Chapter IV
Primary Medical Care

Judith Feinberg, MD, and
Janine Maenza, MDr

I. Introduction  TOP

No field in medicine today is moving as swiftly as that of HIV/AIDS. The speed at which new developments occur and the rapidity with which they are superseded by newer data are nothing short of breathtaking. As a consequence, most studies are typically out of date at the time of publication. Because of the rapid turnover of key information, this chapter focuses on the essential principles of care for the HIV-infected woman. “Cutting-edge” treatment strategies currently being studied will be mentioned but not described in detail. To be truly useful, we indicate the general directions in which this field is moving and how to access updated information.

Several studies have demonstrated that positive clinical outcomes are a function of the clinician’s experience in caring for HIV-infected individuals (Kitahata, 1996). Nonspecialists are urged to seek expert advice and consultation whenever there is any question about the best way to manage a specific patient. This is especially important in the setting of antiretroviral treatment failure and in advanced HIV disease when patients are vulnerable to multiple simultaneous opportunistic processes.

There is as yet no compelling evidence that the clinical course of HIV infection in women differs significantly from that in men, with the obvious exception of the associated gynecologic conditions and obstetric issues (described elsewhere, see Chapters VI and VII). Although recent data have indicated that women may have lower HIV viral loads than men with an equivalent degree of immunosuppression, this does not appear to confer benefit in terms of overall survival or complication-free survival (see Chapter I: Epidemiology and Natural History of HIV Infection in Women). At present, the approach to management of HIV-infected women and men is the same. With prolonged survival now possible, general preventive strategies and health maintenance, such as smoking cessation, control of hypertension, minimizing cardiovascular risk factors, and routine screening for malignancy (cervical, breast, colon), are all part of routine care for HIV-seropositive adults.

II. Initial Evaluation  TOP

A. HISTORY

A comprehensive database is valuable to the primary caregiver in assessing the patient’s current status and in formulating a management plan. It is critical to remember that most patients are anxious and frightened at their initial encounter for HIV care; the ability to empathize, to share knowledge without being patronizing, to provide reassurance, and to remain nonjudgmental are essential to gaining the patient’s trust and to obtaining accurate information (see Chapter II: Approach to the Patient). In addition to all the usual aspects of history-taking, the following areas are of particular importance in HIV disease and deserve special attention.

• 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. If the patient can identify the source of new infection, it is valuable to know if the source patient has been treated for HIV, as the acquisition of drug-resistant infection has increasingly been reported. 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? Was resistance testing done and, if so, are results available? 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 infections 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 2 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); sexual activity with men, women, or both; history of trading sex (oral or intercourse) for drugs or money; history of anal sex.
• Presence of HIV-associated signs and symptoms: Fatigue, lymphadenopathy, 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 2 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. Underscore the importance of adherence.
• 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 leukoplakia (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 infections, 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  TOP

A. INITIAL DIAGNOSIS

Because of the advances made in HIV treatment, with associated decreases in HIV-related morbidity and mortality; concerns about possible increases in HIV incidence; and the new availability of a simple rapid HIV test (Oraquick), the CDC recommends that voluntary HIV testing be made a routine part of medical care for all patients in high HIV-prevalence clinical settings and for those with risks for HIV in low HIV-prevalence clinical settings. (CDC, 2003).

HIV infection is usually diagnosed by serologic tests that detect antibody to the virus. Infection may also be detected by nucleic acid-based assays that either measure the number of copies of the virus in plasma (RNA polymerase chain reaction [PCR]) or detect the virus in cells (DNA). Informed consent, with pre- and posttest counseling, is legally mandatory for performing HIV serologic tests in most locations, and should be procured at all times when the test is offered.

• 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 (rare)(seroreversion);
  • 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.

When indeterminate results are obtained, risk assessment is important, since women in low-risk categories with indeterminate tests are unlikely to be infected and can be reassured. Nevertheless, after indeterminate test results, repeat testing should be performed at 1, 2, and 6 months, and precautions should be taken to prevent HIV transmission to others until seroconversion is ruled out. In general, patients with indeterminate tests who are in the process of seroconversion usually have positive Western blots within 1 month. In high-risk patients or in other situations where seroconversion is suspected HIV nucleic acid amplification (HIV-DNA PCR, HIV-RNA PCR) may be considered and has high sensitivity during acute infection, often before antibodies to the virus have developed.

The window period before seroconversion and agammaglobulinemia are possible causes of false-negative results. Although infection with HIV-2 (more common in West Africa) and HIV-1 subtype O have been associated with indeterminate and false negative results on earlier generation serologic tests, most currently used assays will detect these infections.

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 100–400 copies/mL, but ultrasensitive assays are 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 May 2003. 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: The OraQuick Rapid HIV Test provides results in 10–20 minutes. Sensitivity approaches 100%; specificity is also >99%, but positive results should be confirmed with standard serology. Rapid tests may prove useful in STI 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 (Table 4-1). In addition, routine tests of hematology, chemistry, and lipid profiles are needed at baseline, because HIV and other concomitant illness may affect these values, and detected abnormalities may also have an impact on the choice of therapy for the individual patient.

• 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.

Figure 4-1: Natural History of HIV Infection without
the Use of Antiretroviral Therapy

• 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 immunosuppression, 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). Recent studies have shown that women have lower viral loads than men at comparable CD4 cell counts, although these viral load differences tend to disappear several years after seroconversion and they have not been associated with slower disease progression or longer survival (see Chapter I: Epidemiology and Natural History of HIV Infection in Women).

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 100–400 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 4-2. It is also critical to repeat any HIV RNA result that is being used as the basis for a change in patient management.

Figure 4-2: Likelihood of Developing AIDS within 3 Years

• 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 STIs necessitate routine syphilis serology in all HIV-infected patients. A reactive nontreponemal assay (RPR or VDRL) must be confirmed with the treponemal-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 will identify those who are not immune, and are therefore vaccine candidates. Hepatitis A vaccine should be given to patients with hepatitis C co-infection, other chronic liver disease, and perhaps to all HIV-infected patients. Hepatitis B serologies should be performed routinely: hepatitis B surface antigen (HBsAg) and hepatitis B core or 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 used to confirm the diagnosis if a screening ELISA is positive. HCV RNA, as detected by RT-PCR or bDNA assay, can also be used to confirm the diagnosis and 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 4-3)

• Tuberculosis: A baseline PPD should be obtained in all patients who do not have a history of a positive PPD in the past. A positive PPD is considered >5mm induration in the setting of HIV infection.
• 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 absolute 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, primaquine. 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/STI screening: A Pap smear should be obtained, and testing done for gonorrhea and Chlamydia (see Chapter VI Gynecologic Problems).

C. INTERVAL MONITORING

In an asymptomatic patient not taking antiretroviral therapy with a high (>500/mm³) CD4 count, follow-up every 6 mo may be appropriate. For those patients who are symptomatic and/or receiving antiretroviral therapy, visits should occur at least every 3 mo. For those who have just initiated or changed antiretroviral therapy, follow-up in 4–6 wk may be appropriate. Laboratory evaluation at each of these visits should routinely include the following: complete blood count with differential, CD4 lymphocyte count, and viral load. Chemistry panels may be done less frequently (every 6 mo) in a patient with prior normal values who remains clinically stable.

Hematology and chemistry values are needed to monitor possible medication toxicities, complications of HIV, and other possible illnesses. The CD4 count and viral load allow assessment of disease progression and effects of antiretroviral therapy. In following the CD4 count over time, it is important to recognize the causes of variability discussed above. Use of the CD4 percentage, rather than absolute CD4 count, may help eliminate some of this variability to clarify CD4 response to medications. In interpreting viral load changes over time, the variability of tests results must be noted: .3–.5 log. In a patient who previously had a viral load below the limit of detection of the assay being used (“undetectable”), who now has quantifiable virus, a repeat test should be performed as soon as possible, rather than waiting until routinely scheduled follow-up.

The frequency with which lipid profiles are checked will vary by individual patient characteristics. In patients not taking antiretroviral therapy, a baseline lipid profile should be done with the initial evaluation or before beginning antiretroviral therapy. The profile should include total cholesterol, HDL, LDL, and triglycerides. If the baseline is normal and the patient is not on antiretroviral therapy, there is no need for interval monitoring beyond that which would be done in an HIV-uninfected adult. In patients taking combination antiretroviral therapy, general guidelines are:

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 antihyperlipidemic 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 if the patient belongs to a population with high epidemiologic risk of tuberculosis.

Baseline data and interval monitoring may be followed by the use of a flow sheet such as the one developed at the Johns Hopkins Outpatient HIV Clinic (Figure 4-3).

Johns Hopkins Outpatient HIV Clinic. Baltimore, MD. Reprinted with permission.

IV. Antiretroviral Therapy  TOP

A. GENERAL PRINCIPLES

Three characteristics of HIV infection have significant implications for antiretroviral therapy (see Chapter VII HIV and Reproduction for discussion of antiretroviral therapy in pregnancy).

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 antiretroviral 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).

Figure 4-4: Sites of Action of Antiretroviral Agents

1. Site of Action of NRTIs: Incorporate into DNA and block reverse transcriptase
2. Site of Action of NNRTIs: Bind to reverse transcriptase
3. Site of Action of PIs: Bind to protease to inhibit viral protein cleavage and therefore release of virus from cell
4. Site of Action of Fusion Inhibitors: Interact with virus to inhibit virus-cell fusion

Seven NRTIs are currently licensed in the United States: zidovudine (AZT), didanosine (ddI), zalcitibine (ddC), stavudine (d4T), lamivudine (3TC), abacavir, (ABC) and emtricitabine (FTC). There are also 3 combination NRTIs (Combivir, Trizivir, Epzicom), a nucleotide reverse transcriptase inhibitor (tenofovir) and a nucleoside-nucleotide reverse transcriptase inhibitor combination (Truvada) (Table 4-4).

In addition to the side effects listed for each medication, lactic acidosis with hepatic steatosis is a rare but potentially life-threatening toxicity with the use of NRTIs.

Nonnucleoside Reverse Transcriptase Inhibitors

Nonnucleoside reverse transcriptase inhibitors (NNRTIs) noncompetitively inhibit HIV reverse transcriptase by binding to a site distant from the enzyme’s active site. Three NNRTIS are currently available in the United States: nevirapine, delavirdine, and efavirenz (Table 4-5).

Protease Inhibitors

Protease inhibitors (PIs) prevent maturation of virus protein by competitively inhibiting HIV protease, an enzyme essential for viral protein cleavage. When this enzyme is blocked, immature, noninfectious virus particles are produced. The other important properties that protease inhibitors share include their limited central nervous system penetration and their metabolism by the cytochrome P450 enzyme system and resultant multiple drug-drug interactions (Table 4-6).

In addition to the medication-specific side effects listed here, a number of abnormalities are associated with protease inhibitors as a class. Patients taking protease inhibitors may develop serum lipid abnormalities (hyperlipidemia, hypertriglyceridemia), redistribution of body fat (lipodystrophy), and/or glucose intolerance.

Fusion Inhibitors

Fusion inhibitors interact with HIV directly, rather than with the host cell. This interaction prevents fusion of HIV to the cell. The first fusion inhibitor, enfuvirtide (T-20, Fuzeon) was licensed in the U.S. in March 2003. Enfuvirtide must be given by subcutaneous injection (twice daily). The most common side effect is local injection site reactions.

C. ADVERSE CLINICAL EVENTS ASSOCIATED WITH ANTIRETROVIRAL THERAPY

There are several significant adverse clinical events that have been associated with use of antiretroviral therapy. In some cases these are drug specific, while in others an increased risk of a specific adverse event appears to involve an entire class of antiretroviral drugs. The complications discussed below are of particular clinical significance or concern. In general, decisions about management, including future antiretroviral management, should be made in consultation with an HIV expert.

1. Lactic Acidosis/Hepatic Steatosis: This is a rare but life-threatening complication associated with use, often prolonged, of NRTIs and appears to more commonly seen in women. The initial clinical signs and symptoms are nonspecific and may include nausea and vomiting, diarrhea, anorexia, abdominal pain, generalized weakness, myalgias, ascending neuromuscular weakness, and hepatomegaly. In addition to elevated lactate levels, laboratory evaluation may reveal elevated liver function tests, creatine phosphokinase, lipase, and amylase or increased anion gap. There are technical difficulties associated with serum lactate testing and routine testing is not recommended. However, providers should have a low threshold for measuring serum lactate in the presence of suggestive signs or symptoms or other associated laboratory abnormalities. When interpreting serum lactate levels, levels of 2-5 mmol/dL are considered elevated and need to be correlated with symptoms; levels >5mmol/dL are abnormal; and levels > 10 mmol/dL indicated serious and possibly life-threatening situations. Antiretroviral treatment should be stopped if clinical and laboratory manifestations of lactic acidosis occur.
2. Hepatotoxicity: Hepatotoxicity, defined as a 3–5 fold increase in serum transaminases, may occur with or without clinical hepatitis. It has been reported with all NNRTIs and PIs and may be present with lactic acidosis associated with NRTI use. Most patients with hepatotoxicity are asymptomatic. Nevirapine has the greatest potential for causing hepatotoxicity (up to 12%) and this complication appears to be more common in women (Martinez, 2001; Bartlett, 2003). Nevirapine-associated hepatitis might also be part of a hypersensitivity syndrome, associated with other symptoms such as skin rash, fever, and eosinophilia. In a recent retrospective analysis of controlled and uncontrolled clinical trials, women with CD4 cell counts > 250 cells/mm³, including pregnant women, receiving chronic treatment for HIV infection, were at significantly higher risk (12-fold) of hepatotoxicity. In some cases hepatic injury progressed despite discontinuation of treatment and fatalities have occurred. (Boehringer-Ingelheim, 2004). Approximately two-thirds of nevirapine-associated clinical hepatitis occurs within the first 12 weeks of treatment and the greatest risk for severe hepatotoxicity in the recent analysis occurred in the first six weeks of treatment and was often associated with rash. However, risk continues after this time and patients should be closely monitored for the first 18 weeks of treatment. Initial presentation may include nonspecific gastrointestinal and flu-like smptoms, and liver enzyme abnormalities may or may not be present. However, this syndrome can progress rapidly to fulminant hepatic failure. A two-week lead-in dosing with 200 mg once daily before dose escalation to 200 mg twice daily is recommended to reduce the incidence of hepatotoxicity. Many clinicians advise close monitoring of clinical symptoms and liver enzymes after starting nevirapine (e.g., every 2 weeks for the first month, then monthly for the first 12 weeks, and every 1–3 months thereafter). Nevirapine should not be used in future regimens in women who experience severe liver toxicity while taking nevirapine. PI-associated hepatotoxicity can occur any time during the treatment course. Risk factors for liver toxicity include hepatitis B or C infection, alcohol abuse, baseline elevated liver enzymes, stavudine (d4T) use, and concomitant use of other hepatotoxic agents (DHHS, 2003; http://AIDSinfo.nih.gov) .
3. Hyperglycemia: Hyperglycemia has been reported in 3–17% of patients on PI-containing antiretroviral regimens (DHHS, 2003. http://AIDSinfo.nih.gov). Preexisting diabetes may be exacerbated. Although routine use of glucose tolerance testing is not recommended, patients should be advised about symptoms of hyperglycemia (i.e., polydipsia, polyphagia, polyuria) and fasting blood glucose measurements should be considered at 3–4 month intervals during the first year of PI treatment for patients with no prior history of diabetes. Patients with preexisting diabetes should be monitored closely.
4. Lipodystrophy (Fat Maldistribution Syndromes): Recognition of fat maldistribution syndromes has increased in the era of combination antiretroviral therapy; they are characterized by fat wasting (lipoatrophy) or fat accumulation. The absence of standard case definitions makes it difficult to estimate prevalence. Lipodystrophy might be associated with serum dyslipidemias, glucose intolerance, or lactic acidosis (Joffe, 2001; Carr, 1998). Fat accumulation is most commonly seen in the abdomen, the dorsocervical fat pad, and the breasts. This complication has been most associated with use of PI-containing regimens and prevalence increases with duration of therapy (Miller, 1998). Lipoatrophy most commonly affects the face and extremities and risk has been reported to increase with long-term NRTI exposure (Mallal, 1999). Women seem particularly prone to developing truncal obesity (increased abdominal girth, increased breast size). The etiology of these syndromes is unknown and at the present time, there is no clearly effective therapy. Women who perceive significant changes in body habitus related to their antiretroviral regimen may be at increased risk for nonadherence. It may be useful to obtain some standard measurements, such as minimum waist, maximum hip, and neck circumference at an early visit, before antiretroviral 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.
   
   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.
   
5. Hyperlipidemia: Combination antiretroviral therapy, primarily regimens containing protease inhibitors, has been associated with elevation in total serum cholesterol and low-density lipoprotein (LDL) and in increases in fasting triglycerides (Thiebaut 2000; Romeu 1999). Therapeutic intervention may be needed and, although data remain inconclusive, lipid elevations seen with antiretroviral therapy may be associated with increased risk of cardiovascular complications. Indications for monitoring and treatment of antiretroviral-associated dyslipidemias are the same as among uninfected persons (Adult Treatment Panel III, 2001), although patients with additional risks for atherosclerotic disease should be especially closely monitored (Dube 2000). Low-fat diet, regular exercise, control of hypertension, and smoking cessation should be routinely recommended for all patients, including those treated with antiretroviral agents. When treatment is indicated, statins are generally considered first-line therapy, although potential drug-drug interactions between statins and PIs must be kept in mind and agents that are less affected by the inhibitory effect of PIs via the cytochrome P450 system are preferred (e.g., pravastatin). If lipid elevations are severe or do not respond to other therapy, a change in antiretroviral regimen may be indicated, such as replacement of the PI component with an NNRTI.
6. Bone Disorders: There is evidence that avascular necrosis involving the hips and decreased bone density (osteopenia, osteoporosis) may be linked to combination antiretroviral therapy regimens in adults and children (Tebas 2000; Scribner 2000). Diagnosis of osteonecrosis is generally made with CT or MRI ordered in response to complaints of pain. Diagnosis of osteopenia or osteoporosis is made with bone densitometry (dual energy X-ray absorptiometry or DEXA; quantitative ultrasound). Losses in bone mineralization appear to be more common in PI-containing regimens (Tebas 2000). Women are at increased risk for decreased bone density and adequate intake of calcium and vitamin D and appropriate weight-bearing exercise should be recommended. There are no recommendations for routine monitoring of bone density among asymptomatic HIV-infected persons, but additional risk factors, including estrogen deficiency (e.g., menopausal women), alcohol or tobacco abuse, sedentary lifestyle or immobilization, Caucasian or Asian race, wasting, and thin body habitus, should prompt consideration of screening. When significant decreases in bone density are recognized, treatment with bisphosphonates, raloxifene, or calcitonin may be indicated.
7. Rash: Skin rash most commonly occurs with NNRTI-containing regimens, and is most frequent and most severe with nevirapine. Most cases are mild to moderate and occur within the first weeks of therapy. Women appear to be at increased risk for more serious skin rashes (Bersoff-Matcha, 2001). More serious cutaneous manifestations (e.g., Stevens-Johnson Syndrome and toxic epidermal necrosis) should result in prompt and permanent discontinuation of NNRTI or other offending agents. A severe and potentially life-threatening syndrome consisting of drug rash, eosinophilia, and systemic symptoms (DRESS) has been described (Bourezane, 1998). Outside of the NNRTI drug class, skin rash occurs most frequently with abacavir and amprenavir. If rash is determined to be from an abacavir-associated systemic hypersensitivity reaction, then abacavir should be discontinued and not restarted. Amprenavir is a sulfonamide and should be used with caution in patients with history of sulfa allergy.

D. 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.aidsinfo.nih.gov. The guidelines detail indications for therapy in chronically infected patients, recommendations for initial therapy, considerations for changes in therapy, and possible regimens for such changes (Table 4-7).

Table 4-7: Indications for Initiating Antiretroviral Therapy
for the Chronically HIV-1 Infected Patient

Clinical Category	CD4+ Cell	Plasma HIV RNA	Recommendation
Symptomatic (AIDS or severe symptoms)	Any value	Any value	Treat
Asymptomatic, AIDS	CD4+ cells <200/mm3	Any value	Treat
Asymptomatic	CD4+ cells >200/mm3 but 350/mm3	Any value	Treatment should be offered, although controversial.*
Asymptomatic	CD4+ T cells >350/mm3	>100,000 (by RT-PCR or bDNA)	Some experienced clinicians recommend initiating therapy, recognizing that the 3-year risk for untreated patients to develop AIDS is >30%; in the absence of increased levels of plasma HIV RNA, other clinicians recommend deferring therapy and monitoring the CD4+ T cell count and level of plasma HIV RNA more frequently; clinical outcome data after initiating therapy are lacking.
Asymptomatic	CD4+ T cells >350/mm3	<100,000 (by RT-PCR or bDNA)	Most experienced clinicians recommend deferring therapy and monitoring the CD4+ T cell count, recognizing that the 3-year risk for untreated patients to experience AIDS is <15%.

The strength of the recommendation for starting therapy in an asymptomatic patient must take into account prognosis for disease-free survival, potential benefits and risks of therapy, and the willingness of the patient to take, and adhere to, therapy (see Chapter V on Adherence to HIV Therapies). Prognosis for disease-free survival may be assessed by utilizing the data in Table 4-8. However, given the sex-based differences in viral load and CD4 count (See Chapter 1 Epidemiology and Natural History of HIV Infection in Women), these data, generated from a prospective cohort of men who have sex with men (MSM), should be extrapolated with caution to women.

Among the benefits of therapy are:

• 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,
• potential long-term toxicity of therapy,
• unknown duration of effectiveness of therapy, and
• possible transmission of drug-resistant virus.

Table 4-8: Risk for Progression to AIDS-Defining Illness
Among a Cohort of Men Who Have Sex with Men,
Predicted by Baseline CD4+ T Cell Count and Viral Load*

CD4 200 cells/mm3 Plasma Viral Load (copies/mL)†		Percentage of AIDS-defining illness
bDNA	RT-PCR	n	3 years	6 years	9 years