NBHN Internal Medicine Core Curriculum Review November 26, 2008

NBHN Internal Medicine NBHN Internal Medicine Core Curriculum ReviewCore Curriculum Review

November 26, 2008November 26, 2008

HIV JEOPARDY!HIV JEOPARDY!Jacobi’s Favorite Quiz ShowJacobi’s Favorite Quiz Show

CAN’T WE ALL JUST GET ALONG?CAN’T WE ALL JUST GET ALONG? BORED OF THE BOARDS BORED OF THE BOARDS HIV styleHIV style I’M OK, YOU’RE GOING TO BE OKI’M OK, YOU’RE GOING TO BE OK

$20$20 $20$20 $20$20

$40$40 $40$40 $40$40

$60$60 $60$60 $60$60

$80$80 $80$80 $80$80

$100$100 $100$100 $100$100

THISTHIS

ISIS

CAN’T WE ALL JUST CAN’T WE ALL JUST GET ALONG?GET ALONG?

BORED OF THE BORED OF THE BOARDS BOARDS HIV styleHIV style

I’M OK, YOU’RE I’M OK, YOU’RE GOING TO BE OKGOING TO BE OK

$20 $20 $20$20

$40$40 $40$40 $40$40

$60$60 $60$60 $60$60

$80$80 $80$80 $80$80

$100$100 $100$100 $100$100

final

The MACS studyThe MACS study

•I: <500 c/mL

•II: 501 - 3000 c/mL

•III: 3001 - 10,000 c/mL

•IV: 10,001 – 30.000 c/mL

•V: >30,000 c/mL

www.annals.org/cgi/content/full/126/12/946

Plasma Viral Load & CD4+ Lymphocytes as Prognostic Markers of HIV-1 Infection John W. Mellors, MD; Alvaro Munoz, PhD; Janis V. Giorgi, PhD; Joseph B. Margolick, MD, PhD; Charles J. Tassoni, PhD; Phalguni Gupta, PhD; Lawrence A. Kingsley, DrPH; John A. Todd, PhD; Alfred J. Saah, MD; Roger Detels, MD; John P. Phair, MD; & Charles R. Rinaldo Jr., PhD

15 June 1997 | Volume 126 Issue 12 | Pages 946-954

What is the study that showed VL is prognostic?

Sequence of viral & antiviral responses after HIV infection

Likelihood of Developing AIDS in Three YearsLikelihood of Developing AIDS in Three Years

0%

20%

40%

60%

80%

100%

>750501-750

351-500201-350

<200

Mellors, Muñoz, . . ., Rinaldo - Ann Int Med 1997

June 1997

>30K>55K

10K – 30K20K – 55K

3K – 10K7K – 20K

501 – 3K 1501 – 7K

<500 bDNA<1501 RT-PCR

Plasma Viral Load (copies/ml in thous&s)

CD4+T-lymphocyte

Count(cells/mm3)

Likelihood of progression to AIDS or death in the pretreatment (A) & treatment (B) era.

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An effective way to An effective way to reduce HIV transmission, reduce HIV transmission,

especially in the especially in the developing worlddeveloping world

What is male circumcision? Impact of male circumcision on F-to-M HIV transmission

Follow-up: 4664 person-years, mean 17.9 monthsFollow-up: 4664 person-years, mean 17.9 monthsTrial was stopped after interim analysis by DSMB & circumcision offered Trial was stopped after interim analysis by DSMB & circumcision offered to control groupto control group

HIV incidenceHIV incidence

M0–M3M0–M3 M4–M12M4–M12 M12–M21M12–M21 TotalTotal

Intervention Intervention ((nn=1538)=1538)

22 77 99 1818

Control Control ((nn=1590)=1590)

99 1515 2727 5151

TOTALTOTAL 1111 2222 3636 6969

Unadjusted RR: 0.35 (0.20–0.60); Unadjusted RR: 0.35 (0.20–0.60); pp=0.00013=0.00013

Protection (1-RR): 65% (40%-80%)Protection (1-RR): 65% (40%-80%)

Male circumcision significantly reduced (6 to 7 out of 10) but did Male circumcision significantly reduced (6 to 7 out of 10) but did not prevent HIV infectionsnot prevent HIV infections

Auvert B, et al. 3rd IAS, Rio de Janeiro 2005, #TuOa0402 link

Recommended steps before Recommended steps before initiating HIV therapyinitiating HIV therapy

What is send the following labs?What is send the following labs?

Before Initiating ART:Before Initiating ART:

RPR or VDRLRPR or VDRLPPDPPDChest X rayChest X rayHepatitis A,B,C Hepatitis A,B,C serologyserologyToxoplasma IgGToxoplasma IgGFasting glucose & Fasting glucose & lipidslipids

Gynecologic exam Gynecologic exam with pap smearwith pap smear

Testing for chlamydia Testing for chlamydia & gonorrhea& gonorrhea

Ophthalmology exam Ophthalmology exam (CD4+ T cell count (CD4+ T cell count <100 cells/µL)<100 cells/µL)

Before Initiating ART: Before Initiating ART: consider/optionalconsider/optional

After Initiating ART: After Initiating ART:

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Situations not calling for resistance Situations not calling for resistance testingtesting

What is after d/cing HAART & if VL < 1000 c/mL?

NOT USUALLY NOT USUALLY RECOMMENDEDRECOMMENDED

COMMENTCOMMENT

After discontinuation of drugsAfter discontinuation of drugs Resistance mutations may Resistance mutations may become minor species in the become minor species in the absence of selective drug absence of selective drug pressure.pressure.

Plasma VL <1000 HIV RNA Plasma VL <1000 HIV RNA copies/mLcopies/mL

Resistance assays unreliable Resistance assays unreliable if HIV RNA is low.if HIV RNA is low.

The Use of Drug Resistance TestingThe Use of Drug Resistance TestingRECOMMENDEDRECOMMENDED COMMENTCOMMENT

Acute HIV infection, if Acute HIV infection, if treatment is to be startedtreatment is to be started

To determine if resistant virus was transmitted; guide To determine if resistant virus was transmitted; guide treatment decisions.treatment decisions.

Consider resistance testing if treatment is deferred.Consider resistance testing if treatment is deferred.

Chronic HIV infection Chronic HIV infection before starting ARTbefore starting ART

Transmitted drug-resistant virus is common in some Transmitted drug-resistant virus is common in some areas; is more likely to be detected earlier in the course areas; is more likely to be detected earlier in the course of HIV infection; consider resistance testing earlier in the of HIV infection; consider resistance testing earlier in the course of infectioncourse of infection

PregnancyPregnancy Recommended before initiation of ART or prophylaxis, Recommended before initiation of ART or prophylaxis, or if incomplete viral suppression on ARTor if incomplete viral suppression on ART

Virologic failure during Virologic failure during ARTART

To assist in selecting active drugs for a new regimen. To assist in selecting active drugs for a new regimen.

Suboptimal suppression Suboptimal suppression of VL after starting ARTof VL after starting ART

To guide treatment decisions.To guide treatment decisions.

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>350, asymptomatic>350, asymptomatic

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What is situations where I can hold off on HAART?

Initial Treatment: Initial Treatment: Preferred ComponentsPreferred Components

What is EFV or ATV-r, fos-APV-r, LPV-r (BID or qD), DRV-

r + TDF/FTC?

**Avoid inAvoid in pregnant women & women with significant pregnancy potential. pregnant women & women with significant pregnancy potential.**Emtricitabine can be used in place of lamivudine & vice versa.**Emtricitabine can be used in place of lamivudine & vice versa.

Efavirenz* Efavirenz*

OR

Atazanavir + ritonavir qD Atazanavir + ritonavir qD

Fosamprenavir + ritonavir BIDFosamprenavir + ritonavir BID

Lopinavir/ritonavir BID or qDLopinavir/ritonavir BID or qD

Darunavir/ritonavir qD Darunavir/ritonavir qD

NNRTI Option

PI Options

Tenofovir + emtricitabine**

+

NRTI Options

Initial Treatment: Initial Treatment: Alternative ComponentsAlternative Components

*Nevirapine should not be initiated in women with CD4 counts >250 cells/mm3 or men with CD4 *Nevirapine should not be initiated in women with CD4 counts >250 cells/mm3 or men with CD4 counts >400 cells/mm3counts >400 cells/mm3

**Atazanavir must be boosted with ritonavir if used in combination with tenofovir**Atazanavir must be boosted with ritonavir if used in combination with tenofovir

Nevirapine* Nevirapine*

OR

Atazanavir** Atazanavir**

FosamprenavirFosamprenavir

Fosamprenavir + ritonavir Fosamprenavir + ritonavir (1x/day)(1x/day)

Lopinavir/ritonavir (1x/day)Lopinavir/ritonavir (1x/day)

NNRTI Option

PI Options

Abacavir + lamivudine

Didanosine + (emtricitabine or lamivudine)

NRTI Options

Efficacy of triple-drug ART: Pill count & Efficacy of triple-drug ART: Pill count & virologic response at Week 48virologic response at Week 48

Correlation observed in univariate analysis between pill count (all studies) & response (r=Correlation observed in univariate analysis between pill count (all studies) & response (r=––0.32; 0.32; pp<0.01)<0.01)

No correlation observed in univariate analysis for ≤10 pills per day (r=0.087; No correlation observed in univariate analysis for ≤10 pills per day (r=0.087; pp=0.57)=0.57)

Significant interaction observed between pill count & drug classSignificant interaction observed between pill count & drug class

When adjusted for concomitant factors (eg, drug class) in multivariate linear regression analysis, When adjusted for concomitant factors (eg, drug class) in multivariate linear regression analysis, correlation between pill count & response is not significantcorrelation between pill count & response is not significant

Bartlett J, et al. 12th CROI, Boston 2005, #586

20

40

60

80

100

0 5 10 15 20 25Number of antiretroviral pills prescribed/day

% H

IV R

NA

<50

c/m

L

Bubble size relates to number of patients enrolled

PI triple

NRTI triple

NNRTI triple

BPI triple

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THE MOST APPROPRIATE TREATMENT FOR THE MOST APPROPRIATE TREATMENT FOR aa 21 y.o. HIV+ F w/ progressive SOB & a dry, 21 y.o. HIV+ F w/ progressive SOB & a dry, nonproductive cough of 3 wks’ duration w/ a low-grade nonproductive cough of 3 wks’ duration w/ a low-grade fever. fever. She tested HIV+ 7yrs ago, but has not seen a physician She tested HIV+ 7yrs ago, but has not seen a physician since & is not taking any medications. since & is not taking any medications. P.E. shows she is moderately distressed, with a RR = 28 P.E. shows she is moderately distressed, with a RR = 28 bpm, BP = 126/76, HR =100, Temp = 101. bpm, BP = 126/76, HR =100, Temp = 101. Chest exam reveals crackles in B lower lung fields. Chest exam reveals crackles in B lower lung fields. A CXR is remarkable for diffuse bilateral interstital A CXR is remarkable for diffuse bilateral interstital infiltrates emanating from the hila in “butterfly pattern.”infiltrates emanating from the hila in “butterfly pattern.”

Laboratory Studies Laboratory Studies

ABG on RA = 7.47/32/72ABG on RA = 7.47/32/72

What is add steroids to TMP-SMX?

• The patient most likely has PCP (recently re-classified as The patient most likely has PCP (recently re-classified as Pneumocystis Pneumocystis

jiroveci. jiroveci.

• In mild cases, the clinical exam may be normal.In mild cases, the clinical exam may be normal.

• The characteristic CXR shows B diffuse interstitial infiltrates radiating from The characteristic CXR shows B diffuse interstitial infiltrates radiating from

the hila in a butterfly distribution.the hila in a butterfly distribution.

• CT of the chest will show areas of “ground glass.”CT of the chest will show areas of “ground glass.”

• 11stst-line tx is TMP-SMX, with corticosteroids added if on RA, ABG with pO2 -line tx is TMP-SMX, with corticosteroids added if on RA, ABG with pO2

<70mm Hg or if A-a gradient is > 35<70mm Hg or if A-a gradient is > 35

• At seal level, A-a gradient = 150 – (pO2 +pCO2/0.8) = 150- (72 +32/0.8) = 38At seal level, A-a gradient = 150 – (pO2 +pCO2/0.8) = 150- (72 +32/0.8) = 38

Key Points

•TMP-SMX is the first line tx of PCP

•It is critical to add steroids to TMP-SMX if RA ABG shows pO2<70 or A-a >35

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THE MOST APPROPRIATE EVALUATION FOR THE MOST APPROPRIATE EVALUATION FOR

a 38-year-old homeless F iw/ severe odynophagia & mild a 38-year-old homeless F iw/ severe odynophagia & mild

dysphagia of 7 d duration. dysphagia of 7 d duration.

She cannot eat solid foods & can only drink cold ginger ale & She cannot eat solid foods & can only drink cold ginger ale &

ice water. The patient has a history of injection drug use & ice water. The patient has a history of injection drug use &

chronic HCV, but she is not certain whether she was ever chronic HCV, but she is not certain whether she was ever

tested for HIV. tested for HIV.

PE: unremarkable except for mild dehydration. No oral or PE: unremarkable except for mild dehydration. No oral or

cutaneous lesions. cutaneous lesions.

CBC: normocytic anemia & mild leukopenia with CBC: normocytic anemia & mild leukopenia with

lymphopenia. lymphopenia.

What is FLUCONAZOLE?

• HIV-associated HIV-associated Candida Candida esophagitis is the most likely diagnosis, & esophagitis is the most likely diagnosis, &

empiric tx with fluconazole is the most cost-effective approach. empiric tx with fluconazole is the most cost-effective approach.

• Herpetic esophagitis is much less common & empiric valacyclovir is Herpetic esophagitis is much less common & empiric valacyclovir is

therefore not appropriate. therefore not appropriate.

• Barium swallow studies have low sensitivity & specificity for Barium swallow studies have low sensitivity & specificity for

diagnosing diagnosing Candida Candida esophagitis. esophagitis.

• Although upper endoscopy is highly sensitive & specific, it is an Although upper endoscopy is highly sensitive & specific, it is an

expensive & potentially dangerous procedure & should be reserved expensive & potentially dangerous procedure & should be reserved

for patients with fluconazole-resistant esophagitis or those with for patients with fluconazole-resistant esophagitis or those with

severe symptoms. severe symptoms.

Key PointKey PointEmpiric therapy with fluconazole is the most Empiric therapy with fluconazole is the most appropriate therapy for a patient with suspected appropriate therapy for a patient with suspected HIV-associated HIV-associated Candida Candida esophagitis. esophagitis.

ReferencesReferences

Bluhm CS, Bickerstaff CA, Holt S.Bluhm CS, Bickerstaff CA, Holt S. Refractory esophageal candidiasis in acquired immune deficiency syndrome Refractory esophageal candidiasis in acquired immune deficiency syndrome

(AIDS). Am J Gastroenterol. 1990;85:479-80. PMID: 2327396 [PubMed] (AIDS). Am J Gastroenterol. 1990;85:479-80. PMID: 2327396 [PubMed]

Bonacini M, Young T, Laine L.Bonacini M, Young T, Laine L. The causes of esophageal symptoms in human immunodeficiency virus infection. A The causes of esophageal symptoms in human immunodeficiency virus infection. A

prospective study of 110 patients. Arch Intern Med. 1991;151:1567-72. PMID: 1651690 [PubMed] prospective study of 110 patients. Arch Intern Med. 1991;151:1567-72. PMID: 1651690 [PubMed]

Baehr PH, McDonald GB.Baehr PH, McDonald GB. Esophageal infections: risk factors, presentation, diagnosis, & treatment. Gastroenterology. Esophageal infections: risk factors, presentation, diagnosis, & treatment. Gastroenterology.

1994;106:509-32. PMID: 7980741 [PubMed] 1994;106:509-32. PMID: 7980741 [PubMed]

Vazquez JA.Vazquez JA. Therapeutic options for the management of oropharyngeal & esophageal candidiasis in HIV/AIDS Therapeutic options for the management of oropharyngeal & esophageal candidiasis in HIV/AIDS

patients. HIV Clin Trials. 2000;1:47-59. PMID: 11590489 [PubMed] patients. HIV Clin Trials. 2000;1:47-59. PMID: 11590489 [PubMed]

Bonacini M.Bonacini M. Medical management of benign oesophageal disease in patients with human immunodeficiency virus Medical management of benign oesophageal disease in patients with human immunodeficiency virus

infection. Dig Liver Dis. 2001;33:294-300. PMID: 11407677 [PubMed]infection. Dig Liver Dis. 2001;33:294-300. PMID: 11407677 [PubMed]

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THE MOST APPROPRIATE TREAMENT WHILE YOU ARE THE MOST APPROPRIATE TREAMENT WHILE YOU ARE

AWAITING GENOTYPE RESULTSAWAITING GENOTYPE RESULTS

FORFOR a 37 y.o. M, HIV+ x 3 yrs, DM x 14yrs w/ weakness, myalgias & freq HA a 37 y.o. M, HIV+ x 3 yrs, DM x 14yrs w/ weakness, myalgias & freq HA

that began 8 wks ago after starting his 1that began 8 wks ago after starting his 1stst HAART. HAART.

He has never had any sx’s from HIV. He has never had any sx’s from HIV.

At the start of HAART (AZT/3TC & LPV-r), his CD4=143 & VL = 56,388 w/ At the start of HAART (AZT/3TC & LPV-r), his CD4=143 & VL = 56,388 w/

nl BUN/Cr & CBC, tot chol = 249 (LDL=145). nl BUN/Cr & CBC, tot chol = 249 (LDL=145).

PMH: HTN & hypercholesterolemiaPMH: HTN & hypercholesterolemia

Medications: simvastatin & Metoprolol. He is on a step 2 diet & jogs x 25 Medications: simvastatin & Metoprolol. He is on a step 2 diet & jogs x 25

min 3x /wk. min 3x /wk.

PE: diffuse muscle tenderness of th extremities. The ROM is decr’d PE: diffuse muscle tenderness of th extremities. The ROM is decr’d

because of pain w/ movement. because of pain w/ movement.

LABS: Hb/Hct= 8.2/24, K+ = 5.4 mEq/L, HCO3 =16, BUN/Cr = 35/1.6, tot LABS: Hb/Hct= 8.2/24, K+ = 5.4 mEq/L, HCO3 =16, BUN/Cr = 35/1.6, tot

chol = 308 (LDL=169) & his VL is 49,254.chol = 308 (LDL=169) & his VL is 49,254.

What is d/c simvastatin &/or change the PI to a NNRTI, MVC or Raltegravir?

• Pt has drug interaction between the PI & statin.Pt has drug interaction between the PI & statin.

• PI can increase simvastatin & cause severe myalgias, rhabdomyolysis & PI can increase simvastatin & cause severe myalgias, rhabdomyolysis &

potential renal insuff.potential renal insuff.

• The next necessary step is to d/c simvastatin &/or change the PI to a NNRTI.The next necessary step is to d/c simvastatin &/or change the PI to a NNRTI.

• NVP is one of the most lipid favorable ARV’s.NVP is one of the most lipid favorable ARV’s.

• Pravachol does not require alteration in dose when used with PI’s.Pravachol does not require alteration in dose when used with PI’s.

• AZT can cause anemia & myopathy.AZT can cause anemia & myopathy.

• TDF lacks this problem.TDF lacks this problem.

• Current HAART also cannot be maintained as pts failed to achieve a reduction of VL Current HAART also cannot be maintained as pts failed to achieve a reduction of VL

of 1 log after 8 wks of therapy.of 1 log after 8 wks of therapy.

• In the event of inadequate HIV tx, the best choice wuld be to explore adherence In the event of inadequate HIV tx, the best choice wuld be to explore adherence

& t/c changing/simplifying HAART.& t/c changing/simplifying HAART.

• Genotyping guides the therapeutic choice of all tx failures.Genotyping guides the therapeutic choice of all tx failures.

• At baseline, pt had abnl lipids, DM. With LDL>190, he requires tx for hyperlipidemia.At baseline, pt had abnl lipids, DM. With LDL>190, he requires tx for hyperlipidemia.

INITIATION LEVELINITIATION LEVEL LDL (mg/dL)LDL (mg/dL) GOAL (mg/dL)GOAL (mg/dL)

W/OUT CAD & <2 W/OUT CAD & <2 RISK FACTORSRISK FACTORS

>190>190 <160<160

W/OUT CAD & <2 W/OUT CAD & <2 RISK FACTORSRISK FACTORS

>160>160 <130<130

w/ CADw/ CAD >130>130 <100<100

DRUG THERAPY INITIATION BASED ON LDL LEVELS

AGE: M>45, F>55AGE: M>45, F>55

FAM H/O CAD: M 1FAM H/O CAD: M 1stst degree relative <55 or F 1 degree relative <55 or F 1stst degree <65 degree <65

HTN: BP > 140/80 or on antiHTN txHTN: BP > 140/80 or on antiHTN tx

Current tobacco useCurrent tobacco use

HDL <40HDL <40

DM is the equivalent of CADDM is the equivalent of CAD

NEGATIVE RF: HDL > 60NEGATIVE RF: HDL > 60

RISK FACTORS IN EVALUATING CAD RISK

Key Points

•AZT can cause anemia, myopathy.

•TDF lacks this problem.

•PI’s can incr statins & cause myositis.

•LDL> 190 in a pt with DM requires tx.

•Always be concerned about HAART complexity & adherence

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VIDEO VIDEO

DAILY DOUBLE!!!DAILY DOUBLE!!!

THE BEST TREATMENT OF THISTHE BEST TREATMENT OF THIS31 yo M, HIV+ who comes to your office w/ the appearance 31 yo M, HIV+ who comes to your office w/ the appearance of numerous pinpoint purplish to bright red raised spots & of numerous pinpoint purplish to bright red raised spots & nodules up to 10cm on or just under the skin. nodules up to 10cm on or just under the skin. He also c/o high fever, tender & swollen lymph nodes, He also c/o high fever, tender & swollen lymph nodes, nausea, vomiting, sweats, chills & poor appetite. nausea, vomiting, sweats, chills & poor appetite.

What is erythromycin or doxycycline first line. If either antibiotic is not tolerated, tetracycline or clarithromycin or

azithromycin is used.

BA is caused equally by BA is caused equally by Bartonella quintanaBartonella quintana & & Bartonella Bartonella henselaehenselae. . Result of exposure to flea-infested cats with Result of exposure to flea-infested cats with Bartonella Bartonella henselaehenselae & the human & the human body lousebody louse for for Bartonella quintanaBartonella quintana (cause of trench fever in soldiers during World War I).(cause of trench fever in soldiers during World War I).Now it occurs mainly in AIDS pts. It may also be a Now it occurs mainly in AIDS pts. It may also be a complication of cat scratch diz in immunocompetent pts. complication of cat scratch diz in immunocompetent pts. The infection can also causes blood vessels to grow out of The infection can also causes blood vessels to grow out of control & form tumour-like masses in other organs including control & form tumour-like masses in other organs including the bone, liver, spleen, lymph nodes, heart, gastrointestinal the bone, liver, spleen, lymph nodes, heart, gastrointestinal tract & respiratory tract where airway obstruction may occur. tract & respiratory tract where airway obstruction may occur. The condition can become life threatening if not diagnosed The condition can become life threatening if not diagnosed & treated promptly. & treated promptly. Dx of cutaneous BA remains biopsy with histopathologic Dx of cutaneous BA remains biopsy with histopathologic study. study.

KS: cancer of blood vesselsKS: cancer of blood vessels

KS is associated with infection with HHV 8. KS is associated with infection with HHV 8.

KS may develop at any time during the course of HIV KS may develop at any time during the course of HIV infection. Generally, the greater the immunosuppression infection. Generally, the greater the immunosuppression (CD4<200) the more extensive the kaposi's sarcoma will (CD4<200) the more extensive the kaposi's sarcoma will be. be.

KS presents as red to purplish spots (macules) & raised KS presents as red to purplish spots (macules) & raised bumps (papules & nodules). bumps (papules & nodules).

1st seen on the skin, commonly on legs or feet. They also 1st seen on the skin, commonly on legs or feet. They also occur in the mouth. Initially, the lesions are small & occur in the mouth. Initially, the lesions are small & painless but they can ulcerate & become painful. Their painless but they can ulcerate & become painful. Their visible presence may cause considerable anxiety. visible presence may cause considerable anxiety.

KS can also occur internally; in the gut, lungs, genitals & KS can also occur internally; in the gut, lungs, genitals & lymphatic system. These internal lesions may cause lymphatic system. These internal lesions may cause symptoms e.g. discomfort with swallowing, bleeding, symptoms e.g. discomfort with swallowing, bleeding, shortness of breath, swollen legs, etc. shortness of breath, swollen legs, etc.

If the lesions are not widespread or troublesome, often the best If the lesions are not widespread or troublesome, often the best

approach is simply to treat the underlying HIV infection with potent approach is simply to treat the underlying HIV infection with potent

HAART. These drugs reduce the frequency of KS & may also prevent HAART. These drugs reduce the frequency of KS & may also prevent

its progression or the development of new lesions. It is not yet clear its progression or the development of new lesions. It is not yet clear

why this approach works; one opinion is that the improvement in why this approach works; one opinion is that the improvement in

immune function results in reduced levels of tumour growth-promoting immune function results in reduced levels of tumour growth-promoting

proteins. proteins.

Tx: depends largely on the extent of the disease: Tx: depends largely on the extent of the disease:

Small, localized lesions are generally only treated if they are painful or Small, localized lesions are generally only treated if they are painful or

they are causing cosmetic problems. It should be noted that lesions they are causing cosmetic problems. It should be noted that lesions

tend to recur after local treatments. Treatments include: tend to recur after local treatments. Treatments include:

Freezing with liquid nitrogen Freezing with liquid nitrogen (cryotherapy) (cryotherapy)

Treatment with Treatment with radiation radiation

Surgical removal Surgical removal

Injection with anti-cancer drugs such as vinblastine Injection with anti-cancer drugs such as vinblastine

Topical application of alitretinoin gel (Panretin). Topical application of alitretinoin gel (Panretin).

A B C

D E

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THE MOST APPROPRITE THE MOST APPROPRITE MANAGEMENT AT THIS TIME FORMANAGEMENT AT THIS TIME FORa 27-y.o. M who is BIBA to the E.D. following a witnessed tonic–a 27-y.o. M who is BIBA to the E.D. following a witnessed tonic–clonic sz at work. clonic sz at work. The pt is A&O, but does not remember having the sz. He reports The pt is A&O, but does not remember having the sz. He reports that he stumbled more than usual during the past 3 wks but is that he stumbled more than usual during the past 3 wks but is uncertain whether his legs actually felt weak. HIV was dx’d 8 yrs uncertain whether his legs actually felt weak. HIV was dx’d 8 yrs ago. ago. Current medications are ZDV, 3TC, EFV. Current medications are ZDV, 3TC, EFV. One month ago, his CD4= 175/μL. One month ago, his CD4= 175/μL. Serologic testing for serum IgG ab’s to Serologic testing for serum IgG ab’s to Toxoplasma gondii Toxoplasma gondii was was neg 6 months ago. neg 6 months ago. P.E.: +OHL, mild weakness RLE. A CT scan of the brain shows P.E.: +OHL, mild weakness RLE. A CT scan of the brain shows two large lesions in the left parietal area that measure 2 cm & 3 two large lesions in the left parietal area that measure 2 cm & 3 cm, respectively, enhance slightly with contrast, & are cm, respectively, enhance slightly with contrast, & are surrounded by edema. surrounded by edema.

What is sulfadiazine + pyrimethamine?sulfadiazine + pyrimethamine?

CNS mass lesions in HIV+ pts are most often caused by CNS mass lesions in HIV+ pts are most often caused by Toxoplasma gondiiToxoplasma gondii or by or by lymphoma. lymphoma.

Lesions are occ caused by mycobacteria, endemic mycoses, Lesions are occ caused by mycobacteria, endemic mycoses, NocardiaNocardia, & ameba, & amebaless often by glioblastoma multiforme, metastatic solid tumors, & abscesses due less often by glioblastoma multiforme, metastatic solid tumors, & abscesses due to more common bacterial pathogens.to more common bacterial pathogens.

This patient is very unlikely to have cerebral toxoplasmosis for three reasons: This patient is very unlikely to have cerebral toxoplasmosis for three reasons: CD4 is unusually highCD4 is unusually high recent serologic testing for serum IgG antibodies to recent serologic testing for serum IgG antibodies to T. gondiiT. gondii was negative was negative his prophylactic regimen has been reasonably effective. his prophylactic regimen has been reasonably effective. Another dx must be sought urgently because of the size of the 2 lesions & the Another dx must be sought urgently because of the size of the 2 lesions & the

surrounding edema. surrounding edema. Brain biopsy is the best way to determine the cause of mass lesions & is especially Brain biopsy is the best way to determine the cause of mass lesions & is especially important when toxoplasmosis is unlikely. important when toxoplasmosis is unlikely. Lymphomas are readily dx’d by CT-guided needle bx if the lesions can be visualized by CT Lymphomas are readily dx’d by CT-guided needle bx if the lesions can be visualized by CT scanning & are anatomically accessible. Although stereotactic bx is safer in experienced scanning & are anatomically accessible. Although stereotactic bx is safer in experienced h&s, an open biopsy is an alternative. h&s, an open biopsy is an alternative. Cerebrospinal fluid cytologic studies & Cerebrospinal fluid cytologic studies & T. gondiiT. gondii ab titers are unlikely to provide a dx. ab titers are unlikely to provide a dx. Empiric tx of a suspected CNS lymphoma is undesirable because almost any other entity Empiric tx of a suspected CNS lymphoma is undesirable because almost any other entity that the pt might have could worsen with corticosteroid administration & RT. that the pt might have could worsen with corticosteroid administration & RT. If empiric tx for toxoplasmosis is initiated, the standard regimen is sulfadiazine plus If empiric tx for toxoplasmosis is initiated, the standard regimen is sulfadiazine plus pyrimethamine. Trimethoprim–sulfamethoxazole may be effective, but experience with this pyrimethamine. Trimethoprim–sulfamethoxazole may be effective, but experience with this regimen is limited, & there are theoretical reasons to suspect that this agent may not be as regimen is limited, & there are theoretical reasons to suspect that this agent may not be as effective as sulfadiazine & pyrimethamine. effective as sulfadiazine & pyrimethamine.

Key Points Key Points CNS mass lesions in HIV+ pts are most often caused by CNS mass lesions in HIV+ pts are most often caused by Toxoplasma gondiiToxoplasma gondii or by lymphoma. or by lymphoma.

When the diagnosis is uncertain, biopsy is the most When the diagnosis is uncertain, biopsy is the most effective way to determine the cause of central nervous effective way to determine the cause of central nervous system mass lesions in patients with AIDS. system mass lesions in patients with AIDS.

ReferencesReferences

1.1. Carr A, Tindall B, Brew BJ, Marriott DJ, Harkness JL, Penny R, Cooper DA. Carr A, Tindall B, Brew BJ, Marriott DJ, Harkness JL, Penny R, Cooper DA. Low-dose Low-dose trimethoprim-sulfamethoxazole prophylaxis for toxoplasmic encephalitis in patients with AIDS. trimethoprim-sulfamethoxazole prophylaxis for toxoplasmic encephalitis in patients with AIDS. Ann Intern Med. 1992;117:106-11. PMID: 1351371 [PubMed] Ann Intern Med. 1992;117:106-11. PMID: 1351371 [PubMed]

2.2. Porter SB, S&e MA. Porter SB, S&e MA. Toxoplasmosis of the central nervous system in the acquired Toxoplasmosis of the central nervous system in the acquired immunodeficiency syndrome. N Engl J Med. 1992;327:1643-8. PMID: 1359410 [PubMed] immunodeficiency syndrome. N Engl J Med. 1992;327:1643-8. PMID: 1359410 [PubMed]

3.3. Antinori A, Ammassari A, Luzzati R, Castagna A, Maserati R, Rizzardini G, et al. Antinori A, Ammassari A, Luzzati R, Castagna A, Maserati R, Rizzardini G, et al. Role of Role of brain biopsy in the management of focal brain lesions in HIV-infected patients. Neurology. brain biopsy in the management of focal brain lesions in HIV-infected patients. Neurology. 2000;54:993-7. PMID: 10691003 [PubMed] 2000;54:993-7. PMID: 10691003 [PubMed]

4.4. Gildenberg PL, Gathe JC Jr, Kim JH. Gildenberg PL, Gathe JC Jr, Kim JH. Stereotactic biopsy of cerebral lesions in AIDS. Clin Infect Stereotactic biopsy of cerebral lesions in AIDS. Clin Infect Dis. 2000;30:491-9. PMID: 10722433 [PubMed] Dis. 2000;30:491-9. PMID: 10722433 [PubMed]

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This drug can This drug can ddI levels ddI levels (Videx(Videx®® & Videx EC & Videx EC®®) & ) & atazanavir levelsatazanavir levels

What is Tenofovir?What is Tenofovir?Tenofovir (TDF, VireadTenofovir (TDF, Viread®®) Drug Interactions) Drug Interactions

ddI levels (VidexddI levels (Videx®® & Videx EC & Videx EC®®)) 60 kg: 60 kg: Videx ECVidex EC 250 mg with TDF 300 mg 250 mg with TDF 300 mg

qd qd co-administered with/without foodco-administered with/without food < 60 kg: Videx EC< 60 kg: Videx EC 200 mg with TDF 300 mg 200 mg with TDF 300 mg

qd qd co-administered with/without foodco-administered with/without food

atazanavir levelsatazanavir levels Boost ATV (300 mg qd + RTV 100 mg qd) Boost ATV (300 mg qd + RTV 100 mg qd)

when given with TDFwhen given with TDF

link

These 3 NRTI’s can all lead to These 3 NRTI’s can all lead to potent mitochondrial toxicitypotent mitochondrial toxicity

What is ddI, d4T & ddC?What is ddI, d4T & ddC?“d-drug” Interactions“d-drug” Interactions

Didanosine (ddI), Stavudine (d4T) & Didanosine (ddI), Stavudine (d4T) &

Zalcitabine (ddC) are all:Zalcitabine (ddC) are all:

Agents causing additive neurotoxicity Agents causing additive neurotoxicity

(vincristine, cisplatin, isoniazid)(vincristine, cisplatin, isoniazid)

Agents causing additive pancreatoxicity Agents causing additive pancreatoxicity

(alcohol, pentamidine, valproic acid)(alcohol, pentamidine, valproic acid)

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This drug boosts the levels of This drug boosts the levels of other ARV’s, but has many other ARV’s, but has many drug interactions.drug interactions.

What is RITONAVIR (Norvir)?What is RITONAVIR (Norvir)?Outcomes of Drug Interactions:Outcomes of Drug Interactions:

BeneficialBeneficial

Additive desirable pharmacodynamic effectsAdditive desirable pharmacodynamic effects Combination antiretroviral therapyCombination antiretroviral therapy Use of 2NRTIs + PI or NNRTI Use of 2NRTIs + PI or NNRTI

potency potency

resistanceresistance

PK BoostingPK Boosting Ritonavir for PK boostingRitonavir for PK boosting

bioavailability of other PIbioavailability of other PI

pill burdenpill burden

dosing frequency (sometimes)dosing frequency (sometimes)

Eliminate food restrictions (usually)Eliminate food restrictions (usually)

Drugs That Should Not Be Drugs That Should Not Be Given With PIsGiven With PIs

SimvastatinSimvastatinLovastatinLovastatinAstemizoleAstemizoleTerfenadineTerfenadineCisaprideCisapridePimozidePimozideBepridilBepridil

St. John’s WortSt. John’s WortRifampin (except Rifampin (except ritonavir)ritonavir)RifapentineRifapentineMidazolamMidazolamTriazolamTriazolamErgot alkaloidsErgot alkaloids

•Additionally the following should not be given with ritonavir: amiodarone, flecainide, propafenone, quinidine

•Proton pump inhibitors & Irinotecan should not be used with atazanavir

Interactions with Lipid Lowering AgentsInteractions with Lipid Lowering Agents

Simvastatin & lovastatinSimvastatin & lovastatin are contraindicated are contraindicated

with PIs or the NNRTI delavirdine with PIs or the NNRTI delavirdine

Pravastatin & fluvastatin least likely to interact Pravastatin & fluvastatin least likely to interact

with ARVswith ARVs

PravastatinPravastatin is contraindicated with is contraindicated with DarunavirDarunavir

Use atorvastatin at low-doses with caution (AUC Use atorvastatin at low-doses with caution (AUC

71% with NFV, 5-fold with lopinavir/ritonavir) 71% with NFV, 5-fold with lopinavir/ritonavir)

RosuvastatinRosuvastatin does not rely on CYP3A4 for does not rely on CYP3A4 for

metabolism-no data with ARVsmetabolism-no data with ARVs

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This tuberculosis drug This tuberculosis drug should not be used with should not be used with

NNRTI’s nor PI’sNNRTI’s nor PI’s

What is Rifamycin?What is Rifamycin?Update on Use of Rifamycins with PIs & NNRTIs Update on Use of Rifamycins with PIs & NNRTIs

Rifamycins can induce CYP3A4 enzyme & Rifamycins can induce CYP3A4 enzyme & significantly significantly PI & NNRTI levels PI & NNRTI levels Rifampin > rifapentine* > rifabutinRifampin > rifapentine* > rifabutin

Data has supported the use of rifampin with Data has supported the use of rifampin with certain ARV combinationscertain ARV combinations All single PIs should not be used with rifampin All single PIs should not be used with rifampin

(except ritonavir-rarely used as single PI today)(except ritonavir-rarely used as single PI today)

Rifabutin is also a substrate for CYP3A4 & its Rifabutin is also a substrate for CYP3A4 & its levels can be affected by PIs & NNRTIslevels can be affected by PIs & NNRTIs

*Rifapentine is a long-acting rifamycin that is not recommended for use in HIV-infected patients due to acquired rifamycin resistance

Rifabutin Use with PIs - 1Rifabutin Use with PIs - 1

Rifabutin DoseRifabutin Dose CommentsComments

Single PIsSingle PIs

AmprenavirAmprenavir to 150 mg qd or to 150 mg qd or 300 mg 3X/week300 mg 3X/week

Rifabutin AUC Rifabutin AUC 193% 193%

Fos-amprenavirFos-amprenavir to 150 mg qd or to 150 mg qd or 300 mg 3X/week300 mg 3X/week

Comparable to Comparable to amprenaviramprenavir

AtazanavirAtazanavir to 150 mg to 150 mg qod qod or or 150 mg 3X/week150 mg 3X/week


Indinavir*Indinavir* to 150 mg qd or to 150 mg qd or 300 mg 3X/week300 mg 3X/week


IDV AUC IDV AUC 32% 32%

Nelfinavir*Nelfinavir* to 150 mg qd or to 150 mg qd or 300 mg 3X/week300 mg 3X/week


NFV AUC NFV AUC 32% 32%

*Increase dose of IDV & NFV to 1000 mg q8h

Rifabutin Use with PIs - 2Rifabutin Use with PIs - 2


Single PIsSingle PIs

RitonavirRitonavir to 150 mg to 150 mg qod qod or or 150 mg 3X/week150 mg 3X/week


SaquinavirSaquinavir Do not use Do not use togethertogether

SQV AUC SQV AUC 43% 43%

PI CombinationsPI Combinations

Lopinavir/ritonavirLopinavir/ritonavir to 150 mg to 150 mg qod qod or or 150 mg 3X/week150 mg 3X/week


Ritonavir with Ritonavir with saquinavir, indinavir, saquinavir, indinavir, amprenavir, fos-amprenavir, fos-amprenavir, atazanaviramprenavir, atazanavir

to 150 mg to 150 mg qod qod or or 150 mg 3X/week150 mg 3X/week

Rifabutin Use with NNRTIsRifabutin Use with NNRTIs


NNRTIsNNRTIs

EfavirenzEfavirenz to 450 mg qd or to 450 mg qd or 600 mg 3X/week600 mg 3X/week


NevirapineNevirapine 300 mg qd or 300 300 mg qd or 300 mg 3X/weekmg 3X/week

Levels of rifabutin & Levels of rifabutin & nevirapine not nevirapine not significantly changedsignificantly changed

DelavirdineDelavirdine Do not use Do not use togethertogether


DLV AUC DLV AUC 80% 80%

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DRUG-DRUG DRUG-DRUG

DAILY DOUBLE!!!DAILY DOUBLE!!!

These are the most important These are the most important no-no’s no-no’s

to avoid in terms of ARV drug to avoid in terms of ARV drug interactions interactions

(name at least (name at least 22))

What is AZT/d4T, ABC/TDF, Simvastatin/PIs…

More Fun Facts About Nasty NRTI Interactions

AZT & StavudineAZT & Stavudine should not be used should not be used together; as thymidine analogs they are together; as thymidine analogs they are antagonisticantagonistic

ABC & TenofovirABC & Tenofovir should not be used should not be used together: they select for the K65R together: they select for the K65R mutation (leading to extensive NRTI cross-mutation (leading to extensive NRTI cross-resistanceresistance

Problems to Avoid with PI’s Problems to Avoid with PI’s Do NOT use PPI’s with unboosted atazanavirDo NOT use PPI’s with unboosted atazanavir Be cautious using H2 blockers with ATVBe cautious using H2 blockers with ATV

Be cautious using PPI’s with ATV-rBe cautious using PPI’s with ATV-r

Do NOT useDo NOT use Simvastatin Simvastatin with PI’s (too high of a with PI’s (too high of a

risk of myopathyrisk of myopathy

Similarly, do NOT use Pravastatin with DarunavirSimilarly, do NOT use Pravastatin with Darunavir Instead use Rosuvastatin or AtorvastatinInstead use Rosuvastatin or Atorvastatin

Drug Interaction ResourcesDrug Interaction Resources

www.hiv-druginteractions.orgwww.hiv-druginteractions.org

www.hivinsite.ucsf.eduwww.hivinsite.ucsf.edu

www.medscape.com/px/hivschedulerwww.medscape.com/px/hivscheduler

www.aidsinfo.nih.govwww.aidsinfo.nih.gov (DHHS HIV Treatment Guidelines, TB (DHHS HIV Treatment Guidelines, TB Guidelines)Guidelines)

link

FINAL FINAL JEOPARDY!!!JEOPARDY!!!

The category is The category is

“We’re all in this “We’re all in this together”together”

Something you can do for all of your Something you can do for all of your patients that can make a HUGE patients that can make a HUGE

differencedifference

What is “adhere to the 2006 What is “adhere to the 2006 CDC recommendations CDC recommendations

for HIV screening?”for HIV screening?”

To get a pt tested for HIV, call

x35211 or x36997

Summary of 2006 Revised CDC Recommendations for HIV Screening

Recommendation

Routine HIV voluntary screening of all persons aged 13–64 in healthcare settingsScreening not based on risk or prevalenceScreening performed as opt-out testing (patient advised to have test & patient can refuse test)Formal consent no longer requiredPrevention counseling in conjunction with HIV screening no longer requiredSeparate recommendations apply to correctional facilitiesPatients with positive HIV test should be provided reliable clinical care or referred to qualified provider

To get a pt tested for HIV, callx35211 or x36997




HIV+ persons eligible for & receiving HIV+ persons eligible for & receiving HAART in the US (15–49 years)HAART in the US (15–49 years)

CDC study based on AIDS surveillance data & those under CDC study based on AIDS surveillance data & those under care in the Adult Spectrum of HIV Disease (ASD) cohortcare in the Adult Spectrum of HIV Disease (ASD) cohort

Persons living with AIDS/HIVPersons living with AIDS/HIV 820,000820,000

Eligible for HAART (CD4+ <350 Eligible for HAART (CD4+ <350 cells/mmcells/mm33))

480,000480,000

In careIn care 340,000340,000

Receiving ARTReceiving ART 268,000268,000

Receiving HAARTReceiving HAART 176,880176,880

Teshale E, et al. 12th CROI, Boston 2005, #167

To get a pt tested for HIV, callTo get a pt tested for HIV, callx35211 or x35211 or x36997x36997


ACOG NEWS RELEASE August 1, 2008 Routine HIV Screening Recommended for All Women, Regardless of Individual Risk Factors "ACOG recommends routine HIV screening for all women ages 19 to 64, regardless of pregnancy status or what their risk factors might be." "ACOG also recommends targeted screening for women outside this age range who are at high risk. For example, all sexually active teenagers under 19 should be tested, as well as women older than 64 who have had multiple partners in recent years."

HIV Testing to be Part of a Routine Physical: MSSNY will petition the New York State Legislature & the Department of Health to consider HIV testing, when indicated, as with other disease testing, to be performed without specific written informed consent.


Recommendations for HIV Recommendations for HIV screening in NYCscreening in NYC

When evaluating patients, physicians should When evaluating patients, physicians should routinely consider the possibility of HIVroutinely consider the possibility of HIV

link

To get a pt tested for HIV, callTo get a pt tested for HIV, callx35211 or x35211 or x36997Sx36997S

Documents

NBHN Internal Medicine Core Curriculum Review November 26, 2008