Table of Contents

• Introduction
• An Overview of Opportunistic Infections
• Immune Reconstitution
• Tuberculosis
• Correctional-Specific Issues Relative to the Prevention and Treatment of OIs
• Self-Administered Keep On Person (KOP) vs. Directly Observed Therapy (DOT)
• Quality Review
• Summary
• References

Introduction

Prior to the advent of Highly Active Antiretroviral Therapy (HAART) in 1996, opportunistic infections (OIs) were an inevitable complication of HIV infection, particularly in those patients with a CD4 count of less than 200 cells/mm³. Because of the considerable morbidity and mortality associated with OIs, medical research identified and developed drugs that were active against many of the infections that complicate AIDS. Carefully designed OI prophylaxis and treatment trials resulted in major advances in the management of OIs. Although OI trials continue to build on this foundation of knowledge, the focus of HIV clinical research has shifted to antiretroviral therapy since HAART can prevent and/or reverse the immunological abnormalities that lead to the development of OIs.

With the introduction of HAART, HIV-infected individuals have experienced declining rates of HIV-related deaths. However, there are some notable differences between the U.S. general population and those who are incarcerated. For the year 2000, the overall rate of confirmed AIDS cases in state and federal prisons was four times that of the general population.¹ As a result, correctional health care workers are more likely to encounter OIs in their HIV-infected populations than will health care professionals working outside of jails and prisons. This month's main article focuses on new trends and clinical concepts in the occurrence of OIs that have accompanied effective antiretroviral therapy, as well as up-to-date information on prophylaxis and treatment of OIs.

An Overview of Opportunistic Infections

Since the introduction of HAART, there has been a dramatic decline in both the number of deaths due to AIDS and new diagnoses of AIDS. Overall, this has resulted in an increasing number of patients living with AIDS.² Despite the increased number of AIDS cases, the overall incidence of OIs has declined in patients receiving HAART and appropriate preventive therapy for OIs. This reflects both the widespread use of effective preventative treatments for common OIs, and the effectiveness of HAART in preventing profound immunosuppression in those with HIV infection.

OIs may occur as an acute presentation of previously undiagnosed HIV infection or may complicate the course of known HIV infection. Instituting an appropriate antimicrobial based on the patient's CD4 count can reliably prevent certain OIs. Table 1 summarizes the infections, CD4 thresholds, and agents for primary (instituted prior to the occurrence of active disease) and secondary (instituted after the an episode of active disease to prevent recurrences) prevention of OIs.⁴

Table 1: Primary Prophylaxis for AIDS-associated OIs*

* Adapted from The Sanford Guide to HIV/AIDS Therapy, 2003.

A full description of the presentation, clinical course, methods of diagnosis, and treatment of each OI is beyond the scope of this article; however, it is important for HIV providers to have a quick and reliable source of prevention and treatment information on hand. Some useful pocket guides are: The Sanford Guide to HIV/AIDS Therapy⁴ (published yearly) and Medical Management of HIV Infection, (2003).⁷ Online sources of treatment information can be found at www.AIDSinfo.nih.gov (formerly, www.hivatis.org).^{4, 5}

Some OIs require secondary prophylaxis to prevent recurrence. Secondary prophylaxis is usually a continuation of the medications used to treat the OI, sometimes at reduced dosages. For example, disease due to disseminated MAC can be primarily prevented with azithromycin 1,200 mg po once per week. If active disease develops, the treatment regimen consists of a combination of at least two drugs. Secondary prophylaxis must be maintained for an indefinite period of time in order to prevent recurrence of the infection.

In the pre-HAART era, the infectious agent of many OIs could not be eliminated from the body by a discrete course of treatment because of severe underlying immunodeficiency. Therefore, therapy had to be maintained for an indefinite period, often lifelong. In the era of HAART, the continued need for primary or secondary prophylaxis is determined by the degree of immune reconstitution.

Immune Reconstitution

The immunodeficiency that is associated with untreated HIV infection is complicated and leads to both a decline in CD4 cell numbers and to impairments in CD4 cell function. CD4 cells may lose the ability to respond to many foreign antigens, and these responses are lost in a somewhat predictable sequential fashion. For example, the ability to respond to Pneumocystis carinii antigens is lost well before the ability to respond to herpesvirus antigens or CMV antigens. Thus, serious herpesvirus and CMV infections generally occur later in HIV disease than PCP.

When viral replication is suppressed in response to HAART, the initial rise in CD4 cells that occurs in the first one to three months is largely due to a redistribution of CD4 cells from the reticuloendothelial system and other tissue reservoirs. If HAART is not initiated until severe CD4 cell depletion has occurred, the CD4 cells that make their way back into the circulation may not have the ability to respond to common antigens. As a result of CD4 cell redistribution, immediate exacerbations of pre-existing, subclinical OIs such as CMV retinitis or tuberculosis may occur as the newly circulating CD4 cells respond to these pathogens. These redistributed CD4 cells may cause inflammatory responses to pathogens that were previously present. These reactions are called immune reconstitution syndromes.

Following the initial increase in CD4 cells attributed to redistribution, there is a more gradual and sustained increase in these cells due to the emergence of naive CD4 cells that have the ability to develop a full array of immune responses to various foreign antigens. This differentiation of cells takes time, which is why recommendations regarding stopping prophylaxis for various OIs is based not only on a rise in CD4 numbers to certain thresholds, but also a period of sustained increase that allows the naive cells to develop into clones that can respond to specific foreign antigens (Table 2).⁷

Table 2: OIs for Which Prophylaxis or Maintenance Therapy Can Be Discontinued Following HAART-Associated Immune Reconstitution*

* Adapted from 2001 USPHS/IDSA Guidelines for the Prevention of Opportunistic Infections in Persons Infected with Human Immunodeficiency Virus.

Tuberculosis

The Official Joint Statement for the Treatment of Tuberculosis of the American Thoracic Society, CDC, and the Infectious Diseases Society of America was approved in October 2002, published in 2003^{6, 8} and may be accessed through the CDC website (www.cdc.gov). Treatment regimens for tuberculosis are summarized in Table 3. For a more complete discussion of the diagnosis, prevention, and treatment of tuberculosis, refer to the February 2003 issue of HEPP Report.

Table 3: Drug Regimens for Treatment of Culture Positive Pulmonary Tuberculosis*

Correctional-Specific Issues Relative to the Prevention and Treatment of OIs

Educational efforts are most effective when they are tailored to the population being served. For incarcerated HIV-infected patients, this includes being aware of literacy skills, English language competency, and cultural beliefs about disease and medical treatment. Education can be provided in many ways, including verbally from the treating clinician, in written form via handouts, in video format in clinic waiting areas or over the facility television system, and through peer-to-peer teaching.

The most successful approach integrates multiple strategies, and reinforces the message at each patient encounter. Asking the patient to name all of his or her medications (and the reason that s/he takes them) at each visit is one helpful way to assess patient knowledge.

Self-Administered Keep On Person (KOP) vs. Directly Observed Therapy (DOT)

There are compelling reasons to utilize both DOT and KOP methods of medication delivery (see Table 4). Each facility should evaluate these and other factors and come to a decision that best meets the needs of their program and patient population. One hybrid option is to start all patients on DOT, and then offer KOP to those who 1) demonstrate adherence by maintaining an undetectable HIV viral load over time, and 2) are able to correctly describe their medications and dosing schedule.

Table 4: Self-Administered Keep on Person (KOP) vs. Directly Observed Therapy (DOT)

Quality Review

The provision of quality care to HIV-infected patients demands careful attention to detail. Multi-drug regimens, the potential for drug-drug interactions, and the necessity of close monitoring of laboratory data can overwhelm any paper record system. The use of a computerized database can enable clinicians to rapidly review HAART regimens, detect potential adverse interactions, and track those patients who are candidates for initiating or discontinuing OI prophylaxis. An upcoming issue of HEPP Report will review some of the software programs that are currently in use in major correctional health care systems nationwide.

Summary

The incidence of AIDS and AIDS-associated deaths and diagnoses in the U.S. has declined significantly in both the general population and the correctional population due to the introduction of HAART in clinical HIV practice. Nonetheless, the number of AIDS cases is high and OIs are still a common occurrence. In the correctional population, OIs occur more frequently than in the general U.S. population. Many OIs can be prevented with the appropriate preventive therapy. When OIs do occur, various treatment regimens are effective; however secondary prophylaxis is often indicated unless the immune system becomes reconstituted in response to HAART. TB disease is especially problematic in the correctional setting because of the risk of transmission to others, the occurrence of drug-resistant strains of Mycobacteria tuberculosis and the potential interactions between anti-tuberculosis and antiretroviral medications.

David Paar, M.D. is Associate Professor of Medicine, UTMB Department of Medicine, Division of Infectious Diseases.

Disclosures:
Consultant: Ortho Biotech
Grant/Research Support: GlaxoSmithKline, Agouron, Merck, DCHD, Serono,
Gilead, Chiron Corp. Boehringer Ingleheim, Abbott Labs, Bristol-Myers Squibb
Speaker's Bureau: Roche, Bristol-Myers Squibb, OrthoBiotech

References

1. HIV in Prisons, 2000, U.S. Department of Justice -- Office of Justice Programs, Bureau of Justice Statistics, www.ojp.usdoj.gov/bjs/abstract/hivp00.htm.

2. Update: AIDS -- United States, 2000, Morbidity and Mortality Weekly Report (MMWR), July 12, 2002:51(27);592-595, available at: www.cdc.gov/mmwr/preview/mmwrhtml/mm5127a2.htm.

3. Palella FJ Jr., Delaney KM, Loveless AC, et al., Declining Morbidity and Mortality Among Patients with Advanced Human Immunodeficiency Virus Infection, New EnglJ Med 1998:338 (13);853-860.

4. Sande MA, Moellering RC Jr., and Gilbert DN, The Sanford Guide to HIV/AIDS Therapy, 2003.

5. Paar D and Masur H, Advances in the Management of Major Opportunistic Infections in Patients with Human Immunodeficiency Infection, Journal of Pharmacy Practice, 1992:V(3);131-142.

6. Treatment of Tuberculosis - American Thoracic Society, CDC, and Infectious Diseases Society of America, Morbidity and Mortality Weekly Report (MMWR), Recommendations and Reports, June 20, 2003:52(RR11); 1-77, available at: www.cdc.gov/mmwr/preview/mmwrhtml/rr5211a1.htm.

7. Bartlett JG and Gallant JE, Medical Management of HIV Infection, 2003 edition, H&N Printing and Graphics, Timonium MD.

8. Treatment of Tuberculosis - American Thoracic Society, CDC, and Infectious Diseases Society of America, Am JRespir Crit Care Med 2003, 167:603-662.