Theodoros Kelesidis UCLA CARE Center Prevention, diagnosis, and treatment of key Opportunistic Infections in HIV Infection Theodoros Kelesidis UCLA CARE Center

The Late Phase of HIV-1 1400 Plasma viral titer by PCR or bDNA assay 106 Plasma viral titer by culture or p24 antigen 1200 Number of CD4 cells + 105 1000 104 800 Plasma Viremia CD4+ Count 103 600 102 400 101 200 1 2 9 10 Time (Years) PCR=polymerase chain reaction; bDNA=branched DNA. Adapted with permission from Saag. In: DeVita et al, eds. AIDS: Etiology, Treatment and Prevention. 4th ed. Lippincott-Raven Publishers; 1997:203-213.

Mycobacterial disease 5.07 Toxoplasmosis 5.10 Cryptococcosis 9.00 Risk of Death Associated with ADEs Adjusted Hazard Ratio Herpes simplex 0.97 Mycobacterial disease 5.07 Toxoplasmosis 5.10 Cryptococcosis 9.00 PML 9.56 Non-Hodgkin’s lymphoma 19.31 Mocroft A, and ART Cohort Collaboration CROI 2007# 80.

33 YO with chest pain, fever and productive cough worsening over 3d

Candidiasis  Oropharyngeal candidiasis is the most common opportunistic infection in persons infected with HIV is usually associated with significant immunosuppression (CD4 counts <200 cells/microL) Topical therapy for the initial episode of oropharyngeal candidiasis in HIV-infected patients with mild disease. For patients with recurrent infection, moderate to severe disease, or in those with advanced immunosuppression (CD4 <100 cells/microL) (200 mg loading dose, followed by 100 to 200 mg daily for 7 to 14 days after clinical improvement)

37 YO HIV + male CD4 76 as of six months ago, now has DOE, fever, dry cough, and pleuritic chest pain. His symptoms have been progressing over the last month despite 10 days of Levaquin. 38C 120/70,HR120, pulse ox is 69% on room air. Ill appearing, in mild respiratory distress

Most common findings include interstitial patterns with parenchymal consolidation, multiple <5mm nodules 9% may have neg CxR no finding is pathopneomonic

Pneumocystis We now refer to the organism that causes human disease as pneumocystis jirovecii In ‘80’s AIDS defining illness for 2/3rds of patients Ugandan study found 38.6% of 83 pts admitted with pneumonia had PCP on BAL Presentation: Gradual onset dyspnea, fever, nonproductive cough, unremarkable lung exam, tachycardia CXR: Diffuse bilateral interstitial infiltrates, is a leading cause of pneumothorax. Cavitation, adenopathy and effusion should prompt search for other pathogens

Diagnosis of PCP hypoxemia, elevated LDH nonspecific induced sputum BAL Specific dx should be sought in those with mod-severe disease

Treatment TMP/SMZ treatment of choice Steroids ASAP but at least within 72 hours if pO2<70 or Aa gradient >35 mm/Hg Pentamidine is second choice for moderate to severe disease Discontinue prophylaxis in patients who have responded to ARVs with a CD4 cell >200 sustained for longer than 3 months

39 yo engineer from Belize with right sided weakness, tremor, expressive aphasia, and generalized seizure. Found to be HIV positive, CD4= 32. No history of IVDU.

Toxoplasmosis Most common cause of intracerebral lesions in persons with HIV. 15-30% of US population is seropositive 50-75% in some European countries. Without prophylaxis 30% of seropositive with CD4<50 will develop CNS disease. 95% of persons with Toxoplasmosis are antibody positive. Reactivation of latent tissue cysts Primary Infection can lead to to disseminated disease or encephalitis Primary infection is from undercooked meat ingestion of oocyts that have been shed in cat feces and sporulated in the environment which requires 24 hours IgmMis not usually present In Africa there is a wide variation in antibody prevalence with 34% of people in South Africa, 27% of people in Uganda, 27% of people in Botswana, 54% in blood donors in Kenya, and 75% of people in Nigeria having T. gondii antibodies (Jacobs 1978, Griffin 1983, Zumla 1991, Onadeko 1996).

Toxoplasmosis Presentation: headache, fever, confusion, focal deficits, and seizures Differential: CNS lymphoma, abscess, cryptococcoma, tuberculoma Multiple ring enhancing lesions with a predeliction for the the corticomedullary junction basal ganglia and thalamus IgM absent usually Quantitastive IgG not helpful

You probably won’t get Tox from your indoor cat, but cats that eat raw meat, live prey and consider the world their cat box are responsible for maintaining a good supply of cysts in the environment for others to ingest

Bradyzooites in tissue, oocysts in food, cat feces, water, transfusion products The sexual cycle occurs exclusively in cats and is initiated when a cat eats an infected prey or accidentally ingests feces contaminated with oocysts. Following a typical process of gamete formation and fusion in the intestinal epithelium, the zygote is formed. This ultimately develops into an immature oocyst which, after being shed in the feces will mature into an extraordinarily resistant entity containing 8 sporozoites (representing, we assume, all of the progeny of meiosis). The oocysts are highly infectious not only to other cats (in which case a new sexual cycle is initiated) but to virtually any warm-blooded animal. Herbivorous grazing animals, of course, will be particularly susceptible but it's also found in strict carnivorous animals, as well. How? Well, once in the herbivore, the sporozoites are released from the oocyst in the intestine and invade the intestinal epithelium. There they differentiate into the rapidly dividing tachyzoite form (tachy from the greek for fast (dividing)) which is capable of indefinite replication in vivo and in vitro. These diseminate through the host, infecting virtually any cell in any tissue. As the host's immune response rises to the challenge, the parasites encyst and differentiate to the very slowly dividing form, the bradyzoite (brady = slow in greek). These are very stable and infectious if tissue from the animal is eaten.

DIAGNOSIS CT or MRI with contrast are not specific, Serum and CSF IgG/IgM CSF PCR is specific 96-100%, but sensitivity 50%

Toxoplasmosis-Treatment Pyr + sulfadiazine + leucovorin Preferred alternative Pyr+ clinda + leucovorin TMP-SMX which is inexpensive and readily available in developing countries may be suitable first line therapy for acute TE

Toxoplasmosis treatment Acute therapy for 6 weeks, until resolution of contrast enhancement Adjunctive steroids for mass effect and edema Chronic Maintenance therapy until CD4>200 x 6 months Sulfadiazine 2-4 gm + Pyr 25-50 +leucovorin 10-25

Primary Prophylaxis CD4<100 and Toxoplasma IgG + Discontinue ppx when CD4>200 > 3 months TMP-SMZ SS or DS qd Alternatives Dapsone + Pyrimethamine q week + Folinic acid q week Mepron +/_ Pyrimethamine ? Azithromycin

28YO M, HIV status unknown, brought in by his wife with headache, vomiting and confusion worsening over 9 days. 39.4C, combative, without obvious focal findings. CT with contrast increased intracranial pressure.

Likely diagnoses include? a. Cryptococcal meningitis b. Tuberculous meningitis c. Cocci meningitis d. Lymphomatous meningitis e. Bacterial meningitis

Cryptococcosis PreHAART occurred in 6-10% of persons with AIDS in US, Europe & Australia 7/1000 AIDS pts in 2000 in US Cause of 20-45% of cases of community acquired meningitis in South Africa, moving ahead of tuberculous meningitis

Cryptococcosis Meningitis or meningoencephalitis is the most common manifestation Presents with progressive headache, fever, AMS worsening over several weeks may have symptoms of increased ICP. Meningismus, papillaedema, cranial nerve palsies not uncommon

Diagnosis High organism load in HIV, so India ink usually positive in AIDS, (sensitivity 75-85%) Cryptococcal antigen high sensitivity 95% and specificity for diagnosis but little utility in assessing response to therapy 75% with meningitis also have + blood cultures opening pressure >200mm Hg in 75% CSF lymphocytic pleocytosis elevated protein, low glucose cultures grow in 48-72 hours

Use of Lumbar punctures CT first, always check the opening pressure with each LP Repeat LP for signs of increased ICP (HA, AMS, visual or hearing loss), may require lumbar drain Daily LPs to achieve a closing pressure <20 or 50% of the opening pressure If not improving or new symptoms repeat LP A CT or MRI head scan usually shows normal ventricular size and the mechanism is hypothesized to be the obstruction of CSF outflow by a large burden of yeasts and polysaccharide plugging the arachnoid villi.55 To date, few controlled studies have been completed to evaluate management of this important complication, so that recommendations are based on a few case reports, one small series56 and expert opinion. Medical treatment using mannitol and acetazolamide has not been shown to be effective. Based on small studies and expert opinion

Treatment Guidelines Preferred induction regimen: 2 weeks of AmB + flucytosine Consolidation if CSF culture neg Fluconazole 400 mg/day x 8 weeks Maintenance Fluconazole 200 qd until CD4>200 x 6 months Combination fluconazole and 5-FC, in small studies had response rates of 60–80%, comparable to ampB-based regimens Itraconazole is less effective

SM 59 YO Lebanese male admitted 9/30 with new onset seizures PMH pancytopenia with negative work up PE word finding difficulty, flattening of R nasolabial fold R hand decreased grip strength, decreased strength biceps CT showed L frontal enhancing lesion with mass effect and a small R cerebellar enhancing lesion CT of chest and abdomen showed 2.3 x 1.8 cm mass at the root of the mesentary along the superior mesenteric vessels

What tests do you want? HIV1/2 serology Toxoplasma serology ppd Blood cultures

Mycobacterium avium complex (MAC) Most common bacterial OI in the developed world 10-20% of persons with AIDS independent predictor of mortality Acquired through inhalation or ingestion, spreads through lymphatics Fevers, night sweats, weight loss, Labs: anemia, elevated alkaline phosphatase

Prophylaxis and treatment Prophylaxis: Start CD4<50 Stop CD4>100 x 3 months Azithromycin 1200 q week Combination therapy is essential resistance seen in 46% after 16 weeks on Clarithromycin alone Clarithromycin + Ethambutol +/- Rifabutin or 12 months of treatment and CD4>100 x more than 6 months

Fever in patient with CD4<50 34 YO with fever to 102, weight loss, heartburn and diarrhea, no cough, no visual changes, no headache, no marked adenopathy. Labs: Hct 29, LDH 255, LFTS normal stool studies show a few red blood cells Chest x-ray unremarkable

Fever in patient with CD4<50 Mycobacterium avium complex Cytomegalovirus Cryptococcus M. tuberculosis Lymphoma Endemic mycoses

Epidemiology-CMV Developed world 40-70% healthy adults infected. In persons with HIV especially IVDU and MSM, close to 100% are also seropositive for CMV Autopsy studies show up to 90% of persons dying with HIV in preHAART era had CMV disease 40% developed sight threatening disease after CD4 dropped to <50 CMV retinitis Remains the most common cause of visual loss in developed countries Efficiently transmitted via direct contact. Risk factors: greater number of partners, h/o STD, children in daycare Find CMV on hands, toys and surfaces. Daycare workers acquire CMV at rates of 7-20% /year Parents of children who shed CMV seroconvert at a rate of 45%/ year

Cytomegalovirus Reactivation when CD4<100 85% retinitis 17% GI tract esophagitis, gastritis, duodenitis, colitis 1% encephalitis, polyneuritis, polyradiculopathy ?% pneumonitis

CMV Treatment Ganciclovir- IV, PO or intravitreal Foscarnet- IV, intravitreal Cidofovir- IV +/-Prophylaxis if CD4<50 Preemptive therapy for viremia? Treatment of symptomatic disease with induction followed by maintenance therapy In the absence of immune reconstitution drug resistance emerges with serial accumulation of mutations

Summary of prophylaxis Infection Preferred drug Indications Pneumocystis carinii pneumonia Trimethoprim-sulfamethoxazole (double-strength tablet daily) CD4 count <200 cells/microL; thrush; unexplained fever for more than two weeks; history of PCP Toxoplasmosis CD4 count <100 cells/microL and Toxoplasma sero-positive Mycobacterium avium complex Azithromycin (1200 mg weekly) CD4 count <50 cells/microL

Take home messages OIs are the most common presentations of AIDS/HIV Usually occur when CD4 < 200 Most important: PCP, MAC, Cryptococcus, Toxoplasma, CMV Candida infection is the most common OI and MAC is the most common bacterial OI Life Threatening: PCP, Cryptococcus Prophylaxis if CD4 <200: bactrim, azithromycin