IV. PRIMARY MEDICAL CARE
Judith Feinberg, MD, and Janine Maenza, MD

I. INTRODUCTION

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 The speed at which new developments occur and the rapidity with which they are superseded by newer data are nothing short of breathtaking. As a consequence, most studies are typically out of date at the time of publication.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, no differences in overall survival or complication-free survival have been demonstrated. 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

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.

• HIV diagnosis: When did you first test positive for HIV? Why were you tested? This neutral, open-ended start permits the patient to ask questions about HIV risk behaviors and possible route(s) of transmission, including sexual partners and practices and alcohol/drug use behaviors. Was the patient ever tested for HIV before? If prior test(s) were negative, it is valuable to assess whether HIV has been relatively recently acquired by looking for evidence of the acute seroconversion syndrome within the past 6–9 mo. These symptoms are classically those of seronegative mononucleosis — fever, aches, pharyngitis, lymphadenopathy, and frequently rash, although the range of possible clinical manifestations of acute HIV infection is very broad.
  
• HIV treatment history: If the patient has already been treated for HIV disease, then it is extremely valuable to know the patient’s pretherapy CD4 cell count, HIV viral load, and specific treatment history. What was her prior antiretroviral therapy, including duration? Were there any difficulties with adherence, response to therapy, adverse effects, or history of treatment-limiting intolerance to any agent? It is important to determine what, if any, obstacles she has experienced in taking antiretroviral therapy as prescribed (see Chapter V on Adherence). Has she had any HIV-associated diagnoses and was she treated for these conditions? Has she taken any opportunistic infection prophylaxis? Has she ever been hospitalized? If so, was it for an HIV-related problem?
  
• History of sexually transmitted diseases and other infectious diseases: Including syphilis, gonorrhea, herpes simplex, pelvic inflammatory disease, anogenital warts; tuberculosis (PPD status, exposure to active case, prior prophylaxis or treatment for active disease); hepatitis A, B, or C; prior vaccinations, including those for childhood illnesses, hepatitis A and/or B, pneumococcal infection and influenza; history of chicken pox or shingles; complete gynecologic history (see Chapter VI on Gynecologic Problems), including most recent evaluation, Pap smear, and results.
  
• History of other medical diagnoses: With particular attention to hypertension, type II diabetes, cardiovascular disease, premalignant or malignant conditions.
  
• Sexual practices: Including use of condoms (male and/or female versions) and/or other forms of birth control, consistency of use; number of current partners and their HIV status (if known); history of trading sex (oral or intercourse) for drugs or money; history of anal sex.
  
• Presence of HIV-associated signs and symptoms: Fatigue, lym-phadenopathy, weight loss, skin problems, bacterial pneumonia, thrush (oral, vaginal), as well as signs/symptoms more typical of advanced HIV disease, including fevers, night sweats, persistent diarrhea, severe headache, respiratory symptoms (especially progressive dyspnea on exertion and cough, whether productive or nonproductive), mental status changes, difficulty swallowing, midline substernal discomfort with swallowing, and visual changes, particularly the presence of floaters or visual field deficits.
  
• Mental health history: Past and current problems, evidence of depression (trouble sleeping, early awakening, change in appetite, loss of interest in usual activities, anhedonia).
  
• Family history: Age and health of children, including HIV test results if performed; HIV in other family members; other medical diagnoses, especially hypertension, type II diabetes, cardiovascular disease, malignancy in family members.
  
• Medications taken regularly: Including prescription and over-the-counter remedies; history of and attitude toward regular medication use; use of alternative (nontraditional) medications for HIV or other conditions; drug allergies.
  
• Social history: Place of birth, where patient was raised, where and with whom patient lives and relationship to others in the household; childcare responsibilities; history of domestic violence; pets, especially reptiles (risk of salmonellosis) and kittens (risk of toxoplasmosis); extent of formal education; occupational history and potential toxic exposures; travel history; cigarette, alcohol, and illicit drug use in the past or continuing; misuse of prescription medications.
  
• Sources of support: To whom has the patient disclosed her diagnosis and what were their reactions? Are there friends or family to whom disclosure seems possible either now or perhaps in the future? Are other family members HIV-positive? Are family or friends able to care for the patient’s children in the event of illness? Does she have a job and, if so, does it provide health insurance?
       
       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.

• HIV pathogenesis: What are CD4 lymphocytes and why are they important? How does HIV infection affect CD4 cells?
  
• Natural history of HIV disease: How is “AIDS” different from “HIV infection” (or “HIV disease”)? What is the typical time course between acquisition of HIV and the development of HIV-associated problems? AIDS?
  
• Monitoring the activity of HIV disease: What do CD4 cell counts and HIV viral load tests measure? How are they used, and how often will they be repeated?
  
• Goals of HIV disease management: To maintain or improve the patient’s immune system, control HIV replication; avoiding or minimizing side effects of medications; preventive care (vaccinations, opportunistic infection prophylaxis, periodic Pap smears, other appropriate screening tests).
  
• Principles of HIV treatment: Describe the available viral targets and classes of drugs used, and the value of combination therapy in preserving health and prolonging life.
  
• Preventing spread of HIV infection: Notifying sexual partners and drug use contacts, safer sexual practices, safer needle use including needle exchange programs, ready availability of bleach in the household for cleaning up blood, appropriate wound care for accidental injuries, reassurance about the difficulty of transmitting HIV to casual contacts and to family members even in the close context of everyday family life.

     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.

B. PHYSICAL EXAMINATION

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.

• General: Evidence of wasting, often prominent at the temples; fat redistribution syndromes including the development of a buffalo hump, enlarged breasts, and truncal obesity, which may coexist with or be separate from marked subcutaneous fat loss in the extremities, face, and buttocks.
  
• Eyes: The conjunctival surfaces should be examined for the purplish spots of Kaposi’s sarcoma (KS) and for petechiae. Fundoscopy may reveal “cotton wool”spots (microinfarcts of the retinal nerve fiber layer due to occlusion of retinal capillaries). These must be differentiated from the typical ‘eggs and ketchup’ appearance of the infiltrates and hemorrhages caused by cytomegalovirus (CMV) retinitis in patients with very advanced HIV disease; visual field deficits are common in CMV retinitis and may be uncovered with simple field testing by confrontation.
  
• Oropharynx: Oral examination often yields the earliest physical evidence of HIV infection with thrush (white plaques on buccal mucosa or posterior pharynx that are readily scraped with a tongue blade) and oral hairy leuko-plakia (furry white plaques most often found on the lateral margins of the tongue that cannot be scraped off); purplish spots or plaques on mucosal surfaces, including the area under the tongue, typically indicate Kaposi’s sarcoma but may also be consistent with bacillary angiomatosis. No examination of an HIV-infected person, regardless of disease stage, should be considered complete without a careful assessment of the oropharynx.
  
• Lymph nodes: Nontender or minimally tender generalized adenopathy may wax and wane and most often is related to HIV infection itself, but may also indicate lymphoma. Regional adenopathy is more frequently associated with local pathology, such as intrathoracic adenopathy in tuberculosis or abdominal adenopathy in disseminated Mycobacterium avium complex (MAC) infection. Extremely tender lymph nodes should trigger an evaluation for the etiology.
  
• Lungs: Fine, dry “cellophane” rales are classic for Pneumocystis carinii pneumonia (PCP), but are a late finding and may be absent.
  
• Hepatosplenomegaly: Organomegaly typically reflects disseminated infection with MAC, tuberculosis, or histoplasmosis, or may be a sign of lymphoma.
  

• Pelvic examination:

• External genitalia/perineum: Sores or ulcers are usually indicative of sexually transmitted diseases, especially herpes simplex virus (HSV) or syphilis. In very immunosuppressed patients, ulcers may be caused by other opportunistic pathogens, such as CMV, or may represent -aphthous ulcers. Condyloma acuminata may appear as small, fleshy papules or may be exuberant, florid growths reaching several centimeters in diameter; other human papillomavirus-associated lesions may be recognized only with magnification and/or application of acetic acid. Raised and pigmented lesions may represent premalignant changes (vulvar intraepithelial neoplasia).

• Speculum and bimanual pelvic examination: Abnormal vaginal discharge can be caused by various forms of vaginitis (yeast, bacterial vaginosis, or trichomoniasis) or cervicitis. Pap smears should be obtained to rule out cervical dysplasia. Cervical motion, and uterine and adnexal tenderness suggest possible pelvic inflammatory disease. (Gynecologic exam is discussed in detail in Chapter VI.)

• Neurologic: Motor deficits may reflect space-occupying lesions of the central nervous system (CNS) such as toxoplasmosis, CNS lymphoma, and progressive multifocal leukoencephalopathy, or may be due to neurosyphilis. Symmetrical, distal sensory deficits (especially decrease or loss of vibratory or proprioceptive sensation), typically affecting the feet more than the hands, indicate peripheral neuropathy, which may be due to HIV itself or to drug toxicity from the dideoxy nucleoside analogues. Poor short-term memory, diminished concentration and sensorimotor retardation are the hallmarks of AIDS dementia complex (HIV encephalopathy). Dysphoric mood or flat affect may reveal depression.
  
• Skin: Like the oropharynx, careful examination of the skin often yields early clues about HIV infection, and should be performed regularly. Early manifestations include pruritic papular eruptions that may be bacterial folliculitis, eosinophilic folliculitis, or scabies. Pearly papules, often with central umbilication, are typical of molluscum contagiosum. A painful vesicular rash may be HSV but in a dermatomal distribution is usually shingles (varicella-zoster virus). Seborrheic dermatitis may be severe and appears as scaly, erythematous areas on the face, especially the nasolabial fold and eyebrows, or may be confined to the scalp and hairline. Psoriasis is another common scaling lesion. Purplish macules or plaques may be either KS or bacillary angiomatosis, similar to their appearance on mucosal surfaces; however, in dark-skinned individuals, KS may appear more brown than purple.
  

III. LABORATORY TESTING

A. INITIAL DIAGNOSIS

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.

• Serology: The most common method of HIV detection is with an enzyme-linked immunosorbent assay (ELISA) test for screening, followed by confirmation with a Western blot. For a positive Western blot, the Centers for Disease Control and Prevention (CDC) and Association of State and Territorial Public Health Laboratory Directors require a band pattern indicating antibodies to two of the following proteins: p24, gp41, and gp120/160. A serologic test may be reported as positive if the ELISA is positive and Western blot criteria are met. The test may also be reported as indeterminate if the ELISA is positive, but only a single band is detected by Western blot. Serologic tests generally become positive 3–12 wk after infection occurs. The interpretation of an indeterminate test during this window period may be clarified by a quantitative virology assay with a PCR-based technique (see below). An indeterminate test may reflect the process of seroconversion, but may also be a constant finding in an uninfected individual. Causes of indeterminate results include:

• seroconversion; 

• advanced HIV infection with decreased titers of p24 antibodies;
• HIV-2 (more common in West Africa);
• HIV subtype O (distinct from the more common subtypes A-I, collectively known as M) or nonclade B strains;
• autoantibodies due to autoimmune or collagen vascular diseases or malignancy;
• cross-reactive alloantibodies from pregnancy, blood transfusions, or organ transplantation; and
• previous receipt of an experimental HIV vaccine.
       The window period before seroconversion, agammaglobulinemia, and HIV subtype O are possible causes of false-negative results.
       ELISA assays are now available that detect HIV-2 and some ELISAs are designed to detect both HIV-1 and HIV-2; Western blot detection of HIV-2 remains inconsistent on standard assays, but there are also specific HIV-2 Western blots to confirm reactive HIV-2 ELISAs.
       Accuracy of HIV serologic testing is quite high (> 99% sensitivity and specificity), but the predictive value of a positive or negative test depends on the seroprevalence of HIV in the patient population. In a low prevalence population, the rate of false-positive results of combined ELISA and Western blot testing is < .001%. The frequency of indeterminate results in a low prevalence population is .02%.

• Viral detection

• Nucleic acid amplification. May be used to clarify the diagnosis of HIV infection in acute infection, during the window period (after exposure, before seroconversion), when serologic tests are indeterminant, or with neonatal infection.

• Plasma HIV RNA. Routinely used to monitor the course and treatment of HIV infection (see below). The three most common techniques are reverse transcriptase polymerase chain reaction (RT-PCR), a branched DNA (bDNA) technique, and nucleic acid sequence-based amplification (NASBA). These tests report the number of copies of virus per milliliter of plasma. The assays are considered equally reliable, but vary somewhat in lower levels of detection and dynamic range. Lower limits of detection for standard tests are 400 copies/mL, but ultrasensitive assays are now available that can detect as few as 20–50 copies/mL. Sensitivity is 90–95% overall, but is increased to 98–100% with CD4 counts < 200/mm³. False-positive rates are 2–3%, usually with low HIV RNA titers (Rich, 1999).

• DNA PCR. A qualitative test used to detect intracellular virus, and primarily used for viral detection with neonatal infection and with indeterminant serology. Sensitivity is > 99% at all stages of infection and specificity is approximately 98%.

• Viral isolation. Qualitative or quantitative cultures are used primarily for diagnosis in neonatal HIV infection, and for more in-depth viral analysis. The procedure is expensive and labor intensive. Sensitivity is 95–100%.

 

 

• Alternative tests

• Home testing: Home Access Express Test is the only available home test for HIV as of April 2000. Filter paper with a blood sample obtained with a lancet is mailed in to a laboratory in a coded, anonymous process. Dried blood samples are tested by the same ELISA and Western blot tests used on venous blood. Sensitivity and specificity approach 100%. Results are provided by phone (a recorded message for those with negative results, counseling for those with positive results).

• Rapid tests: There are three available tests that provide results in about 10 minutes: SUDS, Recombigen, and Genie. Sensitivity approaches 100%; specificity is also > 99%, but positive results should be confirmed with standard serology. Rapid tests may prove useful in STD clinics or emergency rooms (where patients often do not return for tests results) or on labor and delivery wards for high-risk pregnant women who have not previously been tested.
• Saliva test: The OraSure test uses ELISA and Western blot testing to detect antibodies to HIV in saliva. Sensitivity and specificity are similar to that with standard serology. This test is useful for people with poor venous access or those who want HIV testing, but refuse blood tests.

• Urine test: The only currently available urine test (Calypte HIV-1 Urine EIA) is licensed for screening only and must be administered by a physician; a positive result requires confirmation by another method.

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. 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.

• CD4 lymphocyte count: The hallmark of HIV infection is the progressive decline in CD4+ (helper) T lymphocytes. Normal laboratory ranges for CD4 lymphocyte counts are usually 500–1400/mm³. CD4 counts may drop precipitously at the time of primary HIV infection, and then usually rebound to near-baseline levels. The natural history of HIV then involves a progressive loss of CD4 cells, averaging 30–60 cells/yr (Figure 4-1). The risk of opportunistic infections increases with declining counts. (See Chapter I on Epidemiology and Natural History.) 

     Knowledge of the baseline CD4 count is of vital importance in assessing the patient: staging of HIV infection (Table 1-3 in Chapter I), recommendations for antiretroviral treatment (see section IV.C), and prophylaxis against specific opportunistic infections (see section V.A) are based on the degree of immunosuppression as quantified by the CD4 count.
Many factors may cause variability in the CD4 count. These include:

• interlaboratory variations;

• seasonal and diurnal variation (lowest levels at noon, highest in the evening)
• the use of corticosteroids (decreases values)
• intercurrent illness (decreases values)
• HTLV-1 coinfection (increases values).
       In addition, because the CD4 count is a value derived by determining the percentage of white blood cells that are lymphocytes, and then the percentage of lymphocytes that are CD4 receptor-positive, there may be variation in other white blood cell compartments (as may occur in pregnancy) that leads to variations in the CD4 count. Because the CD4 percentage is the directly measured value and the absolute CD4 count is the calculated one, it is more useful and accurate to focus on the CD4 percentage to assess trends in this important parameter.
  

• Quantitative virology/viral load assays: The HIV RNA level or “viral load” is also of pivotal importance in assessing the HIV-infected patient. Whereas the CD4 count indicates the current degree of immunosuppres-sion, the viral load indicates the rapidity with which the disease is likely to progress: higher viral loads have repeatedly been shown to be associated with a more rapid rate of disease progression (Figure 4-2).
       The most commonly used methods to quantify HIV RNA are RT-PCR, bDNA, and NASBA techniques (see Viral Detection, above). Standard tests have lower limits of detection of 400 copies/mL, but current ultrasensitive assays can detect as few as 20 copies/mL. Although results of different viral load assays correlate, absolute values differ and there is no standard multiplication factor to translate between results in the different assays. Therefore, the same assay should be used to follow an individual patient longitudinally. Intraperson variability on viral load assays is <.5 log, but this degree of variability is important to consider when determining clinical significance of a reported change in viral load values for an individual patient.

     Indications for plasma HIV RNA testing are shown in Table 4-1. It is also critical to repeat any HIV RNA result that is being used as the basis for a change in patient management.

• Hematology and chemistry panels: The effects of HIV and related infections may involve hematologic, renal, or hepatic abnormalities. A complete blood count is necessary at baseline to evaluate for leukopenia, anemia, and thrombocytopenia. In addition, the total white blood cell count and lymphocyte count are needed to calculate an absolute CD4 count. A chemistry panel that includes an evaluation of renal and hepatic function is also necessary: HIV-associated nephropathy may be indicated by elevations in blood urea nitrogen/creatinine, and the effects of viral hepatitis, alcohol, or medications may cause abnormalities of liver function tests. Any of these findings provide important information in their own right, but will also have an impact on the patient’s options for antiretroviral therapy.
  
• Other serologies:

• Syphilis: High rates of coinfection with other STDs necessitate routine syphilis serology in all HIV-infected patients. A reactive non-treponemal assay (RPR or VDRL) must be confirmed with the tre-ponemal-specific FTA or MTPA. Cerebrospinal fluid evaluation is indicated in HIV-infected persons with latent syphilis, treatment failure (when a nontreponemal test does not decline 4-fold within 6–12 mo after treatment), and those patients with neurologic signs or symptoms.

• Toxoplasmosis: Serologic evidence of latent toxoplasmosis infection, as detected by Toxoplasma gondii IgG, may be relevant for decisions on prophylaxis, evaluation of neurologic symptoms in patients with advanced immunosuppression, and avoidance of exposure in those who have not been previously infected. There is great worldwide variation in the prevalence of latent toxoplasma infection: in the United States the rate is approximately 30%.
• CMV: Latent CMV infection is present in most HIV-infected adults. Knowledge of CMV antibody status can guide the medical provider to the use of CMV-negative blood products if transfusions are required.
• Varicella: In patients who do not have a known history of chickenpox or shingles, varicella serology should be obtained. The knowledge that a patient is varicella IgG-negative is important in the event of a subsequent exposure: postexposure prophylaxis with varicella immune globulin could then be given.
• Hepatitis: Hepatitis A serology is not routinely performed, but given the newly available vaccine for those who are not immune, such testing may be appropriate to determine vaccine candidates. Hepatitis B serologies should be performed routinely: hepatitis B surface antigen (HBsag) and hepatitis B core and surface antibodies (anti-HBc and anti-HBs) allow determination of active hepatitis (HBsag-positive) and of those who are not immune to hepatitis B (anti-HBc-negative, anti-HBs-negative). Hepatitis B vaccination is then recommended in those who are not immune; and antiviral therapy, such as lamivudine (which has anti-hepatitis B activity), can be considered in those who are HBsag-positive. Hepatitis C virus (HCV) serology (anti-HCV IgG) is also routinely recommended. Recombinant immunoblot assays (RIBA) for HCV are also useful, both to confirm the diagnosis if a screening ELISA is positive and to clarify it if a first-generation ELISA test is negative. HCV RNA, as detected by RT-PCR or bDNA assay, allows determination of active HCV infection. Knowledge of hepatitis C antibody status is needed to guide therapeutic decision for possible HCV treatment and may also be relevant for decisions regarding antiretroviral therapy and other potentially hepatotoxic agents, and frequency of assessment of liver function tests during such therapy (see Table 4-2).
  

• Tuberculosis: A baseline PPD should be obtained in all patients who do not have a history of a positive PPD in the past.
  
• Glucose-6-phosphate dehydrogenase: A relative deficiency of glucose-6-phosphate dehydrogenase (G6PD) may be found in up to 2% of African American women and an absoute deficiency is occasionally found in women of Mediterranean descent. Absolute G6PD deficiency predisposes to hemolytic anemia upon exposure to certain medications, including several that are commonly used in HIV treatment: dapsone, sulfonamides, pri-maquine. A relative deficiency is not usually clinically significant. Baseline testing in selected patients is helpful so that these agents may be safely administered at a later date without needing to determine G6PD levels at that point.
  
• Lipid profile: Many antiretroviral agents have been associated with the development of hypertriglyceridemia and hypercholesterolemia. A baseline fasting lipid profile should be performed to determine total cholesterol, triglycerides, high-density lipoprotein (HDL), and low-density lipoprotein (LDL) levels before beginning any antiretroviral therapy.
  
• Pap smear/STD screening: A Pap smear should be obtained, and testing done for gonorrhea and Chlamydia.
  
  

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 antiretro-viral 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, 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:

1.  Get a baseline lipid profile (fasting) before starting therapy.
2.  Follow total cholesterol with routine chemistry panels.
3.  Obtain a complete fasting lipid profile annually or if the total cholesterol begins to increase on routine testing.
4.  Follow complete lipid profiles every 3–6 mo for patients in whom a lipid abnormality has been detected, both before starting any antihy-perlipidemic therapy and once such therapy has been started.

     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.

     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

A. GENERAL PRINCIPLES

Three characteristics of HIV infection have significant implications for anti-retroviral therapy:

1. Between the time of initial infection and the development of clinical disease there is progressive immunosuppression as evidenced by a decline in CD4 lymphocyte counts.
2. Viral replication is extremely rapid: the half-life of HIV in plasma is less than 48 hr and there is turnover of up to 1 billion virions per day (Ho, 1995).
3. HIV has a high degree of inherent genetic mutability: mutations that may confer resistance to antiretroviral therapy arise rapidly.

     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 antriretro-viral therapy in pregnancy and Chapter XV on Resources for sources of complete updated information on antiretroviral therapy.

B. ANTIRETROVIRAL AGENTS

NUCLEOSIDE ANALOGUES

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).

     Six NRTIs are currently licensed in the United States: zidovudine (AZT), didanosine (ddI), zalcitibine (ddC), stavudine (d4T), lamivudine (3TC), and abacavir (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

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.

LIPODYSTROPHY (FAT REDISTRIBUTION SYNDROMES)

A dramatic increase in body shape changes has led some investigators to believe that some antiretroviral drugs may be associated with redistribution of body fat as well. Protease inhibitors, which may certainly produce hypertryg-lyceridemia, were the first agents associated with this syndrome, but other drug classes have recently been implicated as well, such as the nucleoside analogue d4T (stavudine). However, the etiology of this syndrome (or syndromes) is unknown. Women seem particularly prone to developing truncal obesity (increased abdominal girth, increased breast size). Some patients may primarily lose subcutaneous fat in the face, buttocks, and extremities, and a subset may have both fat loss and fat gain in different areas. Abnormal fatty deposits, which may be disfiguring, have been reported in the neck and the dorsocervi-cal area (“buffalo hump”), although cortisol levels are normal. These body shape changes may or may not be accompanied by the development of hyper-lipidemia and/or diabetes mellitus. Our current understanding of these syndromes and what causes them is rudimentary.

     It may be useful to obtain some standard measurements, such as minimum waist, maximum hip, and neck circumference at an early visit, before antiretro-viral therapy is started. It is important to question the patient at regular intervals about any perceived changes in body shape or changes in clothing and brassiere size, and anthropomorphic measurements may be repeated to document any changes. As yet there is no specific antidote to this poorly understood phenomenon.

     Detailed descriptions of medications, drug-drug interactions, and medication use in pregnancy may be found in Chapter XIV on Pharmacologic Considerations in HIV-infected Pregnant Patients.

C. TREATMENT GUIDELINES

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.hivatis.org. 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).

     As indicated in Table 4-7, the strength of the recommendation for therapy in an asymptomatic patient must take into account prognosis for disease-free survival 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 determined by utilizing the data in Table 4-8. In these considerations the potential benefits and risks of initiating therapy should be considered and reviewed with the patient.

Among the benefits of therapy are:

• prevention of progressive immunosuppression by control of viral load,
• delayed progression of clinical disease/progression to AIDS,
• prolongation of life, and
• possible decreased risk of transmission (Quinn, 2000).
  

The risks of starting therapy include:

• a decrease in quality of life associated with adverse drug effects and inconvenience of dosing,
• limitations of future options for therapy if resistance develops to current agents,
• unknown long-term toxicity of therapy,
• unknown duration of effectiveness of therapy, and
• possible transmission of drug-resistant virus.
  

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.

     The regimens listed in the preferred category are all considered highly active antiretroviral therapy (HAART). Although there are multiple possible HAART regimens, a comparison of several different example regimens illustrates the principles used in selecting a regimen for a specific patient.

     One possible HAART regimen is: AZT + 3TC + nelfinavir. This regimen could be taken twice daily, which may help with adherence, and the total pill burden is moderate: AZT and 3TC may be taken in combination as Combivir (1 pill bid) and nelfinavir requires 5 pills twice a day. In a patient with significant bone marrow suppression, the provider may wish to avoid AZT, and might instead select ddI + d4T + nelfinavir or d4T + 3TC+ nelfinavir. It is also possible to take a HAART regimen that does not utilize a protease inhibitor, such as 2 NRTIs and efavirenz. In this example, the pill burden is lower than with PI-containing regimens (efavirenz is taken as 3 pills once a day), reductions in viral load are comparable to those with PI-containing regimens, and the potential class-specific side effects of PIs (e.g., lipid abnormalities) may be avoided, but the long-term effectiveness of an NNRTI-based regimen has been less well studied.

     In addition to regimens designated as HAART, there may be instances in which alternative regimens are utilized. Such situations may occur, for example, when a patient states that she will only take a limited number of pills a day. Options for alternative regimens include AZT + 3TC + abacavir. This regimen only requires 4 pills a day (Combivir bid, abacavir bid) and utilizes only NRTIs, thus preserving both the NNRTIs and PIs for future regimens. Another possible alternative regimen containing only NRTIs is ddI + hydrox-yurea, with or without a second NRTI. Hydroxyurea is not incorporated into most standardized guidelines and has no antiretroviral activity on its own, but has been shown to increase the efficacy of ddI. It has most commonly been used in patients who have exhausted all standard regimens. There are recent concerns, however, about enhanced NRTI toxicity with hydroxyurea that may cause serious, and even life-threatening, pancreatitis. The role of hydroxyurea will likely be better defined after additional safety information is available.

IV

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 lack of therapeutic efficacy.

• Medication toxicity: When the need to change therapy arises because of medication toxicity, it may be possible to simply change one component of a regimen. If the toxicity occurs in a regimen that has provided effective virologic control, the goal is to continue effective therapy by changing the component that causes toxicity. For example, in a patient taking an effective regimen of AZT/3TC/PI, the development of anemia could be attributed to AZT. A different NRTI that does not commonly cause bone marrow suppression (e.g., d4T) could be substituted. The similar toxicities of certain agents must be remembered when making such changes: for example, in a patient taking ddI, the development of peripheral neuropathy would not be expected to be alleviated by substituting d4T.

     There are other situations in which the toxicity is not as easily attributed to a single component of a regimen (e.g., rash, GI symptoms). In these instances, a “drug holiday” (temporary discontinuation) of the entire regimen may be necessary to allow symptoms to resolve, and a new regimen initiated with some change in components. With the exception of abacavir, which has caused hypersensitivity reactions (and should never be reinsti-tuted after symptoms of such a reaction), reinitiation of antiretroviral therapy would not be expected to be associated with any increase in side effects.

• Lack of theraputic efficacy: Changes in regimen for lack of efficacy may be triggered by evidence of clinical progression, progressive decline in CD4 count, and, most commonly, for virologic “failure.” Virologic failure is apparent when a regimen has failed to provide suppression to below the level of assay detection in 4–6 mo after initiation, or when a patient with previously undetectable virus has a rebound to detectable levels. In these circumstances (i.e., where viral load values will be used to determine a change in patient management), the test should always be repeated before a regimen change is made. Although some patients may derive continued clinical benefit and a sustained CD4 increase despite a detectable viral load, the possibility of development of viral resistance should lead the clinician to consider a change in regimen. The fact that continued exposure to an ineffective regimen will allow continued viral replication, and therefore the opportunity for development of additional resistance mutations, provides a rationale for changing therapy in this situation. Increased viral resistance may also lead to cross-resistance to other drugs in the same medication class, and therefore lower chances of effectiveness of any future regimen. It is particularly important that the clinician use caution in this setting to avoid changing to an even more complicated regimen in a patient who is demonstrating virologic failure due to difficulty with adherence (see Chapter V on Adherence to HIV Therapies). In some circumstances (e.g., prior exposure to multiple medications) it may not be possible for the clinician to construct a new regimen that is effective, and some experts choose to continue a virologically failing, but well-tolerated, regimen under these circumstances.

     When a regimen is changed for lack of efficacy, the goal is to use medications “new” to the patient to decrease the likelihood of viral resistance. A general principle is that all medications should be changed at the same time, and that a minimum of two new agents be utilized. If there are two previously unused NRTIs that can be used together, these should be part of a new regimen. There is significant cross-resistance among NNRTIs, although efavirenz may sometimes be used after delavirdine or nevirapine, depending on which mutations have arisen; only resistance testing will tell the clinician when this is possible. If an NNRTI was not used initially, it would be beneficial to include one in a second regimen. For PIs, some resistance mutations are common to several agents in the class, and others may be distinct for an individual agent. In general, it is has proven more effective to salvage a failing PI regimen, by using a second regimen that contains a combination of two new PIs, rather than just substitute one PI for another (Hall, 1999; Tebas, 1999). Recommendations for regimen changes may also be found at http://www.hivatis.org. Testing for resistance mutations may also be a crucial factor when deciding on a regimen change (see “Resistance Testing” below).

     “Intensification” is the theory that some patients with a decrease in viral load, but not complete viral suppression, from an initial regimen may benefit from the early addition of just a single new agent. This may also refer to the situation in which a first rebound occurs after complete viral suppression. In these patients, low levels of detectable virus (e.g., < 5000 c/mL) are present. This may be a unique situation in which it may be reasonable to add only a single medication, or to change only a portion of the combination. However, it is important to realize that at the present time “intensification” represents an unproven hypothesis that is being evaluated in ongoing clinical trials.

     A summary of situations in which a change of therapy should be considered is shown in Table 4-10.

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. These assays are not yet licensed for clinical use, and commercial availability is limited. 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 or each mutation detected:

1. wild-type amino acid,
2. codon involved, and
3. amino acid coded for by mutated codon.

     Figure 4-5 shows the mutations known to be associated with resistance to specific agents (Hirsch, 1998). Updated listings of mutations and associated resistance can be found at: http://hiv-web.lanl.gov or http://www. viral-resistance.com.

     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 4-11.

     At least two studies have shown that patients for whom genotypic 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). Resistance testing may be useful in the following ways.

1. Assessing NRTI resistance/cross-resistance in patients with virologic failure on an NRTI-containing regimen (e.g., to look for mutations associated with pan-NRTI resistance).
2. Assessing cross-resistance between NNRTIs.
3. Defining presence/extent of PI resistance in those with virologic failure on a PI-containing regimen.
4. Determining whether there is drug-resistance in a patient with acute HIV who is considering antiretroviral therapy (see “Treatment of Acute HIV Infection,” below).

     Patients with pan-sensitive virus in the face of virologic failure should be questioned carefully, but nonjudgmentally, about their medication-taking behaviors.

IV

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 2–6 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 4-12.

POSTEXPOSURE PROPHYLAXIS

See Chapter XIII on Occupational Exposure.

TREATMENT IN PREGNANCY

Guidelines for optimal antiretroviral therapy in pregnancy are the same as those for nonpregnant adults (see above). Particular concerns for fetal exposure to medications and for strategies to reduce the risk of viral transmission must also be considered. Please see Chapter VII on HIV and Reproduction. Information is also provided at http://www.hivatis.org.

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. 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 way that does not alienate the patient from her involvement in medical care.

V. COMPLICATIONS: OPPORTUNISTIC DISEASES

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 immuno-compromised 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 4-13).

     At total CD4 cell counts above 500, illnesses are rarely specifically associated with the patient’s HIV serostatus. Non-Hodgkin’s lymphoma and muco-cutaneous 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, crypto-coccal 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 antiretrovi-ral 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 OI prophylaxis can be found at http://www.hivatis.org, or in 1999 Medical Management of HIV Infection by John Bartlett, listed in the Resources Appendix.) (USPHS/IDSA, 1999)

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.hivatis.org, or in the 1999 Medical Management of HIV Infection by John Bartlett. See Table 4-14 for primary pro-phylaxis of the most common OIs.

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 (AaDO2) on blood gas analysis.

     Many diseases may have a similar presentation, including mycobacterial, fungal, viral, or bacterial pneumonias, heart failure, pulmonary KS, and pulmonary emboli. 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 AaDO2 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.

CANDIDIASIS

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 oropha-ryngeal 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, or to oral amphotericin B solution. However, most patients with resistant infection will require intravenous (IV) amphotericin for relief.

CRYPTOCOCCAL MENINGITIS

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. 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 crypto-coccal 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

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 it 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.

HERPES SIMPLEX VIRUS

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 lesions, 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 in this case requires treatment with intravenous fos-carnet. 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 also been reported and is also treated with IV foscarnet.

CYTOMEGALOVIRUS

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 using dilated indirect ophthalmoscopy by an experienced ophthalmologist. Extensive disease may lead to retinal detachment, which may require surgical repair. Treatment is usually begun with intravenous ganciclovir, foscarnet, or cido-fovir for 2–3 wk, followed by chronic suppression with either less frequent IV doses or oral ganciclovir. Chronic use of these 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 ganciclovir 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. There is no clear agreement that CMV disease at sites outside the eye requires chronic maintenance therapy, but with the availability of oral ganciclovir it seems reasonable to provide continued anti-CMV treatment.

DISSEMINATED MYCOBACTERIUM AVIUM COMPLEX (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 nonspecifi-cally with fever, weight loss, diarrhea, anemia, and sometimes abdominal discomfort due to organomegaly and impressive intraabdominal lym-phadenopathy. Mycobacterial blood culture provides a definitive diagnosis. 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.

TUBERCULOSIS

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 three drugs expected to be active according to local susceptibility patterns. Subsequently, when the results of susceptibility testing are available, therapy for drug-sensitive infection can usually be narrowed to two agents (isoniazid and rifampin). 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.

PERIPHERAL NEUROPATHY

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, symptoms 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; 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. 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 ($2 loose stools per day) or chronic weakness and documented fever (intermittent or constant) for at least 30 days that is not attributable to a condition other than HIV itself. Typically wasting syndrome is accompanied by loss of muscle mass, for example in the temporal areas, and complaints of generalized fatigue and modest weakness. In severe cases the serum albumin level will be very low. Wasting can accompany any of the typical end-stage illnesses, such as disseminated MAC, or may occur by itself in the absence of any evident concomitant illness. Loss of weight, and, especially, of lean body mass, portends poorer survival. Appetite stimulants, such as the progestin megestrol acetate or the marijuana derivative dronabinol, may be used although weight gain with these agents typically consists of fat and water, rather than an increase in lean body mass. However, the psychologic benefit of an improved appetite and some weight gain cannot be underestimated, even if the gain is primarily fat. Recombinant human growth hormone has been used with some short-term success for improvement in lean body mass, but it is very expensive and must be given parenterally. Other approaches include enteral and parenteral feedings, anabolic steroids such as nandrolone or oxan-drolone, and thalidomide or pentoxifyline for cytokine suppression. Men with symptoms of hypogonadism often respond to testosterone replacement, but this approach has not been evaluated in women.

KAPOSI’S SARCOMA

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 most likely 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 threat to health. KS of the gastrointestinal mucosa is very vascular and may lead to slow, chronic blood loss. When it involves the lymphatic system, KS can cause massive edema and woody induration, especially of the lower extremities; such patients are prone to severe, recurrent episodes of cellulitus. KS may also 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. Gastrointestinal and bronchial mucosal lesions are also diagnosed by inspection; bronchial lesions may bleed profusely and are generally not biopsied for that reason. 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, with single cytotoxic agents or combinations.

SYSTEMIC LYMPHOMA

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 lym-phoma, 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, 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 may require somewhat 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

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 demonstrate involvement of the white matter that can be focal or fairly diffuse, but is not 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 year after diagnosis.

CHRONIC HEPATITIS B AND C

Many of the same behaviors that put women at risk of acquiring HIV also result in hepatitis B and/or C infection. Both hepatitis B and C may become chronic, resulting in hepatocyte destruction that is manifested as intermittent transaminase elevation (especially ALT), and ultimately leading to fibrosis, scarring, and end-stage liver disease. ALT levels may wax and wane, and may only be modestly elevated. Coinfection with viral hepatitis and HIV results in higher hepatitis B and C viral loads. Conversely, hepatitis C has been associated with acceleration of HIV disease, although hepatitis B has not. Branched-chain DNA (bDNA) tests for either form of hepatitis are more suitable for follow-up of coinfected patients than PCR-based tests, which may be too sensitive. Both entities are treatable, and specific therapy should be considered to prevent or delay cirrhosis and liver failure. Hepatitis B responds to treatment with 3TC (lamivudine) and some investigational agents. Hepatitis C may respond to systemic a-interferon and, better still, to a combination of interferon and ribavirin, although only a minority of patients achieve solid success rates.

ANEMIA

Modest anemia ($9–10 g/dL) is a hallmark of chronic HIV infection and may be complicated by menstrual losses in women of childbearing age. Severe anemia (#9 g/dL) may occur as part of certain opportunistic diseases, especially MAC, disseminated histoplasmosis, and lymphoma, and may also be the result of drug toxicity. Although severe anemia has been shown to be associated with a poorer prognosis for survival in a number of studies, diagnosis and treatment of the opportunistic process is often sufficient to improve anemia in these cases.

     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 4-6).

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 may become capable of mounting an inflammatory response to opportunistic pathogens. This can result in the atypical development of an acute OI in the first couple of months after initiating potent combination therapy, after CD4 cell counts have begun to improve. These cases may be marked by focal symptoms, such as the acute development of a tender, enlarged lymph node with negative blood cultures in the case of MAC lymphadenitis, 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.

     Just as initial presentations may be altered as the result of HAART, continued disease activity may also be modified. 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. However, there is no reason to think that other OIs will behave differently and multiple clinical trials are currently in progress. 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 prophy-laxis for PCP and MAC are at very low risk of developing these OIs if pro-phylaxis is withdrawn after total CD4 cell counts have improved above the threshold levels for risk of a 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. The 1999 revision of the USPHS guidelines on OI prophylaxis describes the data and rationale for discontinuing suppressive therapy and pro-phylaxis in the appropriate patient. These guidelines are likely to be revised in the near future, so it is wise to check the AIDS Treatment Information Service Web site listed in Chapter XV on Resources.

VI. ALGORITHMS FOR DIAGNOSIS AND MANAGEMENT OF SYMPTOMS

Figure 4-7: Fever of Unknown Origin in Patients with AIDS 

Figure 4-8: Acute Diarrhea in Patients with AIDS

Figure 4-9: Chronic Diarrhea (CD4 Count < 300/mm³) 

Figure 4-10: Cough, Fever, Dyspnea 

Figure 4-11: Headache in Patients with AIDS

Figure 4-12: Advanced HIV Infection Plus Altered Status, New Seizures, Headache (Severe or Persistent), or Focal Neurologic Deficits Figure 

4-13: Lower Extremity Symptoms: Weakness and Numbness Figure 

4-14: Lower Extremity Symptoms: Pain Figure 

4-15: Lower Extremity Symptoms: Pain and Numbness Figure 

4-16: Odynophagia in Patients with AIDS

REFERENCES

Bartlett JG. Medical Management of HIV Infection. Baltimore, MD: Johns Hopkins University; 1999.

Baxter J, Mayers D, Wentworth D, et al. A pilot study of the short-term effects of anti-retroviral management based on plasma genotypic antiretroviral resistance testing in patients failing antiretroviral treatment [LB8]. 6th Conference on Retroviruses and Opportunistic Infections, Chicago, IL, 1999.

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.

Durant J, Clevenbergh P, Halfon P, et al. Drug-resistance genotyping in HIV-1 therapy: the VIRADAPT randomized controlled trial. Lancet 353: 2195–9, 1999.

Erbelding EJ. Resistance testing: a primer for clinicians. The Hopkins HIV Report. 11: 1–12, May 1999.

Fauci A, Pantaleo D, Stanley S, Weismann D. Immunopathogenic mechanisms of HIV infection. Ann Intern Med 124: 654–3, 1996.

Gross PA, Barrett TL, Dellinger P, et al. Purpose of quality standards for infectious diseases. Clin Infect Dis 18: 421, 1994.

Hall C, Raines C, Barnett S, Moore R, Gallant J. Efficacy of salvage regimens containing ritonavir and saquinavir after failure of single protease-inhibitor containing regimens. AIDS 13: 1207–12, 1999.

Hanson DL, Chu SY, Farizo KM, Ward JW, and the Adult and Adolescent Spectrum of HIV Disease Project. Distribution of CD4+ T lymphocytes at diagnosis of acquired immunodeficiency syndrome-defining and other human immunodefi-ciency-related illnesses. Arch Intern Med 155: 1537, July 24, 1995.

Hirsch MS, Conway B, D’Aquila RT, et al. Antiretroviral drug resistance testing in adults with HIV infection: implications for clinical management. International AIDS Society — USA Panel. JAMA 279: 1984–91, 1998.

Ho D, Neumann A, Perelson A, et al. Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection. Nature 373: 123–6, 1995.

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 89: 142–6, 1990.

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 334: 701–6,1996.

Maenza J, 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 13: 1687–95, 1999.

Mellors JW, Rinaldo CR, Gupta P, White RM, Todd JA, Kingsley LA. Prognosis in HIV-1 infection predicted by the quantity of virus in plasma. Science 272: 1167–70, 1996.

Quinn TC, Mawer MJ, Sewankambo N, et al. Viral load and heterosexual transmission of human immunodeficiency virus type 1. N Engl J Med 342: 921–9, 2000. 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 130: 37–9, 1999.

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 12: 1619–24, 1998.

Tebas P, Patrick A, Kane E, et al. Virologic responses to a ritonavir-saquinavir containing regimen in patients who have previously failed nelfinavir. AIDS 13: F23–8, 1999.

US Department of Health and Human Services. Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents, January 2000.

USPHS/ISDA Guidelines for the prevention of opportunistic infections in persons infected with human immunodeficiency virus: a summary. United States, July 1995.  MMWR 44 (RR-8), 1995.

USPHS/ISDA Guidelines for the prevention of opportunistic infections in persons infected with human immunodeficiency virus. MMWR 48: 1–67, 1999.

We need YOUR HELP to make the NEXT EDITION as useful as possible!

Please send your comments criticisms corrections suggested changes, and other guidance to one of the addresses below. Be sure to include in your letter/note an address (fax, e-mail, or postal) where you can be reached for follow-up.

Translation Partners Needed

Write to us if you can help us find partners to help us have this Guide translated into your native language. For instance, provide us with a contact who works with translation in your country’s Ministry of Health, or tell us about a group at a medical school that translates medical texts.

Send Us Your Comments

E-mail: womencare@hrsa.gov
Fax to the attention of “Womencare”: 301-443-0791 (USA)

Postal address: Womencare
Parklawn Building, Room 11A-33 
600 Fishers Lane Rockville, Maryland 20857 USA

Note that this and subsequent editions of A Guide to the Clinical Care of Women with HIV will be available online.

Go to the HIV/AIDS Bureau Web site and click on the publication Women’s Guide: http://www.hab.hrsa.gov/