challenges in infectious diseases 2013 - khon kaen university mootsikapun.pdf · challenges in...
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Challenges in Infectious diseases 2013
Piroon Mootsikapun MD.
ID Unit, Department of Medicine
Faculty of Medicine, KKU
Why HIV is difficult to eradicate?
• It can live in long-lived, slow replicated cells such as macrophage
• It can persist in organs with drug barrier.
• It infect immune system itself.
The Berlin Patient
•In 2007, a patient was given a stem cell transplant with the CCR5D32/D32 mutation for Rx of relapse of AML
•4 years after transplant, CD4 T-cell count have returned to the normal range of healthy patients whereas HIV RNA and DNA remain continuously undetectable in plasma and PBMC
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scBMT (X2)
Donor
Hütter. NEJM. 2009; Allers. Blood. 2010
HIV-1+ AML
CCR5+
CCR5–
HIV-1– ?
CCR5–
off ART no viral
rebound
Long-term control of HIV by CCR5 Δ32/Δ32 stem cell transplantation
Chemotherapy (x4) Total-body irradiation
(x2)
The 2 Boston patients
The 2 Boston patients
• Two men with HIV received stem-cell transplants to treat lymphoma
• One of the men received stem-cell transplants to about three years ago, and the other five years ago. Their regimens were similar to one used on Timothy Ray Brown.
• they have now stopped their antiretroviral treatments with no ill effects.
• One has been off medication for 15 weeks and the other for 7 weeks. Neither has any trace of HIV DNA or RNA in his blood.
Mississippi child
• Infant born to untreated HIV+ve mother at 35 wks’ gestation via spontaneous vaginal delivery
• Infant HIV infection confirmed via HIV-1 DNA PCR, HIV-1 RNA analysis of 2 separate samples at 30 and 31 hrs of age
• ZDV/3TC + NVP (at therapeutic dose) initiated at 31 hrs of age, continued for 7 days
• ZDV/3TC + LPV/RTV continued from 7 days to 18 mos of age
• HIV-1 RNA undetectable by Day 30
Persaud D, et al. CROI 2013. Abstract 48LB. .
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Mississippi child
• Assessments at Month 24 and 26
– Western blot negative
– No HIV-specific CD8+ or CD4+ T-cell responses
– Standard HIV-1 RNA and HIV-1 DNA undetectable
– By ultrasensitive assays
• Mo 24: HIV-1 RNA 1 c/mL; HIV-1 DNA < 2.7 c/million PBMCs
• Mo 26: HIV-1 DNA 4 c/million PBMCs
HIV CURE – Two Models
Eradication Remission
Sterilizing cure Functional cure
Elimination of all HIV infected cells
Long term health without cART
HIV RNA < 1 cop/ml HIV RNA <50 cop/mL
Berlin Patient, Mississippi baby , Boston patients
Elite controllers, Post cART controllers
• Inability to control virus without HAART
• With early HAART many progressors achieve characteristics of EC but virus rebounds if HAART is discontinued
• Definition based on CD4 control for 7-10 years without HAART
• VL usually <2,000 HIV RNA copies/ml
• Most ultimately show CD4 decline; better survival if stable for >10 years
• Maintain durable HIV control to <50 copies/mL without HAART
• Rarely progress • Also known as HIV
controllers • Low virus reservoirs
Chronic Progressors (and Rapid
Progressors)
LTNP
Elite Controllers, LTNP and Chronic Progressors
>90%
~5% < 1%
Long term non-progressors Elite Controllers
EC
Deeks SG and Walker BD: Immunity 27:1286, 2007
• All 10 men and 4 women were treated during primary infection and then remained on ARVs for between 1 and 7.6 years; the median length was 36.5 months.
• The individuals terminated treatment for various reasons, including the wish to take a break from ARVs and their participation in a study about treatment interruption.
• The group has remained off ARVs for between 4 and 9.6 years. Eleven of them maintain viral loads below 40, and three of them below five copies.
• But this is only 15% of the group who had Rx interruption
Table 1. Characteristics of PTC included in the study.
Sáez-Cirión A, Bacchus C, Hocqueloux L, Avettand-Fenoel V, et al. (2013) Post-Treatment HIV-1 Controllers with a Long-Term Virological Remission after the Interruption of Early Initiated Antiretroviral Therapy ANRS VISCONTI Study. PLoS Pathog 9(3): e1003211. doi:10.1371/journal.ppat.1003211 http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1003211
แพทย์ไทยสุดเจ๋งรักษา'เอดส์'หายขาด ทั่วโลกตะลึงแพทย์ไทยโชว์ผลงานวิจัยเด็ดรักษา"เอดส์"หายขาดหากตรวจDNAหลังมีเซ็กส์เสี่ยงไม่เกิน 1 อาทิตย์ ยันกินยาติดต่อกันไม่เกิน 5 ปี ควบคุมเชื้อได้ทันที วันศุกร์ที่ 15 มีนาคม 2556
• A total of 96 people participated in the project, which started in 2009
• antiretroviral drugs to 26 people, who had been infected with the HIV virus for no longer than two weeks.
• 92%, had no HIV virus in their white blood cells
• Among patients who received antiretroviral drugs after being infected with the virus for longer than two weeks, only 53% were found with no HIV virus in their white blood cells.
J Ananworanich,C Vandergeeten, N Chomchey, et al. Early ART Intervention
Restricts the Seeding of the HIV Reservoir in Long-lived Central Memory
CD4 T Cells. 20th Conference on Retroviruses and Opportunistic
Infections. Atlanta, March 3-6, 2013.
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Strategies to cure HIV
Treatment optimization & intensification
(eliminate all replication)
Reversal of HIV latency
(increase viral
production) Immune-based
therapies
(reverse pro-latency signaling)
Therapeutic vaccination
(to enhance host-control)
Gene therapy
Gene therapy to eliminate CCR5
NCT01252641 & NCT00842634; Lalezari , CROI’11
CCR5-disrupted T cells engraft, proliferate, and persist in peripheral blood and rectal mucosa
Increase CD4 T-cell counts and normalization of CD4:CD8 ratio after single infusion
The treatment is well tolerated
SB728-902
EMERGING VIRAL INFECTIONS
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Avian and pandemic influenza
Types of influenza viruses
• Influenza viruses are divided into three main types: influenza A, B, and C
• A viruses – infect birds and other animals, as well as humans
• A viruses – source of seasonal influenza epidemics and all pandemics
• B and C viruses – infect humans only and do not cause pandemics
Migratory
water birds Domestic birds
Where does influenza A virus come from?
Humans
and other
animals
Human influenza A viruses start as avian (bird) influenza viruses
Seasonal influenza: minor changes - antigenic drift
• Occurs among influenza A viruses resulting in emergence of new variants of prevailing strains every year
• New variants result in seasonal influenza each winter
• Some years are worse than others – partly related to degree of ‘drift’
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Pandemic influenza: major changes - antigenic shift
• Major changes occur in the surface antigens of influenza A viruses by mutation or reassortment
• Changes are more significant than those associated with antigenic drift
• Changes lead to the emergence of potentially pandemic strains by creating a virus that is markedly different from recently circulating strains so that almost all people have no pre-existing immunity
Pandemic influenza in the 20th Century
1920 1940 1960 1980 2000
H1N1 H2N2 H3N2
1918 “Spanish Flu” 1957 “Asian Flu” 1968 “Hong Kong Flu”
20-40 million deaths 1 million deaths 1 million deaths
Classification
• Influenza viruses are subtyped according to surface glycoproteins: hemagglutinin (HA) and neuraminidase (NA)
– Currently, there are 16 hemagglutinins (H1 to H16) and 9 neuraminidases (N1 to N9)
• 144 possible sub-types
– Hemagglutinin attaches the virus to the surface of the host cell so the virus can replicate
– Neuraminidase lets the newly replicated viruses out of the cell to infect more cells
H7N9 influenza
Avian Influenza A (H7N9)
• On March 30, 2013, three patients in China with fatal cases of rapid, progressive pneumonia were confirmed to be infected with influenza A H7N9
• Virus had not been detected in humans or animals previously
India
Nepal
Russia
Mongolia
Bangladesh
Bhutan
Burma
Thailand
Laos
0
0
500 Kilometers
500 Miles
Vietnam
Philippines
South Korea
North Korea
Pakistan
INNER MONGOLIA
HENAN
ANHUI
ZHEJIANG
SHANGHAI
JIANGSU
FUJIAN
JIANGXI
HUBEI
SHANXI SHANDONG
HEBEI
BEIJING
TIANJIN
LIAONING
Taiwan
Province/City
Number of Cases
Anhui 4
Beijing 3
Fujian 5
Henan 4
Hunan 2
Jiangsuα 27
Jiangxi 6
Shandong 2
Shanghai 34
Zhejiang 46
Location of H7N9 Influenza in China (6/10/13)*
SHAANXI
*133 total cases/39
deaths
GUANGDONG
HUNAN
GUANGXI
CHONGQING
GUIZHOU
NINGXIA
GANSU
SICHUAN
YUNNAN
JILIN
HEILONGJIANG
QINGHAI
XIZANG
XINJIANG
HAINAN
α- includes a case
hospitalized in Taiwan
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Avian Influenza A (H7N9) Origination
• Virus arose from multiple reassortment events
• Four or more influenza A viruses appear to have contributed genetically
• H7 gene is genetically close to sequences isolated from ducks in Zhejiang province
• N9 gene is similar to genes from H7N9 viruses found in wild ducks in South Korea
• The six internal genes are similar to H9N2 viruses isolated from poultry and ducks in China
www.thelancet.com Vol 381 June 1, 2013
H7N9 Characteristics of 111 Patients
•Characteristic
• Median age, years 61(3-88)
• ≥65 yo 47(42.3)
• ≤14 yo 2 (1.8)
• Male 92 (65)
• Preexisting Condition 68 (61) – Hypertension 51 (45.9)
– Diabetes 18 (16.2)
– Immunosuppression 10 (9.0)
– Pregnancy 2 (1.8)
• Exp. poultry prev. 14 days 62 (55.9)
Number (%)
n engl j med 368;24 nejm.org june 13, 2013
H7N9 Complications
•Complication
• Pneumonia 108 (97.3)
• Acute respiratory distress 79 (71.2)
syndrome
• Shock 29 (26.1)
• Acute kidney injury 18 (16.2)
• Rhabdomyolysis 11 (9.9)
No. (%)
n engl j med 368;24 nejm.org june 13, 2013
Outcome of H7N9 Infection
• 109 of 111 hospitalized
• Antivirals initiated in 108 patients
– Median of 7 days after the onset of illness
• 30 (27.0%) died, most from refractory hypoxemia
n engl j med 368;24 nejm.org june 13, 2013
H7N9 and Mild Disease
• Serology survey of 20,000 Chinese persons with influenza symptoms found only 6 cases of H7N9
• Survey of over 3000 contacts of cases found no evidence of disease
• Mild disease seems to be unusual
• Minimal human-to-human transmission seems to have occurred
• No sustained human-to-human transmission has occurred
EID Volume 19, Number 8—August 2013
Middle Eastern Respiratory Syndrome Coronavirus (MERS Cov)
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The first laboratory-confirmed case of
MERS-CoV
On September 23, 2012, WHO Announces: a 60-year-old man from Bisha, the Kingdom of Saudi Arabia, who died of rapidly progressive community-acquired pneumonia and acute renal failure
MERS-CoV from September, 2012-Present
MERS-CoV Clinical Presentation
• Fever
• Cough
• Shortness of breath
• Myalgia
• Diarrhea
• Vomiting
• Abdominal pain
46 [98%]
39 [83%]
34 [72%]
15 [32%]
12 [26%]
10 [21%]
8 [17%]
TheLancet.com Published Online 7/26/13
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•45 (46%) had underlying comorbid medical disorders
• Diabetes
• Hypertension
• Chronic cardiac
disease
• Chronic renal
disease
32 [68%]
16 [34%]
13 [28%]
23 [49%]
No. (%)
TheLancet.com Published Online 7/26/13
MERS CoV Clusters
• Multiple clusters of human cases have occurred
– Healthcare associated events
– Family clusters
• Human to human transmission has occurred, though no sustained community transmission
MERS CoV Infectivity
• Human-to-human transmissibility of MERS CoV appears to be low
• Sustained community transmission has not been seen
• Close monitoring of health-care workers and household contacts has not revealed large numbers of secondary infections
MERS CoV Treatment
• Minimal evidence to indicate antiviral or adjunctive therapy
• Supportive care
• Mechanical ventilation
• Some studies have shown that interferon may have beneficial effects in the treatment of SARS