Opportunistic Infections in the U.S. during the Combination Antiretroviral Therapy Era

		SUMMARY: The incidence of opportunistic infections and cancers declined steeply after the introduction of effective combination antiretroviral therapy (ART) in the mid-1990s and then reached a plateau during the mid-2000s, according to an analysis of the large HOPS cohort reported in the June 19, 2010 issue of AIDS. More than one-third of people who developed opportunistic illnesses, however, did so at CD4 cell counts of 200 cells/mm3 or higher.

By Liz Highleyman

The widespread introduction of multi-class combination antiretroviral regimens starting in the mid-1990s dramatically reduced the incidence of and mortality related to opportunistic illnesses (OIs), or infections and malignancies that occur when the immune system is severely compromised.

But a significant proportion of people with HIV in North America and Europe do not get tested and diagnosed until they already have advanced disease -- and too many people in developing countries still do not have access to state-of-the-art treatment -- so OIs remain a concern.

Kate Buchacz and fellow investigators with the HIV Outpatient Study (HOPS) performed an analysis of AIDS-defining opportunistic illness rates, types, and risk factors in this large cohort -- one of only a few major OI studies reported in recent years.

This prospective cohort study included 8070 HIV positive HOPS participants seen at 12 U.S. HIV clinics. A majority were men, people of diverse race/ethnicity were included, and the median age at baseline was 38 years. The median CD4 cell count was 298 cells/mm3 -- below the U.S. treatment guidelines threshold for initiating antiretroviral treatment.

The researchers calculated incidence (new case) rates per 1000 person-years of follow-up for the first opportunistic infection, first opportunistic malignancy, and first occurrence of each specific OI between 1994 -- just prior to the advent of combination ART -- and 2007. The 3 AIDS-defining cancers are Kaposi's sarcoma (KS), non-Hodgkin lymphoma (NHL), and cervical cancer; anal cancer is not classified as an OI even though it is caused by the same high-risk human papillomavirus strains. They then modeled annual percentage changes in OI incidence rates by calendar period, adjusting for sex, race/ethnicity, and HIV risk category.

Results

	The 8070 participants collectively developed 2027 new opportunistic illnesses during a median 3 years of follow-up per person.
	Opportunistic infection rates fell steeply soon after the introduction of ART, then showed a slower decline:
	1994-1997: 89.0 cases per 1000 person-years; 1998-2002: 25.2 cases per 1000 person-years; 2003-2007: 13.3 cases per 1000 person-years.
	A similar pattern was observed for opportunistic malignancies, though numbers were smaller:
	1994-1997: 23.4 cases per 1000 person-years; 1998-2002: 5.8 cases per 1000 person-years; 2003-2007: 3.0 cases per 1000 person-years.
	Decreases in opportunistic illness rates were similar when looking only at the subset of patients receiving combination ART -- a proportion that rose over time.
	During 2003-2007, there were no significant changes in annual rates of opportunistic infections or malignancies.
	" The most common opportunistic illnesses were as follows:
	Esophageal candidiasis or thrush: 5.2 cases per 1000 person-years; Pneumocystis pneumonia (PCP): 3.9 per 1000 person-years; Cervical cancer: 3.5 per 1000 person-years; Mycobacterium avium complex (MAC): 2.5 per 1000 person-years; Cytomegalovirus (CMV) disease: 1.8 per 1000 person-years.
	36% of opportunistic illnesses occurred at a CD4 cell count of 200 cells/mm3 or higher.

Based on these findings, the study authors concluded, "Opportunistic illness rates declined precipitously after introduction of combination ART and stabilized at low levels during 2003-2007."

In the contemporary combination ART era, they continued, "a third of opportunistic illnesses were diagnosed at CD4 cell counts at least 200 cells/[mm3]" -- the threshold for an AIDS diagnosis and the level usually considered to mark the OI danger zone where prophylaxis therapies should be considered.

Investigator affiliation: Divisions of HIV/AIDS Prevention, National Center for HIV, Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, GA.

8/31/10

Reference
K Buchacz, RK Baker, FJ Palella, and others (HOPS Investigators). AIDS-Defining Opportunistic Illnesses in U.S. Patients, 1994-2007: A Cohort Study. AIDS 24(10): 1549-1559 (Abstract). June 19, 2010.