PET CT Scan in Patients With HIV

One of the greatest advantages of advanced diagnostic imaging systems is that it enables to see the unseen. Even when a disease does not produce an outward indication in the form of symptoms, it may remain hidden in the body, building up strength to make a comeback when least expected. This is also the case for the intracellular pathogen HIV . In higher numbers, the HIV infection exposure and in the immune system and increases susceptibility of the host to opportunistic infections leading to mortality. While Antiretroviral Therapy (ART) is largely proven to be successful in eradicating HIV from circulation and suppressing viral load, residual virus particles may still remain in the body. The detection of the hidden opportunistic infection and HIV associated malignancies in the body can be done using A advanced imaging modalities such as PET Scan

What is the danger of HIV?
HIV infection, in addition to the apparent symptoms, also produces less direct effects even in patients whose infection as been suppressed. HIV gains entry into the body through mucosal surfaces, following which, it rapidly disseminates throughout the body via the lymphatic system. The virus can be detected in lymph tissue within two days of exposure and in the plasma within 11 days. The immune cells positive for HIV are trapped in the lymphoid tissue which makes the lymph nodes themselves reservoirs of the virus and activates inflammatory response. In this way, HIV infection activates the immune system and triggers inflammation activates

Even years after ART, levels of T-cell activation markers can remain high in the blood of HIV-infected patients. A subtype of T cells, called as follicular T cells present in the follicles of lymph nodes have even shown to be rich in HIV DNA, which can be activated to produce active HIV infection. Some of these cells may remain out of reach of immune system because they are located in immunologically privileged sites, where blood and immune cells cannot reach.

In other tissues like vascular endothelium, gut and brain, persistent infection leads to systemic inflammation, and inflammation markers remain elevated in the body of patients even after treatment of HIV.

HIV has also been associated with increased incidence of other conditions like cardiovascular disease, neurological disorders, and blood and solid-tumor malignancies.

Can PET scan detect HIV?
The complete eradication of HIV virus from the body is difficult since the virus particles integrate into the host DNA prior to the initiation of ART. These intracellular viruses often infect the CD4+ T cells which are the most common reservoirs for latent HIV. After integrating, the infected cells have fewer than one copy per million resting CD4+ T cell. In addition, HIV also resides in the lymphoid and other tissues that are outside the reach of peripheral circulation. These factors make it harder to detect by the commonly used testing techniques.

Positron Emission Tomography (PET) which has been critical for the diagnosis, treatment, and management of cancers and other diseases can also be used to study the direct and indirect effects of persistent HIV infection on immune activation, inflammation, and associated clinical comorbidities.

Resting immune cells that are activated by HIV undergo metabolic changes that include an increase in the rates of glucose metabolism by around 20 times. This property can be used by F-FDG PET, which detects the abnormal increase in FDG uptake to identify infected or malignant tissue. Since FDG is a glucose analogue, it is broken down in a similar manner to glucose but remains within the cells where it can be detected using PET. While healthy or suppressed individuals have been reported to have no significant FDG uptake, individuals with significant viral loads (early or advanced) have been reported to have increased uptake of FDG in peripheral nodes. Some reports even indicate that the uptake patterns of FDG were indicative of sites of viral replication.

Thus, PET involves the detection, anatomical location, and kinetics of radioactive tracer uptake, and can provide insights into the design, implementation, and analysis of therapy to reduce HIV reservoir burden, lower inflammation, and reduce HIV-related morbidity. PET-CT scan can also be used to diagnose various malignancies and provide information on potential tumor burden or sites of metastases, disease staging, and response to various treatment strategies.

What are the Applications of FDG PET-CT in HIV?
In context of diagnosis and management of HIV, PET imaging has been useful to:
- Measure cellular metabolic activity in a variety of different clinical scenarios
- Carry out anatomical and functional neuroimaging in HIV-associated neurological diseases
- Detect central nervous system malignancies, and opportunistic infections
- Determine ART-related toxicities
- Characterize the effects of HIV on cardiovascular disease

Is lymphoma common in HIV patients and how to evaluate?
Lymphadenopathy (lymph node swelling) is a common symptom in HIV-infected individuals since lymphoid tissue is a major target and reservoir of HIV. It can occur at any HIV infection stage. Persistent lymphadenopathy often precedes the development of lymphoma and is indicative of an increased risk of lymphoma. However, IRIS (inflammation reaction that can occur due to HAART treatment and causes worsening of symptoms) also shows the symptoms of lymphadenopathy similar to those seen in patients with HIV-associated lymphoma. Thus, it is important to differentiate between benign lymphoid reaction and malignant lymphadenopathy. PET metabolic metrics and assessment of symmetry of nodal uptake can be useful differentiating lymphoma from reactive lymphadenopathy that arises from HAART treatment in HIV -infected patients. However, this requires better specificity, especially in patients with abnormal virological status.

In patients with HIV infection comorbid with lymphoma, PET can assist with identifying the extent of nodal and extra-nodal disease. PET can also distinguish between sites of active disease and inactive residual masses while PET-CT has allowed further improvements in diagnostic accuracy. Using F-FDG, PET can detect active lymphoid tissue during HIV-1 infection, since distinct patterns of lymphoid activation are seen at various stages of disease activity and even in the absence of concomitant lymphoma. This behavior is apparently related to the stage of HIV-1 infection and increased viral loads, both of which activate CD4 + T cells and may yield positive PET findings in lymph nodes. Thus, a distinct pattern of lymphoid tissue activation can be seen in the head and neck region during acute disease, while there is a more generalized pattern of peripheral lymph node activation at the mid-stages, and finally, involvement of abdominal lymph nodes during late disease is seen.

How to Detect Arterial Inflammation in HIV?
Incidence of myocardial infarction, sudden cardiac death, and stroke is higher in HIV-infected patients, even those who have been treated and have suppressed HIV infection. These individuals are known to have increased arterial inflammation which creates the greater risk of cardiovascular diseases. Arterial inflammation is partly caused due to chronic activation of macrophages. These macrophages participate in the atherosclerotic process and reside in the bone marrow and spleen. HIV-infected individuals also show increased inflammation of lymph nodes that harbor the virus even after ART treatment. The inflammation of arteries and other tissues produced in HIV can be assessed using FDG PET-CT, due to the fact that FDG accumulates in immune cells (including those that cause inflammation reaction) because of their unusually high metabolic rates.

Identifying Disseminated AIDS-associated Burkitt's Lymphoma Burkitt's lymphoma is a highly aggressive type of B cell lymphoma and is strongly associated with HIV infection. In Burkitt's lymphoma, the choice of treatment and its duration depends upon the accurate initial staging. Studies have suggested that that FDG PETCT is a sensitive modality for the detection of viable disease in Burkitt's lymphoma.

What are the applications of PET-CT in HIV?
Application of FDG PET scan can further be useful in people living with HIV in several ways such as to:
- Understand the temporal changes that occur within the whole body based on the status of the infection,ART use, or HIV reactivation
- Distinguish opportunistic infections and malignancies from direct or indirect impact of active or suppressed HIV infection and HIV treatments
- Assist in the development of new drugs and therapies
- Aid in patient selection for various therapeutic strategies
- Monitor responses to various therapeutic interventions

The recent years have seen a booming interest in the development of HIV-specific tracers that can provide direct anatomical localization of HIV and identify burden of infection. One example is the use of radiolabelled monoclonal antibodies specific to HIV envelope proteins.

There are still some challenges to address in applying PET imaging for HIV, such as presence of mutations that render cells resistant to the clinically available HIVspecific monoclonal antibodies, low expression of common targets on HIV such as gp120 in patients on suppressive ART and inability of monoclonal antibodies to cross the blood-brain barrier.

Despite these limitations, PET imaging has the potential to enhance HIV curative and persistence research. Novel approaches such as use of high-sensitivity , totalbody EXPLORER imaging, PET imaging during reactivation of latent HIV reservoir, and development of non-viral markers of HIV persistence have the potential to overcome these limitations and can provide important tools for the development of novel therapeutic strategies.