HIV Prevention Of Opportunistic Infections

Opportunistic infections (OI) are those caused by microorganisms that are, in normal circumstances, not virulent enough to cause clinical infection. These organisms can take advantage of a host with an inactive or less active immune system in order to cause disease. OI is relevant to current medical practices because they remain a major cause of morbidity and mortality in patients living with HIV.  With the introduction of highly active antiretroviral therapy (HAART) in 1995, the morbidity and mortality associated with HIV and OI decreased significantly. Risk of opportunistic infections increases when a patient's CD4 count declines under 200 cells/mm3, but can still occur in the setting of higher CD4 counts. Prevention of opportunistic infections in HIV patients involves a multistep approach that is centered around the use of HAART, vaccination and occasional use of prophylactic antibiotics. HAART improves CD4 counts significantly and thus is the single most effective measure in preventing OI. Vaccination is an effective measure but it prevents only some specific infections. The use of prophylactic antibiotics is limited to patients with very low CD4 counts that are at the highest risk for OI, and they are intended as a short term intervention and shouldn’t be the mainstay of treatment. This activity reviews HIV methods of preventing opportunistic infections and highlights the role of the interprofessional team in educating patients on the available options.

Prevention of opportunistic infections in HIV is determined by CD4 count. The following are the most common opportunistic infections in HIV patients according to CD4 count:

CD4 Count Below 500 Cells

• Active Tuberculosis

CD4 Count Below 200 Cells

• Hepatitis A 
• Hepatitis B
• Human papillomavirus 
• Sequential pneumococcal vaccines (PCV 13 and PPSV23)
• Influenza
• Tetanus, diphtheria, and pertussis
• Haemophilus influenza
• Polio

It is important to note that only inactivated vaccines should be given to patients with HIV who have CD4 counts less than 200 cells/mm3. When CD4 counts are higher live vaccines can be administered safely. 

The patient should be instructed to avoid possible exposures to certain microorganisms, for example:

• Toxoplasma gondii: avoid cat litter and undercooked meat.
• Mycobacteria tuberculosis: avoid high-risk populations, such as homeless or incarcerated. 
• Cryptococcus- avoid pigeons. 

Antimicrobial therapy can be started in addition to HAART for the treatment of specific pathogens. It is especially useful in the following scenarios:

• Preventing infection in an at-risk individual, e.g., P. jiroveci
• Preventing infections by dormant body microbes, e.g. T. gondi
• Treating asymptomatic patients who have positive serology, e.g., C. immitis

Antimicrobial therapy should be avoided under the following conditions:

• Low disease incidence.
• High risk of developing drug resistance.
• High adverse-effect profile and fatal drug reactions.

Role of CD4 Count Testing

Certain infections are more likely to surface when the CD4 count falls below a critical threshold. Therefore, CD4 counts play a vital role in making the decision to start targeted prophylaxis.[1]

• ANY CD4 count: All HIV patients, regardless of CD4 counts, should be screened for latent TB using interferon assays or tuberculin testing.
• CD4 250 cells/mm3: Annual IgG and IgM assays against coccidiomycosis. Patients with positive serology should be given systemic azole antifungal therapy with fluconazole or itraconazole. Antifungal therapy can be discontinued when CD4 count remains above 250 cells/mm3 for at least 6 months. 
• CD4 less than 200 cells/mm3: Start prophylaxis against Pneumocystis jiroveci using Trimethoprim/Sulfamethoxazole (TMP/SMX). For patients with allergy to sulfa drugs use pentamidine. 
• CD4 less than 150 cells/mm3: Itraconazole should be started to prevent Histoplasma infection, this should be limited to patients who live in endemic areas. 
• CD4 less than 100 cells/mm3: Administer suppressive therapy with TMP/SMX to prevent reactivation of T. gondii in patients with positive IgG serology. For patients who have contraindications to TMP/SMX, dapsone plus pyrimethamine and leucovorin can be used. If the patient is intolerant or allergic to the previous two regimens, atovaquone without pyrimethamine/leucovorin can be used as a 3rd line therapy option. Monotherapy with dapsone, pyrimethamine, azithromycin, clarithromycin should not be used. Patients receiving antiretroviral therapy can discontinue suppressive therapy when the CD4 count is more than 200 cells/mm3 for at least 3 months.
• CD4 counts less than 50 cells/mm3: For patients who are initiating antiretroviral therapy (ART), there is no need to routinely administer antimicrobial prophylaxis against Mycobacterium avium complex (MAC). However, on rare occasions where there is a temporary delay in initiating ART (e.g., patient refusal), and if there are no concerns that the patient may have active MAC infection (e.g., fevers, weight loss), MAC prophylaxis with azithromycin should be initiated and continued until ART is started. If there is a concern for active infection, a mycobacterial blood culture should first be obtained, and prophylaxis should be delayed for 7 to 10 days, pending the results. A more detailed discussion of MAC prophylaxis is presented elsewhere.

The term "immune reconstitution inflammatory syndrome" (IRIS) describes a collection of inflammatory disorders associated with paradoxical worsening of preexisting infectious processes following the initiation of antiretroviral therapy (ART) in HIV-infected individuals. Preexisting infections in individuals with IRIS may have been previously diagnosed and treated, or they may be subclinical and unmasked by the host's regained capacity to mount an inflammatory response.

If immune function improves rapidly following the initiation of ART, systemic or local inflammatory reactions may occur at the site(s) of the preexisting infection. This inflammatory reaction is usually self-limited, especially if the preexisting infection is effectively treated. Rarely, long-term sequelae and fatal outcomes may occur, particularly when neurologic structures are involved.

Diagnostic Criteria for IRIS

• Presence of AIDS with a low pretreatment CD4 count (often less than 100 cells/mm3).
  • One important exception to this general rule is tuberculosis. IRIS secondary to preexisting M. tuberculosis infection may occur in individuals with CD4 counts greater than 200 cells/mm3.
• Positive virologic and immunological response to antiretroviral therapy (ART).
• No evidence of drug-resistant infection, bacterial superinfection, drug allergy or other adverse drug reactions. Patient noncompliance or reduced drug levels due to drug-drug interactions or malabsorption after appropriate evaluation for the clinical presentation.
• Presence of clinical manifestations consistent with an inflammatory condition.
• Temporal association between ART initiation and the onset of clinical features of the illness.[2]

Many different pathogens have been associated with the development of IRIS.[3][4][5][6][7] The following are the most common pathogens found:

• Mycobacterium tuberculosis
• Mycobacterium avium complex
• Cytomegalovirus
• Cryptococcus neoformans
• Pneumocystis jirovecii
• Herpes simplex virus
• Hepatitis B virus
• Human herpesvirus 8 (associated with Kaposi sarcoma)

Several studies have demonstrated that lower CD4 cell counts or high HIV RNA at the time of treatment initiation increase the risk of developing IRIS. Response to ART also plays an important role in predicting risk.[8][9]

The main take away point is that HIV itself is not responsible for the mortality of patients infected with it, but the opportunistic infections that it allows to take over the immunocompromised host. Up to 2 million patients are still affected by HIV yearly worldwide, but since the introduction of HAART, the mortality has decreased overwhelmingly. This success has been due to a major decrease in the incidence of opportunistic infections.