welcome to i-tech hiv/aids clinical seminar series january 8, 2009 antiretroviral treatment of hiv-1...
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Welcome to I-TECH HIV/AIDS Clinical Seminar Series
January 8, 2009Antiretroviral Treatment of HIV-1 Infected Children
Lisa Frenkel, MD
Antiretroviral Treatment of HIV-1 Infected Children
Lisa M. Frenkel, MDProfessor of Pediatrics and Laboratory MedicineUniversity of Washington and Seattle Children's Hospital
email: [email protected]
• Case 1: A woman brings her 7 month old infant “baby girl” to clinic because the baby is breathing rapidly.
During pregnancy the mother was followed in your clinic and her HIV EIA was (-) at 28 weeks gestation. She has been breastfeeding her child.
“Baby girl” has had routine immunizations. She does not have rhinorrhea, vomiting or diarrhea. She does not have a fever, rales, rhochi or wheezes, but her respiratory rate is 78 breathes/minute.
• What is the differential diagnosis?
• What tests do you recommend?
• What empiric treatment do you provide?
• Case 1: 7 month old “baby girl” with no fever, rales, rhochi or wheezes.
Respiratory rate is 68 breaths/minute.
• What is the differential diagnosis?• Pneumocyctis pneumonia
• Acute bronchospasm
• Acidosis
• What tests do you recommend?• HIV-1 rapid serology of mother
• HIV-1 DNA, RNA or p24Ag of baby
• Chest x-ray
• Sputum for Pneumocystis jirovecii•direct immunofluorescence assay (DFA)
•PCR
• What empiric treatment do you provide?• Co-trimoxazole
• Dapsone
• Atovaquone
• Maternal blood cells and HIV do not cross a healthy placenta, but the mother’s antibodies cross
– Maternal HIV antibodies persist in infant for 18 months
– HIV EIA (+) even when uninfected
• Definitive diagnosis
– Polymerase chain reaction (PCR) amplification of HIV DNA or RNA
– Core HIV protein (p24Ag)
• Presumptive diagnosis
– Maternal antibodies & an ill infant
• Teaching Point -- Case 1: “baby girl” with pneumocystis pneumonia (AIDS) infected by mother with acute, asymtomic HIV infection
• HIV-1 infection of women in late gestation or during breastfeeding frequently is transmitted to their infants either in utero or via breast milk
• Communities with a high incidence HIV-1 should repeat HIV testing in late gestation
• Women not tested during gestation should receive rapid HIV testing in labor
• Interventions can decrease mother-to-child-transmission:• Antiretroviral prophylaxis of fetus in utero and infant after birth
• Elective Cesarean
• Exclusive breastfeeding
• Artificial feeding
• HIV PCR or p24Ag are needed for accurate early diagnosis, however, when unavailable empiric treatment should be based on clinical
diagnosis
Access to HIV-1 Testing during
Gestation and to Antiretrovirals to
Reduce Mother-to-Child-Transmission
Varies but is Improving
Acess to Antiretrovirals to Reduce Mother-to-Child-Transmission Varies but is Improving
• Women do not access prenatal care
• HIV testing not offered as part of routine obstetrical care
• Insufficient time for testing, CD4 counts and initiation of antiretrovirals
• Stigma associated with HIV testing and interventions, ART and artificial infant feeding
MAJOR ISSUE:Multiple impediments to HIV-1 testing during
gestation and to antiretrovirals to reduce mother-to-child-transmission in resource-poor communities
• Teaching Point -- Case 1: “Baby girl” with pneumocystis pneumonia (AIDS), infected by mother with acute, asymtomic HIV infection
• Pneumocystis pneumonia is common in HIV infected infants not
receiving prophylaxis• Pneumocystis jirovecii
• an ubiquitous fungus
• infects most infants - immunocompromised become ill
• slow growing - prophylaxis is effective when begun at 4 - 6 weeks of age
• HIV infected infants should receive prophylaxis until 5 years old, or CD4 counts above threshold for safely stopping prophylaxis
• DFA and PCR on induced sputa are very sensitive, however, when unavailable empiric treatment should be based on clinical diagnosis
• Co-trimoxazole is the most effective prophylaxis and treatment
• Corticosteroids may improve outcome of severe cases
• Case 2: •
A HIV infected woman brings her 7 day old infant “baby boy” to clinic. He appears healthy, and is breastfeeding well.
• You check the baby’s HIV DNA/RNA test from the day of birth.
• His “birth” HIV DNA/RNA is (-).
The mother asks you for advice to keep “baby boy” free of HIV infection.
• What do you recommend?
• HIV infection in infants between 0-24 months after randomized to nevirapine vs. nevirapine/zidovudine vs. placebo
• for 14 weeks after birth• NI Kumwenda et al. NEJM 2008; 359 : 119-29.
•
• Case 1 and 2 -- continued:
The mother chose daily nevirapine prophylaxis for her “baby boy”. He is clinically well, however a HIV DNA PCR is (+) when he is 2.5 months old.
The “baby girl” you treated for pneumocystis improves with a 3 week course of co-trimoxazole.
Both the “baby boy” and the “baby girl” are in your clinic today. The boy is now 3 and girl 10 months old.
• What do you recommend?
Clinical course of HIV infection in children can be “rapid” or “slow”
Inci
den
ce A
IDS
Years since HIV-1 infection
0 10 15
Children, mean 4.7 years
5
D Dunn et al. J Infect Dis 2008:197:398–404
1. Presumptive diagnosis - when PCR unavailable- Seropositive + severe symptoms
- oral thrush- severe pneumonia- severe sepsis
- Severe maternal disease (%CD4<20), AIDS or death
2. At time of infant diagnosis by HIV PCR or p24Ag (+)- ~40% HIV-1 infants die in first 1 years of life (Dabis, AIDS 2001;15:771; Fassinou,
AIDS 2004;18:1905; Newell, Lancet 2004;364:1236; Brahmbhatt JAIDS 2006;41:504)
- ART successful and non-toxic (Luzuriaga, NEJM 2004;350:2471)
- If start ART early, should ART be stopped later when CD4 normal?
3. Clinical symptoms - Stages 3 and 4, and 1 and 2 if low CD4
4. Immunologic status - Low CD4 for age
5. Family/Caregiver “ready”- Understand life-long therapy- Able to adhere to prescribed regimen - gastrostomy tubes- Can store and administer liquids - Teach child to swallow pills
When to start ART in Infants/Children - WHO focus
1. Asymptomatic or persistent generalized lymphadenopathy
2. Mild clinical symptoms- Persistent hepato-splenomegally- Papular pruritic eruptions- Fungal infections- Cheilitis - Linear gingival erythema- Extensive papilomas or molluscum- Herpes zoster- Recurrent upper respiratory tract infections
3. Moderate clinical symptoms - Malnutrition- Persistent diarrhea or recurrent fever- Thrush or leukoplakia- Lymph node or pulmonary TB, - Recurrent bacterial pneumonias- Lymphocytic interstitial pneumonitis- Necrotizing gingivitis
When to start ART - WHO Clinical Stages 1-4
4. Severe clinical symptoms- Severe wasting - stunted growth- Pneumocystis pneumonia- Recurrent severe bacterial infections- Chronic HSV >1 month- Extrapulmonary TB- Esophageal candidiasis- Kaposi sarcoma- CMV retinitis, colitis- CNS Toxoplasmosis- Extrapulmonary cryptococcosis- HIV encephalopathy- Disseminated mycosis- Disseminated non-TB mycobacteria- Chronic cryptosporidiosis- Chronic Isospora- Cerebral or B cell non-Hodgkin lymphoma- Progressive multifocal leukoencephalopathy- Symptomatic nephropathy- Symptomatic cardiomyopathy
When to start ART - WHO Clinical Stages 1-4
1. Asymptomatic children - CD4 tests on 2 occasions if sole basis for ART
2. Immunologic status qualifying for ART without symptoms vary by age
- CD4% or absolute CD4 cells- <12mo: <25% or <1500/uL- 12-36mo: <20% or <750/uL- 3-5yo: <15% or <350/uL- >5: <15% or <200/uL
- Total lymphocyte count (TLC)- <12mo: <4000/uL- 12-36mo: <3000/uL- 3-5yo: <2500/uL- 5-8yo: <2000/uL
When to start ART - WHO Immune Parameters
A trial of early ART:Children with HIV Early Anti-retroviral
Therapy: CHER
A. Violari, et al. Antiretroviral therapy and mortality among HIV-infected infants. NEJM 2008; 359: 2233-2244
Inci
den
ce
AID
S
Years since in utero/peripartum HIV-1 infection
0 10 15
Infants
5
1. HIV-1 infected South African infants 6-12 weeks old- HIV-1 DNA PCR used diagnosed infection- 6-12 week old CD4% >25% randomized to immediate or delayed ART:
- antiretroviral therapy (ART) when the CD4% dropped below 20%- immediate ART with a planned interruption at 1 year of age- immediate ART with a planned interruption at 2 years of age
- ART – Lopinavir/r + zidovudine+ lamivudine
2. Participants characteristics- Perinatal chemoprophylaxis:
- 62% nevirapine- 20% nevirapine + zidovudine- 2% three antiretrovirals- 11% no antiretrovirals
- Started ART at median 7.4 weeks old, CD4 35%- Deaths: 20 infants (16%) vs. 10 (4%) after 32 weeks in study- 76% lower death risk (hazard ratio 0.24, 95% CI 0.11 to 0.52, P = 0.002)
A. Violari, et al. Antiretroviral therapy and mortality among HIV-infected infants. NEJM 2008; 359: 2233-2244
Randomized Trial - When to Start ART in Infants - CHER
CHER Results: Death or CDC stage C or severe B event in infants randomized to early or deferred ART
A. Violari, et al. Antiretroviral therapy and mortality among HIV-infected infants. NEJM 2008; 359: 2233-2244
What antiretroviral therapy (ART) should be used for “baby boy” and “baby girl” in your clinic?
• “ART” composed of 2 nucleosides + either a NNRTI (nevirapine or efavirenz) or a protease inhibitor?
• Nevirapine is utilized for ART worldwide – due to low cost
• Protease inhibitors less available
• If use ART that “fails” select for resistant nucleoside
• Accumulation of nucleoside mutations diminishes efficacy of ALL ART regimens
• What ART do you prescribe?
Efficacy ART (ZDV+3TC+NVP) in Infants Previously Given single-dose Nevirapine (Mashi Trial)
Lockman et al. N Engl J Med 2007;356:135
Infected infants starting ART:
N= 15 sdNVPN= 15 placebo
- CD4<25% or - symptoms, - 2-33 months old (median 8.4)
Difference in Failure Rate: P< 0.001
Efficacy ART (ZDV+3TC+NVP) in Women Previously Given single-dose Nevirapine (Mashi Trial)
Lockman et al. N Engl J Med 2007;356:135
Infected infants starting ART - CD4<25% or - symptoms, - 2-33 (median 8.4 mo)
N= 15 sdNVPN= 15 placeboP< 0.001
Dynamics of NVP resistant HIV-1
Frequency and decay of NVP resistant by timing of HIV-1 infection:
0
20
40
60
80
100
120
0 2 4 6 8 10 12 14
% Mu
tant
14
1
7
12
9
11
13
2
C. Peripartum Infection
0
20
40
60
80
100
120
0 2 4 6 8 10 12 14
% Mu
tant
24
29
32
B. In Utero “Acute” Infection
0
20
40
60
80
100
120
0 2 4 6 8 10 12 14
% Mu
tant
7
10
3
11
1
6
13
9
15
17
16
18
21
A. In Utero “Established” Infection
Infants’ Age (months)
# NVP-resistant / total # infants
N= 20/23 (87%) N= 3/9 (33%) N= 8/21 (38%)(7 missing specimens >6 weeks of age)
What antiretroviral therapy (ART) should be used for “baby boy” and “baby girl” in your clinic?
Remembering --
• If use ART that “fails” select for resistant nucleoside
• Accumulation of nucleoside mutations diminishes efficacy of ALL ART regimens
• CHOOSE ART based on drug-resistance test or history of nevirapine
• Nevirapine-ART for “baby girl”
• Protease Inhibitor-ART for “boy”
• Teaching Point --
Case 1: 8 month old “baby girl” with AIDS Case 2: 3 month old “baby boy” with asymptomatic HIV and history of
prolonged exposure to nevirapine
1. World Health Organization (WHO): - Initiate and modify ART based on clinical disease or CD4 failure
- If ART failure in question, plasma HIV-1 RNA >10,000 copies/mL
2. USA Department of Health and Human Services (DHHS)
HIV Treatment Guidelines: - Maintain plasma HIV RNA <50 c/mL
- Comparison of two cohorts: - NNRTI-ART: 3-month delay until treatment modification
- Death HR= 1.23 (95% CI 1.08, 1.40); P = 0.002 - Immune failure HR= 1.21 (95% CI 1.07, 1.36) P = 0.002
- PI-ART: 3-month delay until treatment modification - Death HR= 0.93 (95% CI 0.87, 0.99) P = 0.03 - Immune failure HR= 1.21 = 0.98 (95% CI 0.94, 1.03) P = 0.45
Peterson et al. AIDS 2008;22:2097-2106
Two Approaches to Management of ART
When should ART be started in children 1-5 years old?And, in adults? Not a clear answer………observational studies suggest….
Phillips AN et al. When should ART for HIV be started? Brit Med J 2007;334:76.
Egger M et al. Prognosis of HIV-1 infected patients starting HAART: a collaborative analysis of prospective studies. Lancet 2002;360:119.
Decreased rate of AIDS when starting ART with higher CD4 cells in cohort study
But, is it better to initiate ART earlier?
Concerns with starting ART early:- Costly (# person/years ART)
- Adherence suboptimal due to:– Toxicities –mild (e.g. head aches); severe (e.g. cardiac)– Psychologic obstacles:
– Recognizes diseased state– Lack of disclosure – inconvenient to take medicine
- Exhaustion of treatment options – due to drug-resistance
Problems with starting ART late:- May be ineffective – higher death rates in the first months of treatment (IRIS?)
- Toxicities may be greater ART started when HIV-1 disease is more advanced
Now many ARV options. Also, more effective and better tolerated ART.
Primary Question:
Are the benefits of ART in children and adults greater if started at CD4 >350, 200-350 or >200 c/uL?
- Goal to assess whether patients will enroll into a randomized study assessing when to start therapy
- Concerned that biases of patients and health care about when to start ART may compromise a study
- Communities currently starting ART at <200 cells/uL are best suited to evaluate “when to start ART”
The multiple new ARV and multiple ongoing trials comparing these, will allow more ART regimens to sequence over a lifetime…………..
Pilot study ongoing by INSIGHT Network
Case 3: A 6 year old HIV infected boy has developed spastic paraparesis, thrush, and lost 10 kg over the past few months . His father and mother have AIDS and active tuberculosis (growing in culture, susceptibility testing incomplete). On a chest x-ray your patient has bilateral pulmonary disease, and his sputum has acid-fast bacilli.
• You initiate:• Isoniazid• Rifampicin • Pyrazinamide• Ethambutol• Pyridoxine
• Do you start ART?
• Would you start ART with pneumocystis or cryptococcal infections?
IRIS - immune reconstitution inflammatory syndrome:- Recovery of immune reactivity can result in symptoms - worsening or unmasking of M. tuberculosis
- increased mortality from Cryptococcus- zoster- worsening vision with CMV retinitis- worsening of multifocal leukoencephalopathy
- Corticosteroids may diminish symptoms
Adjusting for co-administration with rifampicin:
- Nevirapine (and efavirenz) concentrations decreased- Virologic suppression of EFV-ART unaffected, NVP-ART inferior
Boulle et al. JAMA 2008;300: 530-9- Kaletra (LPV/rt (4:1)), when modified to LPV/rt (1:1)
- AUC ~50% less with rifampicin- Cmin similar with and without rifampicin
Ren et al. JAIDS 2008;47:566-9- - Rifabutin does not induce cytochrome P-450, thus, preferred, but costly
ART is often not initiated during acute opportunistic infections (OI) due to concern for: 1)immune reconstitution inflammatory syndrome (IRIS) 2)drug interactions
Study design to assess time to start ART when treating OI: - ART given within 14 days of treating OI vs ART deferred to after OI- Stratified by opportunistic infections and CD4 (< or ≥50 cells/mm3)- Tuberculosis excluded (evaluated in a separate ongoing study)- ART = lopinavir/ritonavir (LPV/r), stavudine (d4T), tenofovir/emtricitabine (TDF/FTC)- Outcomes: death or AIDS progression; no progression and HIV viral load ≥50; or no
progression and viral load <50 copies/mL Results (Feb 2008)
- 141 patients were randomized to each arm (immediate vs. deferred ART).- OI: Pneumocystic carinii pneumonia (PCP) 63%, cryptococcal meningitis 13%, pneumonia
10%, and 30% had more than one OI identified at entry- Immediate ART - median of 12 (range 9-13 days); deferred ART - 45 (range 41-55) days- No statistically significant difference in the primary endpoint:
- 14% vs 24% for death or AIDS progression- 38% vs 31% for no progression and HIV viral load ≥50 copies/mL- 48% vs 45% for no progression and viral load <50 copies/mL
- However, immediate ART had: - Fewer deaths/AIDS progressions (20 vs. 34, p = 0.035) - Longer time to death/AIDS progression (stratified HR = 0.53, p = 0.02)- Faster increase in CD4 counts to >50 and >100 cells/uL
A Randomized Strategy Trial, ACTG 5164, CROI 2008, (abstr. 142)
Randomized trial of ART initiated during or after acute opportunistic infections (OI) – (MTB-excluded)
Percentage of people on treatment who are children, Percentage of people on treatment who are children, by country, 2005by country, 2005
Zambia
0% 2% 4% 6% 8% 10% 12% 14% 16%
AfricaAfrica [Median: 7%]
UR Tanzania
Uganda
Ctr African Republic
South Africa
Kenya
Zimbabwe
Namibia
Rwanda
Mozambique
Malawi
Côte d'Ivoire
Nigeria
Ghana
Haiti
Latin America and CaribbeanLatin America and Caribbean [Median: 8%]
Panama
Honduras
Argentina
Guyana
Brazil
El Salvador
Venezuela
Peru
0% 2% 4% 6% 8% 10% 12% 14% 16%
0% 2% 4% 6% 8% 10% 12% 14% 16%
Cambodia
Viet Nam
India
China
AsiaAsia [Median: 4%]
Source: WHO/UNAIDS (2005). Progress on global access to HIV antiretroviral therapy: An update on “3 by 5.”7.3
Steinbrook R. NEJM 2006;355:1081
Individuals Receiving Needed Antiretroviral Therapy (ART) in Low- and Middle-Income Countries with More Than 25% “Coverage“ in June 2006.
Coverage generally lower in children due to:
- delayed diagnosis
- fewer children, less public health concern
- complex dosing / scarcity of liquid medicines
Goal of Antiretroviral Treatment: Balance Benefits vs. Risks
1. Suppress plasma virus to <50c/uL - persistent CD4+ cell gain
2. Minimize inconvenient, poorly-tolerated or toxic ART
3. Sustainable program within public health system
$$$$$$$$$
$$$
$$$ $$$
Programs with long-term efficacy are costly:
- Test for drug-resistance in newly diagnosed, +/- ART-failure
- Quantification of plasma HIV-1 RNA and CD4
- Provide “new” antiretrovirals, without cross-resistance
Thank you for your attention.Questions?
Mutations Accumulate During Virologic Failure of AZT/3TC/ABC
CNA3005. Melby T et al. 8th CROI, Chicago, 2001. Abstract 448
Increasing NRTI cross-resistance
Su
bje
cts
(%)
10
24 2533
40
56
90
76 7567
60
44
010
20304050
607080
90100
0-8 17-24 25-32 33-40 41-48
Weeks On Therapy After First Genotype Test
M184V + thymidine analog mutations M184V only or wild-type
(n = 16)(n = 39) (n = 34) (n = 28) (n = 24) (n = 20)9-16
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