Introduction
Human Immunodeficiency Virus (HIV) remains a significant global health challenge, transmitted through sexual contact, contaminated blood products, shared needles, and perinatally from mother to child via birth and breastfeeding. The progression of HIV infection is marked by distinct stages: initial viral transmission, acute seroconversion, acute retroviral syndrome, a recovery and seroconversion phase, asymptomatic chronic infection, and finally, symptomatic HIV infection, also known as Acquired Immunodeficiency Syndrome (AIDS). This article delves specifically into AIDS, the advanced stage of chronic HIV infection, exploring its definition, diagnostic criteria, and the far-reaching consequences of profound immunosuppression.
HIV is a retrovirus that selectively targets CD4+ T lymphocytes, crucial components of the human immune system. Over time, HIV-induced destruction of these cells leads to a progressive decline in immune function. When the CD4+ count falls below a critical threshold, the body becomes vulnerable to opportunistic infections and certain malignancies. The diagnosis of AIDS hinges on two primary criteria in an HIV-positive individual: a CD4+ cell count of less than 200 cells per cubic millimeter (cells/mm³) of blood, or the presence of specific AIDS-defining illnesses. Effective management of AIDS necessitates addressing these opportunistic conditions, reducing the HIV viral load, and implementing antiretroviral therapy (ART) to restore immune function by increasing CD4+ cell counts.
Without treatment, most individuals with HIV will progress to AIDS within a decade. However, timely initiation of ART, even after an AIDS diagnosis, can significantly extend lifespan, often allowing individuals to live for many years with a near-normal life expectancy. Conversely, individuals diagnosed with AIDS who do not receive ART face a grim prognosis, with a typical survival time of approximately two years.
Alt: Colorized microscopic image showing HIV virions budding from an infected human cell, illustrating the viral replication process.
Etiology
HIV, the causative agent of AIDS, is classified as a retrovirus, with two main subtypes: HIV-1 and HIV-2. HIV-1 is globally dominant and responsible for the vast majority of AIDS cases worldwide. HIV-2, while less prevalent, is primarily concentrated in Western Africa and typically progresses more slowly than HIV-1. Both subtypes share similar modes of transmission and pathogenic mechanisms, targeting the CD4+ lymphocytes, but they exhibit genetic and epidemiological distinctions.
Epidemiology
The HIV/AIDS pandemic is a global health crisis of immense proportions. Since the initial identification of HIV, it is estimated that over 40 million people have succumbed to AIDS-related illnesses. Currently, more than 38 million individuals are living with HIV infection globally. Paradoxically, the prevalence of HIV/AIDS has increased in recent decades, largely due to advancements in ART, which have dramatically extended the lifespan of people living with HIV.
Global efforts to combat HIV/AIDS have focused on education, prevention strategies, and research to develop effective treatments and ultimately a cure. These initiatives have led to a significant reduction in new HIV infections annually since the peak of the epidemic in the 1990s. While developed countries have witnessed substantial improvements in mortality rates, quality of life for people with HIV, and reduced transmission rates, the burden of HIV and AIDS remains disproportionately high in many regions worldwide. Sub-Saharan Africa, for instance, is home to an estimated 25 million people of all ages living with HIV. Despite ongoing research, a preventative vaccine for HIV remains elusive.
Alt: Global map illustrating HIV prevalence rates in adults aged 15-49, highlighting the disproportionate impact on Sub-Saharan Africa.
Pathophysiology
HIV is a spherical virus that initiates infection by attaching to host cells, primarily CD4+ T lymphocytes, via glycoproteins on its surface. Upon attachment, HIV injects its RNA genome into the host cell. Through a process called reverse transcription, viral RNA is converted into DNA, which is then integrated into the host cell’s DNA. This integration allows HIV to commandeer the cellular machinery of the host cell, forcing it to produce more viral proteins and genetic material. Ultimately, the infected CD4+ cell dies, releasing newly formed HIV virions that can infect other CD4+ cells, perpetuating the cycle of infection and immune cell depletion. Key viral enzymes, including protease, reverse transcriptase, and integrase, are essential for this replication process and are the targets of current ART medications.
In the absence of ART, the CD4+ cell count in an HIV-infected individual typically declines by approximately 50-80 cells/mm³ per year. This decline can accelerate once the CD4+ count drops below 200 cells/mm³, the critical threshold for AIDS diagnosis.
With the widespread use of ART and improved control of HIV replication, cardiovascular disease has emerged as a leading cause of morbidity and mortality in people living with HIV. The precise mechanisms underlying this increased cardiovascular risk are complex and multifactorial, potentially involving direct effects of HIV infection, side effects of ART drugs, metabolic abnormalities associated with HIV infection, or a combination of these factors.
History and Physical Examination
A comprehensive assessment of a patient suspected of having HIV or AIDS requires a detailed medical history and physical examination. Gathering information about the patient’s HIV history, including the date of diagnosis, any prior opportunistic infections or co-infections, current medications (both ART and other chronic medications), and existing comorbid conditions, provides essential context for understanding their overall health status. Crucially, determining the patient’s most recent CD4+ count and viral load is vital for assessing the degree of immunosuppression and the potential for AIDS-related illnesses. However, it is important to recognize that some patients may present without a prior HIV diagnosis, may have delayed testing, or may have experienced interruptions in medical care and ART access. Identifying the patient’s primary care and infectious disease providers, if any, is essential for facilitating coordinated care.
While a thorough HIV-focused history is important, clinicians must also be mindful that with effective ART, many individuals with HIV now present with general medical problems unrelated to HIV or AIDS, particularly if their CD4+ counts are well-maintained. Therefore, the history and physical examination should be guided by the patient’s chief complaint and presenting symptoms, considering that these may or may not be directly related to HIV or AIDS. The following sections will outline potential HIV or AIDS-related illnesses, categorized by the affected body system.
Cardiac System
HIV infection and ART are implicated in an increased risk of cardiovascular disease in people living with HIV. Common presenting symptoms may include chest pain, shortness of breath, or unexplained fatigue. The cardiovascular examination should follow standard protocols for assessing cardiac conditions, including palpation for chest wall tenderness, observation for jugular venous distention and peripheral edema, and auscultation for abnormal heart sounds, murmurs, or signs of pulmonary edema. AIDS-related cardiac complications can include purulent pericarditis or cardiac tamponade, often caused by Mycobacterium tuberculosis. In cases of suspected pericardial effusion, clinicians should assess for Beck’s triad, characterized by low blood pressure, jugular venous distention, and muffled heart sounds, which may suggest compressive pericardial effusion.
Pulmonary System
Pulmonary complications are frequently encountered in HIV and AIDS. HIV infection, even in the absence of AIDS, increases susceptibility to various infectious and non-infectious pulmonary conditions. Common presentations include upper respiratory tract infections and acute bronchitis. Non-infectious pulmonary diseases in this population can include Kaposi’s sarcoma and non-Hodgkin’s lymphoma, sarcoidosis, lung cancer, and emphysema. The pulmonary examination in an HIV or AIDS patient should assess the patient’s work of breathing, looking for signs of respiratory distress such as tripoding posture, tachypnea, retractions, or cyanosis. Auscultation of the lungs may reveal generalized or focal adventitious lung sounds, which can aid in diagnosing the underlying pulmonary pathology.
Oropharyngeal and Gastrointestinal System
Digestive tract complaints in individuals with HIV or AIDS may be unrelated to their HIV status or may arise from opportunistic infections, malignancies, or ART-related complications. HIV medications can induce pancreatitis, hepatic steatosis, or hepatotoxicity. Co-infection with hepatitis B or C is also common in HIV-positive individuals. Patients with lower CD4+ counts are at increased risk for hepatobiliary issues, including acalculous cholecystitis. Well-recognized gastrointestinal complications of HIV or AIDS-defining illnesses include recurrent oral herpes simplex infections, Candida esophagitis, and Cryptosporidium diarrhea.
The history should include detailed characterization of abdominal pain, including onset, duration, location, and severity, as well as associated symptoms like nausea, vomiting, diarrhea, constipation, melena, hematochezia, or urinary symptoms. Assessing the patient’s appetite and ability to swallow is crucial if esophagitis is suspected. Physical examination should include inspection of the oropharynx for lesions or ulcerations, assessment of abdominal distention, auscultation of bowel sounds, palpation for hepatomegaly, and localization of abdominal tenderness, rebound, or guarding. Signs of chronic liver disease, such as caput medusae, spider angiomas, jaundice, or gynecomastia, may be evident in cases of hepatic failure. Rectal examination may be indicated based on symptoms or for evaluating melena or hematochezia, particularly in non-immunosuppressed individuals.
Central Nervous System
CNS-related complications in HIV and AIDS can encompass meningitis, focal demyelinating lesions, and malignancies resulting from immunosuppression. Presenting symptoms can range from headaches, meningismus, altered mental status, vision changes, focal weakness, or seizures. The history and physical examination should be tailored to the patient’s HIV status and the presenting symptoms, with a strong consideration of infectious etiologies. Infection should always be a primary concern, prompting inquiries about CD4+ status, headache characteristics, fever, sick contacts, and prophylactic medications. For patients presenting with headaches, detailed questioning about onset, triggers, severity, pain progression, and associated symptoms like fever, neck pain, or other neurological symptoms is essential. In cases of seizures or focal weakness, information regarding timing, duration, severity, focality, or generalization of symptoms should be obtained. The neurological examination should include a comprehensive assessment of mental status and neurological function. If meningitis is suspected, assessment for nuchal rigidity is critical. Ophthalmoscopy is indicated for any visual complaints, as it may reveal characteristic findings of CMV retinitis, such as “pizza pie” lesions with fluffy white perivascular infiltrates and surrounding hemorrhages.
Oncologic and Hematologic Systems
Individuals with HIV can experience hematologic abnormalities, including anemia, thrombocytopenia, and leukopenia. ART often improves these hematologic issues. However, ART and prophylactic medications can also cause bone marrow toxicity, leading to blood count derangements. Patients with thrombocytopenia may present with concerns about abnormal bleeding or bruising. Physical examination should assess for petechiae, purpura, and signs of internal bleeding. Leukopenic patients are more susceptible to infections, and their evaluation should focus on identifying the source of infection. Anemia may manifest as weakness, fatigue, or shortness of breath, prompting assessment of skin pallor and conjunctival paleness.
AIDS-related lymphoma is a significant oncologic complication in advanced HIV infection. Primary CNS lymphoma, often associated with Epstein-Barr virus co-infection, is also encountered. Systemic symptoms such as weight loss, fever, or night sweats may accompany previously mentioned neurological complaints. Physical examination should focus on general appearance, mental status, and a comprehensive neurological assessment.
Dermatologic System
Acute HIV infection can present with a maculopapular or morbilliform rash. Oral ulcers or lesions, molluscum contagiosum, and human papillomavirus (HPV) infection are also common dermatologic manifestations. Kaposi’s sarcoma, a vascular neoplasm characterized by violaceous patches, nodules, or plaques, is the most frequent AIDS-related cutaneous condition. Disseminated fungal infections in severely immunosuppressed individuals can mimic molluscum contagiosum. The dermatologic history should focus on the timing of skin manifestations in relation to HIV status, recent infections, ART or prophylaxis, and any associated systemic, CNS, or gastrointestinal symptoms.
Evaluation
Diagnosing HIV infection requires a two-step process involving a screening test followed by a confirmatory test. These laboratory assays detect specific HIV antibodies or antigens in blood samples. In patients newly diagnosed with HIV or presenting for evaluation of an acute medical problem, a complete blood cell count (CBC) should be performed to assess for leukopenia, anemia, or thrombocytopenia. Viral load and CD4+ counts should be ordered if these parameters are relevant to patient management; however, results may not be immediately available. The differential count from a CBC can provide an indirect estimate of the CD4+ count. Normal white blood cell and lymphocyte counts suggest a likely normal CD4+ count. Conversely, an absolute lymphocyte count below 950 cells/mm³ may indicate a CD4+ count below 200 cells/µL, suggesting immunosuppression and increased risk of opportunistic infections.
Further diagnostic testing should be guided by the differential diagnosis and the patient’s presenting symptoms. If cardiac issues are suspected, such as acute coronary syndrome, electrocardiogram (EKG) and cardiac biomarkers should be ordered. Bedside ultrasound or echocardiography may be considered for evaluating potential valvular pathology, pericarditis, or cardiac tamponade.
Chest radiography is valuable for evaluating cardiac or pulmonary conditions. If chest radiography is non-diagnostic in cases of suspected lung pathology, computed tomography (CT) of the chest may be warranted. Arterial blood gas analysis can help determine the need for corticosteroids in patients with Pneumocystis pneumonia (PCP). Blood cultures should be obtained before initiating antibiotics in patients with AIDS. Sputum cultures (induced or from bronchoalveolar lavage) or serum and urine bacterial antigen testing can help identify the causative organism in pulmonary infections. Tuberculosis (TB) testing should be performed if clinical suspicion is high. Advanced imaging, such as CT scans, may be necessary to evaluate for extrapulmonary or disseminated TB, particularly in immunocompromised AIDS patients, where presenting signs may be subtle. Patients with suspected TB should be placed in respiratory isolation pending confirmatory test results.
A complete metabolic profile (CMP) is useful for establishing baseline renal and hepatic function and for detecting abnormalities related to ART or acute medical conditions. Individuals with low CD4+ counts or AIDS are more prone to hepatobiliary problems like pancreatitis and acalculous cholecystitis. Measuring liver transaminases, bilirubin, and lipase is helpful in evaluating these conditions. Abdominal CT or ultrasound may be considered based on clinical presentation. Esophagogastroduodenoscopy (EGD) may be necessary for evaluating esophagitis in AIDS patients with odynophagia or dysphagia. AIDS patients are also susceptible to various diarrheal illnesses. Stool testing for ova, parasites, bacteria, and C. difficile toxins is recommended in immunocompromised patients with diarrhea. Colonoscopy may be required in severe or refractory cases.
When evaluating neurological complaints in HIV or AIDS patients, clinicians should have a low threshold for ordering head CT and lumbar puncture with cerebrospinal fluid (CSF) analysis, particularly in immunocompromised patients presenting with altered mental status, focal neurological deficits, or suspected meningitis. Cryptococcal meningitis can have a subtle presentation, and cryptococcal antigen testing should be considered in patients with altered mental status.
Treatment and Management
The cornerstone of HIV treatment is ART, aimed at suppressing viral replication and maintaining or restoring CD4+ cell counts. ART regimens typically involve combinations of antiretroviral drugs and are lifelong. While the specifics of ART are detailed elsewhere, it is important to emphasize that ART is crucial for managing AIDS and preventing disease progression. Many opportunistic infections and conditions associated with AIDS require medical or surgical management similar to that in HIV-negative individuals. This section focuses on prophylaxis and treatment of opportunistic infections and disease states specifically associated with long-term HIV infection or severe immunosuppression (AIDS). ART remains a central component in the management of these conditions, as it helps to reduce viral load and improve CD4+ cell counts, thereby bolstering the immune system.
Empirical antibiotic therapy for bacterial pneumonia should cover both typical and atypical pathogens. For PCP, the treatment of choice is trimethoprim-sulfamethoxazole (TMP-SMX) for 21 days. Corticosteroids should be added to TMP-SMX for PCP treatment if the partial pressure of oxygen (PaO2) is less than 70 mmHg on arterial blood gas analysis. Treatment of TB in HIV-positive individuals requires careful consideration of multidrug resistance and the patient’s degree of immunosuppression. Consultation with an infectious disease specialist is strongly recommended to coordinate TB treatment with ART, particularly in severely immunocompromised AIDS patients. Mycobacterium avium complex (MAC) infection typically occurs in advanced HIV infection with CD4+ counts below 50 cells/µL and is treated with a multidrug regimen including ethambutol, clarithromycin, and rifabutin.
Oral thrush can be treated with topical nystatin swishes. Thrush in otherwise healthy individuals may be an early indicator of acute HIV infection, warranting HIV testing in those with risk factors. If the CD4+ count is below 100 cells/µL, systemic antifungal treatment with an azole should be considered to prevent esophageal candidiasis. Fluconazole is the preferred agent for Candida esophagitis. Other causes of esophagitis include herpes simplex virus (HSV) and cytomegalovirus (CMV), requiring antiviral medications like acyclovir or ganciclovir, respectively. Pain management, hydration, and electrolyte repletion may also be necessary for patients with esophagitis experiencing pain or dehydration. Various opportunistic infections can affect the gastrointestinal tract, and antibiotic therapy should target common pathogens such as Clostridium difficile, Salmonella, Shigella, Campylobacter, and Yersinia. A common antibiotic combination is metronidazole and ciprofloxacin. For diarrhea suspected to be caused by Cryptosporidium, paromomycin is the antibiotic of choice. CMV should be considered in severely immunosuppressed patients (CD4+ count < 50 cells/µL) with diarrhea, and ganciclovir may be indicated. Gastrointestinal TB should also be considered in patients with very low CD4+ counts.
In cases of suspected meningitis, empiric antibiotics should cover common bacterial pathogens. HSV coverage should also be considered pending HSV-PCR results. Cryptococcal meningitis is common when CD4+ counts are below 100 cells/µL. Initial treatment typically involves amphotericin B and flucytosine during an induction phase, followed by consolidation with fluconazole. Repeat lumbar punctures may be necessary to manage elevated intracranial pressure. Toxoplasma gondii infection can cause CNS disease when CD4+ counts fall below 100 cells/µL. Cerebral toxoplasmosis is often characterized by ring-enhancing lesions on head CT and is treated with pyrimethamine and sulfadiazine. Primary CNS lymphoma associated with Epstein-Barr virus infection is treated with ART and chemotherapy. Progressive multifocal leukoencephalopathy (PML), caused by the JC virus, is characterized by demyelinating brain lesions and is primarily managed by immune reconstitution with ART; there is no specific antiviral therapy for PML. CMV retinitis occurs when CD4+ counts are below 50 cells/µL and is treated with valganciclovir, often administered via intraocular implant and oral medication.
Kaposi’s sarcoma can be treated with local therapies such as cryotherapy, radiation, or infrared coagulation. Systemic chemotherapy may be necessary for more extensive or aggressive Kaposi’s sarcoma. Disseminated fungal infections with cutaneous manifestations are treated with systemic antifungals, such as azoles.
Prophylactic measures are crucial in preventing many opportunistic infections in individuals with HIV. PCP prophylaxis with double-strength TMP-SMX is initiated when CD4+ counts fall below 200 cells/µL. Toxoplasma gondii prophylaxis, also with double-strength TMP-SMX, is recommended when CD4+ counts are below 100 cells/µL. MAC prophylaxis with azithromycin is indicated when CD4+ counts drop below 50 cells/µL.
Differential Diagnosis
The diagnosis of AIDS is definitively established when an HIV-positive individual meets either of two criteria: a CD4+ cell count of less than 200 cells/µL, or the presence of an AIDS-defining illness. The presence of an AIDS-defining illness in an HIV-positive person is inherently indicative of severe immunosuppression. Examples of AIDS-defining illnesses include:
- Pulmonary or disseminated tuberculosis
- Invasive cervical cancer
- Esophageal candidiasis
- Cryptococcosis (extrapulmonary)
- Cryptosporidiosis (chronic intestinal)
- Cytomegalovirus (CMV) retinitis or CMV disease in organs other than liver, spleen, or lymph nodes
- Herpes simplex virus (HSV) infection causing chronic ulcers, bronchitis, pneumonitis, or esophagitis
- Kaposi sarcoma
- Pruritic popular eruption of HIV
- Lymphoma (Burkitt’s lymphoma, primary lymphoma of the brain, immunoblastic lymphoma)
- Mycobacterium avium complex (MAC) infection, disseminated or extrapulmonary
- Pneumocystis jirovecii pneumonia (PCP)
- Progressive multifocal leukoencephalopathy (PML)
- Toxoplasmosis of the brain
- HIV-associated encephalopathy (AIDS dementia complex)
- HIV wasting syndrome
- Disseminated histoplasmosis
- Isosporiasis (chronic intestinal)
- Recurrent Salmonella septicemia
- Recurrent bacterial pneumonia
- Wasting syndrome due to HIV
Alt: Graphic listing AIDS-defining conditions as per the 1993 CDC classification, illustrating the breadth of opportunistic illnesses associated with AIDS.
Prognosis
Without antiretroviral therapy, most individuals with HIV will progress to AIDS within ten years of infection. An asymptomatic phase can last for several years, often around eight, followed by a more rapid decline in immune function as CD4+ levels decrease, particularly below 200 cells/µL. However, with the initiation of ART, even after an AIDS diagnosis, individuals can live for more than a decade and may achieve a near-normal lifespan. Conversely, individuals diagnosed with AIDS who do not receive ART have a significantly poorer prognosis, with a median survival of approximately two years.
Postoperative and Rehabilitation Care
Rehabilitation
Rehabilitation plays a vital role in managing the long-term effects of HIV/AIDS. Healthcare providers commonly refer individuals with HIV/AIDS to therapy to address musculoskeletal, neurological, and cardiovascular deficits that may arise as the disease progresses, as well as to manage pain associated with or exacerbated by their condition. Moderate-intensity aerobic and resistance training have been shown to be beneficial for people with HIV/AIDS, improving physical function without negatively impacting CD4+ counts or viral load. These exercise modalities can lead to significant strength gains and improved overall well-being. As the prognosis for HIV/AIDS has improved, rehabilitation also addresses work-related challenges, helping individuals manage the physical demands of their professions and overcome any functional limitations they may experience.
Deterrence and Patient Education
Patient education is paramount in HIV prevention and management. Individuals should receive comprehensive education on HIV transmission routes, modes of acquisition, and strategies to prevent onward transmission. Understanding the significance of CD4+ cell counts and the crucial role of ART in maintaining immune function and managing potential medication side effects is essential. Patients should be informed about the spectrum of opportunistic infections, malignancies, and comorbid conditions that can occur with long-term HIV infection, AIDS, and ART. It is crucial to emphasize that with consistent medical care and adherence to ART, many people living with HIV can lead full and productive lives for many years after diagnosis – a stark contrast to the outlook just a few decades ago.
Pearls and Other Issues
- HIV lipodystrophy, a complication of ART, causes abnormal fat accumulation around the waist and fat loss in the face. Treatment options include tesamorelin, a synthetic growth hormone-releasing hormone, and dermal fillers.
- Prophylactic medications are essential to prevent common opportunistic infections in individuals with HIV. PCP prophylaxis starts when CD4+ counts drop below 200 cells/µL, Toxoplasma gondii prophylaxis when counts are below 100 cells/µL, and MAC prophylaxis when counts fall below 50 cells/µL.
- Cardiovascular disease is now a leading cause of morbidity and mortality in people living with HIV in the ART era.
- Without ART, CD4+ cell counts typically decline by 50-80 cells/µL per year, with an accelerated decline below 200 cells/µL.
- AIDS diagnosis is defined by a CD4+ count below 200 cells/µL or the presence of an AIDS-defining illness in an HIV-positive individual.
- Prominent AIDS-defining illnesses include Candida esophagitis, invasive cervical cancer, PCP pneumonia, disseminated TB, Kaposi sarcoma, and Cryptosporidium diarrhea.
Enhancing Healthcare Team Outcomes
Effective management of HIV and AIDS is complex, lifelong, and requires a collaborative, interprofessional approach. Coordination between primary care physicians and specialists in infectious disease, oncology, gastroenterology, neurology, cardiology, and dermatology is essential to address the diverse complications of chronic HIV infection, ART side effects, and immunosuppression in AIDS. Pharmacists, social workers, mental health providers, and ancillary staff play crucial roles in patient education, medication access, and psychosocial support. An integrated interprofessional team approach has been shown to improve treatment adherence and outcomes for individuals living with HIV.
Review Questions
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References
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Disclosures:
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