A Prospective Study Evaluating the Burden of Cryptococcal Disease Among HIV-infected Population in Pune, India

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By 2008, 33.4 million people were living with HIV globally, with an estimated 2.3 million living in India, representing the third largest absolute burden of HIV globally. [1]  The current statistics as summarized by National AIDS Control Organization (NACO) of India show that of the estimated 750,000 Indians in need of antiretroviral therapy (ART), only 250,000 (33%) are receiving it.[2] The number of patients on ART is expected to increase every year.  
The global annual burden of cryptococcal meningitis (CM) is estimated to be 957,900 cases and results in an estimated 624,700 deaths within 3 months of infection.[3]  India and Southeast Asia have a substantial burden of CM cases annually (estimated 120,000 cases and incidence 3%/yr) with high mortality of 20-50%.  Even with ART availability, there remains a high risk of CM-related mortality. Most CM occurs in patients with advanced immunosuppression.  Among HIV-infected patients with suspected meningitis and CD4counts <100 cells/mm3 admitted to hospitals in India, up to 50% of patients had CM.[4-5]  Most CM occurs in people who are ART naïve;[6]  however, the unmasking of ART-associated CM within the first weeks is also common. A study in Uganda reported a high incidence of ART-associated CM in patients who are cryptococcal antigen (CRAG) positive who are not treated with fluconazole [7-9]
Early diagnosis and treatment is paramount in reducing CM-related mortality. CM is a sub-acute meningitis in which the polysaccharide cryptococcal antigen is detectable in serum a median of three weeks prior to onset of CM clinical symptoms [10-11]. The sub-acute nature allows for effective interventions.  Methods to prevent this CM-related mortality would include: 1) earlier HIV diagnosis and ART initiation prior to AIDS, 2) primary prophylaxis with fluconazole in people with AIDS, and 3) screening and treatment for occult cryptococcosis.  Both earlier ART and primary fluconazole prophylaxis are effective interventions [12-13], yet widespread implementation requires improvements in the HIV test and treat infrastructure. For those people presenting with advanced HIV, options are limited. 
Despite published data on increased mortality in patients with cryptococcal antigenemia, the utility of serum CRAG testing to identify patients with asymptomatic cryptococcal infection and the clinical impact of preemptive fluconazole treatment have not been clearly defined.[3, 13] In a cost-effectiveness analysis based on data from Uganda, the number of HIV-infected people with CD4 ≤100 cells/mm3 who would have to be tested and treated prior to ART initiation to prevent either one case of CM or one death was 11.3 (95% CI: 7.9-17.1) and 15.9 (95%CI: 11.1-24.0), respectively. These estimates are a function of the prevalence of asymptomatic serum cryptococcal antigenemia, which is 15% in Uganda, but unknown in India.  Therefore, we propose to determine whether such a screening strategy should be considered among Indian patients with advanced HIV disease who are admitted to the medicine ward or are about to initiate ART in the outpatient setting.
Aim 1:
To evaluate the burden of cryptococcal disease among HIV-infected population in Pune, India by conducting cryptococcal antigen screening 
Aim 2:
To determine whether cryptococcal screening strategy should be the standard of care in patients with advanced HIV disease who are admitted to medicine ward or about to initiate ART in the outpatient settings.