Primary Care of the HIV-infected Patient
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[edit] Primary Care of the HIV-infected Patient
Cynthia J. Whitener
John J. Zurlo
Before the era of acquired immunodeficiency syndrome (AIDS), immunodeficiency disorders were rare, typically congenital diseases. Comparatively little was known about the immune system, its specialized cells, complex web of interactions, and unique chemical messengers, the cytokines. Care of affected patients typically was relegated to specialized physicians at tertiary care centers. With early recognition that profound immune dysfunction defined the nature of AIDS, medical care was provided by the same specialists at the outset. As the epidemic unfolded through the early and middle 1980s, however, two facts became obvious. First, the numbers of infected patients would quickly outstrip the numbers of available specialists. Second, with both the explosion of scientific information about the immune system and the increased familiarity with the clinical course of AIDS patients, the nonspecialist could play a significant role in management. Since those early days and with the advent of highly active antiretroviral therapy (HAART), which has resulted in a dramatic decrease in hospitalization rates, human immunodeficiency virus (HIV) infection has become an integral part of the outpatient practices of many primary care physicians throughout the United States.
[edit] PATHOPHYSIOLOGY
HIV is a retrovirus and possesses the unique ability to convert its own single-stranded ribonucleic acid (RNA) to double- stranded deoxyribonucleic acid (DNA) for incorporation into the host cell genome. This reaction is catalyzed by the enzyme reverse transcriptase, the major target for two of the three classes of licensed anti-HIV drugs. Two types of HIV, HIV-1 and HIV-2, cause immunodeficiency in humans. HIV-1 is the predominant viral species infecting patients in the United States and throughout most of the developed world. HIV-2 is found almost exclusively in western Africa, where it is the predominant viral type. HIV-1 is divided into distinct subtypes, termed clades. Clades A through I are the M (major) subtypes; a different subtype O (outlier) also has been described. Clade B is by far the predominant type in the United States and Western Europe. Detailed descriptions of HIV structure, life cycle, and molecular pathophysiology can be found in major AIDS textbooks and reviews.
[edit] Host Response and Viral Replication
Immediately after infection with HIV, rapid viral replication occurs (Fig. 32-1).[1] High levels of viremia can be measured early in the plasma. During this period an estimated 50% to 70% of patients develop symptomatic illness (primary HIV infection). Symptoms often include fever, chills, malaise, diffuse lymph node swelling, diarrhea, skin rash, headache, and sore throat. This syndrome typically lasts 1 to 3 weeks and then resolves. The initial host immune response to HIV infection is brisk and aggressive. High antibody levels can be measured to virtually all viral proteins. Cytotoxic T cells appear that specifically target virally infected cells. After acute infection, levels of plasma viremia drop precipitously. The T-helper lymphocyte (CD4) count drops transiently during primary HIV infection, occasionally to very low levels. Along with the development of antiviral antibodies, the CD4 count rises, although not completely back to baseline levels.
After the initial viremic phase of infection, the virus invades its target organs, principally the lymphoid organs. Soon thereafter and continuously over the course of the infection, HIV replicates usually at a high rate, which varies from individual to individual. The rate of replication is determined by a complex interplay between virulence of the particular virus strain and adequacy of host immune response. This replication rate can be estimated by measurement of viral messenger RNA (mRNA, viral load) in plasma. For each infected individual, a unique viral load set-point is reached within a few months after primary infection. Symptomatic primary HIV infection has been associated with a higher viral load set-point compared with asymptomatic infection. The viral load for any given CD4 count has great prognostic value in predicting long-term clinical outcomes. The higher the viral load, the more rapid the clinical decline (Fig. 32-2).[2] The viral load also serves as a measure of response to antiviral therapy. It has therefore become an invaluable prognostic and therapeutic management tool.
With each replication cycle, new virions are produced, which in turn infect and destroy other CD4 cells. The rate of CD4 cell destruction is nearly matched by the host's ability to replace lost cells. Over time the vast majority of patients experience a progressive decline in CD4 cell number, resulting in profound immunodeficiency.
In addition to its high replication rate the virus has a high mutation rate. Over time this combination of high replication and mutation rates results in the generation of multiple viral strains (quasispecies) in a given individual. This potential for wide genetic variability has great implications for the host, since suboptimal antiretroviral therapy selects for the generation of quasispecies with reduced susceptibility to antiretroviral agents.
[edit] Immunologic Abnormalities
The primary target cell for HIV is the CD4 cell, which has a pivotal role in orchestration of the immune response; not surprisingly, therefore, virtually all arms of the immune system are damaged during progressive infection. Qualitative and quantitative CD4 cell defects induced by the virus impair overall T-helper cell function. CD4 cells do not proliferate normally when stimulated, nor do they elaborate the proper complement of cytokines necessary to generate appropriate responses from other arms of the immune system. Cells of the macrophage/monocyte lineage become dysfunctional in antigen presentation. The humoral immune response is impaired and worsens with advancing disease. As a result, patients develop an inadequate antibody response when exposed to neoantigens. All these immune system defects ultimately lead to the host becoming susceptible to a large group of opportunistic pathogens that are common to other cellular immunodeficiency states. Abnormalities in immune surveillance of neoplastic clonal expansion may be one important mechanism by which HIV-infected patients develop neoplasms such as non-Hodgkin's lymphoma.
[edit] Cellular Targets
In addition to lymphocytes and macrophages, HIV can infect several other cells, although the mechanisms of attachment and viral entry may differ. In particular, virus has been isolated from several types of cells in the central nervous system (CNS). CNS invasion probably occurs early in the course of infection, with lymphoid organ seeding during and after primary HIV infection. The clinical implications of CNS infection for the host are great; patients have CNS manifestations ranging from benign aseptic meningitis to encephalopathy and myelopathy. Infection of gut epithelial cells may be important in the diarrhea and weight loss so common in infected patients.
[edit] ACQUISITION AND TRANSMISSION
Although HIV has been isolated from a variety of body fluids, the only fluids recognized to transmit disease are blood and blood products, semen, vaginal fluid, and breast milk (Box 32-1). Other fluids, such as saliva and tears, which contain low concentrations of viral particles, and cerebrospinal fluid, which can have high viral titers, have not been shown to transmit infection. Any body fluid can be rendered infectious if contaminated with blood. The major means of HIV transmission worldwide is by heterosexual intercourse. Other recognized modes of transmission include anal-receptive intercourse among gay men, sharing of contaminated needles among injection drug users (IDUs), transfusion of infected blood products, and vertical transmission (in utero, the intrapartum, or breast-feeding).
| Box 32-1 - HIV Infectivity of Various Body Fluids |
Fluids Known to Transmit Infection
|
[edit] Heterosexual Transmission
During vaginal intercourse, either partner can infect the other, although male-to-female transmission is more efficient than the reverse. In the case of semen, inflammatory cells, which are found in seminal secretions, probably represent the major means by which virus is transmitted. Virus then infects macrophages and lymphocytes within the cervix or higher up in the uterine body, with subsequent dissemination of infection. For HIV-infected women, vaginal secretions also contain cell-associated and cell-free virus, which probably infects macrophages within the male urethra, leading to disseminated infection. The presence of an active sexually transmitted disease (STD) clearly increases the efficiency of transmission. Whether the lesions are ulcerative (e.g., syphilis, chancroid) or nonulcerative (e.g., gonorrhea), the common feature among STDs is the preponderance of inflammatory cells, which from the infected partner can increase the infectivity of the fluid or in the noninfected partner can increase the number of exposed susceptible targets.
[edit] Transmission Among Men Who Have Sex with Men
Among gay men, anal-receptive intercourse has the highest likelihood of HIV transmission. It was originally believed that small tears in the rectal mucosa provided a portal for viral entry. It is now believed that virus attaches to and infects mucosal epithelial cells, from which virus spreads to underlying tissue macrophages, leading to widespread dissemination. As with heterosexual transmission, active STDs increase the efficiency of transmission.
[edit] Transmission Secondary to Infected Blood Products
Within the blood compartment, virus can be isolated in both the cellular compartment (mononuclear cells) and the plasma. Infected cells are probably the more important vehicles of infection because of the absolute number of viral particles that can be detected intracellularly compared with plasma. In the United States, before universal testing of blood products for HIV in 1985, many patients were infected after receiving blood components, including packed red cells, platelets, and fresh-frozen plasma. Patients who received transfusions from donors with late-stage HIV infection tended to progress more quickly than those transfused with blood products from early-stage, asymptomatic donors. This probably reflects the higher viral inoculum transmitted from the blood of patients with late-stage disease and the greater virulence of HIV associated with advanced disease. Patients with hemophilia A and other clotting disorders also have been infected from contaminated blood products pooled from many donors. At present, all blood products in the United States are tested for HIV antibodies and are considered safe. The chance of HIV transmission from a single unit of transfused blood now is estimated to be 1 in 500,000.
[edit] Injection Drug Users
The sharing of needles without sterilization between IDUs results in parenteral exposure to HIV-infected blood. The efficiency of transmission is not clear. The use of a syringe/needle contaminated with blood from an individual with late-stage HIV infection probably imparts the highest risk of transmission.
[edit] Vertical Transmission
An HIV-infected mother can transmit infection in utero, during delivery, or by breast-feeding. In utero and intrapartum transmissions account for the vast majority of vertical infections. In utero transmission occurs transplacentally, most likely during the third trimester. Intrapartum transmission probably takes place as the fetus is exposed to infected body fluids while passing through the birth canal. Strong evidence suggests that many more infections occur intrapartum than in utero, making the intrapartum period an attractive target for infant prevention modalities. Infection of an infant from exposure to infected breast milk is a comparatively uncommon means of transmission in the developed world but remains a significant risk among individuals in such developing regions as Africa and southeastern Asia.
[edit] Other Modes of Transmission
With the exception of a few rare reports, the transmission of HIV by casual contact is extremely unlikely. Family members and close friends who care for sick and dying patients have no appreciable risk of contracting HIV infection provided that they follow standard infection control procedures.
[edit] Transmission in the Health Care Setting
The occupational risk of transmission of HIV to health care workers (HCWs) from infected patients is extremely low but is still a source of great concern. Of the reported cases of work-related HIV transmission, percutaneous exposures from HIV-contaminated needle-stick injuries have been the most common mode of infection. HCWs also have become infected by mucous membrane or nonintact skin exposure, but such events have been extremely rare. The risk of seroconversion after percutaneous exposure to HIV-infected fluid is approximately 0.25% to 0.3%.[3] The seroconversion rate from mucocutaneous exposure to contaminated blood is considerably lower than for percutaneous exposure, probably less than 0.1%. Injuries that impart the highest risk of transmission include deep sticks involving hollow-bore needles contaminated with freshly drawn blood. The risk of transmission of virus from HCW to patient has received much attention in light of infection of a group of six patients by an infected dentist in Florida by unknown means. A possible case of transmission to a patient from an orthopedic surgeon during a procedure was also reported. In the usual health care setting, HCW-to-patient transmission would most likely happen during an invasive procedure, although specific risk factors for this type of transmission have not been identified clearly. Although it cannot be established reliably, the HCW-to-patient rate is likely to be several orders of magnitude less than that for patient-to-HCW transmission.
[edit] COURSE AND NATURAL HISTORY
[edit] Course of Disease
After primary HIV infection, during which a transient fall occurs in the CD4 count, patients typically become asymptomatic (Fig. 32-3). Immune thrombocytopenia, herpes zoster (shingles), and persistent generalized lymphadenopathy (PGL) are among the earliest manifestations. Herpes zoster can be recurrent and involve more than one dermatome during a single outbreak. With PGL, lymph nodes in multiple locations, especially the occipital, posterior cervical, and axillary regions, become enlarged, firm, nontender, and unattached to the underlying tissue. Although some patients note a waxing and waning of lymph node size, the adenopathy generally persists for many months or longer. During this "asymptomatic" period the CD4 count remains at or near the normal range (500 cells/mm3 or higher).
With further CD4 count decline, various constitutional symptoms begin to appear, including fatigue, intermittent unexplained fevers, diarrhea, and night sweats. For the first time, patients feel ill. By now the CD4 count has typically dropped to between 200 and 500 cells/mm3. Pulmonary tuberculosis and bacterial pneumonia can occur during this early stage of HIV infection, as can lymphoma and Kaposi's sarcoma, although all these conditions occur more often with lower CD4 counts.
At a CD4 count of about 200 cells/mm3, patients are at risk for developing Pneumocystis carinii pneumonia (PCP), which, until the widespread use of prophylaxis, was the most common opportunistic infection seen in patients with AIDS in the developed world. With a CD4 count of 100 to 200 cells/mm3, other conditions may include the early peripheral and central nervous system complications of infection. Once the CD4 count has dropped below 50 to 100 cells/mm3, patients become susceptible to the remaining AIDS-related conditions, including cryptococcal meningitis, cytomegalovirus retinitis, toxoplasmic encephalitis, disseminated Mycobacterium avium complex infection, AIDS wasting syndrome, primary CNS lymphoma, and AIDS dementia complex.
In 1993 the Centers for Disease Control and Prevention (CDC) revised its surveillance case definition for AIDS, which was first proposed in 1986 (Box 32-2).[4] Two important changes were made. First, the definition of AIDS was expanded to include all HIV-infected patients with CD4 counts below 200 cells/mm3, whether or not they had a recognized complication. Second, pulmonary tuberculosis, recurrent bacterial pneumonia, and invasive cervical cancer in women were added to the list of AIDS-defining conditions.
| Box 32-2 - 1993 CDC Expanded Surveillance Case Definition for AIDS✢ |
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The preceding account is a stylized description of the typical course of an HIV-infected patient. Unfortunately, there are many exceptions to this course of events. For example, symptomatic primary HIV infection is not recognized in 30% to 50% of patients. Also, the rate of decline of CD4 cells varies considerably among individuals, as largely determined by the viral load set-point (see Fig. 32-2). More important, many patients remain completely asymptomatic, even as their CD4 counts drop to very low levels. Therefore a clinician cannot reliably predict the CD4 count in an asymptomatic HIV-infected patient. In contrast, the CD4 count is predictably low in symptomatic patients, particularly if they have been diagnosed with one of the late-stage, AIDS-defining conditions. As a result, some of the early staging systems used in HIV infection that were based on symptoms alone inaccurately reflected the true stage of disease in many cases. Similarly, staging systems based on the CD4 count alone also are inaccurate because symptoms clearly influence prognosis. Finally, CD4 count recovery as a result of HAART has further complicated the efforts to devise a useful staging system for HIV infection. Table 32-1 lists the current CDC staging system, which is the one used most extensively.[4]
Table 32-1 1993 CDC Classification System for HIV Infection
| 'CD4 count | Clinical categories | ||
|---|---|---|---|
| (A)'Asymptomatic, first-degree HIV infection or PGL | (B)'Symptomatic, not (A) or (C) conditions | (C)'AIDS-indicator conditions | |
| (1) >500/mm3 | A1 | B1 | C1 |
| (2) 200-499/mm3 | A2 | B2 | C2 |
| (3) <200/mm3 | A3 | B3 | C3 |
| PGL, Persistent generalized lymphadenopathy. | |||
[edit] Natural History of Infection
HIV infection causes disease that is measured not in weeks or months but in years. Several studies have examined the time course of infection in selected populations. The Multicentered AIDS Cohort Study (MACS), a study of gay men in four major cities originally begun in the late 1970s to study hepatitis B, was adapted to study HIV. Only 2% of patients developed AIDS within 2 years of seroconversion, and 10 years were required for slightly more than 50% of patients to develop AIDS. Interestingly, a small percentage of patients (less than 5%) remained symptom free with normal CD4 counts for more than 15 years.
The natural history of HIV infection also has been studied for hemophiliac patients and transfusion recipients. Hemophiliacs appear to progress less rapidly than gay men, with one study reporting that only 27% had progressed to AIDS by 7 years from the time of seroconversion. The rate of progression to AIDS correlated inversely with age; younger patients, particularly those less than 17 years of age, had a much slower progression than those over age 35. In contrast, transfusion recipients as a group appear to progress more rapidly than either gay men or hemophiliacs, with approximately 50% of patients developing AIDS by 7 years. Natural history data for HIV-infected IDUs are limited but probably similar to data for gay men.[5] The prognosis for active users with HIV is generally poor because of the lack of ongoing medical care, nonadherence to treatment plans, poor nutrition, and greater exposure to tuberculosis and other infectious agents.
[edit] EPIDEMIOLOGY
[edit] North America
As of December 1999 an estimated 920,000 adults and children were living with HIV/AIDS in North America.[6] In the United States a total of 393,045 adults and children living with HIV/AIDS were reported to the CDC as of June 1999 (Table 32-2).[7] Therefore the majority of patients living with the infection are not reported and presumably undiagnosed. The major recent changes in epidemiology in the developed world have involved a large decline in mortality and in the incidence of new AIDS cases, primarily because of the widespread use of HAART (Fig. 32-4).[8] The rate of decline in the incidence of AIDS has slowed somewhat from 1996-97 (18%) to 1997-98 (11%). In contrast to AIDS cases, new cases of HIV infection, while declining during the middle to late 1980s, have remained relatively unchanged in the 1990s. The World Health Organization (WHO) estimates that 44,000 new cases of HIV infection occurred in North America in 1998-99. Given the declining death rate and stable incidence, the proportion of the population living with HIV infection has increased during the middle to late 1990s.
Table 32-2 Vital Statistics of HIV and AIDS in United States✢ Through June 1999
From Centers for Disease Control and Prevention: HIV/AIDS Surv Rep 11:1, 1999.| Cases/group | Cumulative total |
|---|---|
| Cases of AIDS reported✢ | 711,344 |
| Patients living with HIV infection† | 104,784 |
| Patients living with AIDS | 288,261 |
| Patients living with HIV/AIDS | 393,045 |
✢Adults and children since beginning of epidemic in 1981.
†HIV infection without AIDS. Note that as of June 1999, at least 20 states or dependencies/possessions were not yet reporting cases of HIV infection.
Table 32-3 shows the AIDS cases among adults and adolescents (male and female) by exposure category through June 1999, both cumulative and for the previous 12-month reporting period.[7] For American men, transmission by men having sex with men (MSM) remains the largest cumulative risk category. The percentage of reported cases among gay men decreased from July 1998 to June 1999. Unfortunately, some large cities report that the safe-sex guidelines instituted in the 1980s in the gay community are being ignored by the next generation of gay men now that HAART has been introduced. For women, heterosexual transmission, usually from a past or active IDU, overtook direct injection drug use in the early 1990s as the principal means of HIV transmission.
Table 32-3 AIDS Cases Among Adults and Adolescents Age 13 and Older by Exposure Category Through June 1999
| Risk category | July 1998–June 1999 number (%) | Cumulative total (%) |
|---|---|---|
| Men who have sex with men (MSM) | 15,999 (34) | 334,073 (48) |
| Injection drug user (IDU) | 10,536 (23) | 179,228 (26) |
| MSM and IDU | 1940 (4) | 45,266 (6) |
| Coagulation disorder | 171 (0) | 5010 (1) |
| Heterosexual contact | 7051 (15) | 70,582 (10) |
| Blood component recipient | 266 (1) | 8430 (1) |
| Other risk (not reported or identified) | 10,798 (23) | 60,159 (9) |
| total | 46,761 (100) | 702,748 (100) |
Fig. 32-5 shows the cumulative AIDS cases according to race and ethnicity as of June 1999. The trend of overrepresentation by minority communities has worsened during the 1990s. Africans and Hispanics now account for more than 50% of reported cases. This disproportionate overrepresentation likely results from poverty, greater risk of exposure in inner-city environments, and poor access to preventive health care services.
[edit] Worldwide Perspective
WHO estimates that approximately 33.6 million adults and children were living worldwide with HIV/AIDS as of December 1999 (Table 32-4).[6] The majority of cases are in sub-Saharan Africa, where in some large urban areas, up to one quarter of adults between ages 18 and 45 are HIV infected. Areas that show the largest number of new cases include sub-Saharan Africa, southern and southeastern Asia, central Asia, and Latin America. An estimated 16,000 new infections occur daily, meaning that 5.6 million people were newly infected in 1999 alone. WHO estimates that more than 16 million people already have died from HIV infection.
Table 32-4 Worldwide HIV/AIDS Statistics and Features, December 1999
| Region | Epidemic started | Adults and children living with HIV/AIDS | Adults and children newly infected with HIV | Adult prevalence rate✢ | HIV-positive adults who are women | Main mode(s) of transmission for adults living with HIV/AIDS |
|---|---|---|---|---|---|---|
| Sub-Saharan Africa | Late 1970s-early 1980s | 23.3 million | 3.8 million | 8.0% | 55% | Hetero |
| North Africa and Mideast | Late 1980s | 220,000 | 19,000 | 0.13% | 20% | IDU, Hetero |
| South and Southeast Asia | Late 1980s | 6 million | 1.3 million | 0.69% | 30% | Hetero |
| East Asia and Pacific | Late 1980s | 530,000 | 120,000 | 0.068% | 15% | IDU, Hetero, MSM |
| Latin America | Late 1970s-early 1980s | 1.3 million | 150,000 | 0.57% | 20% | MSM, IDU, Hetero |
| Caribbean | Late 1970s-early 1980s | 360,000 | 57,000 | 1.96% | 35% | Hetero, MSM |
| Eastern Europe and central Asia | Early 1990s | 360,000 | 95,000 | 0.14% | 20% | IDU, MSM |
| Western Europe | Late 1970s-early 1980s | 520,000 | 30,000 | 0.25% | 20% | MSM, IDU |
| North America | Late 1970s-early 1980s | 920,000 | 44,000 | 0.56% | 20% | MSM, IDU, Hetero |
| Australia and New Zealand | Late 1970s-early 1980s | 12,000 | 500 | 0.1% | 10% | MSM, IDU |
| total | 33.6 million | 5.6 million | 1.1% | 46% | ||
| MSM, Sexual transmission among men who have sex with men;IDU, transmission through injection drug use;Hetero, heterosexual transmission. | ||||||
✢Proportion of adults (ages 15 to 49) living with HIV/AIDS in 1999, using 1998 population numbers.
[edit] PATIENT EVALUATION
Since it is presumed that the majority of Americans infected with HIV are unaware of their infection, such patients are not benefiting from early intervention. The role of the primary care physician in diagnosing HIV disease is critical. During the early years of the AIDS epidemic, surveillance focused on members of "high-risk groups" (gay and bisexual men, IDUs, hemophiliacs, individuals from Haiti); however, that approach is less useful today. A growing number of HIV-infected individuals contract their infection through heterosexual contact or are unaware of their mode of transmission. It has become more accurate therefore to think in terms of risk behaviors rather than risk groups. As a result, a thorough history, including nonjudgmental but specific questioning about sexual activity and drug use, has become even more important in identifying patients at risk for HIV infection. Indications for testing also include STDs, pregnancy, and active tuberculosis. HIV testing should be considered in patients with PGL, unexplained dementia, aseptic meningitis, or peripheral neuropathy; chronic, unexplained fever, diarrhea, or weight loss; generalized herpes simplex or multidermatomal herpes zoster infection; unexplained cytopenias; B-cell lymphoma; or other opportunistic conditions suggestive of cell-mediated immunodeficiency.
[edit] Diagnosis
Unfortunately, the diagnosis of HIV disease may still lead to social stigmatization, loss of health insurance, and discrimination in employment and housing. Because of the potential consequences to the patient, informed consent is recommended and in most states required before HIV testing can be initiated. In addition, HIV testing should be accompanied by pretest and posttest counseling, which should include discussion of the purpose of the test, prognosis and natural history of HIV infection, value of early intervention, transmission of HIV and risk reduction, partner notification, and other medical and social issues related to the diagnosis.
The criteria for a positive HIV test are a repeatedly positive enzyme-linked immunosorbent assay (ELISA) followed by a positive Western blot. The accuracy of testing is extremely high. False-negative results are uncommon and usually occur during the window period between infection and seroconversion, a period with a maximum duration of 6 months. False-negative results also have been described in patients infected with subtype O and those with late-stage HIV infection whose serostatus paradoxically becomes negative in the face of very advanced infection. False-positive results are rare. Patients with a positive ELISA and one or two bands on Western blot are reported as indeterminate. Indeterminate tests may occur in seroconverting patients, those with advanced HIV disease, and patients with alloantibodies (pregnancy, transfusions, organ transplantation) or autoantibodies (autoimmune diseases, malignancy).[5] Although patients in low-risk categories with indeterminate tests are unlikely to be infected, repeat tests in 3 and 6 months are usually performed for confirmation. If the indeterminate test is caused by seroconversion, it will usually become positive within 1 month.
Other methods to detect HIV infection include viral isolation, polymerase chain reaction (PCR), and standard HIV viral load testing. Because of the accuracy of the standard HIV test, however, these techniques are rarely necessary. Rapid tests for HIV antibodies are available and comparable in accuracy to the ELISA. They are highly sensitive; a negative result is definitive and can be reported in several minutes. Specificity is lower, however, and all positive results must be confirmed with standard tests.
[edit] Initial Evaluation
Physicians evaluating patients with HIV infection who are new to their practice should take a careful history (Box 32-3). Some patients may be newly diagnosed by the primary care physician doing the evaluation. Other patients have been previously diagnosed and treated by one or more physicians in the past. For either group the physician must ascertain when the patient was likely infected, by what means (if known), and when the patient was diagnosed. Patients should be questioned about their past medical history, including HIV-related opportunistic infections and malignancies, STDs, chickenpox, hepatitis, gynecologic problems (particularly Pap testing), vaccinations, and tuberculosis, both tuberculin skin testing and possible close contacts with individuals with active tuberculosis. Additional questions should focus on common HIV-related symptoms, including fevers, night sweats, weight loss, diarrhea, cough, skin rashes or lesions, oral thrush or ulcerations, headache, and changes in neurologic function or mental status. For the patient previously diagnosed with HIV and treated with antiretroviral agents, the physician should obtain a detailed antiviral history, including start and stop dates, reasons for medication discontinuation, drug failures, and results of genotype and phenotype testing, if available. Records of prior CD4 counts and viral load determinations are also important. In practice, obtaining an accurate antiretroviral history and accompanying test results is often difficult and the historic profile incomplete.
| Box 32-3 - Initial and Follow-up Evaluations of HIV-infected Patient |
Initial Evaluation
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[edit] Physical Examination.
A complete physical examination should be performed, with special attention to the evaluation of lymph nodes, funduscopic examination, oropharynx and skin, abdominal examination to detect enlargement of the liver or spleen, genital examination, and neuropsychologic screening to evaluate cognitive function and detect early dementia. Patients who are cachectic or who report significant weight loss require medical evaluation to look for reversible causes.
[edit] Laboratory Studies.
Several initial laboratory studies are appropriate in patients with HIV infection. Patients who have no documentation of their HIV serology results or who were tested anonymously should have a repeat HIV test. Anemia, leukopenia, and thrombocytopenia are common in HIV-infected individuals and are readily detected with a complete blood count (CBC) with differential, which also is used to calculate the total CD4 lymphocyte count. A chemistry panel also should be performed, including electrolytes, renal and liver profiles, urinalysis, and fasting lipid panel, because of the alterations in lipid metabolism caused by the virus and secondary to antiretroviral therapy. A nontreponemal test for syphilis, such as Venereal Disease Research Laboratories (VDRL) or rapid plasma reagin (RPR), and a tuberculin skin test (purified protein derivative, PPD) should be performed at baseline and repeated yearly.
Serologic testing for prior exposure to Toxoplasma gondii using the anti-Toxoplasma immunoglobulin G (IgG) is useful in determining the need for Toxoplasma prophylaxis. Seronegative patients should probably be retested when their CD4 count approaches 100/mm3. Although the Toxoplasma serology has limited utility diagnostically, a seronegative patient with a CNS space-occupying lesion is less likely to have toxoplasmosis than a seropositive patient.[9]
Because of the high incidence of hepatitis B and C coinfection, all HIV-infected patients should be screened with hepatitis B surface antigen (HBsAg), core antibody (HBcAb), and surface antibody (HBsAb), and hepatitis C antibody. Hepatitis A serostatus also should be ascertained, since a negative result in a hepatitis C–infected patient should prompt consideration for hepatitis A vaccination.[9] Serologic testing for prior cytomegalovirus (CMV) infection is advocated, since those who are seronegative should receive only CMV-negative blood products. Furthermore, although routine prophylaxis against CMV disease is not currently recommended, it may be indicated in the future for seropositive individuals with advanced HIV disease. Serologic testing for varicella should be performed in patients who are unable to give a history of chickenpox. This baseline test helps determine the need for postexposure prophylaxis with varicella-zoster immune globulin (VZIG) in patients exposed to chickenpox or shingles.
Routine screening for glucose-6-phosphate dehydrogenase (G6PD) deficiency is sometimes recommended, especially in black patients and patients of Mediterranean descent. Several oxidant drugs, such as dapsone, primaquine, and sulfonamides, are often used in HIV-infected patients and may lead to hemolysis in G6PD-deficient patients.
Because HIV-infected patients are highly susceptible to a variety of pulmonary complications and infections, a baseline chest radiograph may be useful. Furthermore, the chest radiograph may be helpful in screening for occult tuberculosis.
HIV-infected women are at increased risk for several gynecologic problems, including pelvic inflammatory disease and tuboovarian abscesses, candidal vaginitis, cervical dysplasia, and invasive cervical carcinoma. All HIV-infected women should have a baseline pelvic examination with Pap smear. Screening for clinically silent chlamydial and gonococcal cervicitis is recommended. The use of routine colposcopy is controversial, but the test is indicated in women with abnormal Pap smears or a history of vaginal condylomata. Pap smears should be repeated at least annually in women with normal results and every 6 months in women with a previously abnormal Pap smear.
The CD4 count, CD4 percentage, and HIV mRNA (viral load) are measured during the initial evaluation of a newly HIV-infected individual. The CD4 count and percentage provide the best available clinical data on the relative health of the immune system. The CD4 count is used in (1) staging HIV infection, (2) determining the need for antiretroviral therapy and for prophylaxis of opportunistic infections, (3) assessing the risk of specific HIV-related conditions, and (4) making and reporting the diagnosis of AIDS. The physician and patient must be aware of the substantial variation in the results of CD4 counts. Because in most laboratories the absolute CD4 count is determined by multiplying the white blood cell (WBC) count, percentage of lymphocytes, and percentage of CD4 lymphocytes, variation in any of these components can affect the total CD4 count. Because the CD4 percentage is not subject to variation based on the WBC count and lymphocyte count, it may provide a less variable and more accurate reflection of the patient's immunologic status. Total CD4 counts of 200 and 500/mm3 generally correspond to CD4 percentages of 14% and 29%, respectively.
HIV viral load is the other key measure of the status of HIV-infected patients. Viral load complements the CD4 count. Although the CD4 count provides information on immune system function, viral load indirectly measures the rate of viral replication. Three assays for the measurement of viral load are currently approved in the United States: Roche Amplicor RT-PCR assay, Chiron bDNA assay, and Organon Teknika Nuclisens HIV-1 QT assay.[5] All are accurate and fairly reproducible. Results with the Roche and the Organon Teknika assays are about double those of the Chiron assay. Each assay can measure down to a level of 40 to 50 mRNA copies/ml. The initial viral load measurement should be done twice over 1 to 2 weeks to ensure an adequate baseline, since intercurrent illnesses and even vaccinations can cause significant transient rises in the viral load.
[edit] Vaccinations Specific to HIV-infected Patients.
Advancing HIV infection impairs the host's ability to form specific antibodies with infection or immunization. Therefore vaccinations must be given as early in the course of HIV infection as possible. Although its efficacy is not well established in this population, the pneumococcal polysaccharide vaccine is indicated for all HIV-infected patients with CD4 counts greater than 200/mm3 because of the high incidence of pneumococcal pneumonia and bacteremia associated with HIV disease. It is given as a single dose, with revaccination after 5 years. Patients with lower counts are unlikely to respond but probably should also be vaccinated. For patients vaccinated in this low CD4 count range, the physician should consider revaccination before 5 years after they have had a significant CD4 count response (greater than 200/mm3) to HAART.[9]
The influenza vaccine should be given yearly to prevent influenza and its potential complications, primarily bacterial pneumonia. Because of the high risk of hepatitis B among many HIV-infected patients, hepatitis B vaccination should be offered to all patients who are HBcAb negative.[9] Vaccination is given at 0, 1, and 6 months. A postvaccination titer should be performed 1 to 6 months after the final dose to ensure vaccine efficacy. Hepatitis A vaccine is now recommended for all HIV-infected patients with chronic hepatitis C, since the acute hepatic insult associated with hepatitis A infection in such patients carries substantial morbidity and risk of death. Two doses of vaccine are given at 6-month intervals.[9]
[edit] Follow-up Evaluations
Frequency of follow-up visits depends on stage of disease, stability of the antiviral response, comorbid conditions, and the patient's psychosocial stability. In general, patients with late-stage disease are seen more frequently than those with early-stage disease. For patients just starting antiviral therapy, a follow-up visit should take place in 3 to 4 weeks; adherence to treatment and possible side effects should be discussed in detail, and viral load should be tested to determine the magnitude of the initial drop. Patients should be seen 1 to 2 months later and then at least every 3 months. Viral load measurements should be repeated every 3 to 4 months; the CD4 count should be repeated every 3 to 6 months.[10]
In addition to following response to antiviral therapy, patients need to be followed carefully for both their standard adult preventive care as well as HIV-related preventive care. The standard adult preventive care plan should be similar to the standard plan of age-matched, non-HIV-infected patients (e.g., screening for cardiovascular risk factors, mammograms for women, counseling for smoking cessation). HIV-specific preventive care has many facets. Vaccination status must be continually updated, as discussed. Patients should undergo annual PPD screening and testing for syphilis with a VDRL or RPR. For women, Pap smears need to be performed at least yearly. The CD4 count must be closely watched to determine the need for opportunistic infection prophylaxis. For patients with CD4 counts less than 100 to 150/mm3, an opthalmologist should perform a yearly retinal examination to screen for CMV retinitis. For patients with hepatitis B and C coinfection, liver enzymes should be periodically rechecked. Similarly, given the lipid profile abnormalities associated with some antiretroviral agents, repeat lipid studies should also be performed.
With the complexity of current antiretroviral therapy and the urgent need to keep up with the general health maintenance of this patient group, most physicians prefer to track information in a paper or computed flowsheet. A detailed record of the antiretroviral history is essential, including start and stop dates of medications, reasons for medication and dose changes, and some subjective estimate of patient adherence. Chronologic listing of CD4 counts, CD4 percentages, and HIV viral load measurements should be kept. Ideally these data should be recorded to allow easy comparisons between the antiretroviral regimen and the viral load and CD4 response to facilitate future decisions regarding medication changes. The flowsheet should also contain a record of initial screening results and annual screenings for HIV-related preventive care.
[edit] Mental Health Considerations
In addition to medical management, HIV health care providers must be able to recognize and treat many of the psychiatric complications common in HIV-infected patients. As a group these patients have an increased lifetime risk of major mental illness.
Persistent signs or symptoms of emotional distress in any HIV-infected patient are indications for a thorough psychiatric evaluation. History should focus on any family history of mental illness, substance abuse, present medications, and any previous psychiatric disorders. Laboratory studies to rule out organic etiologies include RPR, thyroid-stimulating hormone (TSH), folate and B12 levels, and CNS imaging in selected patients.
Major depression is the most frequent diagnosed psychiatric disorder in this population. In addition to depressed mood, patients manifest social withdrawal, fatigue, loss of self-esteem, feelings of helplessness, and vegetative features (sleep disturbances, anorexia, weight loss, psychomotor retardation). The incidence of depression appears to increase with advancing HIV infection and declining CD4 counts. Risk assessment for suicidal ideation is an important consideration in any depressed patient. Many patients will benefit from antidepressant therapy.
Anxiety also is common in the HIV-infected population, and providers should attempt to identify specific stressors in the patient's environment. Psychotherapy and the judicious use of anxiolytics may be helpful. Obsessive behavior in the form of fixation with health-related issues is not unusual. Overt psychotic disorders (schizophrenia, mania) may be related to a premorbid condition or a medication or may be secondary to another psychiatric disorder. Conventional treatment with psychotherapy and antipsychotic medications is indicated.
Because a high proportion of HIV-infected patients have a history of substance abuse, the primary care physician often becomes integral in formulating and perpetuating an effective treatment plan. Important components include (1) detoxification and management of withdrawal, (2) continued abstinence (maintenance), and (3) diagnosis and treatment of conditions predisposing to substance abuse. Community programs such as Alcoholics Anonymous, Narcotics Anonymous, and AIDS support organizations are excellent resources.
[edit] Special Management Issues
Although HIV infection shares many features of other chronic diseases, caring for HIV-infected patients also entails certain unique responsibilities. Frequent discussion of the avoidance of transmission is important. Although laws regarding sexual and drug-use contact notification vary from state to state, primary caregivers often play a role in encouraging or assisting with the disclosure of the patient's HIV status. In many communities, physicians care for patients with more immediate concerns of substance abuse, mental illness, homelessness, child care, lack of medical insurance, and poverty. Physicians must be aware of community resources that can assist their patients with these obstacles so that their medical problems can be addressed. Physicians also may become involved in issues of employment or housing discrimination. They may have patients who are rejected by their families or friends because of their disease, leaving them without the support so crucial in maintaining their health. Understanding and management of HIV disease progress rapidly, and patients expect their caregivers to maintain up-to-date knowledge. Patients may ask for unapproved or experimental treatment or may take alternative therapies with or instead of standard drugs. Physicians must be aware of experimental protocols and make them available to their patients, when appropriate. They also must be familiar with the potential risks and benefits of the alternative therapies being advocated in the community so that they can counsel their patients about the use of these therapies and monitor them appropriately if they choose to take them.
As with any chronic disease, physicians caring for HIV-infected patients interact frequently with families and support networks. HIV disease is unique, however, because the patient's spouse, partner, friends, or family members may also be infected. Physicians must recognize the importance of nontraditional families. Among gay couples, for example, the patient's partner is usually a more appropriate decision maker than the next of kin, if the patient is unable to speak for himself. For this role to be legally recognized, however, the partner must have been designated as the "health care proxy" or "durable power of attorney for health." Despite the major improvement in the prognosis imparted by HAART, patients should be encouraged as early as possible in the course of the disease to make their wishes known to their physician and family regarding their proxy for health care decisions, their wishes regarding terminal care and its aggressiveness, and the disposition of their property after death. Whenever possible, their wishes should be formalized with the legal arrangements appropriate to their particular state.
[edit] ANTIRETROVIRAL THERAPY
Specific antiretroviral therapy for HIV infection was made available 5 years after the first descriptions of AIDS and 3 years after the identification of the responsible virus. The unprecedented acceleration of the drug approval and availability process beginning in the 1980s continued through the 1990s. The appropriate use of the growing number of new drugs, however, has been confusing and controversial. Before fall 1995, therapy of HIV infection was generally restricted to persons with advanced disease, those who were symptomatic or who had AIDS. Treatment of asymptomatic individuals with CD4 counts between 200 and 500 cells/mm3 was controversial, and therapy of those patients with over 500 cells/mm3 was discouraged. Decisions regarding initiation or changes of antiretroviral therapy were based on CD4 count trends and patient symptoms. Plasma viral load testing was not available. Zidovudine (AZT, ZDV) monotherapy was the mainstay of therapy. The other three available licensed nucleoside analogs, stavudine (d4T), didanosine (ddI), and zalcitabine (ddC), were used alternatively as monotherapy agents if a patient failed or was intolerant to AZT therapy. Although combination therapy was being considered, it was not employed routinely because early studies, including a large multicenter trial (ACTG 155) that compared AZT alone, ddC alone, and the combination, showed no differences in overall efficacy.
Therapeutic approaches were altered in late 1995 and early 1996 when three large clinical trials demonstrated that combination nucleoside analog therapy delayed HIV progression and improved survival. In addition, the rapid development and availability of new and more potent drugs, such as the protease inhibitors (PIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs), as well as tests to measure plasma viral burden, led to dramatic changes and increasing complexity of the clinical treatment of HIV-infected persons. Viral load testing, now routinely performed, enables the physician to determine better the optimal time to initiate or change therapy, before declining CD4 counts.
In 2000 a typical antiretroviral regimen, HAART, consists of at least three agents: two nucleoside reverse transcriptase inhibitors (NRTIs) combined with one or two PIs or one NNRTI. The goal of therapy is to reduce measurable plasma viral burden to very low levels and restore or preserve immunologic function. The clinical impact of these therapies has been dramatic, with a sharp drop in the incidence of opportunistic infections and other complications, a marked decrease in hospitalization rates for HIV-related disease, and a lower mortality from AIDS nationwide (see Fig. 32-4). HAART has offered substantial hope to many patients.
[edit] Initiation
Before prescribing medications, the physician should factor the patient's prognosis, as predicted by the CD4 counts and plasma HIV RNA levels, into the decision. Prognosis is based on MACS data, which demonstrated a correlation between risk of progression to an AIDS-defining illness and the plasma viral load when stratified according to CD4 count (see earlier discussion and Fig. 32-2).[2]
The Panel on Clinical Practices for Treatment of HIV Infection convened by the U.S. Department of Health and Human Services (DHHS) and the Henry J. Kaiser Family Foundation publishes regularly updated guidelines on the internet for the use of antiretroviral agents.[10] Therapy should be offered to patients with primary HIV infection, those within 6 months of HIV seroconversion, and all patients with symptoms caused by HIV infection. Asymptomatic chronically infected persons are considered for treatment based on virologic and immunologic factors. Those patients with less than 500 CD4 cells/mm3 or plasma HIV RNA levels exceeding 10,000 copies/ml (bDNA assay) or 20,000 copies/ml (RT-PCR assay) should be offered therapy (Table 32-5).[10]
Table 32-5 Indications for Initiation of Antiretroviral therapy in Chronically HIV-infected Patients
| Clinical category | CD4+T cell count and HIV RNA | Recommendation |
|---|---|---|
| Symptomatic (AIDS, thrush, unexplained fever) | Any value | Treat |
| Asymptomatic | CD4+ T cells <500/mm3 | Treatment should be offered. Strength of recommendation is based on prognosis for disease-free survival and willingness of patient to accept therapy.✢ |
| or | ||
| HIV RNA >10,000 (bDNA) or >20,000 (RT-PCR) | ||
| Asymptomatic | CD4+ T cells >500/mm3 | Many experts would delay therapy and observe; others would treat. |
| and | ||
| HIV RNA <10,000 (bDNA) or >20,000 (RT-PCR) |
✢Some experts would observe patients with CD4+ counts of 350-500/mm3 and HIV RNA levels <10,000 (bDNA) or <20,000 (RT-PCR).
The antiviral drug regimens can be complex, cause numerous potential side effects and drug interactions, and require rigid adherence, so an assessment of the patient's interest and willingness to accept the treatment is essential. Despite the clear benefits of therapy for most patients, others may benefit most from deferring therapy, particularly when poor adherence is likely. Compliance of less than 95% of medication doses increases the likelihood of viral resistance and cross-resistance within the drug classes, compromising the effectiveness of future therapies. Thus the potential benefits and risks must be considered carefully before initiating therapy (Box 32-4).
| Box 32-4 - Risks and Benefits of Antiretroviral Therapy in Asymptomatic HIV-infected Patients† |
Possible Benefits
|
The goals of therapy are to (1) suppress viral load completely for a prolonged duration, (2) restore or at least maintain immunologic function, (3) minimize HIV-related morbidity and mortality, and (4) improve quality of life. These goals can be achieved by maximizing adherence to the drug regimen, sequencing drugs rationally, preserving future treatment options, and using resistance testing in certain clinical settings.[10] At this time, therapy is suppressive, not curative, and is lifelong.
[edit] Drugs and Regimens
Combination therapy is superior to monotherapy because of additive antiviral effects, delay in the emergence of resistance, and possibly a decrease in viral fitness. Nucleoside analog combinations are generally more effective when used with NNRTIs or PIs. Table 32-6 lists suggested antiretroviral agents for initial treatment of established HIV infection. Priority is given to regimens for which clinical trials data suggest sustained suppression of HIV RNA and sustained increases in CD4 count, along with favorable clinical outcome. Regimens that have been compared directly with other regimens are emphasized. Additional consideration is given to the regimen's pill burden, dosing frequency, food requirements, convenience, toxicity, and drug interaction profile. Because of the rapidly evolving and complex nature of antiretroviral therapies, HIV clinical expert advice is necessary to determine the appropriate regimen for most patients.[10]
Table 32-6 Recommended Antiretroviral Agents for Initial Treatment of Established HIV Infection
| Recommendation | Column A | Column B |
|---|---|---|
| Strongly recommended: one choice each from columns A and B | Efavirenz | Stavudine+lamivudine |
| Indinavir | Stavudine+didanosine | |
| Nelfinavir | Zidovudine+lamivudine | |
| Ritonavir+Saquinavir [soft gel capsule (SGC) or hard gel capsule (HGC)] | Zidovudine+didanosine | |
| Recommended as alternative: one choice each from columns A and B | Abacavir | Didanosine+lamivudine |
| Amprenavir | Zidovudine+zalcitabine | |
| Delavirdine | ||
| Nelfinavir+saquinavir SGC | ||
| Nevirapine | ||
| Ritonavir | ||
| Saquinavir SGC | ||
| Not recommended | Saquinavir HGC | Stavudine+zidovudine |
| Zalcitabine+lamivudine | ||
| Zalcitabine+stavudine | ||
| Zalcitabine+didanosine | ||
| Not recommended: all monotherapies, whether from column A or B | — | — |
| No recommendation: insufficient data | Hydroxyurea in combination with other antiretroviral drugs | |
| Ritonavir+indinavir | ||
| Ritonavir+nelfinavir |
[edit] Nucleoside Analog Reverse Transcriptase Inhibitors.
The NRTIs bind to viral DNA and inhibit HIV reverse transcriptase, the enzyme essential for transcribing RNA into DNA. Six NRTIs are currently licensed for use: zidovudine (AZT, ZDV, Retrovir), didanosine (ddI, Videx), zalcitabine (ddC, Hivid), stavudine (d4T, Zerit), lamivudine (3TC, Epivir), and abacavir (ABC, Ziagen) (Table 32-7).[10] Serious potential adverse effects are bone marrow suppression from zidovudine; fatal and nonfatal pancreatitis with didanosine alone or in combination with other drugs, particularly stavudine and hydroxyurea; and severe hypersensitivity reaction from abacavir, which could cause death if abacavir is restarted after discontinuance.
Table 32-7 Characteristics of Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
| Zidovudine (AZT, ZDV, Retrovir) | Didanosine (ddI, Videx) | Zalcitabine (ddC, HIVID) | Stavudine (d4T, Zerit) | Lamivudine (3TC, Epivir) | Abacavir (ABC, Ziagen) |
|---|---|---|---|---|---|
| Dosing | |||||
| 200 mg tid | >60 kg: 200 mg bid | 0.75 mg tid | >60 kg: 40 mg bid | 150 mg bid | 300 mg bid |
| or 300 mg bid | or 400 mg qd | <60 mg: 30 mg bid | <50 kg: 2 mg/kg bid | ||
| or with 3TC as Combivir, 1 bid | <60 kg: 125 mg bid | or with ZDV as Combivir, 1 bid | |||
| or 250 mg qd | |||||
| Food effect | |||||
| No significant effect | Levels decrease 55% with food. | No significant effect | No significant effect | No significant effect | No significant effect |
| Take ½ hour before or 1 hour after meal. | |||||
| Adverse effects✢ | |||||
| Bone marrow suppression: anemia, neutropenia | Pancreatitis | Peripheral neuropathy | Peripheral neuropathy | Minimal toxicity | Hypersensitivity reaction, potentially fatal if drug reintroduced after discontinuation |
| Gastrointestinal intolerance | Peripheral neuropathy | Stomatitis | Nausea | Fever, rash, nausea, vomiting, malaise, fatigue, loss of appetite | |
| Headache, insomnia | Nausea, diarrhea | ||||
| Asthenia | |||||
| tid, Three times daily; bid, twice daily;qd, daily. | |||||
✢For all NRTIs, lactic acidosis with hepatic steatosis is a rare but potentially life-threatening toxicity.
[edit] Nonnucleoside Reverse Transcriptase Inhibitors.
Similar to the NRTIs, the NNRTIs inhibit HIV reverse transcriptase, but by a different noncompetitive mechanism. The NNRTIs directly bind to the reverse transcriptase and prevent effective transcriptional activity. The three NNRTIs currently available are nevirapine (NVP, Viramune), delavirdine (DLV, Rescriptor), and efavirenz (EFV, DMP 266, Sustiva). Based on in vitro and in vivo data, efavirenz may be the most potent of the three, and recent evidence suggests efavirenz plus two NRTIs is as effective as PI plus NRTI regimens (Table 32-8).[10] Rash is most common with nevirapine. Efavirenz is unique in the class with regard to its potential for CNS symptoms, such as lightheadedness, abnormal dreams, impaired concentration, agitation, hallucinations, and euphoria. Cross-resistance is great among the three NNRTIs.
Table 32-8 Characteristics of Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs)
| Nevirapine (Viramune) | Delavirdine (Rescriptor) | Efavirenz (Sustiva) |
|---|---|---|
| Dosing | ||
| 200 mg daily for 14 days, then 200 mg twice daily | 400 mg three times daily | 600 mg daily at bedtime |
| Separate dosing with ddI or antacids by 1 hour | ||
| Food effect | ||
| No significant effect | No significant effect | Avoid taking after high fat meal; levels increase by 50%. |
| Adverse effects | ||
| Rash | Rash | Rash |
| Increased transaminase levels | Increased transaminase levels | Central nervous system symptoms |
| Hepatitis | Headaches | Increased transaminase levels |
| False-positive cannabinoid test | ||
| Teratogenic in monkeys | ||
[edit] Protease Inhibitors.
Inhibition of HIV protease stops effective production of infectious virions. HIV protease cleaves protein precursors that eventually comprise the core proteins and enzymes of mature virions. Thus, even if a virion buds through the host cell membrane, the particle will be incapable of infecting new cells. Five PIs are licensed for use: saquinavir (Invirase, Fortovase), indinavir (Crixivan), ritonavir (Norvir), nelfinavir (Viracept), and amprenavir (Agenerase). Their effects have been dramatic when used in combination with NRTIs. The limitations to their use have been the development of resistance, drug-specific intolerance, and more recently the link with some unique potential metabolic adverse effects, including lipid abnormalities, fat redistribution, and hyperglycemia (Table 32-9).[10] Dual-PI combinations often are used as part of an aggressive initial regimen and in salvage therapy. Substantial cross-resistance occurs among the PIs.
Table 32-9 Characteristics of Protease Inhibitors (PIs)
| Indinavir (Crixivan) | Ritonavir (Norvir) | Nelfinavir (Viracept) | Saquinavir SGC (Fortovase) | Amprenavir (Agenerase) |
|---|---|---|---|---|
| Dosing | ||||
| 800 mg q8h | 2-week dose escalation to 600 mg bid | 750 mg tid | 1200 mg tid | 1200 mg bid |
| Separate dosing with ddI by 1 hour | Separate dosing with ddI by 2 hours | or 1250 mg bid | ||
| Food effect | ||||
| Levels decrease 77%. | Levels increase 15%. | Levels increase 2-3 times. | Levels increase sixfold. | Can be taken with or without food, but avoid high-fat meal. |
| Take 1 hour before or 2 hours after meals; may take with skim milk or low-fat meal. | Take with food, which also may improve tolerance. | Take with meal or snack. | Take with large meal. | |
| Adverse effects✢ | ||||
| Nephrolithiasis | GI intolerance, nausea, vomiting, diarrhea | Diarrhea | GI intolerance, nausea, diarrhea, abdominal pain, dyspepsia | GI intolerance, nausea, vomiting, diarrhea |
| GI intolerance, nausea | Paresthesias (circumoral, extremities) | Hyperglycemia | Headache | Rash |
| Elevated indirect bilirubin | Hepatitis | Elevated transaminases | Oral paresthesias | |
| Headache, asthenia, dizziness, rash, metallic taste, thrombocytopenia | Asthenia, taste perversion | Hyperglycemia | Elevated liver function tests | |
| Hyperglycemia | Increased triglycerides, transaminases, creatine kinase, and uric acid | Hyperglycemia | ||
| Hyperglycemia | ||||
| q8h, Every 8 hours; bid, twice daily;tid, three times daily; GI, gastrointestinal. | ||||
✢For all PIs, fat redistribution and lipid abnormalities.
[edit] Hydroxyurea.
Hydroxyurea inhibits cellular ribonucleotide reductase, leading to a lower intracellular store of deoxynucleoside triphosphates (dNTPs), thus increasing the uptake of nucleoside analogs. Hydroxyurea has been used investigationally in combination with antiretroviral agents such as didanosine and stavudine for treatment of HIV infection. Its utility has not been established because of conflicting efficacy data and potential serious toxicities, such as persistent cytopenias, hepatotoxicity, neuropathy, and teratogenic potential.
[edit] Monitoring Therapeutic Response
The impact of effective antiretroviral therapy can be detected quickly. Results of therapy are evaluated primarily with plasma HIV mRNA levels (viral load). At a minimum the HIV mRNA level is expected to decrease by 10-fold (1 log) at 8 weeks and to no detectable virus (less than 50 copies/ml) at 4 to 6 months after initiation of treatment. More than 90% of patients who eventually achieve undetectable viral loads accomplish this within 12 weeks of therapy. The CD4 count change with therapy is variable. The counts may gradually rise during a period of months to years if suppression of the viral load continues. Patients with a stable clinical course and adequate laboratory values can be monitored with viral load measurements every 3 to 4 months and CD4 counts every 3 to 6 months. Persistently detectable virus after 16 to 24 weeks of therapy and repeatedly detectable virus in a patient who previously achieved an undetectable viral load are criteria for drug failure. The recent use of "third-generation" or "ultrasensitive" viral load assays, which can detect HIV RNA to a level of 20 to 50 copies/ml, has led to the identification of a greater number of "virologic failures" at an earlier stage.
[edit] Changing Therapy
Specific criteria that suggest a need to change antiretroviral medications include the following[10]:
- Less than a 0.5-log to 0.75-log reduction in plasma HIV RNA by 4 weeks or less than a 1-log reduction by 8 weeks
- Failure to suppress plasma HIV RNA to undetectable levels within 4 to 6 months
- Repeated detection of virus in plasma after initial suppression to undetectable levels, suggesting the development of resistance
- Any reproducible significant increase, defined as threefold or greater, from the nadir of plasma HIV RNA that is not attributable to intercurrent infection, vaccination, or test methodology
- Undetectable viremia in the patient receiving double nucleoside therapy to decrease the risk of virologic failure
- Persistently declining CD4+ T-cell numbers
- Clinical deterioration
- Regimen intolerance
If therapy has led to virologic suppression but the patient has intolerance or toxicity, a single drug can be substituted to replace the offending drug. When therapy requires alteration because of therapeutic failure, the regimen options are more complex but generally require changing at least two drugs. Before altering therapy, the physician must recognize that the choice of available agents is limited and that new drug regimens may reduce future treatment options. Thus it is preferable for some patients to continue a regimen that has not achieved complete viral suppression. Referral or consultation with an experienced HIV clinician is strongly encouraged when considering a change in therapy.
Regimen changes also are guided by a thorough drug treatment history and more recently by the results of drug resistance testing. Phenotypic resistance assays measure an HIV isolate's ability to grow in the presence of specific drugs in varying concentrations. The assays are time-consuming, labor intensive, and expensive. Currently, genotypic assays are more available and widely used. These assays detect drug resistance mutations that are present in the viral genes. Each mutation identified must be present in at least 20% of circulating viral particles to be detected. Thus mutations that developed in the past but are not predominant at testing may be missed. Interpretation of resistance testing results requires knowledge regarding the range of mutations that antiretroviral drugs select for and the potential of mutations for cross-resistance to other drugs. Again, an expert in HIV care should be consulted.
[edit] Drug Interactions
Many drugs should not be used with certain antiretroviral agents, and many drug interactions can occur between antiretrovirals and other drugs. All PIs are substrates and inhibitors of the hepatic cytochrome P-450 enzyme system with varying degrees of potency; for example, rifampin levels increase and PI levels decrease with coadministration, so these agents should not be used together. Other drug groups whose levels may be altered by antiretrovirals include antifungals (ketoconazole), antihistamines (astemizole, terfenadine), gastrointestinal motility agents (cisapride), oral contraceptives, anticonvulsants, psychotropics, antidepressants, antiarrhythmic agents, ergot alkaloids, analgesics, lipid-lowering agents, and methadone. Some of these drugs may alter antiretroviral drug levels as well. Certain combinations require dosing adjustments, whereas other combinations are contraindicated and should not be prescribed.
Interactions also occur between some antiretroviral agents; for example, coadministration of saquinavir and efavirenz is not recommended because levels of both drugs decrease, especially saquinavir. Higher doses of indinavir are prescribed when used concomitantly with efavirenz because of lower levels of indinavir in this combination. Because of such potential interactions, all prescription and nonprescription medications coadministered with antiretroviral drugs should be evaluated for potential interactions.[5][10]
[edit] Occupational Exposure
HCWs occupationally exposed to HIV by a needle-stick injury or other exposure should receive immediate prophylaxis, preferably within 1 hour. Postexposure prophylaxis with zidovudine may result in an 80% reduction in the risk of infection. The decision to use postexposure prophylaxis depends on the likelihood of HIV infection in the source patient and the nature of the exposure.[3]
[edit] FEMALE AND PREGNANT PATIENTS
Men constituted most cases early in the U.S. HIV epidemic, but throughout the 1990s the numbers of new cases in women increased dramatically. Between July 1998 and July 1999, 32% of new adult cases of HIV infection in the United States were women.[7] Also, the vast majority of HIV-infected women during this period (77%) were black or Hispanic. A large proportion of these women are poor and have inadequate access to health care. Although HIV infection likely progresses at similar rates in women and men, delays in the recognition of a woman's risk of HIV infection may lead to a relatively late diagnosis. Women, particularly adolescents, infected through heterosexual sex often are unaware of the HIV infection status of their male partner and do not think they are at increased risk.
The first HIV-related clinical manifestations in women often involve the reproductive tract. Nearly one third of women have an active gynecologic problem at their first HIV clinic visit, most often (1) recurrent vaginal candidiasis, (2) severe genital HSV-2 infection, (3) cervical dysplasia and neoplasia, and (4) recurrent or severe pelvic inflammatory disease (PID). Recurrent vaginal candidiasis is the most common initial manifestation of HIV, as well as one of the most frequent opportunistic infections during HIV infection in women, which may not be recognized as HIV related. Perineal herpetic infections may be more severe and persistent with HIV infection. Women are at increased risk for cervical dysplasia from human papillomavirus. In general for this population, Pap smears are more often abnormal, cervical dysplasia more severe and extensive, and progression to invasive cancer more common, with poor response to conventional therapy. A high-grade cervical lesion on routine Pap screening should alert the physician to possible HIV infection. PID, as with many other STDs, is common in HIV-infected patients, who may have an increased rate of complications (e.g., tuboovarian abscess) and require surgical intervention more often than HIV-negative women.
The social impact of HIV infection in women has yet to be fully appreciated. No longer a problem predominantly of substance abusers, heterosexually acquired HIV infection will likely continue to expand. Many HIV-infected women are mothers, with tremendous implications for their role as primary caregiver of their families. By the early part of the millennium, millions of children worldwide will be orphaned as a result of the HIV epidemic. Child care and other family-related concerns may drive many women to obtain and comply with medical care. As the numbers continue to increase, the primary care physician needs to assume an integral role in the diagnosis, treatment, and education of women with HIV infection.
[edit] Antiretroviral Therapy
Zidovudine significantly reduces the incidence of perinatal transmission, by 66% in one study. Furthermore, combination antiretroviral therapy (HAART) further reduces the transmission rate. Pregnant women should doubly benefit from HAART: improved maternal health and prognosis and decreased risk of perinatal transmission. Besides zidovudine, however, experience with most antiretrovirals during pregnancy is limited. The physician and patient should make treatment decisions carefully, preferably with the guidance of experts in accordance with the following principles:
- All HIV-infected pregnant women should be treated with antiretroviral therapy during pregnancy, instituted no later than the second trimester if possible. Treatment of the mother should be based on the currently accepted treatment guidelines (see earlier), taking into account the latest data on drug safety in pregnancy.
- Zidovudine should probably be a part of any antiretroviral regimen because it has proven safety and efficacy in pregnancy.
- The therapeutic goal should be reduction in viral load to as low a level as can be achieved, since the nadir viral load predicts durability of response for the mother and since viral load correlates with risk of perinatal transmission.
- Consideration should be given to delaying institution of antiretroviral therapy during the first trimester (the period of organogenesis) if possible.
- Patients on stable therapy before pregnancy should probably continue their medications; if treatment is to be discontinued, all antiviral medications should be discontinued.
Zidovudine monotherapy can be considered for patients with well-maintained CD4 counts (greater than 500/mm3) and viral loads less than 10,000 to 20,000 copies/ml because the development of resistance to ZDV has been observed to be low. Regardless of regimen, the newborn needs to receive ZDV for the first 6 weeks of life.[10]
[edit] Modes of Delivery
Most perinatal transmissions of HIV presumably occur during delivery as the newborn is exposed to infected fluids during transit through the birth canal. Consequently, many studies have examin