The UC San Diego AntiViral Research Center sponsors weekly presentations by infectious disease clinicians, physicians and researchers. The goal of these presentations is to provide the most current research, clinical practices and trends in HIV, HBV, HCV, TB and other infectious diseases of global significance. The slides from the AIDS Clinical Rounds presentation that you are about to view are intended for the educational purposes of our audience. They may not be used for other purposes without the presenter’s express permission.

AIDS CLINICAL ROUNDS

Revisiting AIDS related mycobacterium avium complex (MAC) infection in the IRIS era

Jill Blumenthal, MD Infectious Disease Fellow

Theo Katsivas, MD

Assistant Professor, UCSD

11/22/13

23yo MSM admitted to UCSD 11/3-11/10 for abdominal pain for several weeks, some diarrhea, no n/v/c.

+30 lb weight loss with 1 week of subjective fever.

Found to be HIV positive on rapid test. CD4 20/2% with VL 423,492.

Hospital Course

11/3 CTAP: Segmental enteritis involving the jejunum, with associated enhancing reactive mesenteric lymphadenopathy

CD4 21 and CMV viremia, suspected to be 2/2 CMV colitis, started on IV gancyclovir

Upper and lower endoscopies performed, biopsies show no granulomas or inclusion bodies, some increased lymphocytes in jejunum c/w infection.

All microbiology was negative at that time

Started on azithromycin and bactrim ppx

PMH, PSH, SHx unremarkable

Outpatient Course

11/28: Started on atripla. Stool for AFB culture positive for MAC.

Blood cultures from 11/4 and 11/7 growing MAC.

Outpatient course (cont)

12/5 Started on ethambutol, azithromycin at increased dose and rifabutin.

12/15-1/11 seen frequently for intermittent abdominal pain, nausea and weight loss.

1/2/13 CD4 119/5%, VL 128.

1/8 acutely worsening abdominal pain

CTAP 1/10/13 CTAP shows increased LAD causing compression of the SMV and associated mesenteric engorgement with paraaortic LAD leading to partial outlet obstruction. Increased size of inguinal LNs.

Inpatient Hospital Course

Admitted from 1/11-1/14 for presumed MAC IRIS, started on PO prednisone.

Gained weight with improvement in nausea and vomiting.

Repeat blood and stool culture 1/13 positive for MAC (sensitive to clarithromycin at MIC 10).

Outpatient Course

Beginning of February, abdominal pain returns with tenderness in enlarging inguinal lymph node.

Repeat CTAP 2/8/13 shows interval decrease in size of multiple enlarged retroperitoneal, mesenteric, and iliac lymph nodes.

Steroids increased back after tapering to 50, symptoms improved, continue with slow taper.

2/28 AFB blood culture: positive for AFB

3/6 Inguinal lymph node biopsy: Kaposi sarcoma

Outpatient Course (cont)

3/6 Inguinal lymph node biopsy: Kaposi sarcoma

4/4 Dc’d azithromycin, started on clarithromycin (after 2/28 culture turned positive)

Mid-April to May feeling well, steroids being tapered Decision made to monitor signs for KS but no tx.

Outpatient Course (cont)

Beginning of May- Night sweats, also return of abdominal pain with nausea and vomiting.

5/15/13 CD4 70/7%, VL undectable

5/29/13 CTAP shows increased lymph nodes in inguinal and pelvic sidewall regions. Unchanged size of retroperitoneal and mesenteric nodes.

5/28 AFB Blood culture from 4/24 now positive

Outpatient Course (cont)

6/5 Started on PO moxifloxacin 6/5.

By end of June, steroids down to 10mg.

Still having abdominal pain and pressure with increased nausea and occasional episodes of vomiting, also weight loss.

Concern for active MAC infection, MAC IRIS, possible visceral KS, lymphoma

7/5: First dose of doxil. Had nausea and fatigue initially but then improved.

7/10 steroids stopped

Outpatient course (cont)

7/31 Severe abdominal pain over the previous weeks, which improved with pain meds, suspected related to destroying of KS cells

Continued nausea, vomiting and weight loss.

Decision to admit for failure to thrive and definitive diagnosis with possibly invasive biopsy.

Micro Review:

7/22/13 AFB bcx pending

4/24/13 AFB bcx: MAC (turned pos 5/28)

2/28/13 AFB bcx x2: MAC

2/28/13 stool culture: +AFB

2/27/13 CMV PCR: not detectable

1/13/13 stool: MAC

1/13/13 AFB bcx: MAC - S to clarithromycin MIC 10

1/2/13 CMV PCR 1657

11/28 CMV PCR 609

11/7 CMV PCR 12028

11/7 AFB bcx: MAC

11/4 AFB stool: MAC from enrichment broth

Hospital course (8/1-10/23)

8/2 CTAP shows compression of the third portion of the duodenum by adjacent lymph nodes and mesenteric soft tissue with upstream dilation. Ill-defined soft tissue at the root of the mesentery previously occupied by lymph nodes, causing mass effect on the adjacent duodenum and obliteration of the superior mesenteric vein.

8/2 IR guided biopsy of mesenteric LN neg

Started on TPN

Hospital Course (cont)

8/5 EGD with biopsies: neg

8/8 colonoscopy with negative rectal biopsies

8/16 Heme onc note: “We still have a high suspicion for HIV-associated lymphoma given the fact that LAD worsened while on doxil treatment for his Kaposi's sarcoma and has continued to progress through his appropriate MAC coverage. MAC IRIS remains on the differential but would need to definitively rule out other malignant causes first.”

Hospital course (cont)

8/22 paracentesis negative for infection or malignancy

8/22 Bone marrow biopsy negative for malignancy

8/19 Dr. Dan Lee note: “We remain at a diagnostic dilemma”

8/25 CTAP: Interval development of ascites with peritoneal enhancement concerning for peritonitis. Redemonstrated soft tissue mass at the root of the mesentery, and stable appearance of numerous enlarged mesenteric, retroperitoneal lymph nodes, compatible with MAC infection. Stable hyperenhancing inguinal lymph nodes, compatible with Kaposi's sarcoma.

8/29 PET CT

Hospital course (cont)

8/31 R inguinal LN biopsy c/w KS

9/6 Pleural fluid neg for infection or malignancy

9/12 EUS FNA biopsy negative for malignancy, culture + for C. Albicans, fluconazole added

Hospital course (cont)

9/19 L supraclavicular lymph node AFB smear heavily positive, culture turns positive soon thereafter

Sensitivities from 4/24 Bcx show amikacin 20, clarithro 5, ethambutol >5, rifabutin 2

Ethambutol dc’d

9/21 CTAP: Thickening of the duodenal and proximal jejunal walls. Slight interval increase in infiltrative soft tissue and LAD extending from the root of the mesentery and surrounding the duodenum and portions of the pancreas with associated venous engorgement of the mesentery secondary to central obstruction.

Hospital course (cont)

9/23 linezolid added

9/26 CD4 174/9%, VL undetectable

9/27 open mesenteric lymph node: AFB smear heavily positive

9/29 Meds changed to: IV Zithromax 500mg/d + IV Moxifloxain 400mg/d+ Linezolid 600mg IV q12h + PO rifabutin 450mg/d

Hospital course (cont)

10/1: Ethambutol readded.

Linezolid dc’d with MIC from 4/24 >32 and concern for myelosuppression.

IV amikacin added (MIC of 20 is considered intermediate sensitivity)*

10/2 cycloserine/pyrodixine added

*Brown-Elliott BA. J Clin Microbiol, 2013

Hospital course (cont)

10/9 Drug levels Rifabutin 3-hr post dose level = 0.14 mcg/mL; 7-hr post dose level = 0.34 mcg/mL (goal: 0.3-0.9 mcg/mL) Cycloserine 2-hr post dose level = 15.5 mcg/mL; 6-hr post dose level = 19.0 mcg/mL (goal: 20-35 mcg/mL)

10/10 thalidomide 100 mg daily started as steroid sparing agent for component of IRIS that likely already co-exists (also tx for KS)

10/17 emesis x3

10/22 Tolerating POs, switched to PO clarithromycin when azithromycin MIC >64

10/22 CTAP

Microbiology:

11/4/12 AFB stool: MAC from enrichment broth

11/7/12 AFB bcx MAC

1/13/13 AFB blood cx: MAC - S to clarithromycin MIC 10

1/13/13 stool culture: MAC - S to clarithro MIC 10

2/28/13 AFB blood cx x2: MAC - S to clarithro MIC 10

2/28/13 AFB stool cx: MAC - S to clarithro MIC 10

4/24/13 AFB bcx: MAC (turned pos 5/28) [amikacin 20, azithro >64, clarithromycin 5, ethambutol >5, linezolid >32, moxifloxacin 5, rifabutin 2

7/22 AFB bcx: NGTD

8/1 AFB Bcx: NGTD

9/19 AFB culture IR core biopsy: MAC [Amikacin 10, azithro >64, clofazimine >10, ethambutol >5, ethionamide >5, linezolid >32, rifabutin 2, rifampin >1)

9/27 mesenteric lymph swab AFB: MAC

9/27 mesenteric LN bx: light MAC [Amikacin 10, azithro 64, clofazimine >1.0, ethambutol >5, ethionamide >5, linezolid >32, rifabutin 2, cycloserine 25)

Outpatient course

10/30 Office visit: Nausea, vomiting and 8lb weight loss. Headaches. No abdominal pain or systemic sxs. Increased anti-emetic regimen

Cycloserine dc’d Current MAC regimen: IV amikacin 800mg daily, IV moxi 400mg daily, PO ethambutol 2400mg twice daily, PO clarithromycin 500mg bid, PO rifabutin 450mg daily

11/6 Office visit: “Has lost about 15 lbs since his discharge, very cachectic and weak. Reports that nausea and vomiting is somewhat better but still occurring fairly frequently. Using reglan, zofran and ativan intermittently. Today only vomited up saliva. Appetite is somewhat diminished but not able to hold down a lot of food. No abdominal pain. No f/c/s.”

Cr from 11/4 is 1.58 (from 0.57 on 10/22). CrCl ~ 55

11/8 Direct admission to hospital for FTT and AKI

Hospital course (11/8-present)

11/9 Restarted on TPN

11/14 Thalidomide increased to 150mg

Topics for Discussion

1. Standard dMAC therapy

2. Alternative dMAC therapy

3. MAC MICs: what do they mean?

4. MAC IRIS

5. Therapy for MAC IRIS

Recommendations for Preventing and Treating Disseminated MAC

http://aidsinfo.nih.gov/contentfiles/lvguidelines/adult_oi.pdf. 2013

Recommendations for Treating Disseminated MAC (cont)

http://aidsinfo.nih.gov/contentfiles/lvguidelines/adult_oi.pdf. 2013

Alternative dMAC Treatment

Clofazamine should not be used in HIV because randomized trials have shown lack of efficacy and association with increased mortality

Anecdotal evidence exists for use of other agents, such as ethionamide, thiacetazone and cycloserine in combo with macrolide

Ethionamide and cycloserine rarely used due to toxicity and need for blood level monitoring (cycloserine)

Alternative dMAC Treatment (cont)

Mefloquine active in vitro and in vivo against MAC (Bermudez LE, et al. Antimicrob Agents Chemother, 1999)

No significant effect on bacteremia, however combination of mefloquine + ethambutol showed more activity than either drug alone in liver, spleen and blood

Recent study showed that (+)-erythro-mefloquine is the active

enantiomer of mefloquine against MAC in mice (Bermudez LE, et al. Antimicrob Agents Chemother, 2012)