Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Patients

1. Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Patients Ernesto J. Lamadrid, MD, AAHIVS Director, HIV Services, Alachua County Health Department; Assistant Professor Univ. of Florida College of Nursing; Faculty, Florida/Caribbean AETC

5. This is one of two slides in this series based on national AIDS case surveillance data instead of death certificates. It shows the proportion of persons with AIDS surviving at various months after diagnosis of their first AIDS-defining opportunistic illness for different years of that diagnosis. The proportion surviving has been greater among persons with more recent diagnoses. The proportion surviving 60 months (5 years) increased from 11% of persons whose diagnosis was made in 1984 and 1985 to 60% of those whose diagnosis was made in 1996, and the proportion surviving may be even greater among those with more recent diagnosis because of advances in HIV therapy. This is one of two slides in this series based on national AIDS case surveillance data instead of death certificates. It shows the proportion of persons with AIDS surviving at various months after diagnosis of their first AIDS-defining opportunistic illness for different years of that diagnosis. The proportion surviving has been greater among persons with more recent diagnoses. The proportion surviving 60 months (5 years) increased from 11% of persons whose diagnosis was made in 1984 and 1985 to 60% of those whose diagnosis was made in 1996, and the proportion surviving may be even greater among those with more recent diagnosis because of advances in HIV therapy.

6. Opportunistic Infections in HIV Bacterial/ Mycobacterial Mycobacterium Avium Complex (MAC) Salmonellosis Syphilis Tuberculosis Bacterial pneumonia Fungal Candidiasis Coccidioidomycosis Cryptococcal meningitis Histoplasmosis Protozoal Cryptosporidium Pneumocystis carinii Pneumonia (PCP) Toxoplasmosis Viral Cytomegalovirus Hepatitis Herpes simplex Herpes zoster Human papiloma virus Oral hairy leukoplakia Progressive Multifocal Leukoencephalopathy (PML)

7. When to Start and Stop Prophylaxis?

8. When to Start and Stop Prophylaxis?

10. Pneumocystis jirovecii Pneumonia Infection of pulmonary tissue with this fungus. Commonly seen when CD4 count is <200 Sub-acute presentation: may take 2-3 weeks for onset of symptoms Non-productive cough Shortness of breath Fever Fatigue Hypoxemia (low oxygen concentration)

11. Pneumocystis jirovecii Pneumonia (PCP) Diagnosis Chest x-ray-diffuse bilateral interstitial infiltrates Induced sputum or bronchoalveolar lavage (BAL) Silver stain to identify the cyst form of the organism Complications Pneumothorax and respiratory failure Prognosis Response rates with therapy 60-100%

12. Chest X-ray: Pneumocystis jirovecii Pneumonia

13. Silver Stain

14. Pneumocystis Treatment-Mild to Moderate Able to take PO meds, PaO2 > 70 mmHg First-line Trimethoprim/sulfamethoxazole (TMP 15mg/kg/day 75-100 mg SMX) po TID (round to nearest DS tab, ie 160 mg of TMP) or TMP/SMX DS 2 tablets TID Alternatives Dapsone 100 mg po QD + TMP 15 mg/kg po tid Clindamycin 300-450 mg PO Q 6-8 hrs + primaquine 15-30 mg (base) PO QD Atovaquone 750 mg PO BID with food Duration of therapy 21 days

15. Pneumocystis Treatment-Moderate to Severe Unable to take PO meds, PaO2 < 70 mmHg First-line TMP-SMX 15-20 mg/kg/day of TMP component iv divided q6-8h Alternatives Clindamycin 600-900 mg IV Q 6-8h or 300-450 mg PO Q 6-8 hrs+ primaquine 15-30 mg (base) PO QD Pentamidine 4 mg/kg IV QD infused over >60 minutes in D5W Duration of therapy 21 days

16. Pneumocystis Treatment-Adjunctive Therapy Corticosteroids to inhibit inflammatory response Patients with severe infection (i.e. PaO2 < 70 mmHg) Initiate within 72 hours of anti-PCP therapy Prednisone 40 mg po bid days 1-5, 40 mg po qd days 6-10, 20 mg po qd days 11-21

17. Prophylaxis of P. jirovecii Pneumonia Preferred Regimens: TMP-SMX DS 1/d* TMP-SMX SS 1/d* Alternative Regimens: Dapsone 100 mg/d; can be given as 50 mg BID Dapsone 50 mg/d + Pyrim 50 mg/wk + Leucovorin 25 mg /wk* Dapsone 200 mg/wk + Pyrim 75 mg/wk + Leuco 25 mg/wk* Atovaquone 1500 mg/d* Aerosol pentamidine in sterile water 300 mg/mo via Respirgard II� nebulizer TMP-SMX DS 3/wk Trimethoprim-sulfamethoxazole (TMP-SMZ) is the recommended prophylactic agent (AI). One double strength (DS) tablet per day is preferred (AI). However, one single-strength (SS) tablet per day is also effective and might be better tolerated. (AI). One DS tablet three times per week is also effective (BI). TMP-SMZ ,one DS tablet per day confers cross protection against toxoplasmosis and some common respiratory bacterial infections. Lower doses of TMPSMZ also might confer such protection. For patients who have an adverse reaction that is not life-threatening, treatment with TMP-SMZ should be continued if clinically feasible; for those who have discontinued such therapy because of an adverse reaction, reinstitution of TMP-SMZ should be strongly considered after the adverse event has resolved (AII). Patients who have experienced adverse events, especially fever and rash, might better tolerate reintroduction of the drug with a gradual increase in dose (desensitization) as per published regimens (BI) or reintroduction of TMP-SMZ at a reduced dose or frequency (CIII); up to 70% of patients can tolerate such reinstitution of therapy. If TMP-SMZ cannot be tolerated, prophylactic regimens that can be recommended as alternatives include Dapsone (BI), dapsone plus pyrimethamine plus leucovorin (BI), aerosolized pentamidine administered by the Respirgard IITM nebulizer (Marquest, Englewood, Colorado) (BI), and atovaquone (BI). Atovaquone appears to be as effective as aerosolized pentamidine or dapsone (BI) but is substantially more expensive than the other regimens. For patients seropositive for Toxoplasma gondii who cannot tolerate TMP-SMZ, recommended alternatives to TMP-SMZ for prophylaxis against both PCP and toxoplasmosis include dapsone plus pyrimethamine (BI) or atovaquone with or without pyrimethamine (CIII). The following regimens generally cannot be recommended as alternatives because of insufficient data on efficacy: aerosolized pentamidine administered by other nebulization devices, intermittently administered parenteral pentamidine, oral pyrimethamine plus sulfadoxine, oral clindamycin plus primaquine, and intravenous trimetrexate. However, clinicians may consider using these agents in unusual situations in which the recommended agents cannot be administered (CIII).�Trimethoprim-sulfamethoxazole (TMP-SMZ) is the recommended prophylactic agent (AI). One double strength (DS) tablet per day is preferred (AI). However, one single-strength (SS) tablet per day is also effective and might be better tolerated. (AI). One DS tablet three times per week is also effective (BI). TMP-SMZ ,one DS tablet per day confers cross protection against toxoplasmosis and some common respiratory bacterial infections. Lower doses of TMPSMZ also might confer such protection. For patients who have an adverse reaction that is not life-threatening, treatment with TMP-SMZ should be continued if clinically feasible; for those who have discontinued such therapy because of an adverse reaction, reinstitution of TMP-SMZ should be strongly considered after the adverse event has resolved (AII). Patients who have experienced adverse events, especially fever and rash, might better tolerate reintroduction of the drug with a gradual increase in dose (desensitization) as per published regimens (BI) or reintroduction of TMP-SMZ at a reduced dose or frequency (CIII); up to 70% of patients can tolerate such reinstitution of therapy. If TMP-SMZ cannot be tolerated, prophylactic regimens that can be recommended as alternatives include Dapsone (BI), dapsone plus pyrimethamine plus leucovorin (BI), aerosolized pentamidine administered by the Respirgard IITM nebulizer (Marquest, Englewood, Colorado) (BI), and atovaquone (BI). Atovaquone appears to be as effective as aerosolized pentamidine or dapsone (BI) but is substantially more expensive than the other regimens. For patients seropositive for Toxoplasma gondii who cannot tolerate TMP-SMZ, recommended alternatives to TMP-SMZ for prophylaxis against both PCP and toxoplasmosis include dapsone plus pyrimethamine (BI) or atovaquone with or without pyrimethamine (CIII). The following regimens generally cannot be recommended as alternatives because of insufficient data on efficacy: aerosolized pentamidine administered by other nebulization devices, intermittently administered parenteral pentamidine, oral pyrimethamine plus sulfadoxine, oral clindamycin plus primaquine, and intravenous trimetrexate. However, clinicians may consider using these agents in unusual situations in which the recommended agents cannot be administered (CIII).�

19. Tuberculosis Pulmonary and extrapulmonary infection caused by Mycobacterium tuberculosis. Transmission: airborne after a prolonged exposure to the bacilli Increased risk of transmission in closed environments with poor circulation of air. Immunocompromised patients are at increased risk of infection if exposed to MTB.

20. Symptoms of Pulmonary TB Period of incubation is 2-12 weeks, but can be longer. Symptoms: Productive cough Hemoptysis Fever Night sweats Fatigue Weight loss

21. Diagnosis Chest X-ray Sputum culture: Acid fast bacilli smear and culture Collect a sample every morning X three consecutive days Smear result available in 24-46 hours Nucleic acid amplification result available in 48-72 hours TST: not a diagnostic tool, only for screening

22. X-ray

23. Laboratory

25. Toxoplasmic encephalitis (TE) Toxoplasma gondii Intracellular parasite that infects various warm-blooded animals Infection from humans usually from ingestion of undercooked meat or exposure to cat feces Can infect any organ but most commonly infects the brain and eye

26. Toxoplasmic encephalitis (TE) Clinical presentation Fever, headache, seizures, mental status changes Diagnosis Presumptive: CT Scan of head showing �ring-enhancing lesions� in patient with positive Toxoplasma IgG Definitive: brain biopsy required (rarely done)

27. CT scan with contrast

28. Toxoplasmosis-Treatment First-line Pyrimethamine 200 mg PO x 1 then 50 (if <60 kg) or 75 mg (if = 60 kg) PO QD + sulfadiazine 1 (if <60 kg) or 1.5 gm (if = 60 kg) PO Q6h + leucovorin 10-25 mg PO QD for at least 6 weeks Alternatives TMP-SMX (TMP 5 mg/kg/day + SMX 25 mg/kg/day) PO or IV BID Pyrimethamine + leucovorin as in first-line regimen + one of the following: Clindamycin 600 mg IV OR po q6 hrs Azithromycin 900-1200 mg PO QD

29. Toxoplasmosis-Treatment Preferred Chronic Maintenance: Pyrimethamine 25-50 mg po qd + Sulfadiazine 2-4 g po qd (in 2-4 divided doses) plus leucovorin 10 � 25 mg po qd Alternative Chronic Maintenance: Clindamycin 600mg PO q 8 h + pyrimethamine 25�50mg PO qd + leucovorin 10�25 PO qd [should add additional agent to prevent PCP ]; or Atovaquone 750mg PO q 6�12 h +/- [(pyrimethamine 25mg PO qd + leucovorin 10mg PO qd) or sulfadiazine 2-4 g PO] daily

30. Toxoplasmosis Primary Prophylaxis Preferred Regimen: TMP-SMX DS 1/d po Alternative Regimen: TMP-SMX SS 1/d Dapsone 50 mg/d + Pyrim 50 mg/wk + Leuco 25mg/wk Dapsone 200 mg/wk + Pyrim 75 mg/wk + Leuco 25mg/wk Atovaquone 1500 mg/d + Pyrim 25 mg/d + Leuco 10 mg/d The double-strength tablet daily dose of TMP-SMZ recommended as the preferred regimen for PCP prophylaxis appears to be effective against TE as well and is therefore recommended (AII). If patients cannot tolerate TMP-SMZ, the recommended alternative is dapsone-pyrimethamine, which is also effective against PCP (BI). Atovaquone with or without pyrimethamine also may be considered (CIII). Prophylactic monotherapy with dapsone, pyrimethamine, azithromycin, or clarithromycin cannot be recommended on the basis of current data (DII). Aerosolized pentamidine does not protect against TE and is not recommended (EI).The double-strength tablet daily dose of TMP-SMZ recommended as the preferred regimen for PCP prophylaxis appears to be effective against TE as well and is therefore recommended (AII). If patients cannot tolerate TMP-SMZ, the recommended alternative is dapsone-pyrimethamine, which is also effective against PCP (BI). Atovaquone with or without pyrimethamine also may be considered (CIII). Prophylactic monotherapy with dapsone, pyrimethamine, azithromycin, or clarithromycin cannot be recommended on the basis of current data (DII). Aerosolized pentamidine does not protect against TE and is not recommended (EI).

32. Oral Candidiasis Fungal infection of the oral cavity Can be seen at any stage of the disease, most common in advanced illness Symptoms: white oral lesions, change in taste, tenderness of oral cavity May progress to esophagitis causing heartburn and chest pain

33. Oral Thrush

36. Treatment Esophageal Candidiasis: Fluconazole 100mg (up to 400mg) PO or IV daily (AI) Oral Candidiasis: initial episodes (7�14 day treatment): Fluconazole 100mg PO daily (AI); or Clotrimazole troches 10mg PO 5 times daily (BII) Nystatin suspension 4�6 mL QID or 1�2 flavored pastilles 4�5 times daily (BII)

37. Alternative Therapy Itraconazole oral solution 200mg PO daily (BI); or Posaconazole oral solution 100mg PO BID x 1, then 100mg daily (BI)

38. Fluconazole-refractory oropharyngeal candidiasis Itraconazole oral solution =200mg PO daily (AII) Posaconazole oral solution 400mg PO BID (AII) Amphotericin B deoxycholate 0.3mg/kg IV daily (BII) Anidulafungin 100mg IV x 1, then 50mg IV daily (BII) Caspofungin 50mg IV daily (CII) Micafungin 150mg IV daily (CII) Voriconazole 200mg PO or IV BID (CIII)

40. Cryptococcal Meningitis Fungal infection caused by Cryptococcus neoformans Clinical Presentation Presentation may be subtle Headache, fever, malaise Mental status changes, focal nuerologic signs (minority of patients) Papular rash Diagnosis Serum and cerebrospinal fluid testing for cryptococcal antigen (titer > 1:8) Identification of Cryptococcus neoformans on India ink stain of CSF, culture

41. Cryptococcal Meningitis Treatment Acute treatment Induction Amphotericin B 0.7 mg/kg/day IV + flucytosine (5-FC) 25 mg/kg/dose po q6h x 2 weeks Consolidation: (after at least 2 weeks of successful induction -defined as significant clinical improvement & negative CSF culture) fluconazole 400 mg po qd x 8 weeks or until CSF cultures negative Maintenance therapy Fluconazole 200 mg po qd

43. Mycobacterium avuim Complex (MAC) AKA Mycobacterium intracellulare (MAI) Commonly found in food, water, and soil Clinical presentation High fevers: nocturnal spikes Diarrhea, night sweats, malaise Diagnosis Culture of organism from infected site Fast-growing mycobacteria

44. MAC-Treatment First-line Clarithromycin 500 mg po bid + ethambutol 15 mg/kg po qd � rifabutin 300 mg po qd* *Consider adding rifabutin if severely immunocompromised (i.e. CD4 cell count > 50 cells/mm3) or not on effective CART Caution: drug interactions between rifabutin and ARVs

45. MAC-Treatment Alternative Azithromycin 600 mg po qd + ethambutol 15 mg/kg po qd � rifabutin 300 mg po qd Ciprofloxacin, ofloxacin, or amikacin should be added to regimen in patients not responding to 2-4 weeks of treatment

46. MAC Primary Prophylaxis Preferred Regimen: Azithromycin 1200 mg/wk or Clarithromycin 500 mg bid Alternative Regimen: Rifabutin* 300 mg/d or Azithromycin 1200 mg/wk + Rifabutin* 300 mg/d Clarithromycin or azithromycin are the preferred prophylactic agents (AI). The combination of clarithromycin and rifabutin is no more effective than clarithromycin alone for chemoprophylaxis and is associated with a higher rate of adverse effects than either drug alone; this combination should not be used (EI). The combination of azithromycin with rifabutin is more effective than azithromycin alone; however, the additional cost, increased occurrence of adverse effects, potential for drug interactions, and absence of a difference in survival when compared with azithromycin alone do not warrant a routine recommendation for this regimen (CI). In addition to their preventive activity for MAC disease, clarithromycin and azithromycin each confer protection against respiratory bacterial infections (BII). If clarithromycin or Azithromycin cannot be tolerated, rifabutin is an alternative prophylactic agent for MAC disease although rifabutin-associated drug interactions make this agent difficult to use (BI). Tolerance, cost, and drug interactions are among the issues that should be considered in decisions regarding the choice of prophylactic agents for MAC disease. Particular attention to interactions with antiretroviral protease inhibitors and nonnucleoside reverse transcriptase inhibitors is warranted. Before prophylaxis is initiated, disseminated MAC disease should be ruled out by clinical assessment, which might include obtaining a blood culture for MAC if warranted. Because treatment with rifabutin could result in the development of resistance to rifampin in persons who have active tuberculosis, active tuberculosis should also be excluded before rifabutin is used for prophylaxis.Clarithromycin or azithromycin are the preferred prophylactic agents (AI). The combination of clarithromycin and rifabutin is no more effective than clarithromycin alone for chemoprophylaxis and is associated with a higher rate of adverse effects than either drug alone; this combination should not be used (EI). The combination of azithromycin with rifabutin is more effective than azithromycin alone; however, the additional cost, increased occurrence of adverse effects, potential for drug interactions, and absence of a difference in survival when compared with azithromycin alone do not warrant a routine recommendation for this regimen (CI). In addition to their preventive activity for MAC disease, clarithromycin and azithromycin each confer protection against respiratory bacterial infections (BII). If clarithromycin or Azithromycin cannot be tolerated, rifabutin is an alternative prophylactic agent for MAC disease although rifabutin-associated drug interactions make this agent difficult to use (BI). Tolerance, cost, and drug interactions are among the issues that should be considered in decisions regarding the choice of prophylactic agents for MAC disease. Particular attention to interactions with antiretroviral protease inhibitors and nonnucleoside reverse transcriptase inhibitors is warranted. Before prophylaxis is initiated, disseminated MAC disease should be ruled out by clinical assessment, which might include obtaining a blood culture for MAC if warranted. Because treatment with rifabutin could result in the development of resistance to rifampin in persons who have active tuberculosis, active tuberculosis should also be excluded before rifabutin is used for prophylaxis.

47. MAC Secondary Prophylaxis Indication: history of MAC When to stop: CD4 > 100 for >6 months & Rx 12 months & asymptomatic When to restart: CD4 falls below 100 Adult and adolescent patients with disseminated MAC should receive lifelong therapy (i.e., secondary prophylaxis or maintenance therapy) (AII), unless immune reconstitution occurs as a consequence of HAART. Patients appear to be at low risk for recurrence of MAC when they have completed a course of at least 12 months of treatment for MAC, remain asymptomatic with respect to MAC signs and symptoms, and have a sustained increase , e.g., 6 months, in their CD4+ T-lymphocyte counts to >100cells/�L following HAART (CIII). Some experts would obtain a blood culture for MAC, even in asymptomatic patients, prior to discontinuation of therapy, to substantiate that disease is no longer active. �Secondary prophylaxis should be reintroduced if the CD4+ T lymphocyte count decreases to <100 cells/�L (AIII). � Adult and adolescent patients with disseminated MAC should receive lifelong therapy (i.e., secondary prophylaxis or maintenance therapy) (AII), unless immune reconstitution occurs as a consequence of HAART. Patients appear to be at low risk for recurrence of MAC when they have completed a course of at least 12 months of treatment for MAC, remain asymptomatic with respect to MAC signs and symptoms, and have a sustained increase , e.g., 6 months, in their CD4+ T-lymphocyte counts to >100cells/�L following HAART (CIII). Some experts would obtain a blood culture for MAC, even in asymptomatic patients, prior to discontinuation of therapy, to substantiate that disease is no longer active. �Secondary prophylaxis should be reintroduced if the CD4+ T lymphocyte count decreases to <100 cells/�L (AIII). �

48. MAC Secondary Prophylaxis Preferred Regimen: Clarithromycin 500 mg bid + Ethambutol 15 mg/kg/d � Rifabutin* � 300 mg/d Alternative Regimen: Azithromycin 500 mg/d + Ethambutol 15 mg/kg/d � Rifabutin* 300 mg/d Unless good clinical or laboratory evidence of macrolide resistance exists, the use of a macrolide (clarithromycin or, alternatively, azithromycin) is recommended in combination with ethambutol (AII) with or without rifabutin (CI). Treatment of MAC disease with clarithromycin in a dose of 1,000 mg twice a day is associated with a higher mortality rate than has been observed with clarithromycin administered at 500 mg twice a day; thus, the higher dose should not be used (EI). Clofazimine has been associated with adverse clinical outcomes in the treatment of MAC disease and should not be used (DII).Unless good clinical or laboratory evidence of macrolide resistance exists, the use of a macrolide (clarithromycin or, alternatively, azithromycin) is recommended in combination with ethambutol (AII) with or without rifabutin (CI). Treatment of MAC disease with clarithromycin in a dose of 1,000 mg twice a day is associated with a higher mortality rate than has been observed with clarithromycin administered at 500 mg twice a day; thus, the higher dose should not be used (EI). Clofazimine has been associated with adverse clinical outcomes in the treatment of MAC disease and should not be used (DII).

49. Summary Correctional nurses are the frontline of care of all inmates are you must be aware of the multiple diseases that may affect their life. If you don�t think of a diagnosis, you will miss it.