Antiretroviral Therapy in Special Situations

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Antiretroviral Therapy in Special Situations

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Tuberculosis
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TB in Patients with HIV Infection

• HIV-infected patients markedly increased risk for
  TB
• TB acts accelerate course of HIV infection

• Clinical presentations more common
• Mycobacteremia, extrapulmonary TB
• Abdominal TB visceral lesion intraabdominal LN
• Intracerebral mass

N Engl J Med 1999340367-73.
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TB in Patients with HIV Infection

• CXR findings depends on degree of
  immunosuppression
• Higher prevalence of drug and multidrug-resistant
  TB
• I 10.9 vs 3.5
• R 9.4 vs 2.9
• IR 5.2 vs 0.4

Tuberculin test and treatment of latent infection
not routinely recommended in Thailand
Int J Tuberc Lung Dis 20004537-43.
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Treatment

• Same principles as non-HIV
• DOTS
• Drug interactions
• NNRTIs and PIs metabolized by CYP450

• No current use of NNRTIs or PIs
• 2 IRZE (or S) 4-7 IR (AI)
• Extended Rx cavitation, slow/suboptimal response
  (positive c/s at 2 mos of Rx)

Am J Respir Crit Care Med 2003167603-62.
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Treatment

• Rifampicin induced CYP450
• Rifampicin should not be administered with PIs or
  NNRTIs except
• 2 NRTIs efavirenz (EFV) dose? (nevirapine?)
• 2 NRTIs ritonavir (RTV) (600 mg bid)
• 2 NRTIs saquinavir (SQV) (400 mg bid) RTV
  (400 mg bid)
• 2 NRTIs lopinavir (400 mg bid) RTV (400 mg
  bid)
• 2 ISZE 7 ISZ (BII)
• If S is not used for 9 mos E should be used and
  prolonged to 12 mos

MMWR 200049173-200. MMWR 200449
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Nevirapine (NVP) vs Rifampicin

• J Acquir Immune Defic Syndr 200128450-3.
• Median AUC012h of NVP before and after
  rifampicin 56.2 and 32.8 µg/ml/hr (p .04)
• 31 reduction in serum NVP concentrations
• Cmax decreased from 5.6 to 4.5 µg/ml (p .04)
  (36 reduction)
• 21 decrease in the Cmin not statistically
  significant
• AIDS 200317637-8.
• 32 patients cured of TB
• VL decreased from 4.4 to lt 2.3 (4.1) log, with
  74 of patients reaching undetectable VL
• CD4 cell count increased from 121 to 284 (116)
  cells/mm3

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When to start ART?

• Problems
• Overlapping toxicity profiles
• High incidence of side effects
• Drug interactions
• Non-adherence
• Paradoxical reaction
• Delaying ART ? HIV- related comorbidity and death
• HAART should delay at least 1-2 mo(s) unless
  specific conditions
• Life threatening OIs, CD4 lt 100/mm3

Am J Respir Crit Care Med 2003167603-62. AIDS
20021675-83.
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Paradoxical Reaction

• Up to 36 (after ART) vs 7 (no ART)
• Weeks-months (1-3 months)
• Inflammation from immune response to
  mycobacterial antigen

• Transients enlargement of pre-existing lesions,
  or development of newly foci
• Fever, worsening pulmonary infiltrates,
  adenopathy, and expanding CNS mass lesion

Int J Tuberc Lung Dis 20015370-5.
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Paradoxical Reaction

• Differential diagnosis
• Treatment failure
• Anti-TB side effects
• Other OIs or malignancy

• Self-limited, generally 10-40 days
• Anti-TB and ART need not be changed/stopped
• Prednisolone in severe reaction high fever,
  airway obstruction, ? serosal fluid collections,
  and expanding CNS lesions

Int J Tuberc Lung Dis 20015370-5.
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WHO July 2002
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Pregnancy
Recommendations for Use of Antiretroviral Drugs
in Pregnant HIV-1-Infected Women for Maternal
Health and Interventions to Reduce Perinatal
HIV-1 Transmission in the United State. November
10, 2003 www.AIDSinfo.nih.gov
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Perinatal HIV Transmission

• Without ARV during pregnancy, mother-to-child
  transmission has ranged from 1625 in North
  America and Europe
• With the change in practice, transmission was 11
  in 1995
• Today, risk of perinatal transmission can be
• lt 2 with
• Effective ART
• Elective cesarean section as appropriate
• Formula feeding

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Preconception Counseling/Care for HIV Infected
Women of Childbearing Age

• Goal optimal maternal health for pregnancy
  stable, maximally suppressed VL
• Counseling for all women of childbearing age as a
  part of primary care
• Effective contraception, if wanted, to reduce
  unintended pregnancy
• Counsel about perinatal transmission risks,
  prevention strategies, potential effects of HIV
  treatment on pregnancy and infant
• Screen for and treat infectious diseases, STDs

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Preconception Care (cond)

• Begin or modify ARV therapy
• Avoid ARV medications with toxicities to
  developing fetus
• Choose those that reduce the risk of transmission
• Evaluate/control for therapy-associated side
  effects
• Evaluate and prophylaxis for OIs, give
  immunizations as needed
• Identify risk factors for adverse maternal or
  fetal outcome
• Screen for maternal psychological and substance
  abuse disorders

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Risks of HIV Transmission

• Maternal Factors
• Viral load
• Low CD4
• Other infections, HCV, CMV, bacterial vaginosis
• IVDU
• Lack of AZT during pregnancy
• Obstetrical Factors
• Length of ruptured membranes/chorioamnionitis
• Vaginal delivery
• Invasive procedures
• Infant Factors
• Prematurity

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N Engl J Med 20023461879-91.
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Antepartum Care

• History symptoms, duration of HIV infection
• Physical examination
• Laboratory testing
• Counseling
• Effect of pregnancy on HIV
• Effect of HIV on pregnancy
• Perinatal transmission
• ART
• Mode of delivery

N Engl J Med 20023461879-91.
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• No effect of pregnancy on the progression of HIV
• Not ? frequency of prematurity, LBW, IUGR, or
  birth defects associated with HIV except advanced
  HIV in developing world
• ART may ? rate of preterm birth and drugs adverse
  effects
• Rate of transmission 25-75 without ART vs lt
  2-9 with ART

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Intrapartum Care

• ART
• AZT alone or combination with others
• Continuation of other antiretroviral drugs
• Obstetrical management
• Avoidance of invasive monitoring
• Use of instrument to assist delivery
• Prolonged interval between rupture of membranes
  and delivery

N Engl J Med 20023461879-91.
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Postpartum Care

• Routine postpartum care
• Woman
• Antiretroviral therapy
• Psychological support
• No breast feeding
• Contraception
• Infant
• AZT for 6 wk
• Initiation of PCP prophylaxis
• Determination HIV-infection status

N Engl J Med 20023461879-91.
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d4T ddI, AZT d4T, EFV not recommended !!!
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Mitochondrial Toxicity

• Nucleoside analogs induce mitochondrial
  dysfunction conflicting data on mitochondrial
  toxicity in infants exposed to ARVs
• Lactic acidosis/hepatic steatosis
• Pregnant women with HIV infection on nucleoside
  analogues should have liver enzymes and
  electrolytes monitored frequently in 3rd
  trimester
• d4T ddI combination should be avoided during
  pregnancy

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Nevirapine Rash and Hepatotoxicity

• Risk of NVP-associated hepatotoxicity and rash is
  higher in women particularly if CD4 gt 250
  cells/mm3
• Pregnant women who take NVP should have frequent
  measures of transaminase levels, especially in
  the first 18 weeks of treatment
• Use with caution in ARV-naïve pregnant women who
  are starting ART

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SCENARIO 1 women who have not received prior ART

• Standard clinical, immunologic, and virologic
  evaluation
• Same recommendations for initiation and choice of
  therapy HAART
• Dual nucleoside analog therapy
• AZT monotherapy VL lt 1000 cps/mL
• Three-part AZT initiated after the 1st trimester

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SCENARIO 1 women who have not received prior ART

• Antepartum
• AZT 300 mg bid at GA 14-34 wks and
• continued throughout pregnancy
• Intrapartum
• AZT 300 mg q3h during labor
• Postpartum
• AZT syrup 2mg/kg for newborn
• 6 wks
• 1 wks if mother got AZT gt 4 wks
• 4 wks if mother got AZT lt 4 wks

Modified from MoPH Guideline 2002. N Engl J Med
19943311173-80. (PACTG 076)
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SCENARIO 2 women receiving ART during current
pregnancy

• If pregnancy is identified after the 1st
  trimester, ART should continue and AZT should be
  a component of regimen
• If pregnancy is recognized during the 1st
  trimester
• Woman should be counseled regarding risks and
  benefits
• Continuation of therapy should be considered.
• If therapy is discontinued, all drugs should be
  stopped and reintroduced simultaneously
• AZT during intrapartum period

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SCENARIO 3 women in labor who had no prior ART

• Several regimens
• Intrapartum AZT followed by 6 wks of AZT for
  newborn
• AZT and 3TC during labor, followed by a wk of
  AZT-3TC for newborn
• Single dose NVP at onset of labor followed by
  single dose of NVP for newborn at 48 hrs
• AZT during labor and single dose NVP at onset of
  labor
• Postpartum period assessments (CD4 VL)

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SCENARIO 4 infants who have received no any ART

• 6 wks of AZT for newborn
• Postpartum period assessments (CD4 VL)

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• Cesarean Section to Reduce Perinatal HIV
  Transmission

• Scheduled C/S reduce perinatal transmission for
  pregnant women with VL gt1000 /mL
• Unknown whether scheduled C/S offers any benefit
  to women on HAART with low or undetectable VL
• Complications of C/S similar to HIV uninfected
  women
• Patients decision should be respected and
  honored
• No known benefit of C/S if labor has begun

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Mode of Delivery

• Scenario A presenting in late pregnancy (GA gt 36
  wks), no ART, unknown CD4VL
• Start ART
• Scheduled cesarean section at 38-39 wks

• Scenario B HAART early in the 3rd trimester, but
  VL gt 1000 cps/mL at 36 wks
• Scheduled cesarean section at 38-39 wks after
  discussion

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Mode of Delivery

• Scenario C HAART early in the 3rd trimester, but
  VL lt 1000 cps/mL at 36 wks
• Preferred vaginal delivery

• Scenario D elected scheduled cesarean section
  but present in early labor or rupture of
  membranes
• Start AZT immediately
• Vaginal delivery
• If cervical dilatation is minimal and long period
  of labor is anticipated, may proceed cesarean
  section

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Real Situation in Thailand

• No VL (CD4)
• AZT monotherapy
• At GA gt 14 wks
• During labor
• For newborn 1-6 wk(s)
• GPO-VIR
• NVP single dose other drug (s)
• Vaginal delivery

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Hepatitis B and C Co-Infection
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HBV/HIV Co-Infection

• 80 of HIV-infected patients have serological
  markers of present/past infection.
• HBsAg ve 8-11
• Goals of treatment
• Suppression of HBV replication
• Anti-HBe seroconversion
• Anti-HBsAg seroconversion
• Treatment within clinical trials and in health
  care centers with experience

Clin Infect Dis 2003371678-85.
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HBV/HIV Co-Infection

• Effect of HBV on HIV
• ? HIV replication
• ? CD4
• ? HAART-related hepatotoxicity
• Accelerates the HIV progression?
• Effect of HIV on HBV
• ? HBV replication
• ? hepatitis flares
• ? progression to cirrhosis
• ? anti-HBe and anti-HBs seroconversion
• ? efficacy of treatment
• ? response to IFN and ? 3TC resistance

Clin Infect Dis 2003371678-85.
39
HBV/HIV Co-Infection Assessment

• History IVDU, alcohol, immunization, past
  history of liver disease, family history
  (hepatitis, HCC)
• Clinical examination for evidence of chronic
  liver diseases
• Investigations
• LFT
• HBsAg, anti-HBs
• Anti-HBc, HBeAg, HBV DNA
• Liver biopsy
• Other co-infections HCV, HDV

BHIVA Guidelines HIV and chronic hepatitis.
www.bhiva.org
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HBV/HIV Co-Infection Treatment

• Indications
• HBsAg ve gt 6 mo, active HBV replication (HBeAg,
  HBV RNA gt 105 cps/ml), ALT gt 2x, liver pathology,
  CD4 gt 350-500/mm3

• Treatment only HBV
• IFN-a (pegylated forms) 5 mIU/d or 10 mIU sc
  3x/wk
• Adeforvir monotherapy

• Treatment of HIV
• HAART containing lamivudine, emtricitabine,
  and/or tenoforvir

Vaccination HCWs, HIV/HCV co-infection, multiple
partners (BII)
Clin Infect Dis 2003371678-85. BHIVA
Guidelines HIV and chronic hepatitis.
www.bhiva.org
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Negative
3TC lamivudine TDF tenofovir disoproxil
fumarate CHB chronic hepatitis B
Modified from Clin Infect Dis 2003371678-85. and
Thai Guideline 2003, GAT
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3TC lamivudine TDF tenofovir disoproxil
fumarate CHB chronic hepatitis B
Modified from Clin Infect Dis 2003371678-85. and
Thai Guideline 2003, GAT
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HCV/HIV Co-Infection

• Global prevalence 40
• IVDUs, hemophilics
• Goals of treatment
• Eradication/sustained virological response
• ? progression of fibrosis
• ? extrahepatic manifestations
• ? risk of transmission
• Prevention of clinical outcomes ESLD, HCC, and
  death
• Treatment within clinical trials and in health
  care centers with experience

AIDS 200216813-28.
44
HCV/HIV Co-Infection

• Effect of HCV on HIV
• ? HAART-related hepatotoxicity
• Accelerates the HIV progression?

• Effect of HIV on HCV
• Higher HCV viral load
• Greater severity
• May enhance sexual and vertical transmission of
  HCV
• More rapidly progression to cirrhosis (alcoholic,
  lower CD4)

Science and treatment of HIV and hepatitis C
virus coinfection. www.hivinsite.ucsf.edu
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HCV/HIV Co-Infection Assessment

• History IVDU, alcohol, psychiatric illness,
  previous test for HCV
• Clinical examination for evidence of chronic
  liver diseases
• Investigations
• LFT
• Anti HCV, HCV RNA
• HCV genotype
• Abdominal ultrasonography
• Liver biopsy except genotype 2/3, clinical
  cirrhosis

BHIVA Guidelines HIV and chronic hepatitis.
www.bhiva.org
46
HCV/HIV Co-Infection Treatment

• When to start ALT gt 1.5x gt 6 mos, cirrhosis,
  detectable HCV RNA, CD4 gt 500/mm3 ?
• IFN-a (pegylated forms) ribavirin

• Drug interactions AZT, d4T, and ddI
• Side effects
• IFN neutropenia, thrombocytopenia, fatigue,
  depression, flu-like symptoms, alopecia
• Ribavirin hemolysis
• Contraindication pregnancy, cardiovascular
  diseases, renal failure, thalassemia

AIDS 200216813-28.
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Modified from AIDS 200216813-28. and Thai
Guideline 2003, GAT
48

• Genotype 1, 4/5 preg-IFN2a 180 mg/wk ribavirin
  1-1.2 g/d 48 wks
• Genotype 2/3 preg-IFN2a 180 mg/wk ribavirin
  800 mg/d 24 wks
• Preg-IFN2b 1.5 mg//kg/wk ribavirin gt 10.6 mg/d
  (lt65 kg-800 mg/d, 65-85 kg-1 g/d)