M E N T O R : C A R R I E K O V A R I K , M DU N I V E R S I T Y O F P E N N S Y L V A N I A

M E N T E E : M O N I C A R A N I , M DU N I V E R S I T Y O F M I N N E S O T A

N O R T H W E S T E R N U N I V E R S I T Y

MDS Mentorship Experience

From Philadelphia ------ > Kampala, Uganda …

COAT Trial

Cryptococcal Optimal ART Timing (COAT) Study to determine the optimal timing for initiation of

ART in HIV infected patients with cryptococcal meningitis would chances of survival improve if patients began ART while

receiving CM treatment as inpatients compared to the standard practice of beginning ART as outpatients?

1 million people worldwide infected with CM each year Most common cause of meningitis in Africa Clinical disease most often in immunosuppressed 600,000 deaths (500,000 in sub-Saharan Africa) CM accounts for 13-44% of deaths in HIV infected individuals in

resource-limited settings

Phase IV, randomized clinical trial to compare a 26 weeks survival difference in early versus standard initiation of ART Sponsored by the National Institute of Allergy and Infectious

Disease (NIAID)

2 sites: Uganda and South Africa

Designed to enroll 500 HIV infected study volunteers age 14 and older that are ART naïve.

Study volunteers were randomly assigned to: Early arm: start ART as an inpatient after 7-11 days of

receiving amphotericin plus fluconazole 800mg/day Standard arm: start ART five weeks following hospital

discharge according to standard practice

ART: Efavirenz (EFV) based regimen with two nucleoside reverse

transcriptase inhibitors National guidelines for Uganda and South Africa

Where does dermatology fit into this?

10-25% of patients starting ART experience Immune Reconstituiton Inflammatory Syndrome (IRIS) Paradoxical clinical deterioration noted in individuals with

HIV infection after initiation of ART Occurs within days to months of starting ART Thought to be due to restoration of pathogen-specific immune

responses

52-78% of these cases involve cutaneous features Study in 2009 from South Africa looked at the incidence of

new dermatologic conditions within 6 months of starting ART 5o.8% developed new skin conditions at a median of 8 weeks 104.5 cases per 100 patient years

Karstaedt, AS, Osei-Sekyere, CED 2009

A nested sub-study to evaluate the cutaneous manifestations of HIV positive patients enrolled in the COAT trial

Primary objective: To compare the incidence of dermatologic events between the

experimental group of early initiation of ART versus the control group of standard initiation of ART

The larger picture: Does a greater incidence of cutaneous IRIS predict a poorer

overall outcome?

On site activities

1. Training of clinicians to examine patients, identify, describe and document dermatologic lesions

2. Documentation of cutaneous lesions noted during the initial assessment of patient and follow up study visits

– One page case report form (CRF)to document and describe lesions

3. Photography of the lesions – 3 photos of the lesions during the study visit

• Photo of the region affected (arm, trunk etc)• Two close ups of a representative lesion

– Upload and send CRF and photos

Representative examples

Eosinophilic folliculitis

COAT trial was terminated early Higher mortality was found in the early ART arm compared to

the standard arm (42.5% vs 27.6%) Those randomized to receive early ART were 1.7 times more

likely to have worse survival at any one point compared to the participants in the delayed arm.

Difference in mortality was more evident in participants with Glasgow Coma Scale (GCS) of lower than 15, but there was no evidence of any benefit to participants with normal mental status at time of enrollment

No new patients are being enrolled Total of 177 were enrolled

Those who were already enrolled will continue to be followed for 46 weeks according to study protocol

Data will continue to be collected and trial will conclude in 2015

Conclusions thus far

Early ART in cryptococcal meningitis is harmful Clinicians should delay initiating ART for at least 5-6

weeks in patients with CM and treat the CM first Similar to the managing principles in tuberculosis meningitis Immune Reconstitution Inflammatory Syndrome (IRIS) and

intracranial pressure in meningitis

Preliminary dermatology data from COAT

177 participants enrolled 84 patients had no skin lesions documented upon

enrollment So far 66 have developed skin lesions over the course of the

study

More to come…

Which arm do these patients belong to? What are the spectrum of lesions noted? Are these lesions cutaneous IRIS (based on trend of

CD4 count, viral load)? Can cutaneous IRIS predict poorer overall outcome?

Acknowlegments

Carrie Kovarik, MD David Boulware, MD Kimberly Bohjanen, MD Maria Hordinsky, MD The entire COAT team, especially: Drs. David Meya, Abdu and Henry, Nurse Francis, Study coordinator- Darlisha Williams

And….

Medical Dermatology Society And all of you !