Continuing Education Activity

Human immunodeficiency virus is transmitted sexually, via blood transfusions, sharing intravenous needles, and from the mother to a child during the birth process and breastfeeding. Human immunodeficiency virus has distinct phases: viral transmission, acute seroconversion, acute retroviral syndrome, recovery and seroconversion, asymptomatic chronic infection, and symptomatic human immunodeficiency virus infection or acquired immunodeficiency syndrome. This activity focuses on acquired immunodeficiency syndrome and the sequelae of chronic human immunodeficiency virus infection and reviews the etiology, epidemiology, evaluation, and management options for these conditions. This activity highlights the role of the interprofessional team in managing this complex, lifelong disorder.

Objectives:

• Describe the role of CD4 count and viral load in evaluating the type of acquired immune deficiency syndrome related illnesses that a patient may be experiencing.
• Identify some of the main organ systems involved in acquired immune deficiency syndrome related illnesses.
• Explain why patients should be advised to start trimethoprim-sulfamethoxazole at CD4 counts less than 200 cells/L, and azithromycin at CD4 counts less than 50 cells/µL.
• Summarize collaboration among primary care providers and specialty-trained providers as an interprofessional team when caring for patients with complications of long-term human immunodeficiency virus infection, antiretroviral medication side effects, and complications of immunosuppression.

Introduction

Human immunodeficiency virus (HIV) is transmitted sexually, via blood transfusions, sharing intravenous needles, and from the mother to a child during the birth process and breastfeeding.  HIV disease has distinct phases: viral transmission, acute seroconversion, acute retroviral syndrome, recovery and seroconversion, asymptomatic chronic infection, and symptomatic HIV infection or acquired immunodeficiency syndrome (AIDS.)  This discussion will focus specifically on the sequelae of chronic HIV infection and the AIDS phase.

HIV is a retrovirus that attacks CD4 T lymphocytes, eventually leading to the death of these cells and severe immunodeficiency of the individual who has acquired the infection. Once the CD4 count becomes too low, host immune defenses cannot fend off opportunistic infections and malignancies.  The presence of a CD4 count of less than 200 or an AIDS-defining illness in a patient with HIV is the criteria for a diagnosis of AIDS. Treatment of AIDS is focused on the opportunistic illness or condition and decreasing the HIV viral load, and monitoring for an increase in CD4 cells through antiretroviral therapy (ART.) 

Most patients diagnosed with HIV will develop AIDS within ten years if left untreated. With the initiation of antiretroviral therapy after AIDS diagnosis, the patient may live for greater than ten years and even have a normal life span. Once a patient has been diagnosed with AIDS and they do not receive ART, they will probably die within two years.[1]

Etiology

HIV is a retrovirus with two subtypes: HIV-1 and HIV-2.[2] The HIV-1 subtype is the most common and responsible for AIDS throughout most of the world.  HIV-2 is found primarily in Western Africa and is much less common. 

Epidemiology

HIV infection is considered a pandemic.[3]  Since identification, estimates are that 40 million people have died from HIV infection and that there are currently more than 38 million people living with HIV infection. The prevalence of HIV/AIDS has increased over recent years with advancements in treatment, allowing patients to live longer with HIV.  There have been AIDS-defining efforts in the areas of education, prevention, and research to decrease transmission and treat the virus.  There has been a reduction in the number of new annual infections since the 1990s.[4]  While efforts in developed countries have led to improvements in mortality, quality of life, and transmission rates, the incidence of HIV and AIDS is drastically different across the globe.  For example, in sub-Sarahan Africa, there are an estimated 25 million people of all ages living with HIV.[5]  At this time, no vaccine exists for HIV. 

Pathophysiology

HIV is a spherical virus that attaches to host cells with glycoproteins.  The virus then integrates its chromosomal material into that of the host cell, taking over cellular machinery to generate more viral proteins and genetic material. Eventually, the host cell will die, and other CD4 cells will be infected.  The viral enzymes protease, reverse transcriptase, and integrase are involved in this process and are the targets of ART.[6]

The number of CD4 cells within the affected individual will fall by approximately 50-80 cells/µL per year without the initiation of ART, and the decline may be even faster once the count falls below 200 cells/uL. 

With the addition of ART, cardiovascular disease is now the major cause of morbidity and mortality for HIV patients. It is unclear whether the increase in cardiovascular disease is due to HIV, ART drugs, a metabolic syndrome occurring with HIV infection, or a combination of all of these factors.[7]

History and Physical

Discerning the patient’s HIV history, such as the time of diagnosis, complications opportunistic or co-infections, medications they are on (ART or other chronic medicines), and comorbid illnesses, will help the provider better understand the patient’s overall medical situation. Regarding HIV, knowing the patient’s most recent CD4 count and viral load is very important to understand what type of AIDS-related illnesses they may be experiencing. However, often patients have yet to be diagnosed, have delayed testing, or could not make medical checkups or receive antiretroviral therapy. It is very helpful to find out who the patient’s primary and infectious disease providers are. Collaboration is often crucial to properly caring for this population of patients.

Knowing the details of the patient’s HIV history is important, but providers must be mindful that with ART, HIV patients are often presenting with other general medical problems if their CD4 count is adequate and not HIV or AIDS-specific illnesses. The history and physical examination, as well as the development of a differential diagnosis, should be focused on the patient’s chief complaint and symptoms while keeping in mind this may or may not be an HIV or AIDS-related condition during this encounter. The following will focus on HIV or AIDS-related illnesses, classified by the body system affected. 

Cardiac System[8]

HIV infection and ART likely contribute to increased cardiovascular disease in patients. Common presenting symptoms may include chest pain, shortness of breath, or fatigue. The examination should proceed as one would when assessing for acute coronary syndrome or valvular disease, palpating for chest wall pain, observing for jugular venous distension and peripheral edema, and auscultating for abnormal heart sounds, murmurs, or evidence of pulmonary edema. Cardiovascular AIDS-related illnesses could include purulent pericarditis or cardiac tamponade caused by Mycobacterium tuberculosis. If these conditions are suspected, observing for Beck’s triad of low blood pressure, jugular venous distension, and muffled heart sounds may confirm a compressive pericardial effusion.

Pulmonary System[9]

Pulmonary complications of HIV and AIDS are likely the most often thought of and encountered in the clinical setting. HIV infection, even without AIDS, predisposes the individual to several infectious and non-infectious pulmonary problems. The most commonly seen would be upper respiratory tract infections and acute bronchitis. Non-infectious diseases could include Kaposi’s sarcoma and non-Hodgkin’s lymphoma, sarcoidosis, lung cancer, and emphysema. When evaluating the HIV or AIDS patient for pulmonary disease, observation should be made of the patient’s work of breathing, looking for signs of respiratory distress such as tripoding or posturing, tachypnea, retractions, or cyanosis. Auscultation may reveal generalized or focal adventitious lung sounds, which may aid in the diagnosis of the pulmonary problem.

Oropharyngeal and Gastrointestinal System[10]

Complaints of the digestive tract may be unrelated to HIV or AIDS or due to opportunistic infections, malignancies, or complications of ART. HIV medications can cause pancreatitis, hepatic steatosis, or hepatotoxicity. HIV patients may also have co-infection with hepatitis B or C.  Patients with lower CD4 counts are more susceptible to these hepatobiliary problems and also acalculous cholecystitis. Commonly thought of complications of HIV or AIDS-defining illnesses are recurrent oral herpes simplex infection, Candida esophagitis, or Cryptosporidium diarrhea.

Historical information may include characterizing the presence, timing, location, and severity of pain and any associated symptoms such as nausea, vomiting, diarrhea, constipation, melena, hematochezia, or urinary symptoms. It would be useful to gain an understanding of the patient’s appetite and ability to swallow if esophagitis is suspected. Inspection of the oropharynx for lesions or ulcerations would be helpful if indicated by the patient’s presenting complaints. Further physical examination should focus on observation for the level of pain distress and abdominal distension, auscultation of bowel sounds, assessment for hepatomegaly, palpation, and localization of abdominal tenderness, rebound, or guarding. Stigmata of liver disease such as caput medusa, spider angiomas, jaundice, or gynecomastia may be seen with hepatic failure. If the patient is not immunosuppressed rectal examination may be indicated by symptoms or for evaluation of melena or hematochezia.

Central Nervous System[11]

CNS-related problems may include meningitis, focal demyelinating lesions, or malignancies from immunosuppression. Presenting complaints could range from headaches, meningismus, altered mental status, vision changes, focal weakness, or seizures. History and physical should be directed based on the patient’s HIV status and a weighted differential considering the presenting complaints and symptoms. Infection should always be suspected; therefore, asking about the CD4 status, headache, fevers, sick contacts, and prophylaxis should be explored. For patients with headaches inquiring about the onset, activity at onset, severity, the course of pain, and particularly any worrisome associated symptoms such as fever, neck pain, or other neurologic symptom is necessary. If seizures or focal weakness occurred, the provider should obtain information regarding the timing, duration, severity, focality, or generalization of symptoms. Physical examination should be centered on a comprehensive mental status and neurologic examination. If meningitis is suspected, the provider should assess for nuchal rigidity. Ophthalmoscopy is indicated if there is any visual complaint. In particular, the fundoscopic exam may reveal the characteristic “pizza pie” findings of CMV retinitis with fluffy white perivascular lesions and surrounding hemorrhage.

Oncologic Problems and Hematologic System[12] 

Patients with HIV can experience anemia, thrombocytopenia, and leukopenia. Often ART is helpful in addressing these hematologic problems. ART and prophylactic medications can also cause bone marrow toxicity leading to derangements in blood counts. The patient will often present with concerns for abnormal bleeding or bruising when thrombocytopenic. Assessing for the presence and extent of petechia or purpura, as well as any sites of internal bleeding, should be performed. Leukopenic patients will have concomitant infectious symptoms, and their history and physical should be directed towards searching for the source of infection from the leukopenia. Anemia may present as weakness, fatigue, or shortness of breath. The provider should assess skin tone and conjunctiva for paleness.

AIDS-related lymphoma is the most commonly thought of advanced HIV oncologic complication. Primary CNS lymphoma is also encountered and related to co-infection with the Epstein-Barr virus. Systemic symptoms such as weight loss, fever, or night sweats may be discovered in addition to previously discussed neurologic complaints. Physical examination should focus on general appearance, mental status, and a comprehensive neurologic examination.

Dermatologic System[13]

Acute HIV infection may present with a maculopapular or morbilliform rash. Oral ulcers or lesions may also be present, as well as molluscum contagiosum and human papillomavirus infection. The most common AIDS-related cutaneous manifestation is Kaposi’s sarcoma, a vascular neoplasm characterized by violaceous patches, nodules, or plaques. Disseminated fungal infections may present when the patient is severely immunosuppressed and mimics molluscum. History should focus on the timing of the cutaneous manifestation and how it relates to the patient’s HIV status, recent infections, ART or prophylaxis medications, and any other associated symptoms, particularly systemic, CNS, or gastrointestinal related.

Evaluation

Testing for HIV infection involves both a screening test and a confirmatory test. These laboratory assays are looking for specific antibodies or antigens.  Patients with new diagnoses of HIV or those who are presenting for evaluation of an acute medical problem should have a complete blood cell count performed to evaluate for leukopenia, anemia, or thrombocytopenia.  Viral loads and CD4 counts should be ordered if this information will help with the management of the HIV patient. However, results may not be immediately available.  The differential of a complete blood cell count can help estimate the patient's CD4 count.  If the white blood cell and lymphocyte counts are within normal ranges, then the CD4 count is likely normal. If the absolute lymphocyte count is below 950 cells/mm3, the patient may have a CD4 count of less than 200 cells/µL, which would be low enough to cause immunosuppression and risk of opportunistic infection.[14]

Further testing should be considered based on the differential diagnosis and the patients presenting symptoms.  If a cardiac problem is being considered, such as acute coronary syndrome, then EKG and cardiac biomarkers should be ordered.  Bedside ultrasound or echocardiography may be considered when evaluating a patient who potentially has acute valvular pathology, pericarditis, or cardiac tamponade. 

Chest radiography may also be useful for cardiac presentations or for those patients who need evaluation for pulmonary infections. If chest radiography does not reveal an obvious pulmonary process and there is still concern for lung pathology, computed tomography of the chest may be a consideration for further evaluation. Arterial blood gas analysis will aid the provider in determining if steroids are required for a patient with Pneumocystis pneumonia (PCP.)  Blood cultures should be performed before starting antibiotics in the AIDS patient.  Sputum cultures from induction or bronchoalveolar lavage or serum and urine bacterial antigen testing may identify the causative organism of a pulmonary infection.  Testing for tuberculosis (TB) should be performed if signs and symptoms are suggestive of the disease.  In-depth testing with advanced diagnostic imaging such as CT may be necessary if extrapulmonary or disseminated TB is a possibility, specifically in the more immunocompromised group of patients with AIDS, as presenting signs may be as clear. Patients suspected of having tuberculosis should be placed in respiratory isolation even before confirmatory testing is returned.

A complete metabolic profile is useful in many situations, whether obtaining baseline renal and hepatic function or evaluating for abnormalities due to ART or acute medical conditions. Patients with lower CD4 counts or AIDS are more prone to acute hepatobiliary problems such as pancreatitis and acalculous cholecystitis. Quantifying transaminases, bilirubin, and lipase will be useful in evaluating these conditions. Diagnostic imaging, possibly abdominal computed tomography or ultrasound, may be considered based on the patient’s presentation. Esophagogastroduodenoscopy may be necessary for the evaluation of esophagitis in AIDS patients with odynophagia or dysphagia.  AIDS patients are also prone to acquiring various diarrheal illnesses.  Testing for ova, parasites, bacteria, and C. difficile toxins should be done for immunocompromised patients presenting with diarrhea.  Colonoscopy may be required in severe or refractory cases.

When evaluating neurologic complaints in the HIV or AIDS patient, providers should have a low threshold for computed tomography of the head and lumbar puncture with CSF analysis in HIV patients who may be immunocompromised presenting with altered mental status, focal neurologic complaints or concern for meningitis.  Cryptococcal meningitis may have a subtler presentation, and antigen testing should be considered for patients with altered mental status.

Treatment / Management

The treatment of HIV requires the use of ART to suppress viral load and maintain CD4 counts.[15] Various drug combinations are used to treat HIV, and the treatment is for life.  The specifics of ART are discussed in the HIV–antiretroviral therapy activity.  Several infections or conditions have been described thus far in the reading; many of these conditions require medical or surgical management, very similar to that if the patient were not infected with HIV. Therefore, those specifics will not be reviewed here.  This piece will focus on the prophylaxis and treatment of opportunistic infections and disease states associated with long-term HIV infection or severe immunosuppression (AIDS.). A mainstay of the management of most of these specific HIV or AIDS-related conditions and infections is ART to decrease viral load and increase CD4 cell count.

Coverage for bacterial pneumonia should include typical and atypical antibiotic therapies, as is commonly done.  When PCP is diagnosed, or likely base on a CD4 count below 200, the treatment of choice is trimethoprim-sulfamethoxazole (TMP-SMX) for 21 days.  Corticosteroids should be added for PCP if the PO is less than 70 mmHg on ABG analysis.[16]  When treating TB, consideration must be given for multi-drug resistance and the patient’s immunosuppression status.  Consultation with an infectious disease specialist is highly recommended to coordinate the treatment of TB with that of ART in severely immunocompromised AIDS patients. Mycobacterium avium complex (MAC) occurs in severe HIV infection, with a CD4 count of less than 50 cells/uL, and is treated with a multi-drug regimen of ethambutol, clarithromycin, and rifabutin.

Oral thrush is treatable with nystatin swishes. Thrush in the otherwise healthy patient may be the only sign of acute HIV infection, and confirmatory diagnosis of HIV infection should be explored if there are risk factors for acquiring HIV. If the CD4 count is under 100 cells/µL, systemic treatment with an azole should be considered to prevent esophageal candidiasis.  Fluconazole is the preferred agent for esophagitis due to Candida.  Other causative agents would include HSV or CMV, and antiviral drugs such as acyclovir or ganciclovir may be required to treat these conditions, respectively. Analgesia, hydration, and electrolyte repletion may also be necessary for the patient with esophagitis suffering from pain or dehydration.  Several opportunistic infections occur in the GI tract, and antibiotic therapy should target organisms such as Clostridium difficile, Salmonella, Shigella, Campylobacter, and Yersinia.  A common antibiotic combination would be metronidazole and ciprofloxacin.  If suspicious of diarrhea due to Cryptosporidium, the antibiotic of choice is paromomycin.  CMV should be considered as a causative agent when the CD4 count is below 50 cells/µL, treatment with ganciclovir should be a consideration in severely immunosuppressed patients with diarrhea. TB may also cause gastrointestinal infection if the CD4 count is very low.

When meningitis is suspected, typical antibiotics should be administered to cover the common bacterial pathogens.  Coverage for HSV should also be considered until HSV-PCR testing is returned.  Cryptococcal meningitis commonly occurs when the CD4 count is less than 100 cells/uL. Recommended initial treatment is amphotericin B and flucytosine in an induction phase followed by consolidation with fluconazole.  If elevated intracranial pressure is present repeat lumbar punctures may be performed to help relieve the fluid.  Toxoplasmosis gondii may also cause CNS infection when the CD4 count falls below 100 cells/uL.  This condition is identified by ring-enhancing lesions on CT of the head and is treated with pyrimethamine and sulfadiazine.  If primary CNS lymphoma occurs from EBV infection, treatment is with ART and chemotherapy.  Progressive multifocal leukoencephalopathy is identified by demyelinating lesions in the brain caused by the JC virus and is treated mainly by raising CD4 counts with ART; there is no specific antiviral therapy.  CMV retinitis occurs when the CD4 count is less than 50 cells/µL and is treated with valganciclovir intraocular implant as well as oral administration.

Kaposi’s sarcoma is treated with cryotherapy, radiation, or infrared coagulation.  Systemic chemotherapy may also be required depending on the severity or location of Kaposi’s.  Disseminated fungal infection with cutaneous manifestations can be treated with systemic antifungals such as azoles.

Prophylaxis can be initiated to attempt the prevention of many of the common opportunistic infections described above.[17]  When CD4 counts fall to less than 200 cells/uL, prophylaxis for PCP pneumonia is begun with one double-strength TMP-SMX tablet. Toxoplasma gondii prophylaxis should begin when the CD4 count is less than 100 cells/µL, and first-line treatment is also with one double-strength TMP-SMX.  Disseminated MAC prophylaxis will be necessary when CD4 counts fall below 50 cells/µL and is achieved with azithromycin. 

Differential Diagnosis

When the patient is known HIV positive, and the CD4 count is less than 200 cells/µL, or an AIDS-defining illness is present, this is considered pathognomonic for the diagnosis of AIDS.  There are several AIDS-defining illnesses that in and of themselves suggest a severely immunocompromised state when HIV-positive:

• Pulmonary or disseminated TB
• Invasive cervical cancer
• Esophageal candidiasis
• Cryptococcosis
• Cryptosporidiosis
• CMV retinitis, or infection outside of the liver, spleen, or lymph nodes
• HSV – chronic ulcers, bronchitis, pneumonitis, or esophagitis
• Kaposi sarcoma
• Pruritic popular eruption of HIV
• Lymphoma – Burkitt’s or primary brain
• Mycobacterium avium complex, disseminated or extrapulmonary
• PCP pneumonia
• Progressive multifocal leukoencephalopathy
• Brain toxoplasmosis
• HSV encephalitis
• HIV wasting syndrome
• Disseminated histoplasmosis
• Isosporiasis
• Recurrent salmonella septicemia
• Recurrent bacterial pneumonia

Prognosis

Most patients diagnosed with HIV will develop AIDS within ten years if left untreated.  An asymptomatic phase can last approximately eight years, followed by a rapid decline once CD4 levels drop to a level of around 200 cells/µL.  If antiretroviral therapy is initiated even after an initial AIDS diagnosis (severe immunosuppression on the first presentation), the patient may live for greater than ten years.  Once patients have been diagnosed with AIDS, if they do not receive antiretroviral therapy, they will probably die within two years.

Postoperative and Rehabilitation Care

Rehabilitation 

Providers typically refer individuals with HIV/AIDS to therapy to address residual musculoskeletal, neurological, and cardiovascular deficits that develop as the disease progresses and to address pain related to or exacerbated by this condition. Aerobic and resistance at moderate intensities have been shown to be beneficial to patients while not impairing CD4+ count nor viral load while still allowing patients to make significant strength gains.[18][19][20] As the prognosis for HIV/AIDS has improved, work-related challenges that accompany managing this condition are often addressed with therapies depending on the physical demands of the profession and the deficits the patient is facing.[21]

Deterrence and Patient Education

Patients should be educated on the transmission of HIV, how the virus is acquired, and how it can spread to others. Education regarding the CD4 count level is necessary, as well as the role ART plays in maintaining the patient’s immune function and the side effects of the medications.  Patients should be made aware of the opportunistic infections, malignancies, and comorbid conditions that may occur with long-term HIV infection, AIDS, and ART.  Emphasis should be on the fact that with proper medical care and ART, many patients with HIV can lead very normal lives for many years after diagnosis, which just a few decades ago was not the case for this disease.[22]

Pearls and Other Issues

• HIV lipodystrophy is a complication of ART. It results in abnormal accumulation of fat around the waist and localized loss of fat from the facial area. Current treatment is with tesamorelin, a synthetic growth hormone-releasing hormone (GHRH), and dermal fillers.
• Prophylaxis can be initiated to attempt the prevention of many of the common opportunistic infections described above.  When CD4 counts fall to less than 200 cells/µL, prophylaxis for PCP pneumonia is begun with one double-strength TMP-SMX tablet. Toxoplasma gondii prophylaxis should commence when the CD4 count is less than 100 cells/uL, and first-line treatment is also with one double-strength TMP-SMX.  Disseminated MAC prophylaxis will be necessary when CD4 counts fall below 50 cells/uL, and the treatment of choice is azithromycin.  
• With the addition of ART, cardiovascular disease is now the major cause of morbidity and mortality for HIV patients.  
• The number of CD4 cells within the affected individual will fall by approximately 50-80 cells/µL per year if ART is not initiated, and the decline may be even faster once the count falls below 200 cells/uL. 
• When the patient is known HIV positive, and the CD4 count is less than 200 cells/uL, or an AIDS-defining illness is present, this defines the diagnosis of AIDS. 
• Some more emphasized common AIDS-defining illnesses would include: candida esophagitis, invasive cervical cancer, PCP pneumonia, disseminated TB, Kaposi sarcoma, and Cryptosporidium diarrhea.

Enhancing Healthcare Team Outcomes

The management of the patient with HIV or AIDS is complex and lifelong.  Collaboration amongst primary care physicians and specialty-trained providers such as infectious disease, oncology, gastroenterology, neurology, cardiology, and dermatology will be required to handle the complications of long-term HIV infection, ART medication side effects and the complications of immunosuppression when the patient transitions to AIDS.  Interactions with pharmacists, social workers, mental health providers, and ancillary staff will be necessary to ensure patients are educated about their disease and treatment and also have access to their medications and the medical providers they will need to visit for the rest of their lives. The formation of an interprofessional team has been shown to have improved adherence and outcomes for patients living with HIV.