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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