Target Conditions

a) HIV/AIDS

AIDS has had a devastating impact on Uganda, killing nearly one million people and causing significant morbidity among survivors. Currently over 1 million adults and children in Uganda are living with HIV/AIDS, representing an adult HIV prevalence of 7.3% (Uganda Indicator Survey, 2011) An estimated 64,000 die of AIDS every year. As of January 2010, about 204,000 people in Uganda were receiving ART through the national health system, an ART coverage of ~39% among eligible individuals with a CD4 cell count <350.

b) Lower respiratory tract infections (LRTI)

Lower Respiratory Tract Infections (LRTIs) are a leading cause of death in low-income countries, especially among people living with HIV/AIDS. Tuberculosis (TB) accounts for 25% of these deaths, with the burden of disease highest in sub-Saharan Africa. The epidemiologic and clinical characteristics of other LRTIs are less well-described. Diagnosing and effectively treating LRTIs in people living with HIV remains a major challenge because the causative agent remains unidentified in over half of all patients with LRTIs. Patients without a confirmed etiologic diagnosis are at high risk of mortality. The epidemiology is now changing, however; highly active Anti-Retroviral Therapy (ART) has reduced the incidence of LRTIs in HIV-infected persons by up to 80% in high-income countries, and is now being provided to millions of HIV-infected individuals worldwide. 

Despite these advances, there remains a tremendous unmet need for research that

  1. Elaborates the fundamental mechanisms by which respiratory pathogens evade the immune defenses of patients with HIV; 
  2. Characterizes the epidemiologic features of LRTIs in the setting of increasing ART availability; 
  3. Translates scientific advances into preventive, diagnostic, and treatment interventions for LRTIs, and 
  4. Identifies optimal strategies for implementing and disseminating proven interventions so that they are accessible to all populations, including the poor. 

Well-trained local investigators representing the full spectrum of translational science disciplines are needed to address these unmet needs, especially in Sub-Saharan Africa.

i) TB

Uganda ranks among the 22 countries with the highest burden of TB worldwide. According to WHO’s 2011 Global Tuberculosis Control Report, there were about 70,000 TB cases in Uganda in 2010, representing an estimated incidence of 209 per 100,000. Furthermore, the number of notified TB cases represented only 61% of the total estimated case burden, and only 67% of new smear-positive cases were treated successfully. 54% of patients with TB tested were positive for HIV, a total of 38,000 people.

The World Health Organization (WHO) has endorsed specific interventions to reduce TB-related morbidity and mortality in people living with HIV/AIDS, including Isoniazid Preventive Therapy (IPT), clinic infection control measures, and intensified TB case finding. Recently, molecular diagnostic tests that offer great promise for improving TB patient identification and early detection of drug-resistance have been approved for widespread use, and the first new therapeutic agent in three decades has been brought to market.

ii) Other Pulmonary Complications of HIV/AIDS

Over the past 25 years, >40 studies of the etiology of lower respiratory-tract illnesses in HIV-infected adults and children in sub-Saharan Africa have been published. While these studies have shown bacterial pneumonia to be the leading cause of pneumonia and TB to be the leading cause of death, many other etiologies has been identified, including viral pneumonia (especially cytomegalovirus (CMV) pneumonitis); fungal pneumonia (Pneumocystis pneumonia and cryptococcal pneumonia), and pulmonary Kaposi’s sarcoma (KS). In a consistently large proportion – as high as 25% even in the highest quality studies – no etiologic diagnosis is ever made. Furthermore, these studies show that the lack of a confirmed etiologic diagnosis is the most important risk factor for death, together with immune status and severity of illness.

A major limitation of prior studies has been the lack of standardized inclusion criteria and recruitment strategies, as well as widely varying diagnostic criteria and ad hoc testing procedures. Equally important is the fact that very few prior studies, outside of those focused on TB, have moved beyond etiologic questions to consider potential explanatory mechanisms for these epidemiologic findings (e.g. the frequency of antibacterial drug resistance); evaluate novel therapeutic interventions (e.g. different antibiotic regimens); incorporate lessons from previous studies (e.g. the importance of focusing on patients whose sputum smears are negative for acid-fast bacilli (AFB)); or test quality-improvement strategies (e.g. providing supplemental oxygen to adults). Perhaps most strikingly, very few investigators have published more than a single paper on the pulmonary complications of HIV infection in sub-Saharan Africa, illustrating the shortage of individuals able to sustain a commitment to advancing knowledge in this critically important area.

Together, these factors highlight the need for dedicated individuals trained to contribute to and lead multi-disciplinary translational research teams that are capable of addressing these and other unanswered questions.