HIV/AIDS BOARD REVIEW Harold Henderson, MD

Report
HIV/AIDS BOARD REVIEW
Harold Henderson, MD
Diagnosis
Natural History
Clinical Manifestations
Drug Therapy, Toxicity, Interactions
Opportunistic Infections-diagnosis, treatment, prophylaxis
Sample Test Question
A 57 y/o healthy adult female with hypertension and diabetes comes to
your office for a routine followup appointment. She takes HCTZ and
follows an ADA diet for her diabetes. She feels well and has no
complaints. She received the influenza vaccine from MSDH 3 days
ago. You order HIV serology for routine screening, and the result is a
positive EIA but an indeterminate Western Blot. The best explanation
for this result is:
1. chronic asymptomatic HIV infection
2. acute HIV infection
3. lab error
4. false positive EIA related to the influenza vaccine
DIAGNOSIS
EIA-sensitivity/specificity 99%; antibodies usually detectable within
2-6 weeks of acute infection; virtually 100% reactivity by 6 months
Needs to be confirmed with Western Blot or IFA; indeterminate
results may be due to acute infection period
Causes of false negative EIA-acute infection (“window” period)
Causes of false positive EIA-hematologic malignancies,
autoimmune disorders (SLE), + RPR, influenza and Hep B
vaccination
Other tests: oral (rapid) test; home test; p24 antigen (may be
detectable early in acute infection but <50%); PCR-can be used
but false positive and negative rates are too high as screening tool
Neonatal diagnosis-maternal antibodies cross placenta and may
be detectable for >one year, PCR is test of choice
Sample Test Question
A 23 y/o male is evaluated in the ER with fever-101°, nausea, malaise
and a diffuse, erythematous maculopapular rash for about 3 days. He
denies the use of IV drugs but has multiple sexual partners and says “I
usually use condoms.” He lives in Jackson and works at a local Target,
has always been healthy and takes no meds. PE is normal except for
painless, bilateral, 1x2 cm cervical adenopathy. Labs are
unremarkable except for a platelet count of 77,000. The best
diagnostic test to order is:
1. HIV serology
2. HIV p24 antigen
3. PCR HIV quantitative (viral load)
4. measles serology
ACUTE HIV INFECTION SYNDROME
Common signs/symptoms (>50%)-fever, adenopathy, pharyngitis, rash
(erythematous maculopapular), myalgias
Less common-headache, nausea/vomiting, hepatosplenomegaly,
weight loss, thrush, neurologic symptoms (aseptic meningitis,
meningoencephalitis, Guillain-Barre syndrome), thrombocytopenia
EIA usually negative, PCR is test of choice
Sample Test Question
A 30 y/o HIV+ male is followed by you as his primary care provider. He
is asymptomatic and feels well, has a full time job. Lab results (on two
separate occasions) include CD4 counts-576 & 553, and viral loads36,000 & 59,000. He is interested in starting HAART if you recommend
it. Which of the following is the best treatment plan?
1. Start tenofovir/emtricitabine/efavirenz (Atripla).
2. Delay starting HAART, and follow with repeat CD4s and viral loads
every 3-4 months.
3. Start zidovudine/lamivudine (Combivir).
4. Start trimethoprim/sulfamethoxazole as PCP prophylaxis, and
follow every 3-4 months.
Antiviral TherapyWhen to Start HAART
Status
Recommendation
Symptomatic HIV
disease
Start therapy for all
patients
Asymptomatic
CD4<500
Start therapy
Asymptomatic CD4 > 500
Start therapy
Anti-HIV Drug Regimens
Minimum number of active drugs is three per combination
Usually two NRTIs and one NNRTI (such as
AZT/lamivudine/efavirenz) or two NRTs and one protease inhibitor
(such as abacavir/lamivudine/lopinavir-ritonavir)
PI boosting with ritonavir-commonly done to increase levels of the
PI; ritonavir does not count as an antiviral drug in the combination;
example: AZT, lamivudine, atazanavir/ritonavir is a 3-drug
combination
Resistance testing used to help choose initial regimen and to guide
salvage regimens after drug failure
Current ARV Medications
NRTI
PI
 Abacavir (ABC)
 Didanosine (ddI)
 Emtricitabine (FTC)
 Lamivudine (3TC)
 Stavudine (d4T)
 Tenofovir (TDF)
 Zidovudine (AZT, ZDV)
 Atazanavir (ATV)
 Darunavir (DRV)
 Fosamprenavir (FPV)
 Indinavir (IDV)
 Lopinavir (LPV)
 Nelfinavir (NFV)
 Ritonavir (RTV)
 Saquinavir (SQV)
 Tipranavir (TPV)
NNRTI
 Delavirdine (DLV)
 Efavirenz (EFV)
 Etravirine (ETR)
 Nevirapine (NVP)
 Rilpivirine (RPV)
9
Integrase Inhibitor
(II)
 Dolutegravir (DTG)
 Elvitegravir* (EVG)
 Raltegravir (RAL)
Fusion Inhibitor
 Enfuvirtide (ENF, T-20)
CCR5 Antagonist
 Maraviroc (MVC)
* EVG currently available
only in coformulation with
cobicistat (COBI)/
TDF/FTC
May 2014
www.aidsetc.org
Preferred HAART Regimens
for Initial Therapy
Tenofovir/emtricitabine/efavirenz (Atripla)
Tenofovir/emtricitabine/atazanavir/ritonavir
Tenofovir/emtricitabine/darunavir/ritonavir
Tenofivir/emtricitabine/raltegravir
Tenofovir/emtricitabine/elvitegravir/cobicistat
Tenofovir/emtricitabine/dolutegravir
Abacavir/emtricitabine/dolutegravir
Sample Test Question
A 24 y/o HIV positive female, 15 weeks pregnant, is referred to you
for medical therapy by her obstetrician, who plans to manage her
pregnancy but is not familiar with HIV care. She was recently
diagnosed, is asymptomatic, has no other significant past medical
history and takes no medications. Lab results include a CD4-535
and a viral load-26,000. An HIV drug susceptibility test shows no
drug resistance. Regarding HIV care during her pregnancy, the
following is the best plan:
1. She is asymptomatic with a good CD4 count, HAART is not
indicated.
2. Start zidovudine (AZT) 300 mg BID.
3. Start tenofovir/emtricitabine/efavirenz (Atripla)
4. Start zidovudine/lamuvidine (Combivir) and lopinavir/ritonavir
(Kaletra)
HIV and Pregnancy
Perinatal transmission of HIV is absence of
HAART is 20-30%
HAART decreases transmission to <2-3%, all
pregnant HIV-infected women should be on
HAART after the first trimester
Do not use efavirenz-?teratogenic
Sample Test Question
A 25 y/o male with AIDS (he is asymptomatic but has a CD4 count153, viral load-49,900) is started on zidovudine/lamivudine
(Combivir) and efavirenz (Sustiva) as HAART, and TMP/SMZ
(Bactrim) SS-one tablet daily as PCP prophylaxis. He returns for
followup 8 weeks later. He has no complaints except for very
pronounced fatigue for the past two weeks. Lab findings now
include a Hct-21 (decreased from 34 six weeks ago), MCV-107,
WBC-3.9, a platelet count of 149,000, viral load-undetectable, and
a negative FOBT. The following is the best treatment plan:
1. Zidovudine should be stopped, another NRTI should be started
in its place, and he should receive a blood transfusion.
2. TMP/SMZ should be stopped, monthly aerosolized
pentamidine should be started, and he should receive a blood
transfusion.
3. The same medications are continued, and he should receive a
blood transfusion.
4. Blood should be obtained for B12 and folate levels, and then
he should receive a blood transfusion.
Individual NRTI Toxicity-Hematologic
AZT-anemia and/or neutropenia
Typically early (2-6 weeks), but may occur later in course of
therapy
May be severe
More common in advanced disease with pre-existing bone
marrow suppression
Generally resolves with drug discontinuation, but resolution
may be quite slow
NRTI-Hypersensitivity
Abacavir, up to 5% incidence
Generally occurs within first 8 weeks
Characterized by fever, fatigue, nausea, maculopapular
rash, with myalgias, cough and dyspnea less common
Symptoms occur over several days, and may increase with
each dose
Predicted by HLA B5701 haplotype
Treatment-discontinue the drug
Rechallenge may be life-threatening
NRTI-Nephrotoxicity
Tenofovir may cause proximal renal tubular dysfunction
Occasional decrease in creatinine clearance
Toxicity is usually mild (average increase in creatinine
0.15) and does not require drug discontinuation
Severe nephrotoxicity uncommon (<5%) but does happen
Avoid use in patients with pre-existing renal dysfunction
?Use in diabetics and hypertensives
Sample Test Question
A 37 y/o HIV infected male is admitted from the ER with nausea,
vomiting and abdominal pain for 3 days. HIV infection was
diagnosed two years ago. He has no other illnesses, has never had
an AIDS-defining illness, and on his most recent clinic followup visit
one month ago his viral load was undetectable and his CD4 count
was 415. He drinks a glass of wine “occasionally” and does not
smoke. His medications are tenofovir 300mg qday, didanosine
400mg qday, atazanavir 300mg qday, and ritonavir 100mg qday.
Physical exam findings include orthostatic hypotension and diffuse
epigastric tenderness. Lab results include a lipase-1163, ALT-177,
AST-129, and normal bilirubin. Which of the following statements
is best regarding his condition?
1. He has tenofovir-induced pancreatitis.
2. He has alcohol-induced pancreatitis.
3. He has HIV enteropathy.
4. He has didanosine-induced pancreatitis.
NRTI-GI Toxicity
Pancreatitis-didanosine, uncommon (0.5-5%) but
potentially serious; be aware of interaction between ddI and
tenofovir (dose of ddI needs adjusting)
Hepatotoxicity
1) Mitochondrial toxicity with hepatic steatosis-AZT,
stavudine, didanosine
2) Abacavir hypersensitivity
3) Hepatitis B flares-withdrawal or development of
resistance to tenofovir, lamivudine, or emtricitabine
Test Question
A 30 y/o HIV positive male has been on tenofovir/emtricitabine/
indinavir/ritonavir for 14 months. He has never had any other
medical problems. He has been asymptomatic, his viral load has
gone from its baseline of 114,000 to undetectable and his CD4
count has increased from 258 to 433. He now c/o nausea, right
flank pain and gross hematuria for two days, no fever. He had
normal baseline renal function, but labs now show WBC-6.1, BUN37 and creatinine-2.2. Urinalysis shows hematuria. The following is
the best statement about his condition:
1. He most likely has HIV-induced renal failure and should be
referred to a nephrologist.
2. He has tenofovir-induced nephrotoxicity, and the drug should
be stopped.
3. He has indinavir-induced nephrotoxicity due to nephrolithiasis,
and the drug should be stopped.
4. He most likely has a urinary tract infection. His HAART meds
should be continued, and he should be started on empiric
antibiotics pending results of a urine culture.
TOXICITYINDIVIDUAL PROTEASE INHIBITORS
Indinavir (Crixivan)-nausea, diarrhea, nephrolithisis/nephrotoxicity in
10-20%
Ritonavir (Norvir)-nausea, diarrhea, circumoral paresthesias 5-10%
Nelfinavir (Viracept)-diarrhea
Kaletra, fosamprenavir (Lexiva), tipranavir (Aptivus)-GI intolerance
atazanavir (Retataz)-increased indirect bilirubin, nephrolithiasis
(uncommon)
Sample Test Question
A 33 y/o HIV positive female has been in good health on HAART
(stavudine/lamivudine/lopinavir/ritonavir) for three years. Her most
recent CD4 is 345 with an undetectable viral load 8 weeks ago.
However she now complains of has 3 weeks of worsening fatigue,
anorexia, and nausea, and she has lost 12 lbs during that time.
Physical exam is unremarkable. Initial lab results include an AST-111,
ALT-128, total bilirubin-0.8, lipase-126, Na-138, K-3.8, Cl-102, CO2-16,
BUN-24, creatinine-1.4 and a normal CBC. The best diagnostic test(s)
at this time is:
1. CT of the abdomen/pelvis
2. CK and aldolase levels
3. Arterial Blood Gases
4. lactic acid level
Lactic Acidosis Syndrome
Symptomatic disease uncommon, 0.5-1/100 patient years
of NRTI exposure
Most strongly associated with d4T(stavudine) and d4T/ddI
use; other risk factors are pregnancy, ddI (didanosine) with
ribavirin or hydroxyurea
Non-specific symptoms: fatigue, nausea, vomiting,
diarrhea, abdominal discomfort or distention; hepatic
steatosis
Higher lactic acid levels (>10mM) have worse prognosis
Therapy: stop “d” drug, supportive care, ?vitamins
No value to monitor lactic acid in absence of symptoms
Sample Test Question
A 35 y/o male with AIDS (last CD4-97) is in your care. He also has
peripheral neuropathy and hyperlipidemia. His medications are
tenofovir/emtricitabine/efavirenz (Atripla), TMP/SMZ (Bactrim),
simvastatin, and gabapentin. He now c/o myalgias, anorexia and
fatigue for two weeks. Lab results include total cholesterol-235, LDL161, AST-205, ALT 187, and CK-851. The best plan at this time is:
1. Increase simvastatin dose for better treatment of his
hyperlipidemia.
2. Stop simvastatin because on interaction with efavirenz is causing
drug toxicity.
3. Stop tenofovir because of tenofovir-related hepatotoxicity.
4. Stop tenofovir because of tenofovir-related myopathy.
Drug Interactions and Anti-HIV Agents
Lipid-lowering agents (statins)
PIs, efavirenz (statin)
use pravastatin or rosuvastatin (minimal) or atorvastatin
(moderate)
Anticonvulsants
phenytoin, carbamazepine, phenobarbital-monitor levels
most PIs
Miscellaneous
methadone-some PIs, nevirapine, efavirenz
sildenafil, vardenafil-most PIs
warfarin-most PIs, efavirenz
Drug Interactions and Anti-HIV Agents
Antifungals
• itraconazole-most PIs ( itra), nevirapine and efavirenz ( itra)
• voriconazole-ritonavir, efavirenz ( vori)
Antimycobacterials
rifampin-all PIs, nevirapine,
rifabutin-all PIs, nevirapine, efavirenz (but <rifampin)
clarithromycin-most PIs, nevirapine, efavirenz
Oral contraceptives
most PIs, nevirapine, efavirenz
PCP (Pneumocystis jiroveci)-Clinical features
Usually a CD4 < 200, co-existent thrush common
Sub-acute presentation (weeks)
Common symptoms-fever, weight loss, progressive DOE, cough
Hypoxemia
CXR-bilateral, interstitial infiltrates most common; normal,
pneumothorax less common
Diagnosis-induced sputum (poorly sensitive), BAL >95% sensitivity;
LDH and galactomannan may also be useful
PCP-Treatment
Preferred-Trimethoprim/sulfamethoxazole 15-20 mg/kg/day in 3-4
divided doses IV or oral (Bactrim DS two tabs TID PO)
Hypoxemia-use steroids if room air PO <70mm or A-a gradient
>35mm
Response to therapy may be slow (5-7 days)
Alternatives:
trimethoprim/dapsone
pentamidine IV
clindamycin/primaquine
atovoquone
Tuberculosis
Much more common in setting of HIV disease
May have typical pulmonary TB at higher CD4 counts,
atypical presentation very common at CD4 <100extrapulmonary/disseminated TB and CXR may show
infiltrates or miliary pattern without cavitation
Diagnosis with AFB smears/culture/biopsy
High false-negative rate with PPD
Treatment-4 anti-TB drugs to start; beware of rifampin and
drug interactions
Response to therapy similar to HIV negative persons
OPPORTUNISTIC INFECTION QUESTION
A 36 y/o HIV infected male, CD4-33, is brought to the ER with 5 days of
fever and headache. He has not been in care for more than one year
and is taking no meds. He is lethargic on exam and has white patches
on his tongue and buccal mucosa. An MRI of the head shows focal,
enhancing lesions with surrounding edema-2 in right parietal lobe and
one in left basal ganglia. The best evaluation/treatment plan is:
1. Obtain an LP to evaluate for cryptococcal meningitis.
2. start pyrimethamine and sulfadiazine
3. consult neurosurgery for brain biopsy
4. start HAART as therapy for AIDS-related PML
CNS TOXOPLASMOSIS
Most common cause of brain abscess
CD4 usually <100
Common presentation-fever, headache, altered mental status, focal
neurologic deficits, seizure
Diagnosis: Toxo serology positive in 95%; CNS imaging usually shows
multiple, bilateral, ring-enhancing lesions; single lesions may be
confused with lymphoma
Treatment: pyrimethamine/sulfadiazine  leucovorin, dexamethasone
for mass effect due to edema; alternatives include
pyrimethamine/clindamycin and Bactrim
Clinical and/or radiographic improvement in 1-2 weeks
CRYPTOCOCCAL MENINGITIS
Most common cause of meningitis
Extra-meningeal disease less common, sometimes with papular skin
lesions
CD4 usually <100
Usual presentation-subacute with fever, headache, altered mental
status, seizure
Diagnosis-CSF crypto antigen, culture, India Ink smear; blood cultures;
serum CAG positive in >95%
Treatment-initial (7-14 days) period of amphotericin with flucytosine,
followed by fluconazole 400 mg qday x 8 weeks, then  to 200 mg qday
Elevated intracranial pressure-common, important cause of morbidity
and mortality; treat with serial LPs or VP shunt
CMV DISEASE
Retinitis most common, CD4 usually <50
Common presentation-floaters, visual field defect, loss of visual acuity
Diagnosis via funduscopic exam by ophthalmologist
Treatment: valgancyclovir 900 mg BID P0 x 14-21 days (systemic
therapy required) with or without intraocular gancyclovir implant;
alternatives include gancyclovir, foscarnet, and cidofovir; avoid AZT
CMV GI disease: usually esophagitis or colitis, biopsy for diagnosis,
treat with valgancyclovir
CMV neurologic disease:
encephalitis: lethargy, confusion, fever; dx-CMV PCR of CSF
radiculopathy: rapidly progressive leg paresis, bowel and bladder
dysfunction
PML-Polymorphonuclear
Leukoencephalopathy
Caused by JC viral infection of CNS
CD4 usually <200
Common presentation-progressive cognitive and motor dysfunction
over weeks to months; no fever
MRI of head shows hypodense lesions of white matter; CT not as
sensitive
Diagnosis: compatible clinical syndrome and imaging study with
positive JC viral PCR of CSF (sensitivity-80%); also brain biopsy
Treatment-HAART; no effective direct treatment known
Candidiasis and HIV Infection
Oral candidiasis-very common, CD4 usually <300; can be treated with
local or systemic antifungal therapy; avoid chronic, daily use of azoles
Esophageal candidiasis
thrush usually present, CD4 usually <100
Symptoms: dysphagia, usually no fever; odynophagia suggests
esophageal ulceration
Treatment: fluconazole 200 mg daily for 14-21 days, response usually
within 7 days
Alternatives for fluconazole-refractory disease include itraconazole
elixir PO, IV amphotericin B or IV caspofungin
DISSEMINATED MAC-MYCOBACTERIUM
AVIUM COMPLEX
Usually CD4 <50
Typical presentation-subacute fever, night sweats, weight loss,
diarrhea, anemia and neutropenia
Diagnosis via culture from blood or visceral organ; positive MAC
cultures of sputum or stool document colonization only
Treatment
HAART
clarithromycin plus ethambutol plus/minus rifabutin, prolonged therapy
necessary
watch for clarithromycin or rifabutin drug interactions
DISSEMINATED HISTOPLASMOSIS
CD4 usually <200
Common symptoms include fever (may be up to 105°), fatigue, weight
loss, nausea and diarrhea
Multiorgan disease with lung, CNS, GI tract, liver, or bone marrow
involvement
Diagnosis-cultures of blood or BM, visualization of organisms in
peripheral blood or BM biopsy, urine Histo antigen (>90% sensitive)
Treatment:
severe disease: amphotericin B initially, followed by itraconazole
mild to moderate disease: itraconazole 200 mg BID x 8-12 weeks, then
 to 100 mg BID as maintenance
HERPES SIMPLEX
Any CD4 count
Orolabial and genital ulcerative lesions common; with advanced
AIDS lesions may be more extensive, and may disseminate
Disease tends to be more extensive and refractory to therapy in
AIDS
Treatment:
acyclovir 400 mg TID for 7-10 days for typical lesions, famcyclovir
or valacyclovir also effective
Severe disease: may need IV therapy initially, more prolonged
course
acyclovir-resistant disease-foscarnet IV or cidofovir IV
visceral organ involvement/encephalitis-high-dose acyclovir IV
chronic suppressive therapy for frequent recurrences or advanced
AIDS
HIV-RELATED MALIGNANCIES
Kaposi’s sarcoma-caused by HHV-8, CD4 usually <300,
brown/violaceous skin macules/nodules, may cause visceral organ
involvement, much less common in HAART era
Cervical cancer-associated with HPV, regular screening PAP smears in
women recommended to monitor for dysplasia
Non-Hodgkin’s Lymphoma-CD4 usually <100, associated with EBV,
often high-grade, multiple presentations possible including primary
effusion lymphoma, prognosis much better in HAART era
CNS Lymphoma-CD4 usually <50, associated with EBV, MRI-irregular
enhancing lesions often single by may be multiple usually in
periventricular or periependymal areas, thallium SPECT scan helpful
OIs-PRIMARY PROPHYLAXIS
PCP
risk: CD4 <200, prior PCP or thrush
preferred: TMP-SMX qday
alternatives: dapsone 100 mg qday, weekly
dapsone/pyrimethamine,
aerosolized pentamidine monthly,
atovaquone qday
immune reconstitution: stop prophylaxis if CD4 >200 for >3
months
•
TB
risk: positive PPD (>5mm) or recent close contact
preferred: INH x 9 months
OIs-PRIMARY PROPHYLAXIS
Toxoplasmosis
risk: CD4 <100 plus positive Toxo serology
preferred: TMP-SMX qday
alternatives: dapsone plus pyrimethamine
immune reconstitution: stop prophylaxis if CD4 >200 for >3
months
•Disseminated MAC
risk: CD4 <50
preferred: azithromycin 1200 mg qweek or Biaxin 500 mg BID
alternative: rifabutin 300 mg qday
immune reconstitution: stop prophylaxis if CD4 >100 for >3
months

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