Prophylaxis of Opportunistic Infections HAIVN Harvard Medical School AIDS Initiative in Vietnam M1-07-Prophylaxis of Opportunistic Infections-EN HAIVN Module 1, Revised April 2012

Learning Objectives By the end of this session, participants should be able to: Differentiate between primary and secondary prophylaxis Explain the benefits and indications of cotrimoxazole prophylaxis Describe the process of cotrimoxazole desensitization Describe how to provide isoniazid (INH) prophylaxis

Relationship Between CD4 Count and Opportunistic Infections The lower a person’s CD4 count is, the more vulnerable he/she is to opportunistic infections (OIs) Different infections can occur based on how weak a person’s immune system is The level of the CD4 count determines the OIs a person is at risk for REMIND patients that the risk of OI is directly related to the CD4 cell count.

Sample OIs per CD4 Count CD4 Count OI / Condition Candidal vaginitis > 500/mm3 Candidal vaginitis Persistent generalized lymphadenopathy 200-500/mm3 Pneuomoccal pneumonia Pulmonary tuberculosis Herpes zoster Oropharyngeal candidiasis (Thrush) < 200/mm3 Pneumocystis jiroveci pneumonia Miliary/extrapulmonary TB < 100/mm3 Candida Esophagitis Penicilliosis Toxoplasmosis Cryptococcosis < 50/mm3 Mycobacterium avium complex (MAC) Disseminated cytomegalovirus (CMV) POINT OUT, in particular, the CD4 counts that patients become at risk for PCP, TB, and Toxoplasmosis REFER participants to Handout M1S7.1: Relationship Between Opportunistic Infections and CD4 Count for more information (a fuller list). REMIND participants that syndromes that present at higher CD4 counts generally occur with increasing frequency at low CD4 counts.

Two Types of OI Prophylaxis Primary prophylaxis: Giving medication to prevent an OI from occurring in the first place Secondary prophylaxis: Giving medication after an OI is treated to prevent it from recurring Also known as maintenance therapy EXPLAIN the definitions of primary and secondary prophylaxis.

Cotrimoxazole Prophylaxis (CTP)

Cotrimoxazole (1) Can prevent: PCP Cerebral toxoplasmosis Malaria Parasitic diarrheas Non-typhoid salmonelloses Streptococcus pneumoniae pneumonia STATE that studies of CTX prophylaxis has shown again and again that the death rate and the OI rate of patients falls dramatically when taking CTX.

Cotrimoxazole (2) The benefits greatly outweigh the risks Benefits Decreases morbidity and mortality Inexpensive Well tolerated Prepares patient for daily medication taking (adherence) Concerns Hypersensitivity (allergic) rash Anemia EXPLAIN that studies in Africa show that CTX prophylaxis decreases OI, decreases hospital admissions, and decreases mortality among HIV infected patients. EXPLAIN that CTX, when given at the low doses used in prophylaxis, has few side effects. Some patients may experience anemia, or it may contribute to anemia in addition to the other drugs or conditions affecting the patient. STRESS that the major side effect is hypersensitivity rash, which is common. The benefits greatly outweigh the risks

Cotrimoxazole Allergy (1) Clinically: Maculopapular rash Can have fever Usually within first few weeks of treatment Epidemiology No studies in Asia In Africa, about 2% had allergy to CTX* Resolves when drug is stopped EXPLAIN that there are no published studies of CTX allergy in Asia, but the experience of Tropical Disease Hospital in HCMC is that only a very small percent (1-2%) of patients have allergy to CTX. In the study from Africa, 9/509 patient (2%) had CTX allergy. 8/9 (89%) were able to take CTX without allergy when started again. Source: Lancet. 2004 Oct 16-22;364(9443):1428-34. * Lancet. 2004 Oct 16-22;364(9443):1428-34.

Cotrimoxazole Allergy (2) – How to Manage? Vietnam MOH guidelines on treatment of HIV/AIDS, 2009 Grade Management I – II Continue CTX Give antihistamines Follow closely III Stop CTX Consider desensitization or switch to alternate prophylaxis IV Stop and do not use CTX again Use alternate prophylaxis regimen with dapsone EMPHASIZE that most grade I-II reactions will resolve even when continuing the medication.

Cotrimoxazole Desensitization Desensitization is a rechallenge following an adverse reaction starting with low doses and gradually escalating Review patient daily or give instructions on how to respond to any reaction: Type of reaction Action No reaction Progress to the next stage Minor reaction Continue same dose for 1 extra day or until the reaction subsides Once reaction subsides: progress to the next stage Severe, worsening or persistent reaction Stop CTX REFER participants to Handout M1S7.2: MOH Guidelines for HIV/AIDS Diagnosis and Treatment: Co-trimoxazole Desensitization in Adults for reference EXPLAIN instructions for the desensitization protocol Most patients will be able to progress through the protocol without any reaction Offer antihistamines to patients Any patient who gets a severe reaction must stop immediately. Any patient who develops a minor reaction should delay going up to the next step. That means they continue on the same dose for another day or two until the reaction subsides. When it subsides they can go up to the next dose. If it doesn’t subside or it gets worse the regimen should be stopped.

When to Start CTP in Vietnam? Indications: CD4 ≤ 350 (any clinical stage) WHO Stage 3 or 4 regardless of CD4 count If CD4 testing is not available: clinical stage 2, 3, 4 Pregnant women can use CTX for entire pregnancy Dose: Adult: 960 mg/day or 960mg 3x /week Pediatric: 5 mg/kg/day Source: Vietnam MOH guidelines on treatment of HIV/AIDS, 2009 and MOH Decision No. 4139

When to Stop CTP in Vietnam? No ARV: continue lifelong With ARV: stop cotrimoxazole when CD4 > 350 Source: Vietnam MOH guidelines on treatment of HIV/AIDS, 2009 and MOH Decision No. 4139

What Should You Do When You Cannot Use Cotrimoxazole? ASK participants what should you do when you cannot use Cotrimoxazole? ALLOW time for them to respond, then go to next slide to show the answer.

Dapsone Indications: Dose: Note: not effective against other OIs Prophylaxis of PCP in patients with allergy or adverse reaction to cotrimoxazole Dose: Adults: 100 mg daily Pediatrics: 2 mg/kg once a day Note: not effective against other OIs Side effects (uncommon): rash, haemolytic anemia, hepatitis INTRODUCE that Dapsone is available in Vietnam now. It comes in 50mg tablets and is given as two tablets one time per day. EXPLAIN that it can cause a rash and hepatitis. In patients with G6PD deficiency it can cause haemolytic anemia. Most importantly it is less effective than CTX in preventing PCP and it does not protect against the large range of infections which CTX does.

TB Prophylaxis Therapy

Isoniazid Preventive Therapy (IPT) Indication: PLHIV with negative TB screening Dose: Isoniazid 300 mg (5 mg/kg) once daily for 9 months Must exclude active TB EXPLAIN that the 2009 Vietnam MoH guidelines recommend IPT for all PLHIV with no active tuberculosis on TB screening. Source: Vietnam MOH guidelines on treatment of HIV/AIDS, 2009

Case Study: Duong Duong, a 23-year-old man is newly diagnosed with HIV He is clinical stage 1 His initial CD4 count returns at 89 cells/mm3 You perform a TB symptom screen: He denies fever, cough, sweats, and weight loss What OIs is he at risk for? What prophylaxis would you start? HAVE a participant read the case study presented on this slide. ASK participants “what OIs is he at risk for?” ALLOW time for participants to respond. Answer: CD4 < 100: Tuberculosis, PCP, Candidiasis, Toxoplasma, Cryptococcal meninigits, Penicilliosis. Can refer participants back to Handout M1S7.1: Relationship Between Opportunistic Infections and CD4 Count for more information. ASK participants “what prophylaxis would you start?” Answer: (1) Cotrimoxazole for PCP and Toxoplasma; and (2) INH for TB

Primary Prophylaxis for Select OIs Disease/ Agent Indication Primary Prophylaxis When to stop? Pneumocystis jiroveci CD4 < 200 or WHO Stage 3 or 4 Cotrimoxazole (960mg tab) once daily CD4 > 200 cells/ml for more than 6 months Toxoplasma gondii CD4 < 100 or WHO Stage 4 Mycobacterium tuberculosis Negative TB screening tests INH 300 mg daily x 9 months After treatment course EXPLAIN that primary prophylaxis in this table is for specific etiologies (Pneumocystis jiroveci, Toxoplasma gondii, Mycobacterium tuberculosis). For general primary prophylaxis, according to MOH Decision No. 4139, CPT in adult patients should be started when CD4<350 and stopped when CD4 > 350 for more than 6 months. Source: National Guidelines for the Diagnosis and Treatment of HIV/AIDS. MOH, Vietnam. 2009.

Secondary Prophylaxis

Secondary Prophylaxis of OIs (1) Also called “Maintenance Therapy” OI medication is continued to prevent relapse Continued for life or until the patient: starts ART has an increase in CD4 count which persists over a specified period of time EXPLAIN that after any acute OIs, the patient has a high risk for recurrent infection. Secondary prophylaxis is used to prevent the recurrence of an infection that a patient has already had.

Secondary Prophylaxis of OIs (2) OIs which require secondary prophylaxis include: PCP Cerebral toxoplasmosis Systemic fungal infections Disseminated MAC infection CMV disease EXPLAIN to participants that systemic fungal infections include cryptococcosis and penicilliosis.

Secondary Prophylaxis for Select OIs Disease / Agent Indication Secondary Prophylaxis When to stop? Pneumocystis jiroveci Prior history of PCP CTX (960mg) 1 tablet daily CD4 > 200 cells/ml for more than 6 months Toxoplasma gondii Prior history of Toxoplasma encephalitis Cryptococcus neoformans cryptococcosis Fluconazole 150-200 mg/day Penicillium marneffei penicilliosis Itraconazole 200 mg daily EXPLAIN that in general, patients can stop secondary prophylaxis once their CD4 increases above 200 for more than 6 months MENTION that secondary prophylaxis for other OIs not included on this chart are: MAC: Clarithromycin (500 mg twice daily) plus Ethambutol (15 mg/kg/day) CMV: Ganciclovir IV 5mg/kg/day, Valganciclovir orally 900mg/day, or weekly ganciclovir intravitreal injections (for CMV retinitis) Source: National Guidelines for the Diagnosis and Treatment of HIV/AIDS. MOH, Vietnam. 2009.

Case Study: Nga Nga, a 25-year-old woman, presents to your clinic for follow-up of penicillium infection She is about to complete 10 weeks of intensive phase treatment (Itraconazole 400 mg/day) She has recently been started on ART She is feeling well and wants to know whether she can stop the Itraconazole at the end of the 10 week course What should you recommend regarding the Itraconazole? When can she safely stop it? HAVE a participant read the case study presented on this slide. ASK participants “what should you recommend regarding the Itraconazole?” ALLOW time for participants to respond. Answer: She needs to stay on itraconazole for secondary prophylaxis. Her dose can be reduced to 200 mg/day ASK participants “When can she safely stop it?” Answer: When her CD4 count is greater than 200 cells/mm3 for more than 6 months

Key Points Many OIs can be prevented with the use of primary or secondary CTP is inexpensive, effective against many OIs, and reduces overall morbidity and mortality IPT can prevent latent TB from becoming active TB

Thank you! Questions?