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.

Side effects of HAART are discussed in another chapter. This chapter will focus on the approach to non-pharmacologic complications of HIV/AIDS by organ system. Please note that this chapter summarizes the approach to the hospitalized patient in the United States (US); should the patient be a recent immigrant, the differential diagnosis may need to broadened based on the area of origin.

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.

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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.

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?

Renal complications

The most common cause of chronic kidney disease (CKD) in HIV-infected individuals is HIV-associated nephropathy (HIVAN), which is characterized by proteinuria, lack of hypertension and collapsing focal segmental glomerulosclerosis on renal biopsy. Other causes include immune complex disease, interstitial nephritis from medications or infections, thrombotic microangiopathies, and, as HIV-infected persons are living longer and healthier lives, diabetic and hypertensive nephropathy.

While hospitalized, HIV-infected individuals are at increased risk of developing acute kidney injury (AKI), which is associated with increased mortality. While in the pre-HAART era, most AKI was associated with opportunistic infection and septicemia, currently 38% of AKI is prerenal, and 48% is due to acute tubular necrosis (ATN), commonly from medications. Patients with lower CD4 counts are at greater risk for AKI.

Drug-related renal injury in these patients is often secondary to HAART, bacterial prophylaxis or agents used to treat opportunistic infections. Most commonly implicated are: trimethoprim-sulfamethoxazole (TMP/SMX), tenofovir, cidofovir, adefovir, quinolones, or foscarnet.

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 renal complications.

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 Bactrim prophylaxis, less likely to have bacterial pneumonia, pneumocystis, or toxoplasmosis. If taking azithromycin, less likely to acquire Mycobacterium avium complex (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.

  • Travel history – Mississippi River valley for histoplasmosis; Southwest US for coccidioidomycosis; foreign TB endemic area.

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.

Renal symptoms

Most cases of AKI in patients with HIV who are hospitalized are either medication-related or secondary to hypovolemia, and can be secondary to an infection causing a prerenal state. A careful review of medications and recent changes in doses or additions is warranted.

A renal biopsy is usually not warranted, unless this is the primary presentation or suspected to be HIVAN or immune complex disease, based on history, proteinuria or ongoing chronic infection.

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.

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?

de Silva, TI. “HIV-1 infection and the kidney: an evolving challenge in HIV medicine”. Mayo Clin Proc. vol. 82. 2007. pp. 1103-16.

“Infectious Diseases Society of America: IDSA guidelines”.

Gupta, SK, Eustace, JA, Winston, JA, Boydstun, II. “Guidelines for the Management of Chronic Kidney Disease in HIV-Infected Patients: Recommendations of the HIV Medicine Association of the Infectious Diseases Society of America”. Clin Infect Dis. vol. 40. 2005. pp. 1559-1585.