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

2. 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.

3. 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

4. Starting ART in the setting of an active Opportunistic Infection Introduction

5. Starting ART and OIs: Advantages and Disadvantages
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
Starting ARV is not an emergency, like starting Antibiotics in a bacteremic patient. However, given the clinical severity and low reserve in the typical Vietnamese patient, with low CD4 and wasting disease, ARV is sometimes the appropriate first line therapy. Esp. when that’s the only tx available.
Remember: it’s never an emergency to start ARV
(though one shouldn’t wait too long if pt has low reserve and CD4 count)

6. 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

7. 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)

8. 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.

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

10. 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
In these diseases, there is no alternative treatment available in Vietnam, or the alternative treatments are not very affective. There is also little risk for severe IRIS. Therefore, starting ARV as soon as possible is the best treatment for the OI as well as for the HIV infection. Many non-infectious conditions benefit greatly from ART as well.

11. 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
Clarify “delayed” – meaning waiting some period of time while the OI treatment is given before starting ART

12. OIs for which ART should be delayed
Tuberculosis and other atypical mycobacterial infections
Cerebral toxoplasmosis
Pneumocystis jiroveci Pneumonia (PCP)
Cryptococcosis
Penicillium marneffei
In these diseases, there is risk for IRIS, so the OI should be treated first. In addition, these diseases can be fatal if untreated so treatment is considered an emergency.

13. 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 CD4 is high (> “severe” level), treat the OI through the acute phase before starting ARV
If the CD4 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
The acute phase of treatment is different for each OI. For example, PCP is treated for 3 weeks, cryptococcal meningitis for 8-10 weeks.

14. Early ART Reduces AIDS Progression/ Death in Individuals with Acute OIs
Zolopa et al. PLoS ONE May 2009 | Volume 4 | Issue 5 | e5575
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 CD4 = 29 cells/mm3, VL 5.07 log
Early ARV: median 12 days
Late ARV: median 45 days
There is little data to guide exactly the best time to start ART in the setting of different OIs. This is the results of a recent study that was reported in January 2008 and published in May The research was carried out in the USA to determine the best time to start ARV after the diagnosis of an acute OI. Important to note that the research here excluded patients with TB, but included patients with PCP, cryptococcal meningitis, and severe bacterial infections. In general, the patients were very ill, with low CD4 and high Viral load. Early ARV was started an average of 12 days after the diagnosis of OI, while late ARV was started an average of 45 days after the OI diagnosis.

15. 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
Multiple OIs/BIs
92 (33%)
Majority of patients had PCP
Some cases of bacterial infection and cryptococcal disease
Patients with TB were excluded
Here is the frequency of the different OIs in the study. The majority of the patients had PCP. 12% each had bacterial infections and crypto. Very few had Toxo, CMV, or MAC and TB was excluded from the trial.

16. Early vs. late ART in patients with OI
Outcome
Early ARV
Late ARV p
Death or disease progression
14%
24%
0.035
Weeks to CD4 > 100
4.2
11.8
Undetectable VL at 48 wks
48%
45% NS
IRIS
5.7%
8.5%
Results: there was a clear improvement in survival and disease progression in the patients who started ARV early, and no difference in rates of IRIS. The conclusion for Vietnam is that we should try to start ARV early (about 2 weeks after diagnosis) in patients with severe stage 3 or 4 OI; particularly PCP. Waiting 1-2 months after diagnosis to start ARV may result in increased deaths or disease progression.
Conclusion: Early ARV after OI diagnosis decreases risk of death or disease progression in the first year of treatment.

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

18. 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 CD4<200, early ARV prevents new AIDS defining illness and reduces mortality
Risks of Early ART:
Drug toxicity/intolerance (hepatotoxicity, peripheral neuropathy from INH & D4T, drug hypersensitivity)
Drug interactions (RIF & ARV)
Pill burden (>15 pills/day)
IRIS
Patient may or may not be ready for ARV
There are benefits and risks to starting ARV early, but for patients with low CD4 (<200) the benefits are greater than the risks.

19. HIV and TB: When to start ART If CD4 counts are available
Start TB therapy first. Assess for ART after intensive phase or after completion of TB treatment* CD
Start TB treatment first. Start ARV after intensive phase (2 months) of TB treatment*
CD4 < 250
Start TB treatment then start ARV as soon as TB treatment is tolerated (2 weeks-8 week)
Some clinical trial are in going to determine the best moment to start ARV for patients with < 200 CD4 and active TB. 2 weeks vs 2 months ??
* 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

20. 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

21. 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/d4T + 3TC + ABC
ABC not available: AZT + 3TC + NVP
The child > 3 years and > 10 kg of BW: AZT/d4T + 3TC + EFV

22. 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

23. 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.

24. 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, SpO2 85%, no crackles, tachycardia but no heart murmur

25. 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?

26. Effect on OI drug level when used with
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
Rifampicin, EFV and NVP all increase activity of the Cytochrome P450 enzyme, which increases metabolism of antifungal drugs and some antibiotics, resulting in decreased blood levels of the drugs. It may be necessary to increase doses of itraconazole or use alternative agents.

27. Effect on OI drug absorption when used with:
OI Drug Interactions
Some OI drugs may have decreased blood levels due to decreased absorption:
OI Drug
Effect on OI drug absorption when used with:
DDI
H2 Blockers
PPI
Ant-acids
Itraconazole, Ketoconazole 
 
Fluconazole -
Fluoroquinolones
Itraconazole and ketconazole require an acidic environment for absorption. Therefore, anything which increases the pH of the stomach will decrease absorption of the drugs. Fluconazole does not require acid for absorption and therefore is not affected. Fluoroquinolones bind with cations (positively charged molecules) in the stomach, preventing absorption, but are not affected by the pH of the stomach.

28. 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 CD4 > “severe” level, then ART can wait until the acute treatment of the OI is completed
If CD4 < “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

29. Thank You
Questions?