HIV opportunistic infections


 * , Ujjwal Rastogi, MBBS [mailto:urastogi@perfuse.org]

Overview
Before the widespread use of potent combination antiretroviral therapy (ART), opportunistic infections (OIs), which have been defined as infections that are more frequent or more severe because of immunosuppression in HIV-infected persons, were the principal cause of morbidity and mortality in this population. In the early 1990s, the use of chemoprophylaxis, immunization, and better strategies for managing acute OIs contributed to improved quality of life and improved survival. However, 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.

Etiology
Despite the availability of ART in the United States and other industrialized countries, OIs continue to cause considerable morbidity and mortality for three primary reasons:


 * Many patients are unaware of their HIV infection and seek medical care when an OI becomes the initial indicator of their disease.
 * Certain patients are aware of their HIV infection, but do not take ART because of psychosocial or economic factors.
 * Certain patients are prescribed ART, but fail to attain adequate virologic and immunologic response because of factors related to adherence, pharmacokinetics, or unexplained biologic factors.

Thus, although hospitalizations and deaths have decreased since the implementation of ART, OIs remain a leading cause of morbidity and mortality in HIV-infected persons.

Pathophysiology
Recognizing that the relation between OIs and HIV infection is bidirectional is important. HIV leads to immunosuppression that allows opportunistic pathogens to cause disease in HIV-infected persons. OIs and other coinfections that might be common in HIV-infected persons, such as sexually transmitted infections, can also have adverse effects on the natural history of HIV infection. Certain OIs are associated with reversible increases in circulating viral load and these increases could lead to accelerated HIV progression or increased transmission of HIV. Thus, although chemoprophylaxis and vaccination directly prevent pathogen-specific morbidity and mortality, they might also contribute to reduced rate of progression of HIV disease. For instance, randomized trials using trimethoprim-sulfamethoxazole (TMP-SMX) have documented that chemoprophylaxis can both decrease OI-related morbidity and improve survival.

Historical Perspective
The first guidelines for Prophylaxis against Pneumocystis carinii Pneumonia for persons infected with the human immunodeficiency virus became the first HIV-related treatment guideline published by the U.S. Public Health Service in 1989. This report was followed by guideline on prevention of Mycobacterium avium complex (MAC) disease in 1993.

Initiation of ART in the Setting of an Acute OI (Treatment-Naïve Patients)
When an acute OI is present, initiation of ART is usually expected to improve immune function and contribute to faster resolution of the OI.

Initiation of ART has been documented to be effective for OIs for which effective therapy does not exist; cryptosporidiosis, microsporidiosis, and progressive multifocal leukoencephalopathy (PML) might resolve or at least stabilize after the institution of effective ART. For kaposi's sarcoma (KS), initiation of ART has been documented to lead to resolution of lesions in the absence of specific therapy for the sarcoma.

Benefits of ART in preventing OI:

The initiation of ART in the setting of an acute OI also has preventive benefit; a second OI is less likely to occur if ART is started promptly rather than delaying the initiation of ART.

Disadvantages:

Starting ART in the setting of an acute OI has several potential disadvantages.
 * Severely ill patients might not absorb ART drugs, leading to subtherapeutic serum levels and the development of antiretroviral drug resistance.
 * ART toxicities might be confused with disease manifestations or toxicities associated with drugs used for treating patients with an OI. Drug-drug interactions among ART and anti-OI drugs might be difficult to manage.
 * Renal or hepatic dysfunction during acute OIs might make dosing of ART drugs difficult to estimate.
 * IRIS events can occur and cause manifestations that are difficult to distinguish from other clinical conditions.

When to start the therapy?

For above mentioned reasons, no consensus has been reached concerning the optimal time to start ART in the setting of a recently diagnosed OI. However, one recently completed randomized clinical trial has demonstrated a clinical and survival benefit of starting ART early, within the first 2 weeks, of initiation of treatment for an acute OI, excluding TB.

Management of Acute OIs in Patients Receiving ART
OIs that occur after patients have been started on ART can be categorized into three groups.
 * The first group includes OIs that occur shortly after initiating ART (within 12 weeks).
 * These cases might be subclinical infections that have been unmasked by early immune reconstitution or simply OIs that occurred because of advanced immunosuppression and are not considered to represent early failure of ART. Many of these cases represent IRIS.
 * When an OI occurs within 12 weeks of starting ART, treatment for the OI should be started and ART should be continued.
 * The second group includes OIs that occur >12 weeks after initiation of ART among patients with suppressed HIV ribonucleic acid. levels and sustained CD4+ counts >200 cells/µL Determining whether these represent a form of IRIS rather than incomplete immunity with the occurrence of a new OI is difficult.
 * When an OI occurs despite complete virologic suppression (i.e., late OI), therapy for the OI should be initiated and ART should be continued.
 * If the CD4+ response to ART has been suboptimal, modification of the ART regimen may be considered, although no evidence exists to indicate that changing the ART regimen in this setting will improve the CD4+ response.
 * The third group includes OIs that occur among patients who are experiencing virologic and immunologic failure while on ART. These represent clinical failure of ART.
 * When an OI occurs in the setting of virologic failure, OI therapy should be started, antiretroviral resistance testing should be performed, and the ART regimen should be modified, if possible, to achieve better virologic control.

Treatment Failure
Clinical failure is defined as lack of improvement or worsening of respiratory function documented by arterial blood gases (ABGs) after at least 4--8 days of anti-PCP treatment. Treatment failure attributed to treatment-limiting toxicities occurs in up to one third of patients.

Special Considerations During Pregnancy
Physiologic changes during pregnancy can complicate the recognition of OIs and complicate pharmacokinetics. Factors to consider include the following:


 * Increased cardiac output by 30%--50% with concomitant increase in glomerular filtration rate and renal clearance.
 * Increased plasma volume by 45%--50% while red cell mass increases only by 20%--30%, leading to dilutional anemia.
 * Tidal volume and pulmonary blood flow increase, possibly leading to increased absorption of aerosolized medications. The tidal volume increase of 30%--40% should be considered if ventilatory assistance is required.
 * Placental transfer of drugs, increased renal clearance, altered gastrointestinal absorption, and metabolism by the fetus might affect maternal drug levels.
 * Limited pharmacokinetic data are available; use usual adult doses based on current weight, monitor levels if available, and consider the need to increase doses if the patient is not responding as expected.

Also in regards with risk in Fetus, pregnancy should not preclude usual diagnostic evaluation when an OI is suspected. Experience with use of magnetic resonance imaging (MRI) in pregnancy is limited, but no adverse fetal effects have been noted.

Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents
Outline of the Guideline:

I: Pneumocystis Pneumonia 
 * Preventing Exposure
 * Preventing Disease
 * Initiating Primary Prophylaxis
 * Discontinuing Primary Prophylaxis
 * Treatment of Disease
 * Monitoring and Adverse Events, Including Immune Reconstitution Inflammatory Syndrome (IRIS)
 * Management of Treatment Failure
 * Preventing Recurrence
 * Discontinuing Secondary Prophylaxis (Chronic Maintenance Therapy)
 * Special Considerations During Pregnancy

II: Toxoplasma gondii Encephalitis
 * Preventing Exposure


 * Preventing Disease
 * Initiating Primary Prophylaxis
 * Discontinuing Primary Prophylaxis
 * Treatment of Disease
 * Monitoring and Adverse Events

Related Chapters

 * Opportunistic infections
 * HIV opportunistic infection pneumocystis pneumonia: prevention and treatment guidelines
 * HIV opportunistic infection toxoplasma gondii encephalitis: prevention and treatment guidelines