Pneumocystis jiroveci (previously named P. carinii) is a fungus that causes pneumonia in patients with advanced HIV infection (CD4 count <200) or other severe immune impairment, such as immunosuppression from organ transplantation or cancer chemotherapy. Early in the AIDS epidemic, Pneumocystis pneumonia (PCP) was the AIDS-defining illness for more than 60% of HIV-infected patients and was a leading cause of death. PCP continues to be a common presenting illness for patients who have undiagnosed HIV infection.

Improved techniques for diagnosing PCP using bronchoscopy or sputum induction, use of monoclonal antibodies for the detection of P. jiroveci in sputum or bronchoscopy specimens, availability of effective antibiotics, and use of adjuvant steroids for patients with severe pneumonia have significantly decreased the morbidity and mortality from this infection. Treatment of PCP requires a prolonged course (3 weeks) of antibiotics. Effective antibiotics include combinations of trimethoprim and sulfamethoxazole, clindamycin and primaquine, or dapsone and trimethoprim or single-agent therapy with pentamidine, trimetrexate, or atovaquone. Steroids may be added to prevent the worsening of oxygenation that is otherwise common early in treatment. Guidelines for adding steroids are based on abnormalities in the patient’s oxygenation.

More importantly, PCP can be prevented by the ongoing administration of low doses of trimethoprim and sulfamethoxazole, dapsone, or atovaquone. It is standard practice to prescribe these antibiotics to symptomatic HIV-infected individuals or those who have CD4 counts under 200. This practice, termed primary prophylaxis, has dramatically decreased morbidity and mortality from PCP.

Toxoplasma gondii is a parasite that causes focal encephalitis in patients who have advanced HIV infection. The initial infection is acquired by eating infected, undercooked lamb, pork, or beef or by the ingestion of oocysts shed into the environment in the feces of infected cats. After ingestion, the parasite migrates and encysts in tissues throughout the body. Although this may cause fever and lymphadenopathy, it is usually a mild, self-limited illness that does not come to clinical attention. Subsequently, toxoplasmosis remains as asymptomatic, quiescent cysts in a variety of body sites.

HIV-infected patients with advanced immunosuppression (usually those who have CD4 counts <100) may experience a reactivation of infection, most commonly in the central nervous system (CNS). Patients present with focal neurologic abnormalities such as hemiplegia, tremor, diplopia, or more generalized CNS symptoms such as headache, personality change, confusion, lethargy, disorientation, coma, myoclonus, or seizures. Neurologic abnormalities can be quite profound, making it difficult to imagine that the patient will ever recover functional status. Nevertheless, antibiotic treatment (using combinations of sulfa drugs, pyrimethamine, clindamycin, and/or atovaquone) often leads to complete or nearly complete recovery. Trimethoprim with sulfamethoxazole or dapsone with pyrimethamine are used as prophylaxis to prevent reactivation of infection in patients who have very low CD4 counts (CD4 >100).

The cytomegalovirus (CMV) herpes virus is transmitted perinatally (from mother to baby at or near the time of birth) or through close interpersonal contact, causing a mild viral syndrome in healthy individuals. The virus then establishes a latent, clinically silent infection. Individuals who become severely immunosuppressed (including patients with AIDS who have CD4 counts <50) can experience viral reactivation with devastating consequences.

In patients with AIDS, the most common sites of reactivation include the eyes and the gastrointestinal (GI) tract. Ocular CMV infection, a focal chorioretinitis, leads to retinal necrosis, with loss of vision in the affected areas of the retina. Patients often report curtain-like areas of darkness in their vision, floaters, or more generalized blurring. Because the infection can progress quickly and irreversibly, new or changing visual complaints in a patient with advanced HIV disease should prompt an urgent ophthalmologic assessment.

CMV infection in the GI tract occurs most commonly in the esophagus or colon. The spectrum of disease ranges from minor inflammation to very large, deeply penetrating ulcers. Symptoms include pain, diarrhea, weight loss, anorexia, and fever.

CMV infection may involve the nervous system, presenting as a rapidly progressive peripheral neuropathy that causes burning or shooting pains in the arms or hands or involving the brain itself (ventriculitis or encephalitis). Hepatitis, biliary tract disease, and pneumonitis may also occur.

Treatment of CMV infection is difficult because available medications prevent CMV from replicating, but do not kill the virus. All have significant side effects. Ganciclovir is available intravenously, in a device that can be surgically implanted into the eye, or as a formulation (valganciclovir) that can be taken orally. Foscarnet and cidofovir must be given intravenously. Although medical treatments for CMV infection are suboptimal, treatment of HIV infection with antiretroviral medications often leads to significant immunologic recovery and eventual immunologic control of CMV infection.

Mycobacterium avium is a distant relative of the bacterium that causes tuberculosis. Although M. avium complex (MAC) is common in the environment and humans are exposed through both ingestion and inhalation, it rarely causes disease in healthy people. Patients with far-advanced HIV disease (usually those with a CD4 count of less than 50) may develop disseminated infection that involves the bloodstream, lymph nodes, liver, other sites in the GI tract, or bone marrow. The patient experiences progressive weakness, fever, chills, sweats, weight loss, enlarged lymph nodes, abnormal liver function tests (increased alkaline phosphatase and gamma-glutamyl transferase (GGT)), abdominal pain, pulmonary infiltrates, and bone marrow suppression. Patients usually do not die of MAC per se, but MAC contributes to wasting, catabolism, and susceptibility to other problems; systemic MAC infection is associated with a high short-term mortality rate.

Treatment of MAC with antibiotics is marginally successful. Furthermore, two or more drugs must be used in combination to prevent the rapid development of drug resistance. Azithromycin or clarithromycin, ethambutol, and rifabutin are the drugs of choice. Given the marginal efficacy of these antibiotics, treatment is continued indefinitely unless the patient’s immunologic status improves. Prophylactic antibiotics are moderately effective in preventing MAC; prophylaxis is usually prescribed to HIV-infected patients who have very low CD4 counts (< 100).

Cryptococcus is a ubiquitous environmental fungus. It typically enters the body through inhalation, causes a mild pneumonitis, and then disseminates via the blood stream to the CNS. In patients with AIDS, it is a frequent cause of subacute or chronic meningitis. Patients with cryptococcal meningitis experience vague symptoms such as fever, headache, nausea, vomiting, malaise, and cognitive dysfunction that worsen gradually over days to weeks. Patients sometimes present with altered mentation, personality changes, or behavioral disturbances as the predominant symptoms. A test for cryptococcal antigen can be performed using serum or cerebrospinal fluid (CSF). This test is relatively simple and widely available.

Although ultimately fatal if untreated, this infection usually responds to a prolonged course of antifungal agents (amphotericin or fluconazole with or without flucytosine). Recent attention has focused on the importance of addressing increased intracranial pressure in the setting of cryptococcal meningitis. Repeated lumbar puncture or CSF shunts are helpful when patients have persistently elevated intracranial pressure.

There are numerous other infectious complications of HIV, including some infections that are seen only in limited geographic areas. A full discussion is beyond the scope of this text, but excellent references are available.²

Zidovudine was the first antiviral agent available to treat HIV infection. Clinical trials testing zidovudine against placebo in patients who had AIDS demonstrated significantly improved survival among those who received the drug. These results were met with great enthusiasm. A number of antiviral agents with similar mechanisms of action were developed over the next few years. Unfortunately, these agents were able to only partially suppress the virus. After a few weeks or months of treatment, replication and mutation of the HIV virus facilitated the development of drug resistance and resulted in progression of the infection.

In the mid-1990s, new classes of antiretroviral medications (protease inhibitors and nonnucleoside reverse transcriptase inhibitors) became available. Clinical trials verified dramatically improved efficacy when these medications were used in combinations of three or more agents. Initial skepticism about HIV treatment yielded to overly enthusiastic claims that AIDS would soon be cured.

Although it is now clear that currently available therapies do not cure HIV, antiretroviral combination treatment reduces viral replication dramatically. Such combinations have been referred to as highly active antiretroviral therapy (HAART). Effective antiretroviral therapy stops the progression of immunologic damage, leading to significant recovery of the immune system and a rebound in CD4 counts. Even debilitated patients with advanced AIDS may experience dramatic improvement with restoration of functional status and control or resolution of infections. The development of effective therapies was followed by a precipitous drop in hospitalizations for AIDS and dramatic decreases in AIDS mortality.¹

HIV infection is not curable with currently available therapies. However, HIV infections can be controlled such that HIV infection has become a chronic disease. The initial enthusiasm for antiretroviral medications has been tempered by realization that antiretroviral medications have significant long-term toxicity and that patients have great difficulty with adherence to complicated medical regimens over long periods of time. These realities mean that decisions about initiating HAART should be carefully considered, weighing the risks and benefits for the individual patient. Current guidelines advise antiretroviral treatment for all patients who have experienced opportunistic infections or severe HIV-related illnesses and for patients who have significant immunosuppression, as measured by CD4 counts >200.³,⁴ Conversely, most experts suggest careful clinical monitoring without HAART for patients who have a CD4 count greater than 350. There is continued controversy about management of patients who have CD4 counts between 200 and 350. Some authorities favor treatment, whereas others favor close clinical monitoring, deferring medications for as long as possible. Given the medical uncertainty, patient preference, motivation, and readiness for treatment should weigh heavily in the decision process.