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Chapter
IV
I. Introduction TOP No field in medicine today is moving as swiftly as that of HIV/AIDS. The speed at which new developments occur and the rapidity with which they are superseded by newer data are nothing short of breathtaking. As a consequence, most studies are typically out of date at the time of publication. Because of the rapid turnover of key information, this chapter focuses on the essential principles of care for the HIV-infected woman. “Cutting-edge” treatment strategies currently being studied will be mentioned but not described in detail. To be truly useful, we indicate the general directions in which this field is moving and how to access updated information. Several studies have demonstrated that positive clinical outcomes are a function of the clinician’s experience in caring for HIV-infected individuals (Kitahata, 1996). Nonspecialists are urged to seek expert advice and consultation whenever there is any question about the best way to manage a specific patient. This is especially important in the setting of antiretroviral treatment failure and in advanced HIV disease when patients are vulnerable to multiple simultaneous opportunistic processes. There is as yet no compelling evidence that the clinical course of HIV infection in women differs significantly from that in men, with the obvious exception of the associated gynecologic conditions and obstetric issues (described elsewhere, see Chapters VI and VII). Although recent data have indicated that women may have lower HIV viral loads than men with an equivalent degree of immunosuppression, this does not appear to confer benefit in terms of overall survival or complication-free survival (see Chapter I: Epidemiology and Natural History of HIV Infection in Women). At present, the approach to management of HIV-infected women and men is the same. With prolonged survival now possible, general preventive strategies and health maintenance, such as smoking cessation, control of hypertension, minimizing cardiovascular risk factors, and routine screening for malignancy (cervical, breast, colon), are all part of routine care for HIV-seropositive adults. II. Initial Evaluation TOP A. HISTORY A comprehensive database is valuable to the primary caregiver in assessing the patient’s current status and in formulating a management plan. It is critical to remember that most patients are anxious and frightened at their initial encounter for HIV care; the ability to empathize, to share knowledge without being patronizing, to provide reassurance, and to remain nonjudgmental are essential to gaining the patient’s trust and to obtaining accurate information (see Chapter II: Approach to the Patient). In addition to all the usual aspects of history-taking, the following areas are of particular importance in HIV disease and deserve special attention.
Just as important as the information that the clinician obtains in the history-taking process is the information about HIV disease that is shared with the patient. Counseling and education are important elements of the therapeutic bond with the caregiver, but because this entails an enormous amount of information, it is best broached initially and then reintroduced and reinforced at appropriate intervals. Many patients are in a state of shock following diagnosis, or may be suffering from situational depression or fear of their partner’s response. Be kind. Be patient. Schedule enough time (1 hr) for the initial visit. Make sure the patient knows your purpose is to support her and care for her. Another key bond is the one between the patient and the office/clinic nurse, which should be encouraged. Ensure that she has a path to reach you or the nurse for any questions, complaints, or symptomatic therapy, especially when starting antiretroviral therapy. It is important to convey information in lay language at a level of complexity appropriate to the patient’s level of comprehension (remembering that formal educational levels may not necessarily correlate with the patient’s ability to understand complicated medical concepts). These include the following areas.
Last, because a diagnosis of HIV infection means a chronic, life-threatening disease and still carries a social stigma, the clinician plays a key role in exploring mental health and psychosocial needs, helping the patient identify potential sources of support, and referring the patient for additional medical, psychiatric, and/or social services. The examination may yield clues to specific HIV-associated conditions. Vital signs should be tracked carefully, particularly temperature and weight. The discovery of hypertension, largely ignored in the past, should trigger appropriate attempts at control, including weight loss, reduction of salt intake, and medication if necessary. Special attention should be paid to the following areas.
III. Laboratory Testing TOP A. INITIAL DIAGNOSIS Because of the advances made in HIV treatment, with associated decreases in HIV-related morbidity and mortality; concerns about possible increases in HIV incidence; and the new availability of a simple rapid HIV test (Oraquick), the CDC recommends that voluntary HIV testing be made a routine part of medical care for all patients in high HIV-prevalence clinical settings and for those with risks for HIV in low HIV-prevalence clinical settings. (CDC, 2003). HIV infection is usually diagnosed by serologic tests that detect antibody to the virus. Infection may also be detected by nucleic acid-based assays that either measure the number of copies of the virus in plasma (RNA polymerase chain reaction [PCR]) or detect the virus in cells (DNA). Informed consent, with pre- and posttest counseling, is legally mandatory for performing HIV serologic tests in most locations, and should be procured at all times when the test is offered.
B. BASELINE LABORATORY EVALUATION After the diagnosis of HIV has been confirmed, a baseline laboratory evaluation is needed to establish the stage of disease, and exposure to other infectious diseases (Table 4-1). In addition, routine tests of hematology, chemistry, and lipid profiles are needed at baseline, because HIV and other concomitant illness may affect these values, and detected abnormalities may also have an impact on the choice of therapy for the individual patient.
Figure 4-1: Natural History of HIV Infection without
Figure 4-2: Likelihood of Developing AIDS within 3 Years † Diagnosis of HIV infection made by HIV RNA testing should be confirmed by standard methods such as Western blot serology performed 2–4 mo after the initial indeterminate or negative test. Source: DHHS, 2005.
C. INTERVAL MONITORING In an asymptomatic patient not taking antiretroviral therapy with a high (>500/mm3) CD4 count, follow-up every 6 mo may be appropriate. For those patients who are symptomatic and/or receiving antiretroviral therapy, visits should occur at least every 3 mo. For those who have just initiated or changed antiretroviral therapy, follow-up in 4–6 wk may be appropriate. Laboratory evaluation at each of these visits should routinely include the following: complete blood count with differential, CD4 lymphocyte count, and viral load. Chemistry panels may be done less frequently (every 6 mo) in a patient with prior normal values who remains clinically stable. Hematology and chemistry values are needed to monitor possible medication toxicities, complications of HIV, and other possible illnesses. The CD4 count and viral load allow assessment of disease progression and effects of antiretroviral therapy. In following the CD4 count over time, it is important to recognize the causes of variability discussed above. Use of the CD4 percentage, rather than absolute CD4 count, may help eliminate some of this variability to clarify CD4 response to medications. In interpreting viral load changes over time, the variability of tests results must be noted: .3–.5 log. In a patient who previously had a viral load below the limit of detection of the assay being used (“undetectable”), who now has quantifiable virus, a repeat test should be performed as soon as possible, rather than waiting until routinely scheduled follow-up. The frequency with which lipid profiles are checked will vary by individual patient characteristics. In patients not taking antiretroviral therapy, a baseline lipid profile should be done with the initial evaluation or before beginning antiretroviral therapy. The profile should include total cholesterol, HDL, LDL, and triglycerides. If the baseline is normal and the patient is not on antiretroviral therapy, there is no need for interval monitoring beyond that which would be done in an HIV-uninfected adult. In patients taking combination antiretroviral therapy, general guidelines are:
Recommendations for management of hyperlipidemia may be found at http://www.americanheart.org. Annual monitoring of syphilis serology for reactivation or new infection is generally recommended. PPDs should also be checked annually if the patient belongs to a population with high epidemiologic risk of tuberculosis. Baseline data and interval monitoring may be followed by the use of a flow sheet such as the one developed at the Johns Hopkins Outpatient HIV Clinic (Figure 4-3).
IV. Antiretroviral Therapy TOP A. GENERAL PRINCIPLES Three characteristics of HIV infection have significant implications for antiretroviral therapy (see Chapter VII HIV and Reproduction for discussion of antiretroviral therapy in pregnancy).
Thus, there is a rationale for initiating antiretroviral therapy before the onset of symptoms (i.e., to prevent immunosuppression), and therapy must be maintained to prevent viral replication. Strategies of antiretroviral therapy have therefore evolved to prevent the development of viral resistance. Although monotherapy with any of the antiretroviral agents will increase CD4 count, the clinical benefit of such therapy is very limited, largely because of the development of viral resistance. Combination antiretroviral therapy has been shown to have superior effectiveness in controlling viral replication and in limiting the emergence of resistant virus. These effects translate into greater clinical benefit: combination therapy reduces the risk of HIV progression and death. In addition, patients with levels of circulating virus that are below 400–500 copies/mL (the limit of detection in the past few years), but greater than 20–50 copies/mL (the limit of detection in the newest generation of tests) will experience virologic failure sooner that those with viral loads below 20–50 copies/mL (Raboud, 1998). Therefore, achievement of the lowest possible viral load should be a guiding principle in the selection of a treatment regimen. The specific combination of antiretroviral therapy selected for a patient must take into account many factors. These include the specific side effects, dosing schedules, drug-drug interactions of different medications, and history of antiretroviral therapy. See Chapter XIV on Pharmacologic Considerations in HIV-infected Pregnant Patients for information on highly active antiretroviral therapy in pregnancy and Chapter XV on Resources for sources of complete updated information on antiretroviral therapy. Nucleoside analogue reverse transcriptase inhibitors (NRTIs) were the first class of agents shown to be effective in the treatment of HIV infection. The target enzyme for this group of drugs is HIV reverse transcriptase, an RNA-dependent DNA polymerase (see Figure 4-4). Figure 4-4: Sites of Action of Antiretroviral Agents
Seven NRTIs are currently licensed in the United States: zidovudine (AZT), didanosine (ddI), zalcitibine (ddC), stavudine (d4T), lamivudine (3TC), abacavir, (ABC) and emtricitabine (FTC). There are also 3 combination NRTIs (Combivir, Trizivir, Epzicom), a nucleotide reverse transcriptase inhibitor (tenofovir) and a nucleoside-nucleotide reverse transcriptase inhibitor combination (Truvada) (Table 4-4). In addition to the side effects listed for each medication, lactic acidosis with hepatic steatosis is a rare but potentially life-threatening toxicity with the use of NRTIs. Nonnucleoside Reverse Transcriptase Inhibitors Nonnucleoside reverse transcriptase inhibitors (NNRTIs) noncompetitively inhibit HIV reverse transcriptase by binding to a site distant from the enzyme’s active site. Three NNRTIS are currently available in the United States: nevirapine, delavirdine, and efavirenz (Table 4-5). Protease inhibitors (PIs) prevent maturation of virus protein by competitively inhibiting HIV protease, an enzyme essential for viral protein cleavage. When this enzyme is blocked, immature, noninfectious virus particles are produced. The other important properties that protease inhibitors share include their limited central nervous system penetration and their metabolism by the cytochrome P450 enzyme system and resultant multiple drug-drug interactions (Table 4-6). In addition to the medication-specific side effects listed here, a number of abnormalities are associated with protease inhibitors as a class. Patients taking protease inhibitors may develop serum lipid abnormalities (hyperlipidemia, hypertriglyceridemia), redistribution of body fat (lipodystrophy), and/or glucose intolerance. Fusion inhibitors interact with HIV directly, rather than with the host cell. This interaction prevents fusion of HIV to the cell. The first fusion inhibitor, enfuvirtide (T-20, Fuzeon) was licensed in the U.S. in March 2003. Enfuvirtide must be given by subcutaneous injection (twice daily). The most common side effect is local injection site reactions. C. ADVERSE CLINICAL EVENTS ASSOCIATED WITH ANTIRETROVIRAL THERAPY There are several significant adverse clinical events that have been associated with use of antiretroviral therapy. In some cases these are drug specific, while in others an increased risk of a specific adverse event appears to involve an entire class of antiretroviral drugs. The complications discussed below are of particular clinical significance or concern. In general, decisions about management, including future antiretroviral management, should be made in consultation with an HIV expert.
The Department of Health and Human Services (DHHS) Panel on Clinical Practices for Treatment of HIV Infection continuously updates treatment guidelines. Updated recommendations are available at http://www.aidsinfo.nih.gov. The guidelines detail indications for therapy in chronically infected patients, recommendations for initial therapy, considerations for changes in therapy, and possible regimens for such changes (Table 4-7). * Clinical benefit has been demonstrated in controlled trials only for patients with CD4+ T cells <200/mm3, however, the majority of clinicians would offer therapy at a CD4+ T cell threshold <350/mm3. The strength of the recommendation for starting therapy in an asymptomatic patient must take into account prognosis for disease-free survival, potential benefits and risks of therapy, and the willingness of the patient to take, and adhere to, therapy (see Chapter V on Adherence to HIV Therapies). Prognosis for disease-free survival may be assessed by utilizing the data in Table 4-8. However, given the sex-based differences in viral load and CD4 count (See Chapter 1 Epidemiology and Natural History of HIV Infection in Women), these data, generated from a prospective cohort of men who have sex with men (MSM), should be extrapolated with caution to women. Among the benefits of therapy are:
The risks of starting therapy include:
† MACS numbers reflect plasma HIV RNA values obtained by version 2.0 bDNA testing. RT-PCR values are consistently 2–2.5-fold higher than first-generation bDNA values, as indicated. The version 3.0 bDNA assay provides similar HIV-1 RNA values as RT-PCR, except at the lower end of the linear range (<1,500 copies/mL). § Too few subjects were in the category to provide a reliable estimate of AIDS risk. ∞ A recent evaluation of data from the MACS cohort of 231 persons with CD4+ T cell counts >200 and <350 cells/mm3 demonstrated that of 40 (17%) persons with plasma HIV RNA <10,000 copies/mL, none progressed to AIDS by 3 years (Phair, 2002). Of 28 individuals (12%) with plasma viremia of 10,000 – 20,000 copies/mL, 4% and 11% progressed to AIDS at 2 and 3 years, respectively. Plasma HIV RNA was calculated as RT-PCR values from measured bDNA values. Source: DHHS, 2004. Recommendations For Initial Treatment Regimens Recommendations for antiretroviral treatment continue to evolve with the development of new medications and additional data from clinical trials. The most recent guidelines from the DHHS are shown in Table 4-9. Although these guidelines illustrate generally recommended regimens, nonspecialists should consider expert consultation regarding initiation of a specific regimen whenever there is any question about patient management. Although there are multiple possible effective regimens, individualized decisions about therapy should take into account considerations such as pill burden, dosing frequency, toxicities and side effects, drug-drug interactions, and specific patient variables (e.g., pregnancy, co-morbid conditions, plasma HIV-RNA level, lifestyle, etc). ** Women with child bearing potential implies women who want to conceive or those who are not using effective contraception † Low-dose (100–400 mg) ritonavir § Nelfinavir available in 250 mg or 625 mg tablet ø sgc = soft gel capsule; hgc = hard gel capsule Source: Adapted from DHHS, 2004. Recommendations For Antiretroviral Therapy In The Treatment-Experienced Patient The need for a change in antiretroviral therapy most commonly arises in two situations: medication toxicity and treatment failure.
Resistance Testing There are two main techniques to assess the development of viral resistance to antiretroviral therapy. Phenotypic assays directly determine the amount of a medication required to inhibit HIV. Genotypic assays determine changes in the nucleotide sequences of the genes that code for the protease and reverse transcriptase enzymes. Interpretations of genotypic results require knowledge of which specific changes are associated with resistance. Results are reported as a string of three pieces of information for each mutation detected:
Table 4-11 shows the mutations known to be associated with resistance to specific agents (Bartlett, 2003). Updated listings of mutations and associated resistance can be found at: http://hiv-web.lanl.gov or http://hivdb.stanford.edu. http://www.iasusa.org. (Accessed 3/04.)* The distinction between primary and secondary mutations has been eliminated for NRTIs and NNRTIs by the International AIDS Society Expert Committee; this distinction has been retained for PIs, but with the terms “Major” or “Minor”. ** Thymidine-associated mutations † Major Mutations develop first or are associated with decreased drug binding or reduced viral activity; these effect phenotype resistance. ‡ Minor Mutations appear later and, by themselves, do not significantly change phenotype resistance. Both phenotypic and genotypic assays are difficult to perform if the viral copy number is less than 1000 c/mL. Their utility is also limited by an inability to detect resistant virus that makes up less than 20% of the total viral burden in a sample. It is also critical to recognize that these assays will only reliably detect mutations conferring resistance to medications the patient is taking at the time the assay is performed; samples from patients who are off therapy at the time of resistance testing are likely to show reversion to wild-type (sensitive) virus as the predominant circulating viral strain. Thus, resistance testing is insensitive to mutations secondary to selective pressure that is no longer present after a change in regimen. Virions with these mutations likely still exist as a small percentage of circulating virus and may lead to clinical resistance if inactive drugs that test “sensitive” but are vulnerable to these resistance mutations are used; current assays will not detect their presence. A comparison of genotypic and phenotypic assays is shown in Table 4-12. Many studies have shown that patients for whom resistance analysis is done before a change in antiretroviral therapy have a better virologic response to the new regimen than do patients in whom a change in therapy is based solely on antiretroviral history (Baxter, 1999; Durant, 1999, Zolopa 1999). Resistance testing may be useful in the following ways.
Patients with pan-sensitive virus in the face of virologic failure should be questioned carefully, but nonjudgmentally, about their medication-taking behaviors. Therapeutic drug monitoring (TDM) can also be considered, although data are not yet available demonstrating that TDM improves clinical outcome. Current USPHS recommendations for the use of drug resistance assays are outline in Table 4-13. * See Notes for Table 4-16 for explanation of evidence grading. Treatment Interruptions (Drug Holiday) Interruption of antiretroviral therapy has been considered in a variety of different scenarios. Intermittent therapy was previously hypothesized by some to improve HIV-specific immunity. A clinical trial failed to show evidence for this. There do remain two situations where treatment interruptions are being assessed: 1) as a way to reduce total exposure to medication (which could provide a cost or toxicity benefit), and 2) prior to attempts at salvage therapy in patients with virologic failure and multiple resistance mutations. At the current time, however, treatment interruption should be considered experimental in both of these situations. D. TREATMENT OF ACUTE HIV INFECTION To consider treatment of acute HIV infection, the clinician must first recognize its presence. In more than half of all patients who acquire HIV infection, there are clinical symptoms 1–6 wk after exposure. The symptoms vary in severity, but commonly include fever, lymphadenopathy, fatigue, rash, myalgias, and pharyngitis — a symptom complex that mimics mononucleosis. HIV antibodies will not yet be present at this point, but techniques that detect viral nucleic acids (see “Initial Diagnosis,” above) will confirm the diagnosis: a negative or indeterminate antibody test in conjunction with a positive HIV RNA or HIV DNA test is diagnostic of acute HIV infection. It is important to note, however, that a low level of HIV RNA (e.g., <5000 c/mL) may be a false-positive result and should be repeated (Rich, 1999). In addition, an HIV DNA assay could be performed to clarify the diagnosis; this should almost always be positive in an infected person, regardless of RNA level. Relatively recent infection may also be diagnosed in a patient with negative HIV serologies in the previous 6–9 mo and a first positive result, even in the absence of a seroconversion syndrome. The benefits of treating acute HIV infection are not completely defined. The rationale for early treatment is that there will be early suppression of viremia, which may preserve CD4 cell number and function including HIV-specific CD4 cells. There are also risks associated with early treatment that include the toxicities of the medications used and the possibility of early development of resistance. These unanswered questions about risks and benefits of early therapy should be addressed with the patient; enrollment in clinical trials and observational studies of acute HIV should be considered. In treating acute HIV, it is always important to use a three- or four-drug regimen that would be expected to provide complete viral suppression. In addition, after considering the source of exposure and local epidemiologic information, genotypic resistance testing may prove useful in this setting. In acute HIV infection, the patient’s predominant virus will be the strain that was transmitted, without reversion to the wild-type (pan-sensitive) virus seen in chronically infected patients who have stopped treatment. The potential risks and benefits of treating acute HIV are summarized in Table 4-14. Postexposure Prophylaxis See Chapter XIII on Occupational Exposure. Treatment In Pregnancy Antiretroviral treatment is indicated in pregnancy to reduce the risk of perinatal transmission whether or not therapy is yet needed to treat maternal disease. Specific guidelines for optimal therapy are addressed in Chapter VII (HIV and Reproduction). Information is also provided at http://www.aidsinfo.nih.gov. Immune-Based Therapy Therapy to augment the immune response to HIV may be possible through the use of HIV vaccines or cytokines, such as interleukin-2. Such strategies to enhance the control of HIV already provided by antiretroviral medications are being assessed in clinical trials, but are not part of current standard care. Alternative Or Complementary Therapy Some patients may present with knowledge or questions about alternative or complementary therapy or may indicate that they are already taking such therapy. All patients should be specifically asked about their use of such therapies, as they may not consider these to be medications and may not volunteer the information to their provider. Specific complementary therapies change rapidly, and their use varies widely with geography and patient demographics. For patients who do choose such therapies it is important to make sure that agents that have overlapping toxicities with a patient’s prescribed therapy are avoided and that discussions of alternative therapy are held in a way that does not alienate the patient from her involvement in medical care. V. Complications: Opportunistic Diseases TOP The risk for various opportunistic processes — so called because they take advantage of patients with a weakened immune system — is defined by the total CD4 lymphocyte count. They include opportunistic infections (OIs) and certain malignancies, and are similar to the diseases seen in other immunocompromised hosts such as recipients of solid organ transplants. In fact, AIDS was first recognized as a new entity by the characteristic pattern of opportunistic diseases — especially Pneumocystis pneumonia and Kaposi’s sarcoma — that were being diagnosed in young, previously healthy gay men. The pattern and sequence of OIs that are seen as the total CD4 cell count decreases is so reliable that in most cases the total CD4 cell count limits the differential diagnosis (see Table 4-15). † Some conditions listed as “non-infectious” are probably associated with transmissible microbes. Examples include lymphoma (Epstein-Barr virus [EBV]) and cervical cancer (human papillomavirus [HPV]). Source: Bartlett, 2003. Reprinted with permission. At total CD4 cell counts above 500, illnesses are rarely specifically associated with the patient’s HIV serostatus. Non-Hodgkin’s lymphoma and mucocutaneous KS are occasional exceptions; they can occur at varying CD4 cell counts, but are more frequently diagnosed at lower values. Infections that are virulent among HIV-seronegative individuals, such as tuberculosis and bacterial pneumonia, may, of course, occur at any CD4 cell count but are increasingly more common and more severe as the CD4 count declines. Between 200 and 500 cells, less serious HIV-associated problems begin to manifest themselves, such as oral hairy leukoplakia, various skin problems, shingles, and oral or vaginal candidiasis (thrush). Candida vaginitis, which is also common among women who do not have HIV, may be the first indication of HIV infection (Imam, 1990). According to the 1993 version of the CDC case definition, AIDS may be defined by a number of serious opportunistic illnesses or by a decline in the total CD4 cell count below 200 (see Table 1-3 in Chapter I). This CD4 cell count criterion acknowledges an important threshold for OI risk. Pneumocystis carinii pneumonia (PCP), the most common AIDS-defining OI and leading cause of death, is usually diagnosed as patients approach and drift below this critical number of total CD4 cells. Other OIs, such as toxoplasmosis, cryptococcal meningitis, and disseminated histoplasmosis, tend to occur as the CD4 cell count declines from less than 200 to below 100 cells. Typically, end-stage illnesses such as CNS lymphoma, CMV end-organ disease, and disseminated MAC, tend to occur at very low CD4 cell counts, often less than 25 cells. Antimicrobial therapy works in concert with the individual’s immune system to clear infection. Before the advent of potent combination antiretroviral therapy, HIV-associated opportunistic diseases could not be controlled without ongoing suppressive therapy, because the patients’ immune function was too weak to effect that control. Once an OI was diagnosed and treated acutely (“induction” therapy, borrowing from the language of oncology), treatment would be continued at lower “maintenance” levels or the OI would inevitably recur. “Cure” of OIs was not part of the vocabulary of HIV disease management. With potent combination antiretroviral therapy resulting in dramatic improvement in CD4 cell counts and immune function, both prophylactic and chronic suppressive therapies are being withdrawn successfully in responders. This has opened an entirely new era in the care of people with advanced HIV (see below). A. OPPORTUNISTIC INFECTION PROPHYLAXIS One of the early significant advances in the management of HIV/AIDS was the demonstration that chemoprophylaxis could prevent PCP and thereby improve survival. Before the development of potent combination antiretroviral therapy an important focus of the clinical research effort was to identify effective prophylactic agents for the other common OIs. The success of this research was in part responsible for the slowing of the death rate from AIDS that was first apparent near the end of 1995, just before the era of potent combination antiretroviral therapy began. Recommendations for prophylaxis for specific OIs depend on a number of factors: the CD4 threshold that defines the greatest risk, the overall effectiveness of a given approach, the risk of resistance development, the presence of pregnancy, toxicity, and cost. The USPHS/IDSA guidelines for OI prophylaxis are updated periodically to reflect the most current understanding of disease risk and prevention. Current recommendations for initiating primary OI prophylaxis can be found at http://www.aidsinfo.nih.gov, or in 2003 Medical Management of HIV Infection by John Bartlett, listed in the Resources appendix. (USPHS/IDSA, 2002) Table 4-16 summarizes recommendations for primary prophylaxis of the most common OIs. Letters and roman numerals in parentheses after regimens indicate the strength of the recommendation and the quality of evidence supporting it. Categories reflecting the quality of evidence forming the basis for recommendations regarding the use of a product or measure for the prevention of opportunistic infection in HIV-infected persons: I — Evidence from at least one properly randomized, controlled trial; II — Evidence from at least one well-designed clinical trial without randomization, from cohort or case-controlled analytic studies (preferably from more than one center), or from multiple time-series studies or dramatic results from uncontrolled experiments; III — Evidence from opinions of respected authorities based on clinical experience, descriptive studies, or reports of expert committees. ABBREVIATIONS: Anti-HBc = antibody to hepatitis B core antigen; b.i.w.= twice a week; DS = double-strength tablet; HAART = highly active antiretroviral therapy; HAV = hepatitis A virus; HIV = human immunodeficiency virus; im = intramuscular; iv = intravenous; po = by mouth; q.d. = daily; q.m. = monthly; q.w. = weekly; SS= single-strength tablet; t.i.w. = three times a week; TMP-SMX = trimethoprim-sulfamethoxazole; sc = subcutaneous; and TST = tuberculin skin test. [1] Prophylaxis should also be considered for persons with a CD4+ percentage of <14%, for persons with a history of an AIDS-defining illness, and possibly for those with CD4+ counts >200 but <250 cells/µL. TMP-SMX also reduces the frequency of toxoplasmosis and some bacterial infections. Patients receiving dapsone should be tested for glucose-6 phosphate dehydrogenase deficiency. A dosage of 50 mg q.d. is probably less effective than100 mg q.d. The efficacy of parenteral pentamidine (e.g., 4 mg/kg/month) is uncertain. Fansidar (sulfadoxine-pyrimethamine) is rarely used because of severe hypersensitivity reactions. Patients who are being administered therapy for toxoplasmosis with sulfadiazine-pyrimethamine are protected against Pneumocystis carinii pneumonia and do not need additional prophylaxis against PCP. [2] Directly observed therapy is recommended for isoniazid, e.g., 900 mg b.i.w.; isoniazid regimens should include pyridoxine to prevent peripheral neuropathy. If rifampin or rifabutin are administered concurrently with protease inhibitors or non-nucleoside reverse transcriptase inhibitors, careful consideration should be given to potential pharmacokinetic interactions (54). See discussion of rifamycin interactions in paragraph 11 in section on Tuberculosis. There have been reports of fatal and severe liver injury associated with the treatment of latent TB infection in HIV-uninfected persons treated with the 2 month regimen of daily rifampin and pyrazinamide; therefore it may be prudent to use regimens that do not contain pyrazinamide in HIV-infected persons whose completion of treatment can be assured (CDC. Update: Fatal and Severe Liver Injuries Associated with Rifampin and Pyrazinamide for Latent Tuberculosis Infection and Revisions in American Thoracic Society/CDC Recommendations, United States 2001 MMWR 50 (No. 34), Aug 31, 2001). Exposure to multidrug-resistant tuberculosis might require prophylaxis with two drugs; consult public health authorities. Possible regimens include pyrazinamide plus either ethambutol or a fluoroquinolone. [3] Protection against toxoplasmosis is provided by TMP-SMX, dapsone plus pyrimethamine, and possibly by atovaquone. Atovaquone may be used with or without pyrimethamine. Pyrimethamine alone probably provides little, if any, protection. [4] See paragraph 9, in section on “Disseminated Infection with Mycobacterium avium complex” and references 53-54 for discussion of drug interactions. *During pregnancy, azithromycin is preferred over clarithromycin because of the teratogenicity in animals of clarithromycin. [5] Vaccination may be offered to persons who have a CD4+ T-lymphocyte count <200 cells/µL, although the efficacy is likely to be diminished. Revaccination 5 years after the first dose or sooner if the initial immunization was given when the CD4+ count was <200 cells/µL and the CD4+ count has increased to >200 cells/µL on HAART is considered optional. Some authorities are concerned that immunizations might stimulate the replication of HIV. [6] Although data demonstrating clinical benefit of these vaccines in HIV-infected persons are not available, it is logical to assume that those patients who develop antibody responses will derive some protection. Some authorities are concerned that immunizations might stimulate HIV replication, although for influenza vaccination, a large observational study of HIV-infected persons in clinical care showed no adverse effect of this vaccine, including multiple doses, on patient survival (J. Ward, CDC, personal communication). Also, this concern may be less relevant in the setting of HAART. However, because of the theoretical concern that increases in HIV plasma RNA following vaccination during pregnancy might increase the risk of perinatal transmission of HIV, providers may wish to defer vaccination for such patients until after HAART is initiated. [7] Hepatitis B vaccine has been recommended for all children and adolescents and for all adults with risk factors for hepatitis B virus (HBV). For persons requiring vaccination against both hepatitis A and hepatitis B, a combination vaccine is now available. For additional information regarding vaccination against hepatitis A and B, see CDC. Hepatitis B virus: a comprehensive strategy for eliminating transmission in the United States through universal childhood vaccination. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 1991;40 (No RR13). [8] Oseltamivir is appropriate during outbreaks of either influenza A or influenza B. Rimantadine or amantadine are appropriate during outbreaks of influenza A (although neither rimantadine nor amantadine is recommended during pregnancy). Dosage reduction for antiviral chemoprophylaxis against influenza might be indicated for decreased renal or hepatic function, and for persons with seizure disorders. Physicians should consult the drug package inserts and the annual CDC influenza guidelines for more specific information about adverse effects and dosage adjustments. For additional information about vaccination, antiviral chemoprophylaxis and therapy against influenza, see: CDC. Prevention and Control of Influenza: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 2001;50(No. RR-4). [9] In a few unusual occupational or other circumstances, prophylaxis should be considered; consult a specialist. [10] Acyclovir is not protective against CMV. Valacyclovir is not recommended because of an unexplained trend toward increased mortality observed in persons with AIDS who were being administered this drug for prevention of CMV disease. Source: USPHS/IDSA, 2001. Available at http://www.aidsinfo.nih.gov. B. PRESENTATION AND MANAGEMENT OF THE MOST COMMON COMPLICATIONS OF ADVANCED HIV DISEASE (AIDS) Summaries are presented below. However, specific agents and dosing regimens for acute conditions and secondary opportunistic infection prophylaxis, respectively, can be found at http://www.aidsinfo.nih.gov, or in the 2003 Medical Management of HIV Infection by John Bartlett. Pneumocystis Carinii Pneumonia The diagnosis of PCP can be challenging and requires a heightened index of suspicion. Although there are “classic” symptoms, findings on exam, and chest X-ray manifestations, the presentation of PCP can be subtle and nonspecific. The classic triad of fever, exertional dyspnea, and nonproductive cough occurs in only half of cases, although almost all have at least two of the following: fever, cough, dyspnea, lactate dehydrogenase greater than 460 U/L or an arterial partial pressure of oxygen (PaO2) less than 75 mm Hg. A careful history may reveal longstanding exertional dyspnea that has worsened incrementally over weeks to months. Physical exam findings are also nonspecific. Fine, dry “cellophane” rales may be heard or auscultation may be entirely normal. In 2–6% of patients, PCP may present as spontaneous pneumothorax. The classic X-ray findings are diffuse interstitial or perihilar infiltrates, but a wide range of X-ray abnormalities is possible and radiography is normal in over one third of cases. Extrapulmonary pneumocystosis is uncommon. PCP is suggested by oxygen desaturation with exercise, easily measured in the office or clinic with a pulse oximeter. This is particularly useful when symptoms are minimal, the patient does not appear acutely ill, and the chest X-ray is unimpressive. Severity of illness is indicated by hypoxemia or a widened alveolar to arterial oxygen difference (A-aDO2) on blood gas analysis. Many diseases may have a similar presentation, including mycobacterial, fungal, viral, or bacterial pneumonias, heart failure, pulmonary KS, and pulmonary embolus. The definitive diagnostic test requires bronchoalveolar lavage of affected lung segments that is then concentrated and stained for P. carinii organisms. Experienced sites can make a histologic diagnosis from an induced sputum sample that is concentrated and stained, but this less invasive, cheaper diagnostic test should not be attempted where expertise in both obtaining and interpreting the smear is lacking. Trimethoprim-sulfamethoxazole (TMP-SMX) is the mainstay of treatment for PCP; intravenous or oral administration depends on the severity of the episode. There are a number of alternative regimens for patients who experience treatment-limiting toxicity or who fail to respond to TMP-SMX. PCP should be treated for 21 days. After completing acute therapy, the patient should begin routine daily PCP prophylaxis to prevent recurrence. Patients with PaO2 less than 70 mm Hg or with an A-aDO2 greater than 35 on room air should receive adjunctive steroids, which have been shown to decrease the incidence of ventilatory failure and death. A 21-day course of prednisone (40 mg twice daily for 5 days, then 20 mg twice daily for 5 days, followed by 20 mg once daily for 11 days) is the most popular and cost-effective approach. No additional taper is required. The appearance of mucosal candidiasis is often the first clinical indication of impaired T-cell immunity in HIV-infected individuals. Whereas oral and vaginal thrush are almost ubiquitous and Candida esophagitis is the second most common OI after PCP, candidemia and tissue-invasive disease are rare. Pharyngitis may be asymptomatic or may cause dysphagia. White plaques can be easily scraped from the pharynx or buccal mucosa; severe cases will involve the tongue, gums, and lips. Vaginitis causes a thick white discharge, pruritus, and sometimes dyspareunia, and has a similar appearance on speculum exam. Intense erythema may be the most prominent finding in some patients with either pharyngitis or vaginitis. Scrapings will be KOH-positive by microscopic exam and will grow readily in culture. These forms of candidiasis may be treated with topical or oral antifungals; topical agents are more cost-effective and avoid the risk of systemic side effects or drug interactions. Candida esophagitis is a more serious infection that may result in significant weight loss because of odynophagia. Esophagitis should be considered when the patient describes midline substernal chest discomfort with swallowing instead of pain limited to the throat. It may occur in the absence of oropharyngeal thrush, and can be diagnosed by endoscopy or by barium swallow. Topical agents should not be used for esophagitis. Oral fluconazole, 200 mg once daily for 10 days, is the treatment of choice. Prolonged usage of oral azoles such as fluconazole can result in resistant candidiasis, so it is important to avoid chronic use. Most experts try to use topical antifungals or intermittent courses of azole drugs whenever possible. Prophylaxis for vaginal candidiasis with topical antifungals should be considered when systemic antibiotics are given. Some patients with fluconazole-resistant esophagitis may respond to itraconazole, especially the cyclodextrin solution, oral voriconazole, or to oral amphotericin B solution. However, most patients with resistant infection will ultimately require intravenous (IV) amphotericin for relief. Cryptococcal meningitis may present as nothing more than the worst headache of the patient’s life. Fever is common but meningismus may be minimal or absent. Altered mental status and elevated intracranial pressure above 180 mm of water portend a poorer prognosis. Therefore, it is important for patient management to obtain an opening pressure when performing the diagnostic lumbar puncture. Cranial nerve deficits and seizures are only seen in patients who present very late in the course of their infection and are often antemortem events. The diagnosis is made by detection of cryptococcal capsular antigen in the cerebrospinal fluid (CSF); relying upon a positive India ink stain that demonstrates the organism’s thick capsule is too insensitive. Cryptococcus neoformans may also be cultured from blood and CSF. Computed tomography (CT) or magnetic resonance imaging (MRI) scans may reveal basilar inflammation, and in patients with intracranial hypertension, the ventricles may be enlarged. Very mild cases may be treated from the outset with oral fluconazole, 400 mg once daily for 10 wk, followed by chronic suppressive therapy (200 mg once daily). Most experts prefer using intravenous amphotericin B at a dose of 0.7–1.0 mg/kg per day for the first 2 wk, with or without flucytosine, and then switching to fluconazole as described above if the patient is responding. Intracranial hypertension can be managed with frequent lumbar punctures to remove large volumes of CSF (20–30 mL at a time). Serum cryptococcal antigen may occasionally be positive before the onset of headache. It may also be detectable when extrameningeal infection occurs, and in the evaluation of a fever of unknown origin. In these situations, oral fluconazole is appropriate therapy. Toxoplasmosis manifests almost exclusively as an encephalitis in AIDS patients. The patient presents with a neurologic deficit, and classically one or more ring-enhancing space-occupying lesions can be seen on CT or MRI scan. However, the radiographic appearance of the lesions is not pathognomonic and may mimic other processes such as primary CNS lymphoma. Because serology may be negative and because it is often difficult to obtain a brain biopsy for a definitive diagnosis, the standard approach is a diagnostic trial of antitoxoplasma therapy with pyrimethamine and sulfadiazine for at least 2 wk. Both clinical and radiographic improvement should be evident in response to therapy if the patient has toxoplasmic encephalitis (TE). Clindamycin may be substituted for sulfidiazine if the latter is poorly tolerated. Although TE in AIDS patients results from reactivation of latent infection, a baseline negative IgG test for Toxoplasma gondii does not exclude the diagnosis, and seronegative patients will routinely receive a trial of therapy regardless of their serostatus. For this reason, and because PCP prophylaxis with TMP-SMX will also prevent TE, obtaining a Toxoplasma gondii IgG may not be very cost-effective. A situation where knowledge of Toxoplasma gondii serostatus is helpful is when a patient cannot tolerate TMP-SMX prophylaxis; in this case pyrimethamine should be added to second-line PCP prophylaxis with dapsone to provide protection from TE as well. HIV-infected individuals may have recurrent genital HSV that can be suppressed with oral antiviral drugs such as acyclovir, valacyclovir, and famciclovir. Both treatment and prophylaxis of HSV may require higher doses and, in the case of treatment, longer administration than is required in the management of HIV-negative patients; this is particularly the case in women with more advanced immunosuppression (see Chapter VI on Gynecologic Problems). Definitive diagnosis is usually made by culturing HSV from the base of the lesion(s), although experienced clinicians will often rely on typical appearance, distribution, and symptoms. When patients develop severe mucocutaneous lesions or ulcers that persist for more than 4 wk, this unusually persistent form of HSV is considered an AIDS-defining illness. Similar to fluconazole-resistant candidiasis, injudicious chronic use of antiherpes drugs may result in drug-resistant infection, which then requires treatment with intravenous foscarnet. Varicella-zoster virus, a related member of the herpesvirus family, causes shingles, which responds to higher doses of antiherpes drugs than those needed for HSV. Shingles can be exquisitely painful and patients may have prolonged postherpetic neuralgia. Secondary bacterial infection may occur, so it is important to keep the lesions clean and to use topical or systemic antibiotics as needed. Control of pruritus and pain is essential for patient comfort. Drug-resistant varicella-zoster virus has been reported and is also treated with IV foscarnet. Cytomegalovirus (CMV) causes retinitis in 80–85% of AIDS patients with end-organ CMV disease. Gastrointestinal disease anywhere from the mouth to the anus is diagnosed in another 12–15%. Other diagnoses, such as encephalitis and pneumonitis, are uncommon (~1%). CMV retinitis can cause visual loss, and untreated, progresses inexorably to blindness. Because retinitis is a necrotizing process, with effective antiviral treatment the lesions become quiescent and atrophic, but the affected areas do not regain function. Retinitis near critical structures such as the macula or optic nerve may cause catastrophic visual loss even when the total infected area is small. Patients may be completely asymptomatic, or may complain of floaters (due to inflammatory debris), diminished acuity, or visual field defects when the lesion(s) is(are) in the periphery. Diagnosis is made by visual inspection of the entire retina by an experienced ophthalmologist using dilated indirect ophthalmoscopy. Extensive disease may lead to retinal detachment, which may require surgical repair. Treatment is usually begun with oral valganciclovir or with intravenous ganciclovir, foscarnet, or cidofovir for 2–3 wk, followed by chronic suppression with either less frequent IV doses or oral valganciclovir or ganciclovir. Chronic use of these intravenous agents requires the placement of an indwelling catheter for ease of administration, or IV therapy can be used briefly until an intraocular device can be inserted surgically that slowly releases small amounts of ganciclovir directly into the vitreous. Because CMV is a systemic infection with viremia, patients who receive the ganciclovir implant also need chronic suppressive therapy with oral valganciclovir to prevent the development of extraocular CMV disease. CMV can become resistant to antivirals. Refractory disease is often treated with intraocular injections, which, like the ganciclovir implant, deliver high concentrations of drug to the site of active viral replication. End-organ disease at nonocular sites is treated with 2–3 wk of intravenous induction therapy; oral valganciclovir has not been studied for monocular disease but should be effective. There is no clear agreement that CMV disease at sites outside the eye requires chronic maintenance therapy, but with the availability of oral valganciclovir it seems reasonable to provide continued anti-CMV treatment in patients whose immune systems remain badly damaged (CD4 cells <100/mm3). Disseminated Mycobacterium Avium Comples (MAC) Like CMV, disseminated MAC is one of the OIs that appears at end-stage disease, when the total CD4 cell count is extremely low. It presents nonspecifically with fever, weight loss, diarrhea, anemia, and sometimes abdominal discomfort due to organomegaly and impressive intra-abdominal lymphadenopathy. Mycobacterial blood culture provides a definitive diagnosis; culture of sputum or other specimens is not helpful. Combination oral antimicrobial therapy is required and should include, at a minimum, an azalide (azithromycin or clarithromycin) and ethambutol, 15–25 mg/kg per day. Other drugs, such as ciprofloxacin and amikacin, have been used but do not routinely provide much additional benefit; clofazimine has been shown to have an adverse effect on survival and should not be used. There is a bidirectional interaction between Mycobacterium tuberculosis and HIV; each facilitates acquisition of the other, so it is critical to assess all HIV-infected patients for active tuberculosis (TB), and to test all patients with active TB for HIV. Because TB is virulent enough to cause disease in patients with intact immune systems, it may occur in HIV-infected individuals who still have high CD4 cell counts. TB is especially virulent in HIV seropositive individuals. Aspects of this virulence include the high frequency of positive blood cultures and of disseminated (miliary) infection. However, standard combination antimicrobial therapy is effective as long as the patient is adherent and the acquired strain is not multidrug resistant. It is essential to provide directly observed therapy to ensure an adequate course of treatment and conversion of positive sputum cultures to negative. Until susceptibilities are known, all HIV-infected patients should be treated initially with at least four drugs expected to be active according to local susceptibility patterns; for susceptible TB, typically INH, rifampin or rifabutin, pyrazinamide and ethambutol or streptomycin are given for 2 months, followed by INH and rifampin or rifabutin for 4 months. Subsequently, when the results of susceptibility testing are available, therapy for drug-sensitive infection can usually be narrowed to two agents. Patients with advanced HIV disease or a delayed response to TB treatment (symptomatic and/or culture-positive after 2 months of treatment) should receive a total course of 9 months. Clinicians should work closely with their local health department to ensure that patients receive directly observed therapy, and to track and limit the spread of TB, especially resistant strains. All close contacts — especially young children — must be evaluated for TB so they may be treated promptly for active disease or given prophylaxis as indicated. Cryptosporidiosis And Microsporidiosis These enteric protozoa can cause debilitating diarrhea and weight loss in patients with advanced HIV disease. Diagnosis is made by special stool stains. Unfortunately there is no effective therapy (except for Septata intestinalis, which may respond to albendazole), so care is supportive. Every effort should be made to optimize the patient’s antiretroviral therapy because there are reported cases of clinical resolution (and even clearing of the organism from stool) with potent combination antiretroviral therapy. Patients may develop severe dehydration due to voluminous watery diarrhea. In addition to volume repletion, attempts at slowing the diarrhea should be made as follows by adding (not substituting) each additional agent in a stepwise manner: 1) diphenoxylate or loperamide, increased to their maximum dose, plus 2) tincture of opium or paregoric, with the dose titrated gradually until the desired effect is achieved, and, if additional control is needed, 3) parenteral somatostatin, which is very expensive. Distal, symmetrical polyneuropathy, typically affecting the feet more than the hands, may result from use of the neurotoxic dideoxy nucleoside analogues (didanosine, stavudine, zalcitabine) and much less commonly from dapsone, or may be a consequence of advanced HIV disease itself. Most patients present with paresthesias and/or numbness, but some experience pain that can be disabling. Examination reveals slow or absent ankle jerks, diminished vibratory and proprioceptive responses in both feet, and in patients whose primary complaint is pain, discomfort sometimes even with light touch. If drug toxicity is suspected, the offending agent(s) should be discontinued immediately and replaced. If this is accomplished quickly enough after the onset of symptoms, the syndrome may resolve entirely. When the nerve damage is not attributable to anti-HIV therapy or does not resolve after drug discontinuation, supportive care may be offered. Nonsteroidal antiinflammatory drugs; agents useful in chronic pain syndromes such as amitryptiline, phenytoin, or carbamazepine; the neurotransmitter inhibitor gabapentin; mexilitene, lamotrigine; and, in refractory cases, long-acting narcotics, all have a role in the management of dysesthesias and pain due to peripheral neuropathy. AIDS Dementia Complex (ADC)/HIV Encephalopathy In the pre-HAART era, frank dementia was the AIDS-defining illness in up to 10% of patients. The initial manifestations may be subtle, and can be uncovered by questioning the patient carefully about short-term memory loss and difficulty concentrating. Useful questions about the latter include the ability to balance a checkbook or to make change. In some patients, a depressed affect may be a prominent finding, and in others, unexplained seizures may bring the patient to medical attention. Psychomotor retardation — slowing of the impulses that match actions to thoughts and intentions — is another hallmark of AIDS dementia complex (ADC). CT and MRI scans show diffuse cortical loss with prominent sulci (“walnut sign”). A good sense of the patient’s level of intellectual functioning can often be obtained at the bedside. In subtle or difficult cases, especially when there is a prior history of depression or subnormal IQ, the patient can be referred for a battery of neuropsychologic tests that may clearly demonstrate the losses characteristic of ADC. There is no specific treatment for ADC other than effective antiretroviral therapy, although symptoms may respond in part to methylphenidate or selegiline. Patients may demonstrate a remarkable degree of recovery with antiretroviral therapy even when they present with advanced dementia, so it is valuable to attempt treatment of all patients, even those initially referred for nursing home care. It may be particularly useful to include agents that achieve good CSF levels. Wasting Syndrome (“Slim Disease”) Weight loss is common in HIV disease, especially in its advanced stages, but the CDC surveillance definition of wasting syndrome specifically refers to involuntary weight loss that exceeds 10% of the patient’s baseline weight in the presence of diarrhea ( Kaposi’s sarcoma (KS) is an endothelial cell tumor that, along with PCP, was the harbinger of the AIDS epidemic. It primarily affects gay and bisexual men, and is fairly uncommon among injecting drug users and women. It is caused by human herpesvirus-8. KS can occur at a range of total CD4 cell counts, but prognosis is poorer at lower values. Most commonly it is limited to mucocutaneous surfaces, where it is a cosmetic problem but not a significant threat to health. KS of the gastrointestinal mucosa is very vascular and may lead to slow, chronic blood loss. KS may also involve the lymphatic system, and may invade the viscera, especially lung parenchyma. Experienced clinicians can generally diagnose mucocutaneous KS by inspection, but a punch biopsy showing typical spindle-shaped cells is easy to obtain and is definitive. Visceral KS, which may occur in the absence of mucocutaneous disease, requires a tissue diagnosis. Mucocutaneous KS may be treated with a number of local modalities including intralesional vincristine or vinblastine, radiation, and topical retinoids. Gastrointestinal lesions can be cauterized endoscopically. Visceral disease requires systemic chemotherapy. More recently, KS has regressed in patients begun on potent combination antiretroviral therapy alone. Several different types of lymphoma occur at increased frequency among HIV-infected individuals. These too may occur at any CD4 cell count although once again prognosis is worse at lower absolute numbers of CD4 cells. HIV seropositive patients may develop Hodgkin’s disease, immunoblastic lymphoma, and Burkitt’s lymphoma as well as less common forms, but the most common type is an aggressive non-Hodgkin’s B cell lymphoma. There is a marked tendency for extranodal presentations (Stage 1E), and AIDS patients have been described with non-Hodgkin’s lymphoma at a range of unusual sites. AIDS-associated lymphoma is diagnosed and staged in the same manner as in seronegative patients, and the same types of combination chemotherapy are used. However, HIV-infected patients typically require lower doses or aggressive support with granulocyte colony-stimulating factor because of their baseline bone marrow fragility. Central Nervous System Lymphoma Central nervous system lymphoma occurs at total CD4 cell counts well under 100 cells and is a typical end-stage complication. Definitive diagnosis is made by brain biopsy or CSF cytology in the presence of a space-occupying lesion(s) on CT or MRI scan. A presumptive diagnosis may sometimes be made by nuclear SPECT scan. Because brain biopsy may be difficult to obtain, patients who fail a trial of therapy for toxoplasmosis are often assumed to have CNS lymphoma. There is no effective cytotoxic chemotherapy for this disease, and irradiation is considered palliative. Survival after a diagnosis of CNS lymphoma is usually limited, on the order of a few months. Progressive Multifocal Leukoencephalopathy (PML) Progressive multifocal leukoencephalopathy is another end-stage complication of HIV disease, usually presenting as a focal neurologic deficit(s). It is caused by the JC virus, which can be detected by PCR performed on CSF. MRI scan of the brain demonstrates involvement of the white matter that can be focal or fairly diffuse, but is not usually associated with either mass effect or surrounding edema. Most commonly it affects areas adjacent to the cortex, but lesions can be located anywhere. Definitive diagnosis is made by brain biopsy or positive PCR, which is highly specific in the appropriate clinical context. Where these diagnostic modalities are unavailable, the typical MRI picture usually suffices. There is no specific proven therapy for this condition, although a number of case reports describe clinical remission in patients begun on potent combination antiretroviral therapy. In the pre-HAART era, survival was very limited, but now there are patients alive more than a few years after diagnosis. Figure 4-5: Guidelines for Use of Erythropoietin in the Anemic HIV Patient Goals of Therapy
* If Hgb Source: John Bartlett, 2003. Reprinted with permission. Many of the same behaviors that put women at risk of acquiring HIV also result in hepatitis B and/or C infection. Up to 90% of HIV-infected individuals have evidence of prior exposure to hepatitis B (HBV) and up to 10% have chronic HBV infection (Homann, 1991; Bodsworth, 1991). Risk of developing chronic infection is increased in the presence of HIV co-infection (Bodsworth, 1991; Houssett,1992); limited data also suggest that HIV-HBV coinfection is associated with higher HBV DNA levels and worse prognosis in terms of liver-related morbiditiy and mortality (Thio, 2001; Colin,1999).Persistence of HbsAg for longer than 6 months is indicative of chronic infection; these patients should be tested for HbeAg and anti-Hbe and have periodic assessment (e.g., every 6 months) of transaminases, albumin, prothrombin time, bilirubin, complete blood count, and platelet count. Patients with chronic HBV infection are at increased risk of cirrhosis and end-stage liver disease and hepatocellular carcinoma. Periodic screening every 6–12 months with alfa fetoprotein (AFP) and/or liver ultrasound should be considered in patients with chronic HBV and other high risk characteristics (age >45 years, cirrhosis, family history of liver cancer). Indications for HBV treatment include: HbsAg positive > 6 months, evidence of active viral replication (HbeAg + HBV DNA positive), and moderate or severe liver inflammation on biopsy. The goal of treatment is to prevent or delay the progression of liver disease; eradication of the virus is not possible with current therapies. Agents used to treat HBV include interferon, lamivudine (3TC), tenofovir, adefovir, and emtricitabine; 3TC, tenofovir, and emtricitabine should only be used as part of or in conjunction with a fully suppressive antiretroviral regimen. A recent cross-sectional analysis of a large heterogeneous group of HIV-infected individuals found that 16% had HCV coinfection (Sherman, 2002). Hepatitis C (HCV) becomes a chronic infection in about 85% of cases. Data from a recent meta-analysis indicate that HIV-HCV coinfected patients have a 2.9 times higher risk of progressive liver disease than those infected with HCV alone (Graham, 2001). There is some evidence that HCV may accelerate progression of HIV disease as well (Piroth, 2000). Screening for HCV is recommended using a 2nd or 3rd generation HCV enzyme-linked immunosorbent assay with confirmation using HCV RNA testing. Hepatitis C viral loads do not correlate with severity of liver damage on biopsy. Serum transaminases should be monitored, especially ALT, which is more specific for hepatocellular injury. ALT levels may wax and wane, and may be normal or only modestly elevated. Screening for hepatocellular carcinoma with AFP and/or liver ultrasound should be considered, particularly in patients with cirrhosis. Indications for HCV treatment include: detectable HCV RNA, persistently elevated ALT levels, and liver biopsy with portal or bridging fibrosis and at least moderate inflammation and necrosis. The goals of treatment include eradication of HCV infection and prevention or delay of progressive liver disease. Recommended treatment for chronic HCV is pegylated interferon plus ribavirin; preliminary data suggest that HCV virologic response correlates with CD4 cell count in HIV-HCV coinfected patients (Soriano, 1996). Patients with either HBV or HCV infection should avoid alcohol consumption, which may increase risk of progressive liver disease. Transplantation of coinfected patients with end–stage liver disease has been successful and is being evaluated further. Modest anemia ( Patients who are symptomatic with exertional dyspnea and dizziness can be transfused acutely. Most HIV-infected patients become anemic gradually, and unconsciously limit their activities to control symptoms. These individuals can be managed with changes of antiretroviral or OI therapies known to be toxic to red blood cells, such as AZT (zidovudine) and TMP-SMX. In patients refractory to conservative management, red blood cell production can be stimulated by using recombinant erythropoietin along with sufficient iron replacement to stimulate production of new red cells (see Figure 4-5). C. OPPORTUNISTIC DISEASE IN THE HAART ERA The impact of highly active antiretroviral therapy on the natural history of opportunistic diseases has been profound, and the clinician must be familiar with at least the broad outline of these changes. There may be sufficient immune restoration that even patients with end-stage disease become capable of mounting an inflammatory response to opportunistic pathogens. This can result in worsening of the clinical manifestations of an OI that has been under treatment or atypical presentation of a new acute OI, generally within the first couple of months after initiating potent anitretroviral therapy, after CD4 cell counts have begun to improve. For example, in the case of MAC lymphadenitis, there may be the acute focal development of a tender, enlarged lymph node with negative blood cultures, whereas in the pre-HAART era the typical presentation would have been diffuse, with widespread nontender adenopathy and high-grade mycobacteremia. This seemingly paradoxical development of an OI with rising CD4 cell counts is likely due to an inflammatory response to an OI that was subclinical when HAART was begun. Similarly, immune reconstitution syndromes have been described for TB, PCP, toxoplasmosis, cryptococcal infection, and PML, when these infections have been under treatment. Management includes continuation of antiretroviral therapy while making sure there has been no recrudescence of the underlying OI, plus addition of NSAIDs or corticosteroids to alleviate the inflammatory reaction. Patients who recover pathogen-specific immunity in addition to the overall increase in CD4 cells may be able to discontinue chronic suppressive (maintenance) therapy, because the patient’s immune system is now capable of containing the infection. Thus far this has been best demonstrated for discontinuing chronic suppression for CMV retinitis. Similar phenomena have been described for other OIs, such as disseminated MAC, and there is no reason to think that other OIs will behave differently. Last, patients with previously untreatable opportunistic processes, such as PML or cryptosporidiosis, have had clinical remissions after initiating HAART. A number of studies have shown that patients receiving primary prophylaxis for PCP and MAC are at very low risk of developing these OIs if prophylaxis is withdrawn after total CD4 cell counts have improved above the threshold levels for risk of each specific OI for at least 3–6 mo. Most of these studies have been performed among patients with reasonably well controlled HIV viral loads, with the majority undetectable or at most, less than 10,000 copies. At this point, it is clear that specific prophylaxis can be safely stopped for any OI when CD4 cell counts have increased above the threshold of risk VI. Algorithms for Diagnosis and Management of Symptoms TOP Figure 4-6: Fever of Unknown Origin in Patients with AIDS Figure 4-7: Acute Diarrhea in Patients with AIDS Figure 4-8: Chronic Diarrhea (CD4 Count <300/mm3) Figure 4-9: Cough, Fever, Dyspnea Figure 4-10: Headache in Patients with AIDS Figure 4-11: Advanced HIV Infection Plus Altered Status, New Seizures, Headache (Severe or Persistent), or Focal Neurologic Deficits
Figure 4-12: Sensory Neuropathies in Patients with AIDS
Figure 4-13: Odynophagia in Patients with AIDS Evaluation
VII. References TOP Adult Treatment Panel. Executive summary of the 3rd report of the National Cholesterol Education Program (NCEP) Expert panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA. Bartlett JG and Gallant JE. 2001-2002 Medical Management of HIV Infection. Baltimore, MD: Johns Hopkins University; 2001. Bartlett JG and Gallant JE. 2003 Medical Management of HIV Infection. Baltimore, MD: Johns Hopkins University; 2003. Baxter J, Mayers D, Wentworth D, et al. A pilot study of the short-term effects of antiretroviral management based on plasma genotypic antiretroviral resistance testing in patients failing antiretroviral treatment. 6th Conference on Retroviruses and Opportunistic Infections; January 30–February 4, 1999; Chicago, IL. Abstract LB8. Bersoff-Matcha SJ, Miller WC, Aberg JA et al. Sex difference in nevirapine rash. Clin Infect Dis. 2001;32:124–129. Bodsworth NJ, Cooper DA, Donovan B. The influence of human immunodeficency
virus type 1 infection on the development of the hepatitis B carrier state. J Infect Dis. Boehringer-Ingelheim. Viramune package insert. January, 2004. Bourezane Y, Salard D, Hoen B et al. DRESS (drug rash with eosinophilia and systemic symptoms) syndrome associated with nevirapine therapy. Clin Infect Dis. CDC. Advancing HIV prevention: new strategies for a changing epidemic– United States, 2003. MMWR. 2003;52:329–332. CDC. Hepatitis B virus: a comprehensive strategy for eliminating transmission in the United States through universal childhood vaccination. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR. 40(RR-13), 1991. CDC. Prevention of hepatitis A through active or passive immunization. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR. 45(RR-15), 1996. CDC. Prevention and control of influenza. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR. 48(RR-4), 1999. Carr A, Samaras K, Burton S, et al. Syndrome of peripheral lipodystrophy, hyperlipidemia and insulin resistance in patients receiving HIV protease inhibitors. AIDS. 1998; 12:F51–58. Colin JF, Cazals-Hatem D, Loriot MA, Martinot-Peignoux M, Pham BN, Auperin A et al. Influence of human immunodeficiency virus infection on chronic hepatitis B in homosexual men. Hepatology. 1999;29:1306–1310. D’Acquila, RT, Schapiro JM, Brun-Vezinet F, et al. Drug resistance mutations in HIV-1. Topics in HIV Medicine 2002;10:21-25. Deeks SG, Wrin T, Liegler T et al. Virologic and immunologic consequence of discontinuing combination antiretroviral-drug therapy in HIV-infected patients with detectable viremia. N Engl J Med. 2001;344:472–480. DHHS (US Department of Health and Human Services). Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents. Rockville, MD: Department of Health and Human Services. 2004. Available at: http://www.aidsinfo.nih.gov. Accessed March 21, 2004. Dube MP, Sprecher D, Henry WK. Preliminary guidelines for the evaluation and management of dyslipidemia in adults infected with human immunodeficiency virus and receiving antiretroviral therapy: recommendations of the Adult AIDS Clinical Trials Group Cardiovascular Disease Focus Group. Clin Infect Dis. 2000;31:1216–1224. Durant J, Clevenbergh P, Halfon P, et al. Drug-resistance genotyping in HIV-1 therapy: the VIRADAPT randomized controlled trial. Lancet. 1999;353: 2195–2199. Fauci A, Pantaleo G, Stanley S, Weismann D. Immunopathogenic mechanisms of HIV infection. Ann Intern Med. 1996;124:654–663. Graham CS, Baden LR, Yu E et al. Influence of human immunodeficiency virus infection on the course of hepatitis C virus infection: a Meta-analysis.
Clin Infect Dis. Ho D, Neumann A, Perelson A, et al. Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection. Nature. 1995;373:123–126. Homann C, Krogsgaard K, Pedersen C, Andersson P, Nielsen JO. High incidence of hepatitis B infection and evolution of chronic hepatitis B infection in patients with advanced HIV infection. J Acquir Immune Defic Syndr. 1991;4:416–420. Houssett C, Pol S, Carnot F et al. Interactions between human immunodeficiency virus-1, hepatitis delta virus and hepatitis B virus infections in 260 chronic carriers of hepatitis B virus. Hepatology. 1992;15:578–583. Imam N, Carpenter CC, Mayer KH, Fisher A, Stein M, Danforth SB. Hierarchical
pattern of mucosal candida infections in HIV-seropositive women. Am J Med. Joffe BI, Panz VR, Raal FJ. From lipodystrophy syndromes to diabetes mellitus. Lancet. 2001;35:1379–1381. Kitahata MM, Koepsell TD, Deyo RA, Maxwell CL, Dodge WT, Wagner EH. Physicians’ experience with the acquired immunodeficiency syndrome as a factor in patients’ survival. N Engl J Med. 1996;334:701–706. Lawrence J, Mayers D, Huppler Hullsiek K et al. CPCRA 064: a randomized trial examining structured treatment interruption for patients failing therapy with multi-drug resistant HIV. 10th Conference on Retroviruses
and Opportunistic Infections; February Mallal S, John M, Moore C et al. Protease inhibitors and nucleoside analogue reverse transcriptase inhibitors interact to cause subcutaneous fat wasting in patients with HIV infection. 1st International Workshop of Adverse Drug Reactions and Lipodystrophy in HIV; June 26–28, 1999; San Diego, CA. Abstract 019. Martinez E, Blanco JL, Arnaiz JA et al. Hepatotoxicity in HIV-1-infected aptients receiving nevirapine-containing antiretroviral therapy. AIDS. 2001;15:1261–1268. McNaghten AD, Hanson DL, Jones JL, Dworkin MS, Ward JW, and the Adult/Adolescent Spectrum of Disease Group. Effects of antiretroviral therapy and opportunistic illness primary chemoprophylaxis on survival
after AIDS diagnosis. AIDS. Mellors JW, Rinaldo CR, Gupta P, White RM, Todd JA, Kingsley LA. Prognosis in Mellors JW, Munoz A, Gigorgi JV, et al. Plasma viral load and CD+ lymphocytes as prognostic markers of HIV-infection. Ann Intern Med 1997;126:946-954. Miller KD, Jones E, Yanovski JA et al. Visceral abdominal fat accumulation associated with use of indinavir. Lancet. 1998;351:871–875. Phair JP, Mellors JW, Detels R, Margalick JB, Muñoz A. Virologic and immunologic values allowing safe deferral of antiretroviral therapy. AIDS. 2002;16:2455–2459. Piroth L, Grappin M, Cuzin L et al. Hepatitis C virus co-infection is a negative prognostic factor for clinical evolution in human immunodeficiency virus-positive patients. J Viral Hepatol. 2000;7:302–308. Quinn TC, Mawer MJ, Sewankambo N, et al. Viral load and heterosexual transmission of human immunodeficiency virus type 1. N Engl J Med. 2000;342:921–929. Raboud J, Montaner J, Conway B, et al. Suppression of plasma viral load below 20 copies/ml is required to achieve a long term response to therapy.
AIDS. Rich JD, Merriman NA, Mylonakis SE, Greenough T, Flanigan T, Mady B, Carpenter CCJ. Misdiagnosis of HIV infection by HIV-1 plasma viral load testing: a case series. Ann Intern Med. 1999;130:37–39. Romeu J, Sirera G, Rego MJ et al. Cumulative risk for developing hyperlipidemia in HIV-infected patients treated with protease inhibitors. 39th Interscience Conference on Antimicrobial Agents and Chemotherapy; Sept 26–29, 1999; San Francisco, CA. Abstract 1293. Scribner AN, Troia-Cancio PV, Cox BA, et al. Osteonecrosis in HIV: a casecontrol study. J Acquir Immune Defic Syndr Hum Retrovirol. 2000;25:19–25. Sherman KE, Rouster SD, Chung RT, Rajicic N. Hepatitis C virus prevalence among patients infected with human immunodeficiency virus: a crosssectional analysis of the US adult AIDS Clinical Trials Group. Clin Infect Dis. 2002;34:831–837. Soriano V, Garcia-Samaniego J, Bravo R et al. Interferon alpha for the treatment of chronic hepatitis C in patients infected with human immunodificiency virus. Hepatitis-HIV Spanish Study Group. Clin Infect Dis. 1996;23:585–591. Tebas P, Powderly WG, Claxton S et al. Accelerated bone mineral loss in HIV-infected patients receiving potent antiretroviral therapy. AIDS. 2000;14:F63–67. Thiebaut R, Daucourt V, Mercie P et al. Lipodystrophy, metabolic disorders,
and human immunodeficiency virus infection: Aquitaine Cohort, France, 1999. Group d’Epidemiologie Clinique du Syndrome d’Immunodeficience Acquise en Aquitaine. Thio CL, Seaberg E, Skolasky RL, Kingsley LA, Phair J, Visscher B et al. HIV infection increases liver-related mortality in HBV-infected individuals. Hepatology. 2001;34:469. USPHS/ISDA. Guidelines for the prevention of opportunistic infections in persons infected with human immunodeficiency virus. November 28, 2001. Available at: http://www.aidsinfo.nih.gov. Accessed March 21, 2004. Zolopa AR, Shafer RW, Warford A, Montoya JG, Hsu P, Katzenstein D, Merigan
TC, Efron B. HIV-1 genotypic resistance patients predict response to saquinavir–ritonavir therapy in patients in whom previous protease inhibitor failed. Ann Intern Med. |
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Confirm HIV diagnosis (usually with ELISA and Western blot)
350/mm3
Cmax, Cmin, 
3-4 TAMs associated with ABC resistance. ABC selects for mutations that may confer cross-resistance to 3TC, ddl, and TDF.![Figure 4-5: Guidelines for Use of Erythopoietin in Anemic HIV Patient. Flow diagram which begins at the top with a block labeled: Patient Candidate; Anemic HIV patient, Hgb<11g/dL or Hct <33%. Next block down is “Exclude Other Causes of Anemia,” which includes: Bleeding (guaiac stools), Hemolysis (smear), Iron deficiency (serum iron, transferrin, % saturation, ferritin), and B12, folate deficiency (serum B12, rbc folate if macrocytic). If the answer to any of these conditions is “Yes,” flow points to “Correct underlying cause” and the process stops. If the answer is “No,” flow leads to next block which is “Start EPO 40,000 units sc/wk. Consider iron supplementation.” Next step is “Monitor Response”: Full response will generally not be seen for at least 4 wk. Three options for next step (left to right): “At wk 4, if Hgb increases >1g/dL, continue at this dose.” Second option (which appears at bottom of page because there is a second path to this option): “When Hgb approaches 13/gdL, decrease EPO by 10,000 units/wk*. Titrate to maintain desired hemoglobin.[ † ]” Third option: “At 4 wk, if Hgb increases <1g/dL, increase dose to 60,000 units/wk.” From this third option, the flow branches two ways. The first leads to an end point box: “At 8 wk. if Hgb increases <1g/dL, check iron, folate and B12 levels. If adequate, discontinue EPO.” The second branch leads down to “At 8 wk, if Hgb increases >1g/dL, continue at this dose.” From this box, the flow leads back to the second option mentioned earlier, that is “When Hgb approaches 13g/dL, decrease EPO by 10,000 units/wk*. Titrate to maintain desired hemoglobin.[ † ]”](images/WG05fig4_5.gif)
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