Complications of HIV Infection:
Opportunistic Infections and
Malignancies
Rafael E. Campo, MD
Slides courtesy of Luis A. Espinoza, MD
Division of Infectious Diseases,
University of Miami Miller School of Medicine
Organs of the immune system and the
normal immune response
Foreign antigens are ingested and
processed by macrophages
Processed antigens are presented to
helper T-lymphocytes that recruit Blymphocytes
B-lymphocytes produce antibodies
Antibodies attach to the antigens on
pathogens and recruit macrophages
and other cells to destroy the
pathogen
Once the pathogen is eliminated,
suppressor T-cells shut down the
immune response
Effects of HIV infection on the immune
system
HIV infects helper T-cells (also known as CD4+ cells)
The infected CD4+ cells become “HIV factories”
Infected CD4+ cells die because of HIV infection itself
and because of the immune response directed at
destroying HIV
After years of ongoing infection, immune exhaustion
leads to massive CD4+ cell depletion and the inability to
fight off opportunistic infections and unusual
malignancies
Patient #1
24 y/o male
Graduate student at UM
In good health all his life
MSM; sexually active without protection
Abruptly develops fever, chills, a reddish rash on
the skin, a very sore throat, swollen lymph nodes
in his neck, intense headache made worse by
light, nausea and vomiting
What is wrong with Patient #1?
1.
2.
3.
4.
5.
Acute mononucleosis
Acute HIV retroviral syndrome
Acute strep throat
All of the above
None of the above
Natural history of HIV infection and
its stages
Stage
Duration
CD4+ count
Clinical
manifestations
Acute infection
A few weeks to a few
months
May decrease <500
for a short time but
will recover
Acute retroviral
syndrome
Clinical latency
Up to 7-10 years*
200-500
Few if any symptoms
(+/- adenopathies)
AIDS
Beyond 7-10 years
<200
Opportunistic
infections, unusual
malignancies,
profound wasting
In <5% of patients, latency may last for the remainder of their lives
Clinical manifestations of the acute
retroviral syndrome
Occurs in 50-90% of
individuals infected with
HIV
Occurs 2-4 weeks after
the infection
Typically, the process
goes on for 2-4 weeks and
is self-limited
Described as “the worst
flu ever”
Common manifestations
–
–
–
–
–
–
–
Fever 80-90%
Fatigue 70-90%
Rash 40-80%
Headache 32-70%
Adenopathies 40-70%
Pharyngitis 50-70%
Myalgias, arthralgias 5070%
– Meningitis (25%)
Clinical course for Patient #1
He goes to Student Health
Work up reveals acute HIV infection
Referred to an Infectious Diseases specialist; what
should be done next?
1. Careful observation
2. Prompt initiation of antiretroviral therapy
When to Start ART:
Global Consensus and Diversity
AIDS or
HIV-Related
Symptoms
<200
200-350
350-500
>500
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
British HIV Association (2013)
Yes
Yes
Yes
Consider
Defer
European AIDS Clinical Society
(2014)
Yes
Yes
Yes
Consider
Consider
WHO (2013)
Yes
Yes
Yes
Yes
Defer
United States
DHHS (2015)
IAS-USA (2014)
DHHS. http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Revision April 8, 2015.
Günthard HF, et al. JAMA. 2014;312:410-425.
EACS. http://www.europeanaidsclinicalsociety.org. Revision November 2014.
BHIVA. www.bhiva.org. Revision November 2013.
WHO. http://www.who.int/publications/guidelines/hiv_aids/en/index.html. Revision June 2013.
CD4 Count (cells/mm3)
START Study:Initiation of ART in Early
Asymptomatic HIV Infection
Randomization
1:1
Immediate ART (n=2326)
Multicontinental Study (n=4685)
HIV-positive adults
Treatment-naive
CD4 >500 cells/mm3
Deferred ART (n=2359)
(CD4 Declined to <350 cells/mm3 or AIDS-related event)
5//2015: DSMB recommends stopping trial:
Deferred arm offered ART
Primary outcome a composite outcome of 2 major components:
• Any serious AIDS-related event
- Death from AIDS or any AIDS-defining event, Hodgkin’s lymphoma
• Any serious non–AIDS-related event
- CVD (myocardial infarction, stroke, or coronary revascularization) or death from CVD, end-stage renal disease (initiation of dialysis or
renal transplantation) or death from renal disease, liver disease (decompensated liver disease) or death from liver disease, non–AIDSdefining cancer (except for basal-cell or squamous cell skin cancer) or death from cancer, and any death not attributable to AIDS
Lundgren J, et al. 8th IAS Conference. Vancouver, 2015. Abstract MOSY0301.
The INSIGHT START Study Group. N Engl J Med. 2015;July 20. [Epub ahead of print].
START Study Outcomes:Composite Primary
Endpoint and its Components
Immediate ART was superior to deferral
of ART
96
Both for serious and non-serious AIDS
events
Majority (68%) of the primary endpoints
occurred in patients with a CD4 >500
cells/mm3
Similar significant reductions were
noted across all patient subgroups
No increase in adverse events associated
with immediate versus deferred ART
Mean CD4 count in immediate ART arm
was 194 cells/mm3 higher versus deferred
ART arm
Deferred ART (n=2359)
Immediate ART (n=2326)
57%
Reduction
(P<0.001)
Number of Events
–
Number of Serious Events
50
42
72%
Reduction
(P<0.001)
47
29
14
Composite
Endpoint
AIDSRelated
Non-AIDS Related
Components
(Serious Events)
Lundgren J, et al. 8th IAS Conference. Vancouver, 2015. Abstract MOSY0301.
The INSIGHT START Study Group. N Engl J Med. 2015;July 20. [Epub ahead of print].
39%
Reduction
(P=0.04)
At what CD4+ count should antiretroviral therapy
optimally be started in HIV infected individuals?
1.
2.
3.
4.
<200
<350
<500
>500
Common manifestations of advanced
HIV infection/AIDS by organ system
Pulmonary diseases
– Pneumocystis pneumonia
– Tuberculosis
– Pneumococcal pneumonia
Central nervous system
– Toxoplasmosis
– Cryptococcosis
– Cytomegalovirus
Eyes
– Cytomegalovirus
Disseminated diseases
– Mycobacterium avium
intracellulare
– Bacterial infections (e.g.
salmonellosis)
Skin
– Candidiasis
– Kaposi’s sarcoma
Immune system
– Non-Hodgkin’s lymphoma
Gastrointestinal diseases
Common manifestations of advanced
HIV infection/AIDS by pathogen
Fungal diseases
–
–
–
–
Pneumocystis pneumonia
Oral and esophageal candidiasis
Cryptococcosis
Other endemic mycoses:
histoplasmosis,
coccidiodomycosis
Mycobacterial diseases
– Mycobacterium tuberculosis
– Mycobacterium avium
intracellulare
– Cytomegalovirus
Protozoal diseases
– Toxoplasmosis
– Various gastrointestinal
pathogens
Viral diseases
– Cytomegalovirus
– Epstein-Barr virus
– Human herpes virus 8
Bacterial diseases
– Streptococcus pneumoniae
– Salmonellosis
Pneumocystis Pneumonia (PCP)
Pneumocystis jiroveci : Fungus
Most common site
: Lungs
Other sites
: Retina, skin, liver, bone marrow,
and lymph nodes
Signs and symptoms
Diagnosis
Pneumocystis Pneumonia
CD4 count threshold: - 200 cell per uL or < 14%
- Oral thrush, HSV, weight loss
Recomm Prophylaxis - TMP/SMX (160/800)
Alternative agents:
- Dapsone +/- Pyrimethamine +
folinic acid
- Atovaquone
- Aerosolized Pentamidine
Pneumocystis Pneumonia
Therapy:
- TMP/SMX +/- Corticosteroids
- Pentamidine
- Atovaquone
- Clindamycin + Primaquine
- Dapsone + TMP
Toxoplasmosis (I)
Toxoplasma gondii
Carried by cats, birds and other domesticated animals;
soil contaminated by cat feces, and in meat
Most common site is the brain
It can infect lungs, retina of the eyes, heart, pancreas,
liver, colon and testes
Symptoms
Diagnosis
Toxoplasmosis (II)
CD4 count threshold: - Usually < 100 per uL.
- With (+) antitoxoplasma IgG.
Recomm prophylaxis - TMP/SMX (160/800)
Alternative agents:
- TMP/SMX (80/400)
- Dapsone + Pyrimethamine +
folinic acid
- Atovaquone
Toxoplasmosis (III)
Therapy:
Sulfadiazine + Pyrimethamine + Folinic acid
Clindamycin + Pyrimethamine + Folinic acid
Atovaquone + Pyrimethamine + Folinic acid
Azithromycin + Pyrimethamine + Folinic acid
Atovaquone + Sulfadiazine
Mycobacterium avium (I)
Mycobacterium avium complex and immunosupression
Sources are food, water, and soil
Localized or disseminated infection
Symptoms of fever, weight loss, night sweats, fatigue,
anemia, loss of appetite, loose stools or diarrhea,
abdominal pain, enlarged liver or spleen
Diagnosis
Mycobacterium avium (II)
CD4 count threshold - 50 cells per uL.
Recomm. prophylaxis - Azithromycin
- Clarithromycin
Alternative agents
- Rifabutin
- Azithromycin + Rifabutin
Mycobacterium Avium (III)
Therapy:
Clarithromycin + Ethambutol +/- Rifabutin
Azithromycin + Ethambutol +/- Rifabutin
Alternatives as second line drugs: Ciprofloxacine,
Ofloxacine, Amikacin, Kanamycin.
Mycobacterium Tuberculosis (I)
CD4 count threshold: - Any, for TST (+) > 5 mm
- Anergic but with high risk
- Known exposure to active
contagious case
Recomm prophylaxis - INH + Vitamin B6
- Rifampin or Rifabutin
Alternative agents:
- Rifampin + Pyrazinamide
MDR Tuberculosis*: - Rifampin or Rifabutin +
Pyrazinamide
Mycobacterium Tuberculosis (II)
Therapy:
First line drugs:
- Isoniazid
- Rifampin
- Ethambutol
- Pyrazinamide
Second line drugs:
- Ethionamide
- Ofloxacin, Ciprofloxacin
- Streptomycin
- Cycloserine
- Capreomycin
- Kanamycin
Cytomegalovirus (I)
Herpesvirus
- Mucous-membrane contact.
- Tissue transplant.
- Blood transfusion.
May affect retina, colon, esophagus; lungs, brain, heart,
thymus, pancreas, larynx, thyroid, adrenal glands, liver,
and gallbladder.
Symptoms
Diagnosis
Cytomegalovirus (II)
CD4 count threshold: - 50 cell per uL
- 100 cells per uL if prior OI
- CMV antibody positivity
Recomm Prophylaxis - Ophthalmologic evaluation
- Oral ganciclovir
Multifocal CMV Retinitis
Syntex Lab
Cytomegalovirus (III)
Therapy:
Ganciclovir PO or IV or intraocular
Valganciclovir (oral)
Foscarnet IV
Cidofovir IV + Probenecid
Kaposi’s Sarcoma
Human Herpesvirus-8 (HHV-8 or KSHV)
Malignancy versus angiogenic disorder
Detected in tissue of KS lesions, in semen and peripheral
blood monocytes
Signs and symptoms
Diagnosis
From: Atlas o HIV DIsease
f
Kaposi’s Sarcoma
Therapy:
Antiretrovirals
Local excision, liquid nitrogen, radiation therapy.
Intralesional therapy (sotradecol, vinblastine, alitretinoin)
-Interferon
Chemotherapy: Doxorubicin + Bleo + Vincristine
- Etoposide, Paclitaxel (Taxol)
- Liposomal Doxorubicin and Daunorubicin
Fungal Infections
CD4 count threshold: - No determined.
- Usually < 100 per uL.
Recomm Prophylaxis - ? Fluconazole
Alternative agents:
- ? Ketoconazole
- ? Clotrimazole
- ? Itraconazole
Cryptococcal Infections
Cryptococcus neoformans
Areas heavily contaminated with bird excrement.
Infects meninges, skin and lungs
Signs and symptoms
Diagnosis and prognosis
Therapy: - Amphotericin-B +/- Flucytosine
- Fluconazole +/- Flucytosine
- Itraconazole
HIV-Related Candidiasis
Candida albicans, Candida parapsilosis, Candida krusei,
Candida tropicalis, Candida glabrata.
Skin and mucous membranes
Signs and symptoms
Diagnosis
Therapy: - Clotrimazole, Nystatin, Ketoconazole
- Fluconazole, Itraconazole
- Amphotericin-B
- Caspofungin
Other Fungal Infections
Histoplasmosis: Lungs, skin, GI system.
Itraconazole, Fluconazole.
Aspergillosis: Lungs and sinuses.
Extrapulmonary dissemination.
Amphotericin-B, Itraconazole, Caspofungin
Coccidiomycosis: Lungs, kidneys, spleen, lymph
nodes, brain, thyroid gland.
Itraconazole, Fluconazole.
Bacterial Infections
Salmonellosis : Systemic and disseminated.
Pneumonia
: Streptococcus pneumonia.
Haemophilus influenza.
Enteritis
: Shigella, Campylobacter.
Sinusitis
: Staphylococcus epidermidis.
Pseudomona aeruginosa.
Syphilis/Neurosyphilis.
Bacillary angiomatosis: Bartonella henselae.
Nocardiosis.
Viral Infections
Hepatitis: HAV, HBV, HCV, HDV, HGV.
Herpes simplex virus: HSV-1, HSV-2.
Herpes zoster virus.
Human Papilloma Virus.
Molluscum Contagiosum.
Oral Hairy Leukoplaquia.
Progressive Multifocal Leukoencephalopathy.
HSV Esophagitis
Protozoal Infections
Cryptosporidiosis: Cryptosporidium parvum
Food or water contaminated by fecal material.
Paromomycin, Clarithromycin, Azithromycin.
Isosporiasis: Isospora belli.
Cotrimoxazole, Pyrimethamine + Leucovorin.
Microsporidiosis: Enterocytozoon bieneusi,
Encephalitozoon hellen, Encephalitozoon cuniculi,
Septata intestinalis.
Albendazole, Metronidazole, Thalidomide.
Other Disorders
Thrombocytopenia
Diarrhea and malabsortion
Wasting syndrome
Aphthous ulcers
Peripheral neuropathy
Dementia syndrome
Malignancies
Progressive multifocal leucoencephalopathy
All of the following are pulmonary
conditions associated with AIDS except:
1.
2.
3.
4.
Pneumocystis pneumonia
Tuberculosis
Asthma
Pneumococcal pneumonia
All of the following are central nervous system
conditions associated with AIDS except
1.
2.
3.
4.
Alzheimer’s disease
Toxoplasma encephalitis
Cryptococcal meningitis
AIDS-associated dementia
All of the following are viral infections
commonly seen in AIDS patients except:
1.
2.
3.
4.
Cytomegalovirus retinits
Human herpes virus 8-associated Kaposi’s
sarcoma
Dengue fever
Human papillomavirus-associated genital
condylomas
Patients on antiretroviral therapy
(ART)
Modern ART successfully suppresses viral
replication and leads to gradual restoration of
CD4+ cell counts in >90% of patients
However, there is ongoing systemic inflammation
and these patients are not immunologically
normal
Many organ systems are aging prematurely
Systems affected by ongoing inflammation and
premature aging in patients on successful ART
Cardiovascular: heart attacks, strokes
Central nervous system: neurocognitive impairment
Metabolic: diabetes and glucose intolerance, abnormal
lipid levels, abnormal fat distribution (lipodystrophy)
Bones: osteoporosis and premature fractures
Renal: impaired kidney function
Hepatic: greatly accelerated progression of chronic
hepatitis B and C
Among patients successfully treated with
antiretroviral agents with complete viral
suppression, there is no more systemic
inflammation and the aging process is normal
1.
2.
True
False