 100,000 c/ml
             When Do You
            Choose To Treat?
• Remember
  – ARV/HAART is potent and effective
  – Toxicities may occur
     • BUT are managable
  – Regular monitoring is essential
     • For success (Viral load, T-cell subsets, Clinical Status)
     • ADRs
• Don‟t forget
  – Regular monitoring before Rx is essential
     • T-cell subsets, Clinical Status, (Viral load)
  Initial ARV Regimens for the Naïve Patient
        ART in Patients with Tuberculosis


• TB should always be Mx by TB Clinics
• Interactions with ARV and TB Rx
  – Frequent drug-drug interactions
  – Overlapping toxicity
• If CD4+ > 200 cells/cmm
  – Defer ARV for 6/12
• If CD4+ < 200 cells/cmm
  – Defer ARV for 2/12 (post intensive phase)
ARV Interactions with Rifampicin

ARV             Interaction
                Mild reduction in EFV - ?  EFV dose to
EFV
                800mg NOCTE PO
                Moderate reduction in NVP – ltd data
NVP
                Increased overlapping toxicity
RTV/SQV         No significant interaction

All other PIs   Marked reduction in PI levels - avoid
    Mx of ARV Side Effects

• Long-term toxicities
• Immediate & short-term toxicities
  – Up to 50% of patients
  – Usually minor and transient
• Monitoring
  – NVP: ALT
  – AZT: FBC
  – PIs: Lipid profiles
          HIV-Related Drugs With
           Overlapping Toxicities
   Bone        Periph-  Pan-       Nephro-    Hepatotoxicity   Rash   Diarrhoea   Ocular
  Marrow         eral  creatitis   toxicity                                       Effects
Suppression    Neuro-
                pathy
 Cidofovir      ddI        ddI     Aminogly      DLV       ABC        ddI      EMB
 Chemo         d4T        3TC      -cosides     EFV      NNRTIs      NFV      RFB
 Dapsone        ddC       CTX      Ampho B       NVP       APV        RTV    Cidofovir
Flucytosine     INH     Pentam     Cidofovir     NRTIs     CTX       LPV/r
      HU                 -idine    Foscarnet      PIs    Dapsone Clindamycin
     IF-                              IDV   Fluconazole
  Pentam-                           Pentam- Ketoconazole
    idine                             idine      INH
  Ribavirin                                      RFB
Sulfadiazine                                      RIF
     CTX
     AZT
          Toxicities of ART

• Common pathway
  – Induction of mitochondrial dysfunction
  – NRTIs inhibit DNA polymerase
     • mtDNA depletion
• Interindividual variation and tissue
  specific toxicity not clearly understood
     • Clinical features of genetic mtDNA defects
• Possible role of CYP450
               Hepatotoxicity
Risk Factors for Susceptibility to Drug-induced
                Hepatotoxicity


                              Genetic Factors
   Toxic Potential of Drug
                              Drug metabolism
     Reactive metabolite
                               Detoxification
       Acylglucuronide
                                 Transport
     Mitchondrial effects
                                  Others

                Environmental Factors
                     Other drugs
                       Ethanol
                       Age/sex
                 Underlying diseases


                                                N Kaplowitz, CID 2004:38 (S2)
               Hepatotoxicity

• Most common with NVP
  – 10-15% biochemical hepatitis
  – 1% clinical hepatitis
• Monitoring
  – Full LFT @ baseline
  – ALT @ 2, 4 & 8/52: ALT 3 monthly thereafter
• Co-infection with HBV/HCV
  – ?flare of hepatitis from immune reconstitution
  – ?flare due to underlying liver damage  less
    capacity to tolerate NVP
                    Hepatotoxicity
       And HBV or HCV Co-infection
                         HCV or HBV
           Direct                         Immune-
         cytotoxicity                     mediated
                                         cytotoxicity
                           Chronic      “restoration”
         Alcohol
         Drugs             Hepatitis
          Meds                         Drug-related
                                       hepatotoxicity

            NASH*                      HIV     HAART


*NASH = Nonalcoholic steatohepatitis

                                                        Pol et al, CID 2004:38 (S2)
                Hepatotoxicity

• PIs (IDV/ATV)   BR (unconjugated)
     • Benign
• GGT/ALP
  – Exclude infiltration/obstruction
  – Fatty liver due to NRTIs (d4T)
• Other drugs
  – TB Rx
  – Cotrimoxazole
     • Rare cause of cholestatic jaundice
        Mitochondrial Toxicity
                    Hyperlactataemia
•  lactate in pts on NRTIs common
   – Up to 20% per annum
• Symptomatic hyperlactataemia
   – 1-2% per annum
• Lactic acidosis is rare
   – 0.1% per annum
   – Life threatening
   – Risk for lactic acidosis
      • ddC > d4T > ddI > AZT > 3TC = ABC = TDF
   – Highest risk
      • Combination of d4T+ddI
          – Highest in pregnancy
        Mitochondrial Toxicity
                  Hyperlactataemia
• Other risk factors
  –   Female
  –   Obesity
  –   Prior NRTI toxicity
  –   Prolonged use of NRTIs
• Symptoms
  –   Nausea, vomiting, abdominal pain
  –   Malaise, weight loss
  –   Liver dysfunction (hepatic steatosis)
  –   Tachycardia
            Mitochondrial Toxicity
            Management of Hyperlactataemia
                                      Lactate+

            2.1 mmol/l                                >2.1 mmol/l

          Repeat Lactate+                            Repeat Lactate+
           Every 2-4 months
                               2.1-5 mmol/l

                                   Symptoms             >5 mmol/l

                              No          Yes
       Repeat Lactate+                             Change/Stop Therapy#
          Every 1-4 weeks

+Assess liver function, transaminases, hepatic steatosis/necrosis
#Consider supportive Rx: thiamine, riboflavin, nicotinamide, pydridoxine,

dexpanthenol, L-carnitine.
                                                                Montaner et al, CID 2004:38 (S2)
            Lipodystrophy

• Fat redistribution
• PIs implicated in:
  – Fat accumulation
  – Insulin resistance
  – Hyperlipidaemia
• NRTIs implicated in:
  – Lipoatrophy
     • d4T > ddI > AZT
              Lipodystrophy
                  Risks Factors
• Duration of exposure to PIs & NRTIs
    – Esp. if used simultaneously (esp d4T)
•   Increasing age
•   Greater duration of HIV infection
•   More advanced HIV infection
•   Greater degree of virus suppression
    – ?translates into adherence  drug
      exposure
             Lipodystrophy
                   Management
• CVS risk factor modifications
  – TLC – diet and exercise
• Substitution of d4T with TDF or ABC
• Substitution of PI with ATV
• ?use NVP-based regimen for already-at-risk
  patients
• Steroids
  – Megestrol acetate, dronabinol, rHG Hormone
  – May increase CVS risk
• Cosmetic surgery – transient benefit
  – Polyacrylamide gel yields best results > 6/12
Laboratory Monitoring for HAART Efficacy


• CD4+ cell increase
  ± 50 cells/cmm in first 4/months
  ± 100 cells/cmm/year thereafter
  • May be slower in individuals with low CD4+
• VL = best measure of response
  • PCR, bDNA, NASBA
  • Use same assay for same pt each time
 Criteria for Virological Success
            SAHIV Clinicians‟ Society

•  in VL of  1 log10 by 6-8 weeks
•  in VL to < 400 c/ml by 24 weeks
  – Preferably < 50 c/ml by 16-24 weeks


• Prognosis
• VL < 50 c/ml for  18/12
  – Likely to achieve long-term suppression
              Criteria for Failure
                      DHHS

• Virologic
  – VL > 400 c/ml @ 24/52
  – VL > 50 c/ml @ 48/52
  – VL rebound to > 400c/ml after viral suppression
• NB – blips (50 – 1,000 c/ml) are not
  considered failure
• VL > 1,000 c/ml usu. Considered failure
• VL of 1,000-5,000 c/ml
  – No consensus on Mx
  – ? Implications for changing therapy
          Criteria for Failure
                     DHHS

• Immunologic
  – Failure of CD4+ count to  by > 25-50
    cells/cmm


• Clinical Failure
  – Occurrence or recurrence of HIV-related
    event after  3/12 on HAART
 Indications & Options for Changing
               Therapy
• Intolerance
  – Despite adequate intervention
• Side effects
  – e.g. anaemia (AZT)
• Virological failure
• If changing for S/E, can change suspect drug
• If changing for VL failure
  – Preferably do resistance assay first
  – Change  2 drugs
  Indications & Options for Changing Therapy
                    NNRTIs

• Toxicity
  – Rash
     ± 50% rash with EFV if had rash on NVP
  – Hepatotoxicity
     • Can switch from NVP to EFV
  – CNS S/E
     • Can switch from EFV to NVP
• Resistance
  – K103N or Y181C give broad cross-resistance
     • Cannot change from one NNRTI to another
  – Rather switch to PI
  Indications & Options for Changing Therapy
                      PIs

• S/E common
  – Resultant poor adherence
     • Risk of resistance
• Avoid unboosted PIs
  – Use RTV to boost other PI
     • Better tolerated
• Resistance – sequential mutations
  – Can use RTV-boosted LPV, ATV or SQV for VL
    failures
  Mechanisms of Mutation & Drug Resistance
                     HIV „Fitness‟


• 1-10 billion virions produced daily
• RT enzyme error prone
   – Mutations during RNADNA process
   – AA substitutions @ active sites of RT enzyme
• Quasipecies in untreated individuals
   – Consistent process in individuals
• Wild type (wt) virus  mutant/resistant (mu) if
  suboptimal drug pressure
Mechanisms of Mutation & Drug Resistance
                                 Requires Both Drug & Viral Replication

 Increasing possibility of the
 emergence of resistance


                                       Selective pressure       Viral replication




                                              dual therapy

                                                                           Optimum ARV
                                         monotherapy                      therapy


                                 0%       Increasing drug activity       100%
  Mechanisms of Mutation & Drug Resistance
                         HIV „Fitness‟


• Most mutations  less fit
  – wt dominates
• Suboptimal drug pressure
  – Mutant virus  dominant population
     • As long as the drug is administered
         – mu virus is less fit (cf 3TC and PI resistance)
  – If drug is withdrawn
     • wt virus re-emerges
     • mu virus archives
         – May re-emerge if drug pressure reapplied
  Mechanisms of Mutation & Drug Resistance
 Rate of Appearance & Disappearance of Resistance


• Single AA substitution
  – 3TC
     • High level resistance
     • Minimal cross-resistance
  – NNRTIs
     • High level resistance within class
     • Other classes spared
• Sequential mutations
  – PIs
     • Slowly increasing resistance
Factors Influencing Long-term
      Viral Suppression

                                                    Genetic          Baseline
Durability   =    Adherence +     Drug Levels   +                –
                                                    Barrier          Mutations




                 Convenience       Height and      Number of         Number of
                      and        duration of drug mutations          mutations
                  tolerability      exposure      required for       present at
                                                   resistance         start of
                                                                      therapy
Development of Resistance in the Context
  of Multi-drug and Multi-class Therapy
• Prognosis
   – Baseline resistance predicts therapy failure
   – Susceptibility may not guarantee a good response
• Effect of baseline resistance on therapy response
  depends partly on regimen used
• In case of HAART failure, cannot assume that
  resistance has developed to all components of
  the combination therapy
   – Resistance to 3TC in 3TC-containing failures is likely to
     arise if viral breakthrough occurs, but it is unlikely to
     lead to clinically relevant cross resistance
      • i.e. despite M184V, Abacavir could still be a good drug to
        use in a second-line option
 Drugs Involved in Drug-Drug Interactions

                          P450 INHIBITORS
•PIs                            •NNRTIs
•Macrolides                     •H2-Antagonists
•Azoles
                          P450 INDUCERS
•Rifampicin                     •NNRTIs
•PIs                            •Certain anticonvulsants
  METABOLIZED DRUGS WITH NARROW THERAPEUTIC INDICES
•Non-sedating antihistamines    •Ergotamines and dihydroergotamine
•Long-acting analgesics         •Illicit recreational drugs
•Promotility agents             •Coumarin anticoagulants
•Antiarrhythmics                •Oral contraceptives
•Long-acting benzodiazepines
 Drugs Involved in Drug-Drug Interactions

RENALLY CLEARED DRUGS WITH NARROW THERAPEUTIC INDICES
•Ganciclovir
•Foscarnet
•Aminoglycosides
    DRUGS WITH SPECIFIC REQUIREMENTS FOR ABSORPTION
•Ketoconazole
•Itraconazole
•Didanosine
•Fluoroquionolones
       Adherence to HAART
                Risk Factors

•   Lack of knowledge about HIV/AIDS
•   Lack of knowledge about medication
•   Health beliefs
•   Poor relationship with clinician
•   Untreated depression
•   Active substance abuse
•   NB, adherence threshold 95%
               Adherence to HAART
              Patients' and Doctors‟ Perspectives
    National survey (1999) : 1599 patients, 138 AIDS physicians

                                                    Patients     Doctors
                          Number of pills
               Number of daily intakes
                                  Pills size
                              Side-effects
    Need to take drugs while fasting
        Need to take drugs with food
          Need for long-life treatment
  Integration of ART in everyday life

AIDES, Fédération Nationale, Nov 1999          0   20      40              60               80 %
                                                                Raffi, F. 2nd International HIV/AIDS
                                                                Colloquium, Mexico, May 2000.
        Adherence to HAART
               Improving Adherence
• Rx when pt is ready
• Communicate with pt
    – Preferably in pt‟s own language
•   Rx depression
•   Rx substance abuse
•   Use OD or BID regimens
•   Aim for low pill numbers
    – esp. non-ART medications
    – esp. 1st few months of Rx
• Non-judgmental adherence support
                     PEP Talk
•   Important initiating events in HIV pathogenesis
•   Can PEP delay time to seroconversion
•   ?Avoid overuse
•   Access to experienced reference base
•   Adherence to PEP
•   Source patient‟s prior ARV exposure & PEP
•   Source patient and unknown status
•   Source patient with high VL
•   Recurrent use of PEP
•   PEP and the pregnant HCW
Occupational Transmission Risks
                       HBV

HBV is found in
  –   Saliva
  –   Nasopharyngeal washings
  –   Sweat
  –   Breast milk
  –   Semen
  –   Faeces
  –   Bile
  –   CSF
  –   Synovial fluid
  –   Blood
Occupational Transmission Risks
       HBV and HCV & Sharps Injury

                                Risk for
                    Risk for
                                Clinical
                   Infection
                                Hepatitis

Source HBe Ag+     37-62%       22-31%

Source HBe Ag–     23-37%        1-6%

Source HCV          1-7%
Occupational Transmission Risks
                  HIV

                  Estimated
                                 Range
                    Risk


Percutaneous        0.3%       (0.2-0.5%)


Mucous Membrane    0.09%      (0.006-0.05%)
Occupational Transmission Risks
          Factors Affecting HIV Transmission
General             •HIV prevalence
                    •Nature of HCW‟s practice
                    •Type & frequency of procedures
                    •Adherence to infection control guidelines
Exposure            •Route of exposure
                    •Size of device causing injury
                    •Extent of contamination (time)
                    •Type of contamination
                    •Depth/severity of exposure
Source              •Viraemia or viral load
                    •Stage of illness
                    •Circulating free virus
                    •ARV chemotherapy
                  HIV PEP
                     Rationale
• Follicular Dendritic Cells (FDCs)
  – Prolific in skin & mucous membranes
  – Defence against HIV
  – Disseminate HIV
• AZT
  – Increases number of FDCs in HIV+ persons
  – Decreases copies of HIV provirus
  – Blocks infectivity of FDCs infected with HIV


PEP may  prevent spread of HIV from FDCs
 to T-lymphocytes
                      HIV PEP
                          Efficacy
• Animal models
  – PEP efficacy
     •   Decreased by large viral inocula
     •   Decreased if PEP initiation delayed
     •   Decreased if PEP duration shortened
     •   Decreased if ARV dosage decreased
• Human studies
     •   AZT monotherapy  81% reduction in transmission
     •   AZT for MTCT  up to 67% reduction in transmission
     •   HAART for MTCT  > 98% reduction in transmission
     •   Heterosexual sexual transmission not evident for VL <
         1,500 c/ml1

                                                      Quinn et al, AIDS 2000
                     HIV PEP
                          Failure
• AZT monotherapy or combined with ddI
• Source patients treated with ARV prior to the
  incident
   – ARV resistance
• Viral factors
   – Large inoculum or high VL
• Delayed initiation, short duration, suboptimal
  ARV
   – Ideally initiate within 1-2 hours
   – No benefit after 72 hours
      • Probably no benefit after 36-48 hours
                          PEP
                     HBV and HCV
• HCW exposure
   – Hepatitis B immunoglobulin (HBIG)
   – And/or vaccine
• Perinatal exposure (HBeAg+ mother)
   – HBIG + vaccine
      • 80-95% effective in preventing transmission
• HBV vaccines safe in pregnancy
   – Non-infectious HBsAg particles
• HCV
   – No vaccines
   – Immunoglobulins of no value in PEP
     ARV PEP Considerations
                           HIV
•   Toxicity of ARVs
•   Drug interactions
•   Adherence
•   Medical Hx of exposed individual
•   Pregnancy & Breastfeeding
•   Written informed consent for PEP
•   Administered ASAP
    – 1st dose stat, then evaluation, counseling, etc
• PEP to be taken for 28 days
                              HIV PEP
                       Percutaneous Injuries


  Exposure                           Status of Source

                          Low Risk1        High Risk2              Unknown

  Not severe:
                                                                 Usually 0, ?2
  solid needle,             2 ARV3           3 ARV3
                                                                    ARV4
  superficial
  Severe: large
  bore, blood on                                                 Usually 0, ?2
                            3 ARV3           3 ARV3
  device, needle                                                    ARV4
  in pt artery/vein
1Asymptomatic/VL   < 1,500 c/ml       2Symptomatic/Aids/Seroconversion/High       VL
3Concern for resistance               4Consider   if high risk or HIV suspected
                               HIV PEP
        Mucous Membranes & Non-Intact* Skin


  Exposure                           Status of Source

                          Low Risk1            High Risk2          Unknown


  Small volume                                                   Usually 0, ?2
                       Consider 2 ARV            2 ARV
  (drops)                                                           ARV3

  Large volume
                                                                 Usually 0, ?2
  (major blood              2 ARV                3 ARV
                                                                    ARV3
  splash)

1Asymptomatic/VL    < 1,500 c/ml          2Symptomatic/Aids/Seroconversion/High   VL
3Consider if high risk or HIV suspected   *Dermatitis/abrasion/wound
  Selection of Drugs for PEP

• Basic two drug regimen
  – AZT + 3TC
  – d4T + 3TC
  – (d4T + ddI)
• Expanded three drug regimen
  –   Basic + LPV/r
  –   Basic + IDV
  –   Basic + NFV
  –   Basic + EFV`
                 ARV PEP
           Monitoring and Follow Up
• Bloods
  – Baseline, post two weeks
  – FBC, ALT, U&E/Cr
• HIV serostatus
  – Baseline, 6/52, 3/12, 6/12
     • ELISA
  – Place of molecular testing controversial
• Counseling and education
  – Side effects, interactions, adherence
  – Secondary transmission
HIV Infection In Children
         HIV Transmission

• Horizontally
  – Sexual contact
  – Mucous membranes, non-intact skin,
    bloodstream
• Vertically
  – MTCT
         HIV Transmission

• HIV-1 and HIV-2
  – Same routes
• Transmission rate for HIV-2 is much less than
  for HIV-1
  – HIV-2 MTCT < 10%
  – HIV-1 MTCT ± 30%
• STIs   risk of transmission
  – Disruption of membranes
  – Pooling of CD4+/macrophages locally   risk
  Approximate Risk of Acquiring HIV

Exposure                                 Approximate Risk

Vaginal Intercourse                           0.1%

Anal Intercourse                               1%

Percutaneous exposure (HCW)                   0.3%

Needle Sharing (IVDU)                          1%

MTCT                                         20-40%

Blood Transfusion (HIV-infected donor)        100%
                 MTCT

• During pregnancy
  – 25-30% in non-breast-feeding mothers


• During labour and delivery

• Via breast feeding
    MTCT Risk for Perinatal
       Transmission
– Plasma & genital tract VL
– Primary infection or late stage HIV
– Low CD4 count
– STIs
– Preterm delivery & prolonged rupture of
  membranes
– Placental disruption & invasive monitoring
– Vaginal delivery
– Lack of ARV
     HIV And Breastfeeding

• MTCT risk
  – 12% to 29%
• WHO/UNAIDS/UNICEF statement
  – in all populations, irrespective of HIV infection
    rates, breastfeeding should continue to be
    protected, promoted and supported; counseling for
    women who are aware of their HIV status should
    include the best available information on the
    benefits of breastfeeding, on the risk of HIV
    transmission through breastfeeding, and on the
    risks and possible advantages associated with
    other methods of infant feeding…
  Vertical Transmission Risks

• In established infection
   – 15%
• Infection acquired in breastfeeding period
   – 29%
• Breastfeeding for 2 years
   – 14%
• Breastfeeding for 6 months
   – 5%
  Vertical Transmission Risks
             Additional Risk Factors
• Mixed feeding
  – 26.1% vs 19.4% for exclusive breastfeeding or
    exclusive formula
• Recent infection
  – Perinatal infection
• Advanced infection
  – Low CD4+ count, high VL
• Mastitis, cracked nipples
• Infant oral thrush
Vertical Transmission Risks
        Exclusive Breastfeeding

  The provision of breastmilk only
 No other form of milk, water or food

     Oral antibiotics are allowed
     Oral vaccines are allowed
       HIV And Breastfeeding
                      Benefits
•   Provision of excellent nutrients
•   Easily digested
•   Fewer allergies
•   Protection against infectious diseases
    – esp., diarrhoea and pneumonia
• Infants infected at birth progress more slowly
  if breastfed
• Birth spacing
• Cost
    HIV And Breastfeeding
             Disadvantages

• Transmission of HIV
• Transmission of other infections
  – CMV
     Breast Milk Substitutes

Advantages
• No transmission of HIV
• No transmission of other infections
Disadvantages
•  incidence of diarrhoea and pneumonia
• Milk allergy and milk intolerance
• Malnutrition
• Loss of contraceptive benefit
Issues In Choosing Formula Feeding

• Risk of MTCT
• Access to clean water
• Financial implications
  – Electricity/fuel
  – Cost of formula
  – Cost of bottles/teats
  – Cost of sterilizing utensils
• Disclosure to family
  Cessation of Breastfeeding

• Stop breastfeeding at 6 months of age
  – Stop rapidly
• Nature of complementary foods
  –   High energy and protein
  –   High in micronutrients
  –   High in calcium
  –   In addition to replacement milk
• Counseling remains important throughout
• Provision of ongoing care for mother and
  infant
     Childhood HIV Infeciton

• Route of infection
  – Vertical transmission (95%)
     • Transplacental [in utero] (± 10%)
     • Peripartum [in utero or birth canal] (± 60%)
     • Breast-feeding (± 30%)
  – Sexual abuse
  – Blood product transfusion
     • Extremely rare because of excellent screening
  – Unexplained
     •   ? Mix-up in nursery
     •   Surrogate breast-feeding
     •   Nosocomial infection with contaminated equipment
     •   Occult sexual abuse
Proportion of Children Testing HIV+
 At A Sexual Abuse Clinic, Harare,
         Zimbabwe, 98-99

16%
14%
12%                                     Observed to
10%                                     seroconvert after
                                        abuse
 8%
                                        Tested HIV + on arrival
 6%
 4%
 2%
 0%
      0-4     5-8      9-12     13-16
            Age Group (Years)               Family Support Trust, Zimbabwe, 1999
    Perinatally Acquired HIV

• Developed World
  – 10 – 20% progress to AIDS in < 1 year
  – 50% may reach 10 years with no ARV
• Resource poor settings
  – 80% mortality by 2 years
• Developing World
  – If symptomatic in 1st year of life
     • Survival generally  3 years
Dx of HIV Infection in Children

• HIV DNA PCR = test of choice
• Most diagnosed by 1/12
• 40% can be dx by 48 hours
  – Esp for in utero infection
  – NB, never use cord blood
• 93% Dx by 2/52
  – In absence of breast-feeding
• Positive PCR – repeat @ next visit
• Negative PCR @ 1/12 – repeat @ 3–4/12
Dx of HIV Infection in Children

Antibody testing
  – 50% will be ELISA negative by 9/12
  – Can do serial Ab testing from 6/12
     • Every 3/12
  – Outer limit of persistence of Abs
     • 18/12 = CDC recommendation
     • 15/12 = supported by South African data
                   Classification
                          Immunological
                                          Age of Child
                             < 12                 1–5               6 – 12
                            Months                Years             Years
 Immunological Category    CD4+      CD4+      CD4+      CD4+      CD4+    CD4+
                             /l      (%)        /l      (%)       /l     (%)

1.   No
     Immunosuppression      1,500     25      1,500     25      500     25


2.   Moderate              750 –               500 –               200 –
                                     15 - 24             15 - 24           15 - 24
     Immunosuppression     1,499                999                 499
3.   Severe
     Immunosuppression     < 750      < 15     < 500      < 15     < 200    < 15
HIV Infection In The Newborn

• Majority of infections occur perinatally
• No increase in neonatal sepsis
•  incidence of congenital TB
  – Non-resolving pneumonia
• Unexplained thrombocytopaenia
  – In both HIV- and HIV+ neonates
  – Rx with IVI immunoglobulins
     Common Presentations
              Early – first 2 years
• Oral candida
  – Recurrent, more severe
• Severe pneumonitis or pneumonia
  – PCP common at ages 3 to 9 months
• Chronic/recurrent diarrhoea
• Protein energy malnutrition
  – Marasmus > Kwashiorkor
• Developmental delay
• Unexplained encephalopathy
  – With UMNL signs
       Common Presentations
                            Any Age
• Invasive bacterial disease
    – Bacteraemic pneumonia, meningitis, septic arthritis, osteitis
        • S pneumoniae > H influenzae > S aureus
• CSOM, mastoiditis, recurrent sinisitus
• Zoster
• Severe HSV stomatitis
• Tuberculosis
• Generalized lymphadenopathy +
  hepatosplenomegaly
• Severe dermatitis
• Unexplained CMO
• Rectovaginal or –vesical fistulae
      Common Presentations
                  Older Children

•   Lymphoid interstitial pneumonitis
•   Parotomegaly & parotitis
•   Digital clubbing
•   Bronchiectasis
•   Non-infective polyarthritis
    – Often with psoriasis
                Management

• „Road to Health‟ card is important
    – Length often < 3rd centile in HIV+ children
    – Head circumferences often low in infants with
      encephalopathy
•   Check all growth parameters
•   Enquire after parents, siblings
•   Check for TB contacts
•   Check immunization status
•   Check perinatal data
    – Mother‟s RPR/TPHA status
• Thorough and regular physical examintation
             Management
                    Baseline

• CXR
  – Majority of HIV children develop chronic
    lung disease
• FBC & CD4+ count and percentage
• HIV RNA
  – Not critical – defer until therapy if no funds
                  Management
                  HIV-Exposed Infants
• PCP prophylaxis
  – CTX from 6/52 of age
       • All infants exposed to HIV, until proven negative
• Multivitamins
  – To include vitamin A
• Immunizations
  –   Give all routine childhood vaccines
  –   Except in stage 3 disease – withhold measles
  –   Annual influenza vaccination
  –   Chickenpox vaccination after 1 year of age
       • To all with mild disease
           ART In Children

• South African guidelines - Rx
  – All category B
  – Asymptomatic if CD4+ percentage < 20%
  – Any child with category C or stage III
• Consider Rx
  – Clinical category B, CD4+ percentage < 20%, high
    VL
• Possibly Rx
  – Asymptomatic with CD4+ percentage > 20% BUT
    consistently declining percentage
  – Infants < 12 months of age
          ART In Children

• WHO criteria for Rx
      For resource poor settings
  – Stage III disease
  – Stage I & II disease
    • < 18 months
       – If CD4+ percentage < 20%
    • > 18 months
       – If CD4+ percentage < 15%
          ART In Children
                  Dosages

• According to surface area (SA) for some
  – AZT, ddI and NVP


• The child will gain weight
  – Review/increase dose at each visit


                     weight (kg)  height(cm)
              SA 
                                                60
                 ART In Children
                             Regimens

                    2X    NRTI + 1   PI
First Choice
                    OR 2X    NRTI + 1X    NNRTI

NB: EFV only if > 3 years of age


Second Choice: 3 NRTIs


Third Choice: 2 NRTIs
            ART In Children
           When To Change Therapy
• Progressive neurological,
  neurodevelopmental or clinical deterioration
• Change in immunological classification
  – Progressive decline in CD4+ percentage or
    absolute number
• Inadequate virological suppression by 12
  weeks on therapy
  – < 10 fold decrease for triple therapy
• Detectable HIV RNA by 4 to 6 months
• > 0.5 log10 increase in HIV RNA above nadir
        Treating HIV




       Like acquiring HIV,
TREATING it can also be hit and miss,
       CHOOSE WISELY

				
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