Continuing Education Activity

HIV/ AIDS patients with a low CD4 count have decreased humoral and cellular immunity, predisposing them to opportunistic infections. These diseases are associated with significant morbidity and mortality in patients with HIV/AIDS. This activity will highlight the prevalence and risk factors of common opportunistic infections in HIV/AIDS patients. It will proved a concise review for an interprofessional team of physicians, specialists, and nurses in the current guidelines for prophylactic antibiotic use and vaccinations against common opportunistic infections.

Objectives:

• Explain the pathophysiology and risk factors of opportunistic infections.
• Describe the role of antiviral therapy, vaccinations and immunizations in the prevention of opportunistic infections.
• Identify the development of immune reconstitution syndrome after initiation of HAART.
• Outline the common opportunistic infections in HIV patients, risk factors for exposure and prophylactic antibiotics.

Introduction

Opportunistic infections (OI) are a significant cause of morbidity and mortality in patients with HIV/AIDS. Although the incidence of OI has reduced since the introduction of highly active antiretroviral therapy (ART) in 1995, it continues to add to the burden of HIV-related hospitalizations and deaths in patients. This is particularly true in patients who have not received HAART therapy or who have been non-compliant to it.[1][2] These infections generally lack the virulence and pathogenicity to cause disease in immunocompetent hosts and are hence an uncommon phenomenon.[3]However, due to the immunodeficiency, the risk of OI in HIV/AIDS is substantially increased, particularly in the absence of ART and antimicrobial prophylaxis. 

There is a progressive decrease in CD4+ counts in HIV/AIDS when left untreated. CD4+ cells play an important role in mounting an immune response against infections. These cells release cytokines that lead to the activation of antigen-presenting cells, phagocytic cells, natural killer cells, and cytotoxic T cells.  They also support the conversion of B-lymphocytes into long-lived plasma cells and memory B cells. A decrease in CD4+ T cell count thus leads to a decline in both humoral and cell-mediated immunity. Ultimately it predisposes patients to a higher risk of contracting opportunistic diseases due to viruses, bacteria, fungi, and protozoa.[4][5][6][7][8] As the dogma of medicine is "Prevention is better than cure", preventing opportunistic infections in HIV/AIDS patients is paramount to seeing a decrease in both disease burden and associated mortality. In this review article, we discuss the methods of preventing opportunistic infections in HIV/AIDS patients. 

Function

Strategies to prevent opportunistic infections in HIV/AIDS:

Prevention of opportunistic infections in HIV/AIDS involves a multidisciplinary approach that includes primary care physicians, infectious disease agents, and social workers for support. Early initiation of HAART remains the most efficient method for preventing OI.[9][10][11]Additional methods include the felicitous application of several strategies including vaccinations, screenings for co-infections, avoidance of exposures, patient education, and antibiotic prophylaxis. 

1. Screening for co-infections:  

It is highly recommended that patients with a newly diagnosed HIV infection be screened for the following infections, commonly found concurrently with HIV infection:

 2. Role of antimicrobial prophylaxis:

Antimicrobial prophylaxis, in addition to ART, is indicated in patients with severe immunosuppression and resultant increased risk of opportunistic infections. Low CD4 + cell count acts as a marker of the severity of an immunosuppressed state. [27][28][29]

Antimicrobial prophylaxis can be safely discontinued once CD4+ cell count is > 200 cells/microL for more than six months after the initiation of ART. The following table shows the common organisms that cause opportunistic disease in HIV/AIDS patients below certain thresholds of CD4 + cell count.[30][31][32]

There is little or no evidence to suggest a clinical benefit of starting antimicrobial prophylaxis against the following organisms:

1. Histoplasma capsulated

2. Mycobacterium avium complex (MAC)

3. Bartonella spp

4. Cytomegalovirus (CMV)

5. Cryptosporidium 

6. Candida spp. 

These organisms have a low incidence in HIV/AIDS patients and there is potential for significant drug interactions with HAART therapy if prophylaxis is started concomitantly.  Thus, the timely initiation of HAART and subsequent improvement in CD4 + cell count alone is thought to provide adequate prevention against disease. 

3. Role of vaccinations: 

 The therapeutic efficacy or immunogenic potential of vaccines has not been fully established in HIV/AIDS patients. The decline in immune response in HIV/AIDS patients with low CD4+ cell counts poses a major hurdle in obtaining a robust and long-lasting protective benefit against disease.[33][34][35]Despite these limitations, vaccinations are strongly encouraged in this population given the potential benefit in alleviating the severity and mortality from a vaccine-preventable disease. In general, inactivated vaccines are generally preferred over live vaccines due to the potential risk of vaccine-related illness. If there is any doubt regarding immunogenicity or subsequent testing does not show an appropriate antibody response, it is revaccination is recommended once CD4+ cell count > 200 cells/microL has been achieved. [30][36][37]

The following vaccines are routinely recommended in HIV/AIDS patients:

1. Seasonal influenza vaccine inactivated form administered annually. 
2. Tetanus, Diptheria, acellular pertussis (TdaP): Recommended in all patients 11 years or older who have not yet received it yet followed by Tetanus, Diptheria (Td) booster dose every 10 years. 
3. Human papillomavirus (HPV): Generally administered during adolescent years of 11 -12 years, but in HIV patients, it is recommended up to 26 years of age. Administration of this vaccine even beyond 26 years of age has been recommended in patients with high-risk sexual behavior. 
4. Pneumococcal vaccine: Patients older than 2 years old are recommended to get a Pneumococcal conjugate vaccine (PCV13 or Prevnar) with any CD4+ cell count followed by Pneumococcal polysaccharide vaccine  (PPSV23 or Pneumovax) after at least 8 weeks. It is recommended that this booster be given after the CD4+ cell count improves to >200 cells/microL. A further dose of PPSV23 is recommended after 5 years of the first PPSV23 administration. 
5. Hepatitis A and Hepatitis B vaccine: Administered to patients who are found to be non-immune during routine screening.  It is recommended to check for an appropriate antibody response after one month of vaccine administration. If a poor response is seen, the administration of a vaccine after CD4+ cell count improves to >200 cells/microL is recommended. 
6. Meningococcal vaccinations: Administration of meningococcal conjugate vaccine with serogroups A, C, W, Y is recommended in patients above the age of 2 months. In addition to this, the serogroup B vaccine is recommended in patients with asplenia, complement deficiency, and during meningococcal outbreaks involving serogroup B. 

Certain vaccines are recommended when patients fulfill certain indications, such as:[31]

1. Haemophilus influenza b: Only indicated in children aged 5 to 8 years of age or in adults at risk of disseminated Hemophilus infections such as asplenia or complement deficiency. 
2. Measles, Mumps, Rubella: For patients without severely immunocompromised state (CD4 count < 200cells/microL in adults or less than 15 % in children less than 5 years old), two doses of MMR vaccine 28 days apart is recommended if they do not have any evidence of previous immunity. For someone with a clear history of prior immunization, laboratory finding of an immune response, or birth before 1957 AD, vaccinations are not necessary. 
3. Varicella vaccine: Recommended in patients born after 1979 and who do not have anti-varicella IgG or clearly documented history of receiving two doses of varicella vaccine when their CD4 count was >200 cells/microL.
4. Zoster vaccine: HIV patients 50 years or older should receive two doses of non-live recombinant Zoster vaccine (RZV), intramuscular, 8 weeks apart as per the US department of health and human services. 

4. Minimizing the risk of exposure:

 Opportunistic infections can be contracted by immunocompromised hosts in several ways:

• Presence of high-risk environments to contract the disease (patients who contract Tuberculosis due to close proximity to other infected individuals e.g in prison or homelessness) 
• Presence of high-risk practices (e.g. Hepatitis B, Hepatitis C in patients using intravenous drugs, men who have sex with men, or people with multiple sexual partners).
• Close proximity to certain vectors, who are carriers of the disease can also increase the risk of exposure and result in disease. For example, Crytococccas can be transmitted by pigeons and Toxoplasmosis from cat droppings. 

It is understandable that certain risks of exposure such as being incarcerated or homeless might be difficult to remedy. However, patients should be counseled regarding avoidable exposures such as pets (cats, birds), high-risk sexual practice, and prevention of sexually transmitted diseases with the use of barrier contraceptives. 

Issues of Concern

Immune Reconstitution Syndrome (IRIS)

Immune reconstitution inflammatory syndrome is a clinical phenomenon that occurs after the initiation of antiretroviral therapy. It represents a paradoxical worsening of preexisting infectious processes following improvement in immune response and a subsequent state of elevated inflammatory response.  The preexisting infections can be subclinical (e.g. Toxoplasmosis) or previously treated infections (Tuberculosis). The clinical presentation depends on the location and severity of inflammation.[38][39][40][41][42]

IRIS has been found to occur in up to 30 % of HIV/AIDS patients receiving ART. Low CD4 cell counts or high HIV RNA load at the time of initiation of ART has been thought to be important risk factors for IRIS.[43][44][45] 

There are no universally accepted diagnostic criteria for IRIS, but the presence of the following features is thought to be highly suggestive:[46][47][48]

1. Presence of AIDS with a low pretreatment CD4 count (often less than 100 cells/mm3). However, IRIS secondary to preexisting M. tuberculosis infection may occur in individuals with CD4 counts greater than 200 cells/mm3.
2. Patients should have no evidence of resistance to ART or lowered therapeutic efficacy due to drug interactions.
3. Temporal association initiation of ART and the onset of illness. There must be evidence of immunological response to antiretroviral therapy with improving CD4+ cell count.
4. Presence of clinical manifestations consistent with an inflammatory condition, such as:

• CMV associated IRIS: painless floaters, blurred vision, ocular pain.
• MAC associated IRIS: Fever and tender lymph node enlargement. 
• Cryptococcal infection-associated IRIS: fever, neck rigidity

      5. Other causes of clinical deterioration such as drug allergies (e.g. with abacavir), new opportunistic infections must be considered and ruled out. 

The most common pathogens that are commonly associated with IRIS are Mycobacterium tuberculosis, Mycobacterium avium complex, Cytomegalovirus, Cryptococcus neoforman, Pneumocystis jirovecii, Herpes simplex virus, Hepatitis B virus, Human herpesvirus 8.[39][49]A detailed explanation of pathophysiology and management of IRIS is beyond the scope of this review article. However, a crucial learning point regarding the management of IRIS is that it is directed towards the management of underlying opportunistic infection, and at no point should ART be stopped. 

Clinical Significance

The timely introduction of ART to improved CD4+ counts is the most efficient method of minimizing the risk of opportunistic infections. The use of ART can however lead to IRIS due to inflammatory response once improvement of CD4+ cell count is seen and immune response has been achieved. The presentation of IRIS can be nonspecific and depends on the type of opportunistic infection, location, and severity of inflammatory response. Due to its nonspecific presentation, it can be hard to differentiate it from active infections (e.g hospital-acquired pneumonia), a progression of previously diagnosed opportunistic infections, or drug-related side effects. Continuation of ART and symptomatic management is the cornerstone of managing IRIS. The use of steroids is reserved for severe forms of IRIS. [50][51][52]

Enhancing Healthcare Team Outcomes

HIV patients who are untreated are prone to multiple opportunistic infections due to the progressive lowering of their CD4 + T cells. Because of the high morbidity and mortality of these infections, every attempt should be made that these patients have enough resources for early diagnosis of HIV, timely initiation of ART, regular follow up to ensure medication adherence.

These patients should be managed by an interprofessional team that includes an infectious disease specialist, internist, specialist nurse, pharmacists, and social workers. They also need close monitoring with regular lab work to evaluate for improvement of CD4+ cell count, assessment of medication-related side effects, and the emergence of opportunistic infections. Patients with HIV often face social stigma due to their infections. The team must additionally ensure adequate social and financial support, rehabilitation for intravenous drug abusers along with patient education regarding safe sex practices, and avoidance of high-risk behaviors.