Prevention of Opportunistic Infections

1. Prevention of Opportunistic Infections Jose A. Montero MD, FACP Florida/Caribbean AETC Faculty Division of Infectious Diseases University of South Florida Please include the title of your presentation, your full name and affiliations (including your role within the AETC, if applicable).Please include the title of your presentation, your full name and affiliations (including your role within the AETC, if applicable).

2. Disclosure of Financial Relationships This speaker has no significant financial relationships with commercial entities to disclose. Use this slide if you have no significant financial relationships with any commercial entities. If you use this slide, please delete slide 3.Use this slide if you have no significant financial relationships with any commercial entities. If you use this slide, please delete slide 3.

3. Risk of Opportunistic Infection Many correlate with CD4 count: CD4 < 200 Pneumocystis jiroveci CD4 < 100 Toxoplasma gondii, Cryptococcus neoformans CD4 < 50 Mycobacterium avium complex & Cytomegalovirus monocytogenes, JC virus

4. Risk of Opportunistic Infections cont’d - Others occur at varying CD4 counts: Mycobacterium tuberculosis S. pneumoniae Varicella zoster virus Cryptosporidium Bartonella sp. Herpes simplex Candida sp. infections Hepatitis A, B, C STD’s

5. OI Prophylaxis Primary - prevention of the first episode of infection Secondary - prevention of recurrence of infection after a successful treatment course

6. OIs for Which Primary Prophylaxis is Recommended Pneumocystis pneumonia Tuberculosis Toxoplasmosis M. avium complex Varicella zoster S. pneumoniae infections Hepatitis A & B Influenza

7. P. jiroveci Pneumonia Primary Prophylaxis Indication: CD4 <200 or thrush When to stop: CD >200 for > 3 months When to restart: CD4 falls to <200 Secondary prophylaxis Same as primary Adults and adolescents who have HIV infection (including pregnant women and those on HAART) should receive chemoprophylaxis against PCP if they have a CD4+ count of less than 200/µL (AI) or a history of oropharyngeal candidiasis (AII). Persons who have a CD4+ percentage of less than 14% or history of an AIDS-defining illness but do not otherwise qualify should be considered for prophylaxis (BII). When monitoring the CD4+ count at least every 3 months is not possible, initiation of chemoprophylaxis at a CD4+ count of greater than 200 but less than 250 cells/µL also should be considered (BII). Primary pneumocystis prophylaxis should be discontinued in adult and adolescent patients who have responded to HAART with an increase in CD4+ counts to >200 cells/µL for at least 3 months (AI). Prophylaxis should be reintroduced if the CD4+ count decreases to <200 cells/µL (AIII).  Patients who have a history of PCP should be administered chemoprophylaxis (i.e., secondary prophylaxis or chronic maintenance therapy) for life (AI) unless immune reconstitution occurs as a consequence of HAART. Secondary prophylaxis should be discontinued for adult and adolescent patients whose CD4+ T cell count has increased from <200 cells µL to >200 cells/µL for at least 3 months due to HAART (BII). If the episode of PCP (leading to secondary prophylaxis) occurred at a CD4+ count >200 cells/µL, it is probably prudent to continue PCP prophylaxis for life regardless of how high the CD4+ count rises as a consequence of HAART (CIII). Prophylaxis should be reintroduced if the CD4+ count decreases to < 200 cells/µL (AIII), or if PCP recurred at a CD4+ count >200 cells/µL Adults and adolescents who have HIV infection (including pregnant women and those on HAART) should receive chemoprophylaxis against PCP if they have a CD4+ count of less than 200/µL (AI) or a history of oropharyngeal candidiasis (AII). Persons who have a CD4+ percentage of less than 14% or history of an AIDS-defining illness but do not otherwise qualify should be considered for prophylaxis (BII). When monitoring the CD4+ count at least every 3 months is not possible, initiation of chemoprophylaxis at a CD4+ count of greater than 200 but less than 250 cells/µL also should be considered (BII). Primary pneumocystis prophylaxis should be discontinued in adult and adolescent patients who have responded to HAART with an increase in CD4+ counts to >200 cells/µL for at least 3 months (AI). Prophylaxis should be reintroduced if the CD4+ count decreases to <200 cells/µL (AIII).  Patients who have a history of PCP should be administered chemoprophylaxis (i.e., secondary prophylaxis or chronic maintenance therapy) for life (AI) unless immune reconstitution occurs as a consequence of HAART. Secondary prophylaxis should be discontinued for adult and adolescent patients whose CD4+ T cell count has increased from <200 cells µL to >200 cells/µL for at least 3 months due to HAART (BII). If the episode of PCP (leading to secondary prophylaxis) occurred at a CD4+ count >200 cells/µL, it is probably prudent to continue PCP prophylaxis for life regardless of how high the CD4+ count rises as a consequence of HAART (CIII). Prophylaxis should be reintroduced if the CD4+ count decreases to < 200 cells/µL (AIII), or if PCP recurred at a CD4+ count >200 cells/µL

8. P. jiroveci Pneumonia Preferred Regimens: TMP-SMX DS 1/d* TMP-SMX SS 1/d* Alternative Regimens: Dapsone 100 mg/d 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 300 mg/mo 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). 

9. Toxoplasmosis Primary Prophylaxis Indication: Positive Toxo lgG + CD4 <100 When to stop: CD4 >200 for 3 months When to restart: CD4 falls to <100-200 Toxoplasma-seropositive patients who have a CD4+ T-lymphocyte count of less than 100/µL should be administered prophylaxis against toxoplasmic encephalitis (TE) (AII).  Toxoplasma-seronegative persons who are not taking a PCP prophylactic regimen known to be active against TE should be retested for IgG antibody to Toxoplasma when their CD4+ T-lymphocyte count declines below 100/µL to determine whether they have seroconverted and are therefore at risk for TE (CIII). Patients who have seroconverted should be administered prophylaxis for TE as described above (AII). Prophylaxis against TE should be discontinued in adult and adolescent patients who have responded to HAART with an increase in CD4+ T-lymphocyte counts to > 200 cells/µL for at least 3 months (AI). Prophylaxis should be reintroduced if the CD4+ T lymphocyte count decreases to <100-200 cells/µL (AIII).   Toxoplasma-seropositive patients who have a CD4+ T-lymphocyte count of less than 100/µL should be administered prophylaxis against toxoplasmic encephalitis (TE) (AII).  Toxoplasma-seronegative persons who are not taking a PCP prophylactic regimen known to be active against TE should be retested for IgG antibody to Toxoplasma when their CD4+ T-lymphocyte count declines below 100/µL to determine whether they have seroconverted and are therefore at risk for TE (CIII). Patients who have seroconverted should be administered prophylaxis for TE as described above (AII). Prophylaxis against TE should be discontinued in adult and adolescent patients who have responded to HAART with an increase in CD4+ T-lymphocyte counts to > 200 cells/µL for at least 3 months (AI). Prophylaxis should be reintroduced if the CD4+ T lymphocyte count decreases to <100-200 cells/µL (AIII).  

10. 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).

11. ToxoplasmosisSecondary Prophylaxis Indication: Completion of therapy for toxoplasmosis unless immune reconstitution occurs with HAART When to stop: CD4 >200 for 6 months & completed initial treatment & asymptomatic When to restart: CD4 falls below 200 Patients who have completed initial therapy for TE should be administered lifelong suppressive therapy (secondary prophylaxis or chronic maintenance therapy) (AI) unless immune reconstitution occurs as a consequence of HAART. Adult and adolescent patients receiving secondary prophylaxis (chronic maintenance therapy) for TE appear to be at low risk for recurrence of TE when they have successfully completed initial therapy for TE, remain asymptomatic with respect to signs and symptoms of TE, and have a sustained increase in their CD4+ Tlymphocyte counts to >200 cells/µL following HAART (e.g., 6 months). While the numbers of patients who have been evaluated remain small and occasional recurrences have been seen, based on these observations and on inference from more extensive cumulative data suggesting the safety of discontinuation of secondary prophylaxis for other OIs during advanced HIV disease, it is reasonable to consider discontinuation of chronic maintenance therapy in such patients (CIII). Some experts would obtain a magnetic resonance image of the brain as part of their evaluation to determine whether or not discontinuation of therapy is appropriate.   Secondary prophylaxis (chronic maintenance therapy) should be reintroduced if the CD4+ T lymphocyte count decreases to <200 cells/µL (AIII).   Patients who have completed initial therapy for TE should be administered lifelong suppressive therapy (secondary prophylaxis or chronic maintenance therapy) (AI) unless immune reconstitution occurs as a consequence of HAART. Adult and adolescent patients receiving secondary prophylaxis (chronic maintenance therapy) for TE appear to be at low risk for recurrence of TE when they have successfully completed initial therapy for TE, remain asymptomatic with respect to signs and symptoms of TE, and have a sustained increase in their CD4+ Tlymphocyte counts to >200 cells/µL following HAART (e.g., 6 months). While the numbers of patients who have been evaluated remain small and occasional recurrences have been seen, based on these observations and on inference from more extensive cumulative data suggesting the safety of discontinuation of secondary prophylaxis for other OIs during advanced HIV disease, it is reasonable to consider discontinuation of chronic maintenance therapy in such patients (CIII). Some experts would obtain a magnetic resonance image of the brain as part of their evaluation to determine whether or not discontinuation of therapy is appropriate.   Secondary prophylaxis (chronic maintenance therapy) should be reintroduced if the CD4+ T lymphocyte count decreases to <200 cells/µL (AIII).  

12. ToxoplasmosisSecondary Prophylaxis Preferred Regimen : Sulfadiazine 500-1000 mg qid + Pyrimethamine 25-50 mg/d + Leucovorin 10-25 mg/d Alternative Regimen : Clindamycin 300-450 mg q 6-8 hr + Pyrimethamine 25-50 mg/d+ Leucovorin10-25 mg/d Atovaquone 750 mg q 6-12 hr + Pyrimethamine 25 mg/d + Leucovorin 10 mg/d The combination of pyrimethamine plus sulfadiazine plus leucovorin is highly effective for this purpose (AI). A commonly used regimen for patients who cannot tolerate sulfa drugs is pyrimethamine plus clindamycin plus leucovorin (BI). Atovaquone with or without Pyrimethamine plus leukovorin is also used. However, only the combination of pyrimethamine plus sulfadiazine appears to provide protection against PCP as well (AII). The combination of pyrimethamine plus sulfadiazine plus leucovorin is highly effective for this purpose (AI). A commonly used regimen for patients who cannot tolerate sulfa drugs is pyrimethamine plus clindamycin plus leucovorin (BI). Atovaquone with or without Pyrimethamine plus leukovorin is also used. However, only the combination of pyrimethamine plus sulfadiazine appears to provide protection against PCP as well (AII).

13. MACPrimary Prophylaxis Indication: CD4 <50 When to stop: CD4 >100 for 3 or more months When to restart: CD4 falls to <50-100 Adults and adolescents who have HIV infection should receive chemoprophylaxis against disseminated MAC disease if they have a CD4+ T-lymphocyte count of less than 50 cells/µL (AI). Primary MAC prophylaxis should be discontinued in adult and adolescent patients who have responded to HAART with an increase in CD4+ T lymphocyte count to >100 cells/µL for at least 3 months (AI). Primary prophylaxis should be reintroduced if the CD4+ T lymphocyte count decreases to < 50-100 cells/µL (AIII).  Adults and adolescents who have HIV infection should receive chemoprophylaxis against disseminated MAC disease if they have a CD4+ T-lymphocyte count of less than 50 cells/µL (AI). Primary MAC prophylaxis should be discontinued in adult and adolescent patients who have responded to HAART with an increase in CD4+ T lymphocyte count to >100 cells/µL for at least 3 months (AI). Primary prophylaxis should be reintroduced if the CD4+ T lymphocyte count decreases to < 50-100 cells/µL (AIII).  

14. MACPrimary 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.

15. MACSecondary 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/µL 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/µL (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/µL 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/µL (AIII).  

16. MACSecondary 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).

17. Comparison of Indications to Discontinue Primary & Secondary Prophylaxis

18. Tuberculosis Prevention Tuberculosis skin testing at time of HIV Dx No routine anergy testing 5mm or more induration indicates (+)PPD Annual testing for those who have (–)PPD Treatment for latent TB indicated for: (+)PPD and no evidence of active TB Close contacts of those with infectious TB

19. Treatment of Latent TB Preferred regimen: INH daily for 9 months Pyridoxine should be given to avoid neuropathy Alternative regimens: Rifampin daily for 4 months Careful with drug interactions with rifamycins Pyrazinamide + Rif for 2 months Avoid use due to reports of severe liver injury

20. OIs for Which Prevention Is Not Routinely Indicated Primary Prophylaxis Bacteria (neutropenia) † Cryptococcosis† Histoplasmosis† Cytomegalovirus † Secondary Prophylaxis Herpes simplex virus § Candida §

21. OIs for Which Secondary Prevention is Recommended Cryptococcosis Histoplasmosis Coccidioidomycosis Cytomegalovirus Salmonella bacteremia

22. Cytomegalovirus Disease Chronic maintenance therapy following induction Preferred Regimen: Ganciclovir IV or PO Foscarnet IV Ganciclovir implant + PO (for retinitis) Alternative Regimen: Cidofovir IV + probenecid PO Fomivirsen injection in vitreous Valganciclovir PO Prevention of Recurrence CMV disease is not cured with the currently available antiviral agents. Following induction therapy, chronic maintenance therapy is recommended for life (AI), unless there is immune reconstitution as a consequence of HAART. Regimens demonstrated to be effective for chronic suppression include parenteral or oral ganciclovir, parenteral foscarnet, combined parenteral ganciclovir and foscarnet, parenteral cidofovir, and (for retinitis only) ganciclovir administration via intraocular implant or repetitive intravitreous injections of fomivirsen (AI). Oral valganciclovir has been approved by the FDA for both acute induction therapy and for maintenance therapy. Repetitive intravitreous injections of ganciclovir, foscarnet, and cidofovir have been reported to be effective for secondary prophylaxis of CMV retinitis in uncontrolled case series. Intraocular therapy alone does not provide protection to the contralateral eye or to other organ systems and typically is combined with oral ganciclovir. The choice of a chronic maintenance regimen for patients treated for CMV disease should be made in consultation with an expert. For patients with retinitis, this decision should be made in consultation with an ophthalmologist and should take into consideration the anatomic location of the retinal lesion, vision in the contralateral eye, the immunologic and virologic status of the patient, and the patient's response to HAART (BIII). Discontinuation of Chronic Maintenance Therapy should be considered in patients with a sustained, (e.g., 6 months) increase in CD4+ count to >100-150 cells/ L in response to HAART (BII). Such decisions should be made in consultation with an ophthalmologist and should take into account such factors as magnitude and duration of CD4+ increase, anatomic location of the retinal lesion, vision in the contralateral eye, and the feasibility of regular ophthalmologic monitoring (BII). All patients who have had anti-CMV maintenance therapy discontinued should have regular ophthalmologic monitoring for early detection of CMV relapse (as well as for immune reconstitution uveitis) (AIII). CMV viral load or other markers of CMV infection, .g., antigenemia, or viral DNA tests are not well standardized; their role in predicting relapse remains to be defined. Relapses have been reported rarely in patients with CD4+ count >100-150 cells/µL. Restarting Secondary Prophylaxis . Relapse of CMV retinitis occurs in patients whose anti-CMV maintenance therapy has been discontinued and whose CD4+ T-lymphocyte count has decreased to 50 cells/ L . Therefore, reinstitution of secondary prophylaxis should be reinstituted when the CD4+ count has decreased to 100-150 cells/ L (AIII). Relapse has been reported in patients whose CD4+ counts are higher then 100 cells/µL, but such reports are rare to date.Prevention of Recurrence CMV disease is not cured with the currently available antiviral agents. Following induction therapy, chronic maintenance therapy is recommended for life (AI), unless there is immune reconstitution as a consequence of HAART. Regimens demonstrated to be effective for chronic suppression include parenteral or oral ganciclovir, parenteral foscarnet, combined parenteral ganciclovir and foscarnet, parenteral cidofovir, and (for retinitis only) ganciclovir administration via intraocular implant or repetitive intravitreous injections of fomivirsen (AI). Oral valganciclovir has been approved by the FDA for both acute induction therapy and for maintenance therapy. Repetitive intravitreous injections of ganciclovir, foscarnet, and cidofovir have been reported to be effective for secondary prophylaxis of CMV retinitis in uncontrolled case series. Intraocular therapy alone does not provide protection to the contralateral eye or to other organ systems and typically is combined with oral ganciclovir. The choice of a chronic maintenance regimen for patients treated for CMV disease should be made in consultation with an expert. For patients with retinitis, this decision should be made in consultation with an ophthalmologist and should take into consideration the anatomic location of the retinal lesion, vision in the contralateral eye, the immunologic and virologic status of the patient, and the patient's response to HAART (BIII). Discontinuation of Chronic Maintenance Therapy should be considered in patients with a sustained, (e.g., 6 months) increase in CD4+ count to >100-150 cells/ L in response to HAART (BII). Such decisions should be made in consultation with an ophthalmologist and should take into account such factors as magnitude and duration of CD4+ increase, anatomic location of the retinal lesion, vision in the contralateral eye, and the feasibility of regular ophthalmologic monitoring (BII). All patients who have had anti-CMV maintenance therapy discontinued should have regular ophthalmologic monitoring for early detection of CMV relapse (as well as for immune reconstitution uveitis) (AIII). CMV viral load or other markers of CMV infection, .g., antigenemia, or viral DNA tests are not well standardized; their role in predicting relapse remains to be defined. Relapses have been reported rarely in patients with CD4+ count >100-150 cells/µL. Restarting Secondary Prophylaxis . Relapse of CMV retinitis occurs in patients whose anti-CMV maintenance therapy has been discontinued and whose CD4+ T-lymphocyte count has decreased to 50 cells/ L . Therefore, reinstitution of secondary prophylaxis should be reinstituted when the CD4+ count has decreased to 100-150 cells/ L (AIII). Relapse has been reported in patients whose CD4+ counts are higher then 100 cells/µL, but such reports are rare to date.

23. Cytomegalovirus Disease Chronic maintenance therapy following induction When to stop: CD4 >100-150 x 6 months - no active disease & negative ophthalmologic exam When to restart: CD4 below 100-150 Prevention of Recurrence CMV disease is not cured with the currently available antiviral agents. Following induction therapy, chronic maintenance therapy is recommended for life (AI), unless there is immune reconstitution as a consequence of HAART. Regimens demonstrated to be effective for chronic suppression include parenteral or oral ganciclovir, parenteral foscarnet, combined parenteral ganciclovir and foscarnet, parenteral cidofovir, and (for retinitis only) ganciclovir administration via intraocular implant or repetitive intravitreous injections of fomivirsen (AI). Oral valganciclovir has been approved by the FDA for both acute induction therapy and for maintenance therapy. Repetitive intravitreous injections of ganciclovir, foscarnet, and cidofovir have been reported to be effective for secondary prophylaxis of CMV retinitis in uncontrolled case series. Intraocular therapy alone does not provide protection to the contralateral eye or to other organ systems and typically is combined with oral ganciclovir. The choice of a chronic maintenance regimen for patients treated for CMV disease should be made in consultation with an expert. For patients with retinitis, this decision should be made in consultation with an ophthalmologist and should take into consideration the anatomic location of the retinal lesion, vision in the contralateral eye, the immunologic and virologic status of the patient, and the patient's response to HAART (BIII). Discontinuation of Chronic Maintenance Therapy should be considered in patients with a sustained, (e.g., 6 months) increase in CD4+ count to >100-150 cells/ L in response to HAART (BII). Such decisions should be made in consultation with an ophthalmologist and should take into account such factors as magnitude and duration of CD4+ increase, anatomic location of the retinal lesion, vision in the contralateral eye, and the feasibility of regular ophthalmologic monitoring (BII). All patients who have had anti-CMV maintenance therapy discontinued should have regular ophthalmologic monitoring for early detection of CMV relapse (as well as for immune reconstitution uveitis) (AIII). CMV viral load or other markers of CMV infection, .g., antigenemia, or viral DNA tests are not well standardized; their role in predicting relapse remains to be defined. Relapses have been reported rarely in patients with CD4+ count >100-150 cells/µL. Restarting Secondary Prophylaxis . Relapse of CMV retinitis occurs in patients whose anti-CMV maintenance therapy has been discontinued and whose CD4+ T-lymphocyte count has decreased to 50 cells/ L . Therefore, reinstitution of secondary prophylaxis should be reinstituted when the CD4+ count has decreased to 100-150 cells/ L (AIII). Relapse has been reported in patients whose CD4+ counts are higher then 100 cells/µL, but such reports are rare to date.Prevention of Recurrence CMV disease is not cured with the currently available antiviral agents. Following induction therapy, chronic maintenance therapy is recommended for life (AI), unless there is immune reconstitution as a consequence of HAART. Regimens demonstrated to be effective for chronic suppression include parenteral or oral ganciclovir, parenteral foscarnet, combined parenteral ganciclovir and foscarnet, parenteral cidofovir, and (for retinitis only) ganciclovir administration via intraocular implant or repetitive intravitreous injections of fomivirsen (AI). Oral valganciclovir has been approved by the FDA for both acute induction therapy and for maintenance therapy. Repetitive intravitreous injections of ganciclovir, foscarnet, and cidofovir have been reported to be effective for secondary prophylaxis of CMV retinitis in uncontrolled case series. Intraocular therapy alone does not provide protection to the contralateral eye or to other organ systems and typically is combined with oral ganciclovir. The choice of a chronic maintenance regimen for patients treated for CMV disease should be made in consultation with an expert. For patients with retinitis, this decision should be made in consultation with an ophthalmologist and should take into consideration the anatomic location of the retinal lesion, vision in the contralateral eye, the immunologic and virologic status of the patient, and the patient's response to HAART (BIII). Discontinuation of Chronic Maintenance Therapy should be considered in patients with a sustained, (e.g., 6 months) increase in CD4+ count to >100-150 cells/ L in response to HAART (BII). Such decisions should be made in consultation with an ophthalmologist and should take into account such factors as magnitude and duration of CD4+ increase, anatomic location of the retinal lesion, vision in the contralateral eye, and the feasibility of regular ophthalmologic monitoring (BII). All patients who have had anti-CMV maintenance therapy discontinued should have regular ophthalmologic monitoring for early detection of CMV relapse (as well as for immune reconstitution uveitis) (AIII). CMV viral load or other markers of CMV infection, .g., antigenemia, or viral DNA tests are not well standardized; their role in predicting relapse remains to be defined. Relapses have been reported rarely in patients with CD4+ count >100-150 cells/µL. Restarting Secondary Prophylaxis . Relapse of CMV retinitis occurs in patients whose anti-CMV maintenance therapy has been discontinued and whose CD4+ T-lymphocyte count has decreased to 50 cells/ L . Therefore, reinstitution of secondary prophylaxis should be reinstituted when the CD4+ count has decreased to 100-150 cells/ L (AIII). Relapse has been reported in patients whose CD4+ counts are higher then 100 cells/µL, but such reports are rare to date.

24. Prophylaxis Summary Fungal Agents

25. Salmonella Prevention of Recurrence Indication: Salmonella septicemia Regimen: Preferred: Fluoroquinolones (ciprofloxacin) for susceptible organisms Evaluate household contacts for carriage so that hygienic measures and/or antimicrobial therapy can be instituted HIV-infected persons who have Salmonella septicemia require long-term therapy (i.e., secondary prophylaxis or chronic maintenance therapy) to prevent recurrence. Fluoroquinolones, primarily ciprofloxacin, are usually the drugs of choice for susceptible organisms (BII). Household contacts of HIV-infected persons who have salmonellosis or shigellosis should be evaluated for persistent asymptomatic carriage of Salmonella or Shigella so that strict hygienic measures and/or antimicrobial therapy can be instituted and recurrent transmission to the HIV-infected person can be prevented (CIII).HIV-infected persons who have Salmonella septicemia require long-term therapy (i.e., secondary prophylaxis or chronic maintenance therapy) to prevent recurrence. Fluoroquinolones, primarily ciprofloxacin, are usually the drugs of choice for susceptible organisms (BII). Household contacts of HIV-infected persons who have salmonellosis or shigellosis should be evaluated for persistent asymptomatic carriage of Salmonella or Shigella so that strict hygienic measures and/or antimicrobial therapy can be instituted and recurrent transmission to the HIV-infected person can be prevented (CIII).

26. Vaccines Update tetanus Pneumovax Hepatitis B if negative titers - repeat titers after vaccine series Hepatitis A vaccine if negative titers Influenza - annually

27. “Common Sense” Barrier precautions to prevent STD’s Avoid: Uncooked eggs Undercooked/raw meats Unpasteurized milk, soft cheeses Untreated water, untested well water Hand washing and personal hygiene

28. “Common Sense” cont’d - Pets New pets: puppies > 6 months, cats > 1 year Cats - change litter daily, avoid bites/scratches, flea control Avoid contact with reptiles Gloves to clean aquarium - M. marinum

29. “Common Sense “ cont’d - Travel - by all means do, but plan ahead Bottled water Thoroughly cooked foods Peel fresh fruits/vegetables Seek expert travel advice - “know before you go” - Vector avoidance, malaria prophy, endemic fungi, no live virus vaccines http://www.cdc.gov/travel/

30. Acknowledgements 2001 USPHS/IDSA Guidelines for the Prevention of Opportunistic Infections in Persons Infected with Human Immunodeficiency Virus MMWR Recommendations to Help Patients Avoid Exposures to or Infection from Opportunistic Pathogens 51(RR08):47-52, 2002.