Case 13

Published on 18/02/2015 by admin

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CASE 13

You have been Anthony’s general practitioner since childhood. Other than the usual run of minor childhood disorders, there has been nothing of note in his medical history. Both parents and a younger sibling are well. He is currently 22 years of age and is home for the summer, on vacation from college. Anthony had called your office, requesting a complete physical examination, and, as a precursor to that visit, you have ordered a series of routine tests, including serum blood cell counts and electrolyte determinations, chest radiograph, and urinalysis. The day before the appointment the laboratory results become available and show, somewhat surprisingly to you, a marked increase in some liver enzymes (transaminases) and an elevated bilirubin level. Physical examination of this young man when he did come in revealed, not surprisingly, a mild jaundice, with some tenderness at the liver edge. There were no other significant abnormalities, although you also note some healing bruises and pinpricks in the forearm. He seems to be sniffing a lot, as though he has a perpetual postnasal drip, and he seems to be somewhat more edgy in your presence than usual. How are you going to open up a conversation? What do you want to address? Do you have significant concerns?

QUESTIONS FOR GROUP DISCUSSION

1. Given the conglomeration of findings, how are you going to open up a conversation to address the overriding concern of drug use/abuse?
2. Cocaine may explain the sniffles and edginess, but resolving track marks and liver disease should alert you to intravenous drug use. As such, you should request serologic tests to determine if this patient has been exposed to a number of infections. For which infectious agents would you request an antibody titer?
3. At early stages of infection, serologic tests often provide false-negative results. Explain why this is so, and how one would confirm these results and the principle underlying the confirmatory tests.
4. Anthony’s confirmatory test was positive for HIV. Draw a schematic illustrating HIV infection of a CD4+ T cell. See Figure 13-2. Identify gp120, gp41, CD4, and the chemokine receptor. Also, explain the term “facilitated HIV infection in trans.” (Hint: What is the role of DC-SIGN in HIV infection?)
5. When Anthony was informed that he was HIV positive, he asked his physician if he could begin highly active retroviral therapy (HAART). What is the underlying principle of the drugs that constitute HAART? Explain why antiretroviral therapy (HAART) is effective by illustrating the steps these drugs target during productive viral infection of a cell.
6. As Anthony’s physician, you realize that you have to convince him that there are limitations to HAART. Discuss the advantages and disadvantages of HAART.
7. In addition to the advantages and disadvantages of HAART, you also explain to your patient that the “hit hard, hit early” slogan does not represent the current recommendations regarding when to commence therapy. What are the generally accepted guidelines for commencing HAART therapy?
8. HIV has evolved a number of viral evasive strategies. Describe several of these and explain how these contribute to viral persistence in a normal individual such that individuals develop acquired immunodeficiency syndrome (AIDS).
9. Interleukin (IL)-2 is a growth factor for T cells. Therefore, it seems reasonable to consider IL-2 as a therapeutic agent to expand the population of CD4+ T cells, which are the primary target of HIV infection. However, clinical trials have shown that IL-2 therapy can actually lead to an increase in viral load. Despite this, some advocates of IL-2 therapy argue that therapy with this cytokine in the presence of HAART is a good idea. Explain.
10. Describe the various approaches in attempts to develop an effective HIV vaccine and explain why an effective HIV vaccine is not likely in the immediate future.
image

FIGURE 13-2 Structure of human immunodeficiency virus-1 (HIV-1). An HIV virion is shown interacting with a CD4+ T cell. HIV interacts first with the primary receptor, CD4, via its envelope glycoprotein, gp120. Binding to CD4 creates a complex that allows gp120 to bind to CCR5 or CXCR4. Following this binding, gp41, which is a fusion protein, enters the cell membrane to initiate fusion of the viral envelope and subsequent delivery of the viral proteins and genome into the cell.

(From Abbas A, Lichtman A: Cellular and Molecular Immunology, 5th ed. Philadelphia, Saunders, 2003; Modified from front cover, The New Face of AIDS. Science 272:1841–2102, 1996. © Terese Winslow.)

RECOMMENDED APPROACH

Implication/Analysis of Family History

There is nothing remarkable about the family history and because you have been Anthony’s physician since childhood you are more concerned about recent lifestyle changes now that he is attending college.

Implications/Analysis of Clinical History

You should be concerned about the conglomeration of findings and need to find out if they are all symptomatic of the same problem. An overriding concern here is drug use/abuse. Cocaine may explain the sniffles and edginess, but the evidence for resolving track marks and liver disease should alert you to intravenous drug use. Anthony admits to intravenous drug use, although he claims it was a short period (less than 2 weeks) and that he has not had heroin for more than a month. Unfortunately it seems as though there was at least one episode of shared needle use. Further questioning reveals a recent history of fever (lasted >10 days ˜2 weeks ago) but no cough and no hematuria. There is no candidiasis. He casually mentions that he had diarrhea for days after he got home, attributing that to eating at a pretty run-down roadside café when he was driving home for the holidays.

Implications/Analysis of Laboratory Investigation

Based on the clinical history, physical examination (track marks on the arm, healing bruises, jaundice), and laboratory test results (elevated liver enzymes) you should be concerned about hepatitis and HIV infection. These infections are increased, depending on the setting in which intravenous drug use is occurring.

Additional Laboratory Tests

A complete blood cell count with differential was requested, along with enzyme-linked immunosorbent assays (ELISAs) to detect anti-hepatitis (A/B/C) antibodies. Additionally, a repeat liver enzyme assessment was ordered. The white blood cell count and differential was normal, and there was no evidence of anti–hepatitis B or anti–hepatitis C antibodies. However, there was evidence for hepatitis A seroconversion (anti-hepatitis A antibodies). Repeat blood work suggested the liver tests were normalizing. HIV serology was negative. At this stage you are a little more relieved.

Recognizing, however, that in the early stages of infection there are significant false-negative results in viral diagnostic tests that are based on antibody detection, you order more sensitive tests (viral load using nucleic acid amplification, e.g., polymerase chain reaction) for HIV and both hepatitis B and C. In most individuals the viral load (number of viral particles in circulation) is highest just before seroconversion. The viral load analysis for HIV comes back positive.

DIAGNOSIS

On the basis of the nucleic acid amplification tests, Anthony is informed that he is infected with HIV, the causative agent of acquired immunodeficiency disease (AIDS). Anthony’s CD4+ T cell count will need to be monitored. As the number of CD4+ T cells decreases, the number of opportunistic infections increases (Fig. 13-1).

image

FIGURE 13-1 Section of duodenum from HIV-infected patient with opportunistic infection by Cryptosporidium. Note small spherical bodies (schizonts) on the surface epithelium, weakly staining with hematoxylin and eosin (×400). The lamina propria is heavily infiltrated with plasma cells.

THERAPY

Highly active antiretroviral therapy (HAART) is the treatment of choice for HIV-infected patients. This drug regimen includes two antinucleoside analogue inhibitors and a protease inhibitor or a non-nucleoside reverse transcriptase inhibitor. Even though the use of HAART is not a controversial issue, the “when” to initiate therapy is highly debated. This controversy follows the realization that the “hit hard, hit early” slogan of the mid 1990s does not lead to the eradication of the virus in patients despite long term, and early, drug therapy. HIV is detectable in latent infected cells even after prolonged therapy, and so the approach to drug therapy has had to be modified.

Advantages and Disadvantages of HAART

There are advantages and disadvantages to HAART. In patients receiving HAART, plasma HIV RNA levels fall to below the level of detection within 2 to 6 months. There is an increase in CD4+ T cell count and therefore delayed progression to AIDS. As well, in some cases HAART is accompanied by enlargement of the thymus. Whether this enlargement is due to regeneration of the thymus and active thymopoiesis or from the migration of peripheral blood cells into the thymus is currently being addressed using in vivo TREC (T cell receptor excision circles) assay of thymic function (see Case 2). On the down side, hepatotoxicity is a serious consideration, as is the development of viral variants that are resistant to the drugs. Additionally, HAART therapy does not eliminate HIV from resting memory CD4+ T cells carrying an integrated copy of the viral genome. Therefore, on discontinuation of HAART, viral load measures (plasma HIV-1 RNA) become significant when the latently infected cells are activated even by stimulatory molecules normally present in lymphoid tissues.

Patient Compliance with Treatment

The emergence of variants that are resistant to the ongoing drug therapy is substantially increased by the lack of patient adherence. In some cases this may reflect a regimen too complicated for the patient, a very large number of pills, or poor tolerance to the medication. In other cases, the patient’s desire for such intense treatment is not sufficient to merit adherence to therapy.

When to Begin Therapy

The question still remains as to when to begin therapy. Issues at stake are whether viral load or CD4+ T cell count should be used as a guideline for initiating therapy. Even those that advocate using CD4+ T cell count as the marker for therapy do not agree as to what that CD4+ T cell number should be. Those that believe that therapy should be initiated when the CD4+ T cell count falls below 200 cells/μL support their argument by emphasizing the reduced time for toxicity, enhanced quality of life before therapy, and a decrease in potential for viral resistance.

On the other hand, those that believe that therapy should be initiated when CD4+ T cell count is 350 cells/μL argue that initiating therapy at this time prevents irreversible immune damage, minimizes the spread of HIV to more restricted sites (e.g., central nervous system), and minimizes the potential for development of more virulent HIV. The initiation of HAART when the CD4+ T cell count is less than 350 cells/μL, or sooner if the HIV RNA load is higher than 5000 copies/mL, is another option that is under consideration. Once drug therapy is initiated, patient adherence and viral load should be monitored regularly.

Role of Cytokines in Therapy

Although HAART is changing the course of HIV infections, the reality is that the toxicity of the drugs and the emergence of drug-resistant escape mutants indicate that immunologic therapies should be pursued. Furthermore, the realization that discontinuation of therapy results in a rebound of viral burden emphasizes the need for immunologic forms of therapy.

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