HIV AIDS overview

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Serge Korjian M.D., Tarek Nafee, M.D. [2]

Overview

Acquired immune deficiency syndrome (AIDS) is a disease caused by the human immunodeficiency virus (HIV) that leads to the progressive deterioration of the immune system. In late stages of the condition, individuals become susceptible to opportunistic infections and neoplastic proliferation. HIV is transmitted via direct contact of an exposed mucous membrane or the bloodstream with bodily fluids (e.g., blood, semen, vaginal fluid, preseminal fluid, or breast milk) that contain HIV particles. HIV is a global pandemic with an estimated 35 million individuals living with the disease. Although several treatment regimens for HIV exist, they serve only to decelerate the progression of the virus. There is currently no known cure. Still, modern antiretroviral therapy has significantly decreased the morbidity and mortality associated with the disease.

Classification

Many definitions have been developed for epidemiological surveillance of HIV/AIDS; these include the Bangui definition and the 1994 Expanded World Health Organization AIDS Case Definition. However, these systems are neither sensitive nor specific for clinical staging. In developing countries, the World Health Organization staging system for HIV infection and disease, which uses clinical and laboratory data, is widely employed. The Centers for Disease Control (CDC) Classification System for HIV/AIDS is another primary system used that is chiefly based on CD4 T-lymphocyte counts.

Pathophysiology

HIV causes AIDS by depleting the body's supply of CD4+ T helper lymphocytes. The virus is acquired via either sexual contact, exposure to contaminated blood, or mother-to-child transmission. Once the virus is acquired, it disseminates to the majority of lymphoid organs where it enters a period of rapid viral replication. This leads to the acute phase of the infection, which is characterized by a very elevated viral titer and an acute drop in CD4 T-lymphocyte count. As the immune response mounts, viral replication and the CD4 T cell depletion rate drops. The immune system continues to deteriorate, but at a slower pace. This is known as the chronic phase of HIV infection. The HIV virus causes CD4 T cell death through a variety of mechanisms, including cytopathic single-cell destruction, syncytia formation, autoimmunity, and superantigen formation.

Causes

AIDS is caused by the human immunodeficiency virus (HIV). HIV is a retrovirus classified into the family Retroviridae and the sub-family orthoretroviridae.. Two main subspecies of HIV exist: HIV-1 and HIV-2. HIV-1 is composed of two copies of single-stranded RNA enclosed by a conical capsid comprising the viral protein p24. The genome consists of several major genes that code for structural and functional proteins. These include the gag, pol, env, tat, and nef genes. Two enzymes that are critical for all retroviruses are reverse transcriptase, which transcribes the viral RNA into double-stranded DNA and integrase, which integrates this newly formed DNA into the host genome. It is a well known fact that no two HIV genomes are the same, not even from the same person, causing some to speculate that HIV is a "quasispecies" of a virus.

Differentiating AIDS from other Diseases

Acute HIV infection may be asymptomatic or may cause a mononucleosis-like syndrome. It must be differentiated from similar diseases that cause fever, fatigue, sore throat, myalgia, and lymphadenopathy such as acute toxoplasmosis, acute CMV/EBV infections, and acute viral hepatitis. AIDS should be considered in all patients presenting with symptoms of immunodeficiency or opportunistic infections. It should be distinguished from various medical states that cause immunosuppression including common variable immune deficiency (CVID), chemotherapy treatment, steroid therapy, and severe malnutrition.

Epidemiology and Demographics

HIV is a global pandemic. In 2013, an estimated 35 million people worldwide were living with the disease. An estimated 39 million people have died from AIDS or AIDS-related causes, including approximately 1.5 million patients in 2013 alone. Over three-fourths of these deaths are confined to Sub-Saharan Africa. Despite advances in antiretroviral therapy (ART) and reduction of both the mortality and the morbidity of HIV infection with regular use of these agents, routine access to ART is not available in all countries. At the end of 2013, 11.7 million people were receiving ART in low- and middle-income countries, which represents just 36% of people living with HIV in these countries.

Risk Factors

The majority of HIV infections are acquired through unprotected sexual intercourse. The exposures with the highest risk of contracting disease include contaminated blood transfusions, childbirth, needle sharing, and receptive anal intercourse. Needle sharing is the cause of one-third of all new HIV infections. Infectivity varies throughout the course of the disease and is closely associated with the HIV viral load.

Screening

The primary determinant of the morbidity and mortality of HIV infections is adequate antiretroviral therapy. For that reason, early detection is essential in improving outcomes. In 2006, the Centers for Disease Control announced an initiative for voluntary, routine testing of all Americans aged 13–64 during visits to healthcare facilities. An estimated 25% of infected individuals were unaware of their status. Routine prenatal HIV testing was also recommended for all women as part of their normal gestational screening tests.

Natural history, complications, and prognosis

There is currently no cure for HIV/AIDS. HIV infection leads to progressive decline in CD4+ T-lymphocyte count increasing the risk for opportunistic infections and malignancies. Despite having a variable rate of progression determined by specific host and viral factors, the median time from infection to the development of AIDS ranges from 8 to 10 years among untreated individuals. With the advent of highly active antiretroviral therapy (HAART), both morbidity and mortality have dramatically decreased. Survival and the rate of CD4-count recovery is influenced by age, baseline CD4 cell count, baseline viral load and initial and sustained viral suppression. In areas where HAART is widely available, the development of HAART as effective therapy for HIV infection and AIDS reduced the death rate from this disease by 80%, and raised the life expectancy for a newly-diagnosed HIV-infected person to near normal (assuming full compliance to HAART). HIV infection makes individuals highly susceptible to severe opportunistic infections and neoplastic disease. Major complications of HIV/AIDS include Pneumocystis jirovecii pneumonia, disseminated Mycobacterium avium complex infection, cryptococcal meningitis, cytomegalovirus retinitis, Kaposi sarcoma, and primary CNS lymphoma.

Opportunistic infections

Major opprtunistic infections characteristic of AIDS include viral infections such as CMV retinitis, mucosal HSV, and varicella zoster, bacterial infections such as bacillary angiomatosis, tuberculosis, mycobacterium avium complex, and syphilis, and fungal infections such as cryptococcosis, mucocutaneous candidiasis, coccidiomycosis, and pneumocystis jirovecii pneumonia. It is important to recognize that the relationship between opportunistic infections (OIs) and HIV infection is bi-directional. HIV causes the immunosuppression that allows opportunistic pathogens to cause disease in HIV-infected persons. OIs, as well as other co-infections that may be common in HIV-infected persons, such as sexually transmitted infections (STIs), can adversely affect the natural history of HIV infection by causing reversible increases in circulating viral load that could accelerate HIV progression and increase transmission of HIV. The widespread use of ART starting in the mid-1990s has had the most profound influence on reducing OI-related mortality in HIV-infected persons in those countries in which these therapies are accessible and affordable.

HIV Co-infections

Tuberculosis, hepatitis B and hepatitis C are three of the most common co-infections found in patients with HIV owing mostly to their mode of transmission and epidemiological distribution. These co-infetions may manifest differently in patients with HIV due to the altered immune response. Accordingly, screening for these infections is recommended in all patients diagnosed with HIV.

HIV and pregnancy

Approximately one out of four HIV positive women are unaware of their disease, which puts them at high risk of passing the virus to their children. Mother-to-child transmission is the most common way children become infected with HIV. Approximately all AIDS cases in U.S. children are because of mother-to-child transmission. HIV transmission is reduced from 25% to less than 2% in women taking antiretroviral therapy (ART) before and during birth, and if their babies are given therapy after birth. Accordingly, universal “opt-out” HIV testing is recommended for all pregnant women early in every pregnancy. Triple therapy should be administered to all pregnant women diagnosed with HIV. However, regardless of the antenatal ART regimen, zidovudine should be administered to the mother as an intravenous infusion during labor, and to the neonate orally for 6 months after birth.

HIV infection in infants

The use of ART during pregnancy in HIV-infected women has resulted in a dramatic decrease in the transmission rate to infants, which is currently less than 2% in the United States, and the number of infants with AIDS in the United States continues to decline. For infants born to mothers with unknown HIV status, rapid HIV antibody testing of the mother and/or infant is recommended as soon as possible after birth, with immediate initiation of infant antiretroviral prophylaxis if the rapid test is positive. Virologic assays that directly detect HIV must be used to diagnose HIV infection in infants younger than 18 months. HIV antibody testing cannot establish HIV infection in this age group because maternal HIV antibodies may persist and interfere with the interpretation of a positive HIV antibody test. Children living with HIV infection bring new challenges of adherence, drug resistance, reproductive health planning, management of multiple drugs, and long-term complications from HIV and its treatments.

Diagnosis

Case Definition

AIDS is defined as an the presence of either of the following in a patient with HIV infection: a CD4+ T-cell count below 200 cells/µl, a CD4+ T-cell percentage of total lymphocytes of less than 15%, any of the 27 specified AIDS-defining illnesses.

History and symptoms

Acute HIV should be suspected in patients with flu-like or mononucleosis-like symptoms within 2-4 weeks of exposure to HIV virus or participation in high risk behaviors. Important historical questions for patients with diagnosed HIV/AIDS include: most recent CD4 count and viral load and date of testing, previous and current ART regimens and adherence to treatment, prior drug-resistance testing, current antibiotic prophylaxis, and history of AIDS-defining illnesses. Although a significant proportion of patients are asymptomatic, those who manifest an acute illness present with fever, lymphadenopathy, rash, fatigue, and myalgia. This stage is usually followed by a clinical latency period throughout which patients may not experience any symptoms. AIDS defines the final stage of HIV infection and indicates significant immune compromise. AIDS classically presents with weight loss, night sweats, fatigue, and symptoms of opportunistic infections (or AIDS-defining illnesses) such as diarrhea, mucosal sores, cough, and cognitive and neurological deficits.

Physical examination

The physical examination of a patient with HIV/AIDS can be variable depending on the stage of the disease. Physical exam findings may be related to the virus itself or secondary to the opportunistic infections of late disease. Findings include fever, lymphadenopathy, rash, oral thrush, retinal infiltrates, crackles on auscultation, and focal neurologic deficits.

Laboratory Findings

Important laboratory tests for the initial evaluation of patients with suspected HIV infection include screening tests with high sensitivity such as ELISA, dot blot, and latex agglutination assays, and confirmatory tests with high specificity such as western blot assays, P24 antigen assays, and nucleic acid testing. Two surrogate markers, the CD4 T-cell count (CD4 count) and the plasma HIV RNA viral load, are routinely used to asses immune function and levels of viremia. Resistance testing is becoming of greater importance in the management of HIV/AIDS patients given the increased resistance to certain antiretroviral agents.

Electrocardiogram

Cardiac abnormalities observed in patients with HIV include pericardial effusion, myocarditis, dilated cardiomyopathy, and/or endocardial involvement at any stage of the disease. On ECG, patients may exhibit increased heart rate, prolonged QT interval, and non-specific ST-T changes.

Chest X Ray

Chest X-ray findings in HIV/AIDS are related to the development of opportunistic lung infections. They include ground-glass infiltrates suggestive of Pneumocystis jirovecii pneumonia, lobar consolidation, pleural effusions, loculated empyemas, and lymphadenopathy.

CT

CT scans of chest are an important part of the work-up of HIV patients presenting with pulmonary symptoms. CT scans may show similar findings observed on chest X-rays but carry the advantage of having greater sensitivity in the detection of early interstitial lung disease, lymphadenopathy, and pulmonary nodules.

MRI

Magnetic resonance imaging is the neuroimaging modality of choice for the work-up of HIV-positive patients with suspected CNS disease. MRI can aid in the diagnosis of primary CNs lymphoma, AIDS dementia complex, and cerebral toxoplasmosis. AIDS-Dementia complex is characterized by diffuse cerebral atrophy, enlargement of the cerebral ventricles, and diffuse white matter hypoattenuation. Cerebral toxoplasmosis demonstrates ring enhancing lesions with surrounding edema that mayy closely resemble primary CNS lymphoma.

Treatment

Medical Therapy

The primary goal of antiretroviral therapy (ART) is to reduce HIV-associated morbidity and mortality. This goal is best accomplished by using highly-active ART to maximally inhibit HIV replication, as defined by achievement and maintenance of plasma HIV RNA (viral load) below detectable levels, restoration of normal CD4 cell count, and prevention of transmission of the disease.. Major classes of agents used in the treatment of HIV are: Non-nucleoside reverse transcriptase inhibitors (NNRTIs), nucleoside reverse transcriptase inhibitors (NRTIs), protease inhibitors (PIs), fusion inhibitors, CCR5 antagonists, and integrase inhibitors. All regimens are combinations of at least 3 agents, preferably with 2 NRTIs. Durable viral suppression improves immune function and quality of life, lowers the risk of both AIDS-defining and non-AIDS-defining complications, and prolongs life. Based on emerging evidence, additional benefits of ART include a reduction in HIV-associated inflammation and its associated complications.

Surgery

HIV infected patients may require surgery to treat infections and diseases associated with the condition. Childbirth and organ transplant are two of the many conditions that may require surgery in a HIV patient.

Primary Prevention

There is currently no vaccine or cure for HIV or AIDS. The only known methods of prevention are based on avoiding exposure to the virus or, failing that, an antiretroviral treatment directly after a highly significant exposure, called post-exposure prophylaxis (PEP).

Secondary Prevention

Secondary prevention encompasses measures to reduce the complications of HIV as well as spread of the disease in the population.

Cost-Effectiveness of Therapy

HIV and AIDS retard economic growth by destroying human capital. Without proper nutrition, health care, and medicine that is available in developed countries, large numbers of people are falling victim to AIDS. They will not only be unable to work, but will also require significant and expensive medical care. It is expected that this will likely cause a collapse of economies and societies in certain regions. In some heavily infected areas, the epidemic has left behind many orphans who are cared for by elderly grandparents.

Future or Investigational Therapies

Research to improve current treatments includes decreasing side effects of current drugs, further simplifying drug regimens to improve adherence, and determining the best sequence of regimens to manage drug resistance.