Complications of human immunodeficiency virus

I. Problem/Condition.

Complications of human immunodeficiency virus (HIV) infection include a wide array of clinical problems that can affect virtually every organ system. Prior to the advent of highly active antiretroviral therapy (HAART), the bulk of the complications were comprised of opportunistic illnesses (OIs), which included infections and malignancies. In current times, the spectrum of disease encompasses more non-acquired immune deficiency syndrome (AIDS) defining cancers, complications of concomitant illnesses and side effects of HAART.

HIV-infected individuals commonly present to the hospital setting with shortness of breath, lymphadenopathy, diarrhea, rashes, or general systemic symptoms such as weight loss and fever. The list of differential diagnoses broadens in direct proportion to the degree of immunocompromise as measured by the cluster of differentiation (CD4) count.

While patients with CD4 counts above 200 often present with infections common to immunocompetent hosts, they also have higher rates of certain HIV-associated illnesses, such as tuberculosis (TB), candidal infections, lymphomas, and Kaposi’s sarcoma. As CD4 counts fall, hosts are susceptible to more and more infections and cancers.

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This group of patients often presents a challenge to the clinician because they may not fit Occam’s razor; they may have multiple infectious or oncologic complications at one time. Additionally, many symptoms such as wasting, lymphadenopathy and diarrhea may be a manifestation of AIDS itself. Furthermore, patients can suffer systemic symptoms with immune reconstitution inflammatory syndrome (IRIS, discussed elsewhere). This can closely mimic disseminated infection.

Important points to remember are: 1) the level of immunocompromise dictates the differential diagnosis and what testing need to be ordered and 2) regardless of degree of immunocompromise, individuals with HIV often suffer from common illnesses unrelated to their immunodeficiency.

II. Diagnostic Approach

A. What is the differential diagnosis for this problem?

Oncologic complications

Kaposi’s sarcoma, Non-Hodgkin’s lymphoma (NHL), and cervical cancer can occur at any CD4 count in HIV-infected individuals and are termed AIDS-defining cancers. In the HAART era, it has become clear that HIV-infected individuals are also at increased risk for other malignancies. Most common appears to be lung cancer and HIV-infected individuals tend to present at a younger age than the general population.

Other cancers that occur with increased frequency in HIV-infected persons are: Hodgkin’s lymphoma (mostly Epstein-Barr virus [EBV]-associated), anal cancer (human papilloma virus [HPV]-associated), and liver cancer. The pathophysiology is not completely understood, but most cancers noted above are linked to a viral pathogen; it is postulated that the increased frequency of these cancers is due to immune suppression.

Central nervous system (CNS) lymphoma is associated with a greater degree of immunosuppression than systemic NHL and occurs at CD4 less than 50. It is usually EBV-associated.

B. Describe a diagnostic approach/method to the patient with this problem

The diagnostic approach will depend on a careful history and physical examination, in addition to understanding the patient’s HIV treatment history. A recent CD4 count (and preferably a recent trend) is the single most helpful element in formulating a differential diagnosis.

All HIV-infected individuals, regardless of CD4 count, are at increased risk of the following oncologic complications:

  • Human herpes virus 8 (HHV-8) (Kaposi’s sarcoma)

  • HPV (cervical and rectal cancers)

  • NHL

HIV-infected individuals with CD4 less than 50 are at risk for all of the above, and the following:

  • CNS lymphoma

1. Historical information important in the diagnosis of this problem.

Important questions to ask include the following:

  • Careful history and timing of chief complaint.

  • Associated symptoms – there may be more than one diagnosis.

  • History of HAART and adherence – presentation may be related to drug side effects.

  • Any bacterial prophylaxis and adherence – if on trimethoprim/sulfamethoxazole (TMP/SMX, also known as Bactrim) prophylaxis, less likely to have bacterial pneumonia, pneumocystis, or toxoplasmosis. If taking azithromycin, less likely to acquire MAC.

  • CD4 count and history – previous AIDS-defining illness or CD4 count less than 200 predisposes to more serious infection even if counts are currently above 200.

  • Careful sexual history for epidemiology – Kaposi’s sarcoma is much more common in men that have sex with men (MSM). Anal intercourse may be linked to anal cancer.

  • Careful social history – intravenous drug use (IVDU) increases risk for bacterial pneumonia, TB, and viral hepatitis, Smoking increases the risk for lung cancer and heart disease.

2. Physical Examination maneuvers that are likely to be useful in diagnosing the cause of this problem.

In the scope of focusing on a HIV-infected individual presenting to a hospital setting, it is of utmost importance to perform a thorough physical examination, including skin, oropharynx, and abdominal exam regardless of the chief complaint. Skin findings such as Kaposi’s or bacillary lesions can suggest level of immunocompromise and point at the causative process. Organomegaly and lymphadenopathy can suggest the presence of a systemic process.

3. Laboratory, radiographic and other tests that are likely to be useful in diagnosing the cause of this problem.

Oncologic complications

Biopsy is typically diagnostic, though Kaposi’s sarcoma lesions are very characteristic by clinical exam.

C. Criteria for Diagnosing Each Diagnosis in the Method Above.

Please see disease-specific chapters for exact diagnostic criteria.

D. Over-utilized or “wasted” diagnostic tests associated with the evaluation of this problem.

This is a population of patients, especially the ones with severe immunocompromise, in which it is worthwhile to cast a wide net for diagnostic purposes. HIV-infected patients often have extended hospital stays, and undergo multiple costly tests and procedures. This is hard to avoid because of the high morbidity and mortality associated with complications of this disease.

The utility of obtaining a CD4 count in the setting of acute illness is questionable. There is a body of literature showing that patients with acute illness in the intensive care unit (ICU) have falsely depressed CD4 counts even if they do not have HIV infection. This likely applies to HIV patients with acute illness; the CD4 count obtained will be falsely low leading to unnecessary investigations. Thus, if a patient has a recent CD4 count from an outpatient clinic, it is appropriate to assume those are accurate and forego obtaining a new confounding lab in the hospital.

That said, patients with a new diagnosis and no previous CD4 count should have one obtained on presentation.

Also, viral loads obtained in the hospital are often seen, but there are usually no therapeutic decisions that depend on them.

III. Management while the Diagnostic Process is Proceeding

A. Management of complications of human immunodeficiency virus.

The severity of presenting illness will dictate the amount of resuscitative effort. After stabilization, a focused investigation should be expedited based on presenting symptoms and likelihood of particular diseases based on level of immunocompromise. If the patient does not have a previous CD4 count, one should be obtained.

For management of specific complications once diagnosed, please see disease-specific chapters. In general, malignancies should be treated in the same way in patients with HIV as in those without HIV. Early stage cancers should be treated with curative intent, and systemic therapy should be considered for late-stage or metastatic cancers. For Kaposi’s sarcoma patients, the goal is palliation, prevention of progression, and antiretroviral therapy.

It is ideal in these cases to have the help of a specialist who has experience in HIV, not only to aid with the diagnosis, but also to make decisions about whether to stop or continue HAART as it relates to the acute illness, and when to start HAART if the patient is not currently on antiretrovirals. The guidelines for these decisions are changing and the decision process is complex and disease-dependent.

B. Common Pitfalls and Side-Effects of Management of this Clinical Problem

Generally, both HAART and specific treatments for the conditions above have significant toxicities. Please see disease-specific chapters for a discussion on those and specific treatment regimens.

IV. What's the evidence?

“Infectious Diseases Society of America: IDSA guidelines”.

Dezube, BJ, Pantanowitz, L, Aboulafia, DM. “Management of AIDS-related Kaposi sarcoma: advances in target discovery and treatment”. AIDS Read. vol. 14. 2004. pp. 236(This article adds support to ART treatment for Kaposi’s sarcoma.)

Nguyen, ML, Farrell, KJ, Gunthel, CJ. “Non-AIDS-Defining malignancies in patients with HIV in the HAART era”. Curr Infect Dis Rep. vol. 12. 2010. pp. 46-55.