Starting ART in the setting of Opportunistic Infections

Starting ART in the setting of Opportunistic Infections in children HAIVN Harvard Medical School AIDS Initiative in Vietnam

Learning Objectives At the end of this presentation, each trainee should be able to: • Cite 3 opportunistic infections where ART is part of the treatment • Cite 4 opportunistic infections where ART initiation may lead to IRIS • Cite the recommendation of the MOH of the use of NVP with a rifampicin (RIF) containing TB therapy • Cite the best time and clinical conditions that a patient with an acute OI can be started on ART • List drug interactions between antifungal drugs and at least 4 other drugs commonly used for HIV patients. 2

Outline of Presentation • Introduction • Interactions between OI and ART – OIs for which ART facilitates their management – OIs that may require delay of ARV • When to start ARV after an OI • Tuberculosis – When to start ARV – ARV regimens • Interactions between OI medications and other drugs commonly used in HIV patients 3

Starting ART in the setting of an active Opportunistic Infection Introduction

Starting ART and OIs: Advantages and Disadvantages • Advantages – – Recovery of immune system Mortality reduction Facilitate OI management Prevention of other OIs and complications due to HIV disease • Disadvantages – – Risk of IRIS Drug interactions Drug adverse effects Number of pills: adherence Remember: it’s never an emergency to start ARV (though one shouldn’t wait too long if pt has low reserve and CD 4 count) 5

General Principles • Specific data are limited to guide for: – when to start ART in children with an acute OI – how to manage ART when an acute OI occurs in a child already receiving ART 6

General Principles When to start ART in children with an acute OI • The decision of when to start ART in a child with an acute or latent OI – needs to be individualized – vary by the degree of immunologic suppression in the child prior to ART • Check to ensure the child – Is responding to OI therapy, clinically stable, – Is tolerating the OI drugs with no side effects (eg. rash) 7

General Principles How to manage ART when an acute OI occurs in a child already receiving ART • In a child already receiving ART who develops an OI, management will need to account for: – the child’s clinical, viral, and immune status on ART – the potential drug-drug interactions between ARVs and the required OI drug regimen • If the patient is already on ARV, then do not stop – Continue the ARV and start treatment for the OI. – Change ARV if necessary to avoid interactions with the OI drugs. 8

In the setting of which OIs can you start ARVs right away? OIs that require immune restoration to resolve

OIs that require ARV as part of their treatment • • Diarrheal agents: Cryptosporidiosis, Microsporidiosis Kaposi’s Sarcoma Progressive Multifocal Leucoencephalopathy (PML) Non-infectious causes such as: – malignancy (lymphoma, carcinoma) – autoimmune (atopic dermatitis, psoriasis) – skin (pruritic papular eruption, eosinophillic folliculitis, seborrheic dermatitis) In these cases, ART should be started as soon as possible 10

In the setting of which OIs should ARV be delayed? OIs that are likely to cause immune recovery inflammatory syndrome (IRIS), or whose treatments have complicated drug interactions with ARVs

OIs for which ART should be delayed • Tuberculosis and other atypical mycobacterial infections • Cerebral toxoplasmosis • Pneumocystis jiroveci Pneumonia (PCP) • Cryptococcosis • Penicillium marneffei 12

Starting ART in the presence of an acute OI General Principles: • Treat the OI first: the patient should be responding to treatment with improvement in OI symptoms and tolerating the OI drugs. • If the CD 4 is high (> “severe” level), treat the OI through the acute phase before starting ARV • If the CD 4 is low (< “severe” level), the patient is at risk for other OIs or death and should start ARV as soon as possible, usually about 2 weeks after starting treatment for the OI 13

Early ART Reduces AIDS Progression/ Death in Individuals with Acute OIs • Zolopa et al. PLo. S ONE May 2009 | Volume 4 | Issue 5 | e 5575 • Randomized study of early (< 14 days) versus deferred (> 28 days) ART in patients with acute OIs or serious bacterial infections (BIs). • 282 patients enrolled: – – Patients with TB excluded. Median CD 4 = 29 cells/mm 3, VL 5. 07 log Early ARV: median 12 days Late ARV: median 45 days 14

Early vs. late ART in patients with OI # (%) PCP 177 (63%) BI 34 (12%) Cryptococcus 35 (12%) Toxoplasmosis 13 (5%) Histoplasmosis 10 (4%) CMV 6 (2%) MAC 6 (2%) Multiple OIs/BIs 92 (33%) • Majority of patients had PCP • Some cases of bacterial infection and cryptococcal disease • Patients with TB were excluded 15

Early vs. late ART in patients with OI Outcome Early ARV Late ARV p 14% 24% 0. 035 4. 2 11. 8 Undetectable VL at 48 wks 48% 45% NS IRIS 5. 7% 8. 5% NS Death or disease progression Weeks to CD 4 > 100 Conclusion: Early ARV after OI diagnosis decreases risk of death or disease progression in the first year of treatment. 16

Starting ARVs in the setting of an active Opportunistic Infection Tuberculosis When should we start ARV? What ARV should we start?

Antiretroviral Therapy and TB: Early vs. Late ART Benefits of early ART: § TB is associated with increased HIV disease progression § Reduced HIV RNA levels and slow HIV disease progression. § Reduced risk of developing other opportunistic infections § For patients with CD 4<200, early ARV prevents new AIDS defining illness and reduces mortality Risks of Early ART: § Drug toxicity/intolerance (hepatotoxicity, peripheral neuropathy from INH & D 4 T, drug hypersensitivity) § Drug interactions (RIF & ARV) § Pill burden (>15 pills/day) § IRIS § Patient may or may not be ready for ARV 18

HIV and TB: When to start ART If CD 4 counts are available CD 4 > 350 Start TB therapy first. Assess for ART after intensive phase or after completion of TB treatment* CD 4 250 -350 Start TB treatment first. Start ARV after intensive phase (2 months) of TB treatment* CD 4 < 250 Start TB treatment then start ARV as soon as TB treatment is tolerated (2 weeks-8 week) * If the patient is at clinical stage 4, provide ART immediately after his/her tolerance of TB drugs (between 2 and 8 weeks). Guidelines for Diagnosis and Treatment of HIV/AIDS, Ministry of Health, Vietnam. 2009. 19

What ARVs to start? • If the child is on ART already, do not stop • If the TB regimen contains RIF and the child is on: – Non-NVP/LPV/r regimen, continue the ART regimen – NVP regimen: • The child < 3 years or < 10 kg of BW: substitute ABC for NVP • The child > 3 years and > 10 kg of BW: substitute EFV for NVP • ABC and EFV not available: continue NVP – LPV/r regimen: add more ritonavir • Ratio 1 LPV: 1 ritonavir 20

What ARVs to start? • If the child is on TB regimen with RIF and starts ART: – The child < 3 years or < 10 kg of BW: • AZT/d 4 T + 3 TC + ABC • ABC not available: AZT + 3 TC + NVP – The child > 3 years and > 10 kg of BW: AZT/d 4 T + 3 TC + EFV 21

ARV for other acute OIs • For severe infections such as PCP, penicillium, bacterial infections: ARV can be started after 2 weeks if the patient is responding to the OI treatment and is clinically stable • For oral and esophageal candidiasis, ARV can be started as soon as patient can swallow pills • For non-systemic infections such as herpes zoster, herpes simplex, STDs, there are no contraindications to starting ARV early 22

Case study • A 4 month infant was brought by her mother to the clinic with a chief complain of cough. • The mother has HIV and got MTCT prophylaxis some days before her labour. • The infant got some drugs (her mother doesn’t remember) for some days after birth. • She was not able to buy formula, so has breast-fed her infant. 23

Case study • The cough occurred 2 weeks before, with mild fever (no exact temperature) • The infant sucks quite well, but frequently vomits due to coughing. • Examination reveals dyspnea with in-drawing chest, Sp. O 2 85%, no crackles, tachycardia but no heart murmur 24

Case study • A clinical diagnosis of PCP is followed by treatment with a combination of CTX and methylprednisolon. • What about ART? – Wait for: • • • Confirming HIV status? Complete PCP treatment? Consent of the mother? Approval of the ART Board? Others? 25

OI Drug Interactions • Some OI drugs may have decreased blood levels due to increased metabolism: OI Drug Effect on OI drug level when used with Rifampicin EFV NVP Itraconazole, Fluconazole, Ketoconazole Clarithromycin - Erythromycin - - 26

OI Drug Interactions • Some OI drugs may have decreased blood levels due to decreased absorption: OI Drug Itraconazole, Ketoconazole Fluoroquinolones Effect on OI drug absorption when used with: H 2 DDI PPI Ant-acids Blockers - - - 27 27

Key Points • For OIs with no disease-specific treatment, ART should be started ASAP • Conditions that are caused by immune dysregulation (malignancy, autoimmune diseases) will improve with ART • If CD 4 > “severe” level, then ART can wait until the acute treatment of the OI is completed • If CD 4 < “severe” level, then ART should be initiated sooner, with careful monitoring for drug toxicity and IRIS • Be aware of potential interactions between OI drugs and ARVs 28

Thank You Questions?