Acquired Immunodeficiency Syndrome

Key concepts

•Despite efforts at disease prevention there are still over 50 000 new HIV infections in the US every year, and HIV infection remains a global epidemic.

•HIV vasculopathy with cottonwool spots and retinal hemorrhage is the most common manifestation of the disease.

•HIV infection can be treated with highly active antiretroviral therapy (HAART), a combination of antiviral drugs. Despite therapy, HIV is has not been eradicated from any individual with our current medications.

•CMV retinitis is the most common opportunistic infection of the eye in patients with HIV infection.

•Treatment of CMV retinitis is based on location of the disease in the eye and time on HAART.

•Once the immune system improves on HAART and CD4+ T cell counts increase, specific anti-CMV therapy can be stopped without progression of the disease.

•An immune recovery uveitis (IRU) can occur in patients receiving HAART, and may require therapy.

•There are a number of opportunistic infections in HIV disease that can affect the eye. These should be looked for and treated appropriately.

Scott M. Whitcup

increase in many areas, including sub-Saharan Africa and parts of Asia.

HIV-1 is a retrovirus and therefore has only RNA copy in its genome. RNA viruses have both genetic diversity and latency, which makes control and eradication difficult. The virus can infect many types of human cell, but much of its pathologic effect is related to infection of the helper CD4+ T cell, which occurs within hours of entering the body.2 Because this cell is crucial for the development of cellmediated immune responses, infection of CD4+ T cells and subsequent cell death result in severe immunosuppression. The virion gp 120 Env protein binds to the CD4+ T cell, and once in the cell its RNA is translated into DNA by viral reverse transcriptase (Fig. 11-1). This DNA then enters the nucleus and incorporates into the cell genome with the assistance of integrase. The viral DNA is then capable of directing protein synthesis of new viral proteins using the infected cell’s apparatus. Proteases are involved in processing HIV proteins into new viral particles, which are then shed from the cell. The infected cell eventually dies.

The earliest evidence of HIV-1 infection was obtained from a blood sample of a patient in the Congo. Clinical evidence of HIV-1 infection in the United States began in the late 1970s. Currently, HIV in humans is thought to originate from primate to human transmission. HIV-2 is classified as a separate virus, and although it causes effects that are clinically similar to those of HIV-1 infection, it is predominantly found in Western Africa.

Human immunodeficiency virus

The clinical course and disease manifestations of human immunodeficiency virus (HIV) infection have dramatically changed since the widespread use of potent antiretroviral therapy. It has been over 25 years since HIV was first established as the cause of the acquired immunodeficiency syndrome (AIDS). Although the use of combinations of antiviral drugs called highly active antiretroviral therapy (HAART) has led to greatly improved survival, a number of treatment challenges remain. First, nearly perfect adherence to complicated treatment regimens is required for sustained virologic suppression.1 Adherence in the range of 50–70% is associated with poorer outcomes and development of drug resistance, and the goal should be greater than 90% adherence. Second, although patient outcomes have improved, eradication of the virus – the ‘cure’ – has remained elusive. Third, the initial hope of a vaccine for HIV has also proved problematic. Finally, access to therapy is limited for many, and as a result the incidence of HIV-1 infection continues to

Epidemiology

Infection is spread mostly through sexual transmission. Until the mid-1990s homosexual and bisexual activity was responsible for most of the transmission. Now, heterosexual activity is the major route of transmission in developed countries. Intravenous drug abuse is another common cause of disease transmission. Perinatal transmission from an infected mother to her offspring can occur in utero. Transmission can also occur during delivery or by breastfeeding. Finally, transmission to healthcare workers can also occur, usually as the result of a needlestick injury. Seroconversion to HIV after a needlestick injury is about 0.3% depending on viral load; this is about 10–100 times less than that with hepatitis C or B. Before the availability of a serologic test for HIV antibody, large numbers of patients, including those with hemophilia, were exposed to the virus through transfusion of blood products.

Although the number of patients with newly diagnosed HIV infection appears to be declining in the United States,

Part 4 • Infectious Uveitic Conditions

Chapter 11 Acquired Immunodeficiency Syndrome

HIV particle

Figure 11-1.  Diagram of the lifecycle of human immunodeficiency virus (HIV). (From Weiss RA. Gulliver’s travels in HIV land. Nature 2001; 410: 963–7.)

HIV disproportionately affects certain segments of the population, including injection drug users, commercial sex workers, people living in poverty, and men who have sex with men. According to Morbidity and Mortality Weekly Report

2001, HIV infection has caused approximately 20 million deaths, and about 30 million people are infected.3 In 2006, an estimated 39 400 persons were diagnosed with HIV in 22 states.4 Extrapolation from these data suggests 56 300 new infections and an annual incidence rate of 22.8 per 100 000 population.

Diagnosis

HIV infection can be detected by the presence of antibody to viral antigens, 2–8 weeks after infection. The antibodies do not control the infection nor prevent its sequelae. Diagnosis of HIV infection is usually made by an enzyme-linked immunosorbent assay (ELISA) and is then confirmed by a Western blot test.5,6 Some strains of HIV are not detected by some ELISA tests. Nevertheless, these tests are almost 100% sensitive, albeit not 100% specific, so false-positive results can occur. The virus can also be cultured from blood, semen, and solid tissues, but only rarely from saliva and tears. In the eye, the virus has been found in the cornea,7 vitreous, and retina.8 Rapid tests are now commercially available for HIV, although testing algorithms for these tests are still being assessed.

HIV disease

An acute retroviral syndrome usually occurs within 1–6 weeks after HIV infection. Patients typically develop fever, rash, myalgias, headache, or gastrointestinal symptoms. The CD4+ count is reduced, and many patients have elevated liver enzyme levels. Without treatment, CD4+ counts decline by about 75 cells/ L/year. The time from initial infection to the development of a disease that meets the definition of AIDS is about 10 years. AIDS is the most severe manifestation of HIV infection and occurs at a point at which the immune system is so damaged by the infection that opportunistic infections such as Pneumocystis jiroveci, Cryptococcus neoformans, cytomegalovirus (CMV), oral candidiasis, or unusual malignant processes such as Kaposi’s sarcoma can

emerge.5,6 There is also an encephalopathy caused by direct HIV infection of the brain.

Progression of HIV disease is related to the CD4+ lymphocyte count. The amount of HIV-1 viral RNA predicts the course of HIV disease, specifically, how rapidly the disease is likely to progress. Persons with HIV loads >30 000 copies/ mL have an 80% likelihood of developing AIDS within 6 years. In contrast, those with HIV loads <500 copies/mL have a 5.4% chance of developing AIDS.9 CD4+ lymphocyte counts are good predictors for the development of specific clinical manifestations of the disease, particularly opportunistic infections. For example, most cases of P. jiroveci pneumonia occur when CD4+ counts fall to <200 cells/ L. Typically, CMV retinitis occurs when CD4+ counts are <50 cells/ L.

HIV therapy

There is still some debate on when to start antiretroviral therapy for HIV disease. The decision regarding initiation of treatment should be individualized but can be based on symptoms, HIV-1 RNA level and CD4+ count. The potential benefit of antiretroviral therapy must be based on the risks of therapy and the impact on quality of life of adhering to a strict therapeutic regimen which is required to avoid drug resistance. Some clinicians start treatment as soon as HIV infection is diagnosed, although many begin treatment when the CD4+ count drops to <350 cells/ L or if symptoms are present. The rapidity of the decline in CD4+ count and HIV load are other factors in the decision of when to start therapy. Others wait until there is a significant risk of the patient developing HIV disease in the near future.

When therapy is started, a highly active regimen consisting of a combination of antiretroviral agents should be employed to minimize resistance. The goal of therapy is to suppress plasma HIV-1 RNA to below detectable limits using a sensitive assay. This highly active antiretroviral therapy (HAART) regimen has also been called the ‘AIDS cocktail’ or ‘triple therapy,’ because it usually consists of three medications. All regimens should combine drugs with synergistic antiviral activity. Regimens can include nucleoside or nucleotide analogue reverse transcriptase inhibitors with a protease inhibitor or combinations of two nucleoside reverse transcriptase inhibitors with a non-nucleoside reverse trans­ criptase inhibitor.10 Other combinations have also been used successfully. Therapy is changed based on tolerability, HIV-1 RNA levels and CD4+ T-cell counts. Box 11-1 lists currently available antiretroviral agents. HAART regimens involve multiple medications that need to be taken at specific times. Again, lack of adherence to these regimens can lead to resistance and failure of therapy, so this must be closely monitored.

Ocular manifestations of HIV infection

Ocular manifestations of HIV infection occur in every tissue of the eye, from the eyelids to the optic nerve (Box 11-2). The most common findings include dry eye, a retinal microvasculopathy, and CMV retinitis. Although direct HIV infection in the brain appears to produce a severe encephalopathy, there is still no definitive evidence that HIV infection of ocular tissue leads to clinically important pathologic effects. However, subclinical infection of retinal neural and