HIV Mandell Clinical Manifestations

121
General Clinical Manifestations of Human Immunodeficiency Virus Infection (Including the Acute Retroviral Syndrome and Oral, Cutaneous, Renal, Ocular, Metabolic, and Cardiac Diseases)
TIMOTHY R. STERLING | RICHARD E. CHAISSON stitutional wasting syndrome were observed in persons from AIDS risk groups who had deficits in cellular immunity.15-19 The term AIDSrelated complex was coined to describe the signs and symptoms of immunodeficiency recognized with increasing frequency in persons at risk for AIDS.20 In 1982 to 1983, several investigators postulated an asymptomatic carrier state of the AIDS agent in healthy homosexual men, heterosexual partners of intravenous drug users, and Haitians who were noted to have laboratory evidence of impaired cellular immunity.21 After HIV was first described in 1983 to 1984,22-24 serologic tests to identify persons infected with HIV were developed that allowed large serologic surveys of at-risk populations to estimate the number of individuals infected with the virus and to delineate the spectrum of HIV-associated diseases. Retrospective studies of serum and tissue indicated that the virus was present in Africa as early as 1959 and that disease associated with HIV occurred in the United States in 1968.25-28 The CDC expanded its case definition of AIDS in 1985 and again in 1987 to accommodate the increased number of manifestations of impaired cellular immunity that had become associated with HIV infection.29,30 The World Health Organization (WHO) also promulgated a case definition for AIDS for use in developing countries that lacked sophisticated diagnostic resources.31 The AIDS case definition and HIV staging system were revised again in 1993 to include individuals with advanced immunodeficiency and with several other clinical manifestations of HIV disease.32 The surveillance case definitions for HIV and AIDS were again revised by the WHO in 2007.33 In 2008, the CDC revised the HIV classification system and the surveillance case definitions for HIV infection and AIDS in adults and adolescents, and combined them into a single case definition for HIV infection.34 Both the WHO and CDC revised surveillance case definitions now require laboratory confirmation of HIV infection. Insights into the pathogenesis of HIV disease have emphasized the critical role of viral dynamics in the natural history of HIV infection,35-37 leading to clinical management schemata based largely on viral load and CD4+ cell levels (see later).
Human immunodeficiency virus (HIV) infection results in a wide
range of clinical consequences from asymptomatic carriage to lifethreatening opportunistic disease. In persons infected with HIV, ongoing viral replication produces a sequential decline in and ablation of cell-mediated immunity, giving rise to diverse manifestations of opportunistic disease. The acquired immunodeficiency syndrome (AIDS) is the most advanced stage of this illness, in which the infected host can no longer control opportunistic organisms or malignancies that rarely cause illness in immunocompetent individuals. The clinical features of HIV may vary according to the individuals age, gender, race, geographic location, treatment status, and behavioral history. This chapter reviews selected clinical aspects of HIV infection, from the acquisition of the virus to death with AIDS, and discusses the classification and staging of this important viral infection and the acute retroviral syndrome and oral, cutaneous, renal, ocular, and cardiac diseases.
History
Disease caused by HIV-induced immunosuppression was first described in late 1980 and early 1981, when physicians in Los Angeles, New York, and San Francisco observed opportunistic infections in homosexual men.1-4 Simultaneously, an outbreak of Kaposis sarcoma (KS), a previously rare malignancy, was reported in young homosexual men from the same three cities.5,6 These patients had a selective defect in cell-mediated immunity that was manifested by low numbers of CD4+ T lymphocytes and the development of opportunistic infections. That opportunistic disease occurred in homosexual men who had previously been healthy suggested that immunodeficiency developed because of an acquired rather than a congenital trait. In 1982, the Centers for Disease Control and Prevention (CDC) developed a case definition, based on the clinical, immunologic, and epidemiologic features of the first clusters of cases, for what was called the acquired immunodeficiency syndrome.7 AIDS was defined as the occurrence of a reliably diagnosed disease at least moderately indicative of underlying cellular immunodeficiency in a person without a condition known to be associated with an increased incidence of diseases related to cellular immunodeficiency. AIDS became a reportable condition in the United States in 1983. Soon after the initial case reports of AIDS, additional cases were observed in persons other than homosexual men. In 1981 and 1982, heterosexual intravenous drug users and immigrants from Haiti were reported to have AIDS.8-12 AIDS cases in hemophiliacs, recipients of blood transfusions, and Africans were soon reported.13,14 As the groups of persons at risk for AIDS expanded, clinicians noted an increasing spectrum of clinical manifestations of AIDS-associated immunodeficiency. Unexplained generalized lymphadenopathy, idiopathic thrombocytopenia, oral candidiasis, herpes zoster, and a con-
Classification of Human Immunodeficiency Virus Infection

HIV infection represents an ongoing active viral process in most untreated individuals associated with progressive immunodeficiency that is likely to result in serious clinical consequences. Although there may be a prolonged state of clinical latency, during which many patients are unaware of their infection, HIV infection is usually not virologically latent, and infection with the virus should be considered a disease state. Individuals who are infected but asymptomatic may not be ill but do have a chronic and progressive condition that without treatment may ultimately result in significant impairment and death. Although distinguishing between HIV infection and AIDS has been
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Part II Major Clinical Syndromes
121-1 Stage Stage 1
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Human Immunodeficiency Virus (HIV) Infection Staging Systems Laboratory Evidence* Laboratory confirmation of HIV infection and CD4+ T-lymphocyte count of 500 cells/L or CD4+ T-lymphocyte percentage of 29 Laboratory confirmation of HIV infection and CD4+ T-lymphocyte count of 200-499 cells/L or CD4+ T-lymphocyte percentage of 14-28 Laboratory confirmation of HIV infection and CD4+ T-lymphocyte count of <200 cell/L or CD4+ T-lymphocyte percentage of <14 Laboratory confirmation of HIV infection and no information on CD4+ T-lymphocyte count or percentage Clinical Evidence None required (but no AIDS-defining condition)
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WHO Clinical Staging of Established HIV Infection WHO Clinical Stage 1 2 3 4
HIV-Associated Symptoms Asymptomatic Mild symptoms Advanced symptoms Severe symptoms
Stage 2
None required (but no AIDS-defining condition)
Stage 3 (AIDS)
Stage unknown
or documentation of an AIDS-defining condition (with laboratory confirmation of HIV infection) and no information on presence of AIDS-defining conditions
*The CD4+ T-lymphocyte percentage is the percentage of total lymphocytes. If the CD4+ T-lymphocyte count and percentage do not correspond to the same HIV infection stage, select the more severe stage. Documentation of an AIDS-defining condition supersedes a CD4+ T-lymphocyte count of 200 cell/L and a CD4+ T-lymphocyte percentage of total lymphocytes of 14. Although cases with no information on CD4+ T-lymphocyte count or percentage or on the presence of AIDS-defining conditions can be classified as stage unknown, every effort should be made to report CD4+ T-lymphocyte counts or percentages and the presence of AIDS-defining conditions at the time of diagnosis. Additional CD4+ T-lymphocyte counts or percentages and any identified AIDS-defining conditions can be reported as recommended. From Schneider E, Whitmore S, Glynn KM, et al; Centers for Disease Control and Prevention (CDC). Revised surveillance case definitions for HIV infection among adults, adolescents, and children aged <18 months and for HIV infection and AIDS among children aged 18 months to <13 yearsUnited States, 2008. MMWR Recomm Rep. 2008;57(RR-10):1-12.
historically useful for epidemiologic purposes, the distinction is somewhat arbitrary and is less meaningful from a clinical perspective in an era of potent antiretroviral drug therapy. As noted, current clinical staging approaches favor use of the CD4+ lymphocyte counts and plasma viral load assays. Several systems for classifying HIV infection and disease have been developed and have evolved over the past 2 decades. The 1986 CDC classification system placed HIV-infected persons into four categories: group I, acute infection; group II, asymptomatic infection; group III, persistent generalized lymphadenopathy (PGL); and group IV, symptomatic HIV disease.38 This system had limited prognostic usefulness and was supplanted by the 1993 classification system and revised case definition.32 The 1993 CDC classification system for HIV categorized HIV-infected individuals according to clinical and CD4+ cell count groupings. The clinical categories were as follows: group A, asymptomatic, acute HIV infection, or PGL; group B, symptomatic HIV disease; and group C, AIDS indicator conditions, encompassing the 1987 case definition with the addition of recurrent bacterial pneumonia, pulmonary tuberculosis, and invasive cervical cancer. The revised 2008 CDC
surveillance case definition includes three stages based on CD4+ lymphocyte count and percentage and clinical evidence including AIDSdefining conditions (Table 121-1).34 The CDC classification system for HIV infection recognizes the prognostic significance of the CD4+ cell count in individuals with HIV infection, but it is important to recognize that there is considerable variation in risk of opportunistic complications and prognosis in individuals with CD4+ cell counts below 200/mm3. Those with CD4+ counts below 50/mm3, for example, are generally considered to have advanced HIV disease and are at much higher risk for death and for the development of opportunistic infections such as cytomegalovirus (CMV) disease or disseminated Mycobacterium avium complex infection. The CDC classification system was initially developed at a time when the inevitable course of HIV infection was progression toward advanced immunodeficiency and death, and when drug therapy was of limited and transient efficacy in stemming the course of the disease. According to the CDC classification system, HIV-infected individuals are classified on the basis of the most advanced stage that they have reached.34 In the present era, patients treated with combination antiretroviral therapy often experience marked improvement in cellular immune function and have a dramatically lower risk of developing opportunistic disease than they had before receiving treatment. There is no current mechanism for reclassifying patients on the basis of immunologic and clinical improvement resulting from antiretroviral therapy, a situation that understandably curtails use of the CDC and WHO systems. In areas in which combination antiretroviral therapy is not widely used, these classification schemes more reliably reflect the maturity and status of the HIV epidemic within populations. The WHO classification system (Tables 121-2, 121-3, and 121-4) is used primarily in developing countries. However, there are limitations that make it difficult for this staging system to be uniformly implemented. Many of the classifications require the diagnosis of opportunistic infections that cannot be readily confirmed in most resource-poor settings; clinical criteria for establishing presumptive or definitive diagnoses might be useful. Estimates of weight loss and other constitutional symptoms are also difficult in such settings. A comparison of the CDC and WHO staging systems is presented in Table 121-5.
Natural History of Human Immunodeficiency Virus Infection

The clinical spectrum of HIV infection includes primary infection (the acute retroviral syndrome), asymptomatic infection, early symptomatic infection, and advanced immunodeficiency with opportunistic
121-3
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WHO Immunologic Classification for Established HIV Infection Age-Related CD4 Values
HIV-Associated Immunodeficiency None or not significant Mild Advanced Severe
<11 mo (% CD4+) >35 30-35 25-29 <25
12-35 mo (% CD4+) >30 25-30 20-24 <20
36-59 mo (% CD4+) >25 20-25 15-19 <15
>5 yr (Absolute No./mm3 or % CD4+) >500 350-500 200-349 <200 or <15%
121 General Clinical Manifestations of Human Immunodeficiency Virus Infection
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121-4
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WHO Clinical Staging of HIV/AIDS for Adults and Adolescents with Confirmed HIV Infection
Clinical Stage 1 Asymptomatic Persistent generalized lymphadenopathy Clinical Stage 2 Moderate unexplained weight loss (<10% of presumed or measured body weight)* Recurrent respiratory tract infections (e.g., sinusitis, tonsillitis, otitis media, pharyngitis) Herpes zoster Angular cheilitis Recurrent oral ulceration Papular pruritic eruptions Seborrheic dermatitis Fungal nail infections Clinical Stage 3 Unexplained* severe weight loss (>10% of presumed or measured body weight) Unexplained chronic diarrhea for longer than 1 month Unexplained persistent fever (above 37.6 C, intermittent or constant, for longer than 1 month) Persistent oral candidiasis Oral hairy leukoplakia Pulmonary tuberculosis (current) Severe bacterial infections (e.g., pneumonia, empyema, pyomyositis, bone or joint infection, meningitis or bacteremia) Acute necrotizing ulcerative stomatitis, gingivitis, or periodontitis Unexplained anemia (<8 g/dL), neutropenia (<0.5 109/L), or chronic thrombocytopenia (<50 109/L) Clinical Stage 4 HIV wasting syndrome Pneumocystis jirovecii Recurrent severe bacterial pneumonia Chronic herpes simplex infection (orolabial, genital or anorectal, longer than 1 months duration, or visceral at any site) Esophageal candidiasis (or candidiasis of trachea, bronchi, or lungs) Extrapulmonary tuberculosis Kaposis sarcoma Cytomegalovirus infection (retinitis or infection of other organs) Central nervous system toxoplasmosis HIV encephalopathy Extrapulmonary cryptococcosis, including meningitis Disseminated nontuberculous mycobacterial infection Progressive multifocal leukoencephalopathy Chronic cryptosporidiosis (with diarrhea) Chronic isosporiasis Disseminated mycosis (coccidiomycosis or histoplasmosis) Recurrent nontyphoidal Salmonella bacteremia Lymphoma (cerebral or B-cell non-Hodgkins) or other solid HIV-associated tumors Invasive cervical carcinoma Atypical disseminated leishmaniasis Symptomatic HIV-associated nephropathy or symptomatic HIV-associated cardiomyopathy
*Unexplained refers to where the condition is not explained by other causes. Some additional specific conditions can also be included in regional classifications (such as reactivation of American trypanosomiasis [meningoencephalitis and/or myocarditis]) in the World Health Organization Region of the Americas and disseminated penicilliosis in Asia.
1200 Primary Acute HIV syndrome infection Wide dissemination of virus 1100 Death Seeding of lymphoid organs 1000 Opportunistic diseases 900 Clinical latency CD4+ T lymphocyte count (cells/mm3) 800 700 600 500 400 300 200 100 0 0 3 6 9 12 Weeks 1 2 3 4 5 6 7 8 9 10 11 Years Constitutional symptoms
107
Culturable plasma viremia (dilutional titer)
HIV RNA copies per mL plasma
1 512 1 256 1 128 1 64 1 32 1 16 1 8 1 4 1 2
106
105
104
103
102
Figure 121-1 Natural history of human immunodeficiency virus (HIV) infection in the absence of therapy in a hypothetical patient. (From Fauci AS, Pantaleo G, Stanley S, Weissman D. Immunopathogenic mechanisms of HIV infection. Ann Intern Med. 1996;124:654-663.)
complications. Figure 121-1 shows a schematic diagram of the key immunologic, viral, and clinical features of HIV infection in untreated individuals. Viral load or viremia is monitored by measurement of HIV RNA in plasma, and immunologic status is reflected by the absolute number of CD4+ lymphocytes or the proportion of lymphocytes that express CD4+. Primary HIV infection is characterized by a high concentration of HIV RNA in plasma and suppression of the CD4+ cell count. Plasma viremia declines precipitously with antibody seroconversion and the development of an anti-HIV immune response, usually reaching a steady-state level within 6 to 12 months.39,40 In most untreated asymptomatic patients, the CD4+ cell count declines gradually over several years. The slope of decline is a function of the plasma viral load. Plasma viremia increases, accompanied by a more rapid decline in CD4+ count, before the onset of symptomatic disease. As the viral load rises and the CD4+ cell count falls, the risk of opportunistic infections, malignancies, wasting, neurologic complications, and death increases substantially. There is considerable variation in the progression of HIV disease, with some individuals progressing from infection to AIDS in less than 5 years41 and so-called long-term nonprogressors remaining asymptomatic without treatment or evidence of immunologic decline for many years.42,43 Long-term nonprogressors appear to fall into at least two categories. Most have detectable viremia but maintain CD4+ cell
121-5
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Comparison of WHO and CDC Staging Systems* WHO T-Lymphocyte Count and Percentage CD4 T-lymphocyte count of 500 cells/L
+
WHO Stage Stage 1 (HIV infection) Stage 2 (HIV infection) Stage 3 (advanced HIV disease [AHD]) Stage 4 (acquired immunodeficiency syndrome [AIDS])
CDC Stage Stage 1 (HIV infection) Stage 2 (HIV infection) Stage 2 (HIV infection) Stage 3 (AIDS)
CDC T-Lymphocyte Count and Percentage CD4+ T-lymphocyte count of 500 cells/L or CD4+ T-lymphocyte percentage of 29 CD4+ T-lymphocyte count of 200-499 cells/L or CD4+ T-lymphocyte percentage of 14-28 CD4+ T-lymphocyte count of 200-499 cells/L or CD4+ T-lymphocyte percentage of 14-28 CD4+ T-lymphocyte count of <200 cells/L or CD4+ T-lymphocyte percentage of <14
CD4+ T-lymphocyte count of 350-499 cells/L CD4+ T-lymphocyte count of 200-349 cells/L CD4+ T-lymphocyte count of <200 cells/L or CD4+ T-lymphocyte percentage of <15
*For reporting purposes only. Among adults and children aged 5 years. Percentage applicable for stage 4 only. Among adults and adolescents (ages 13 years). CDC also includes a fourth stage, stage unknown; laboratory confirmation of HIV infection but no information on CD4+ T-lymphocyte count or percentage and no information on AIDS-defining conditions.
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121-6 <500
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Probability of Developing Acquired Immunodeficiency Syndrome* in 1604 Men in the Multicenter AIDS Cohort Study Baseline CD4+ Count >750 <750 Any >750 <750 >750 351-750 350 >500 351-500 201-350 <200 Number Studied 66 56 257 93 300 64 259 73 141 121 104 70 Number with AIDS 3 13 90 39 179 42 194 63 105 111 92 67 % AIDS at 3 Years 0 3.7 2.0 3.2 8.1 9.5 16.1 40.1 32.6 47.9 64.4 85.5 % AIDS at 6 Years 1.7 9.6 16.6 14.2 37.7 36.7 54.9 72.9 66.8 77.7 89.3 97.9 % AIDS at 9 Years 3.6 22.3 35.4 59.7 62.4 62.4 76.3 86.2 76.3 94.4 92.9 100
Baseline Viral Load
501-3000 3001-10,000 10,001-30,000
>30,000
*1987 Centers for Disease Control and Prevention case definition. Based on baseline HIV branched-chain DNA viral load and CD4+ cell count. HIV RNA copies/mL of plasma by branched-chain DNA. Viral load determined by reverse transcriptasepolymerase chain reaction approximately twofold greater. CD4+ cells/mm3. AIDS, acquired immunodeficiency syndrome; HIV, human immunodeficiency virus. From Mellors JW, Munoz A, Giorgi JV, et al. Plasma viral load and CD4+ lymphocytes as prognostic markers of HIV-1 infection. Ann Intern Med. 1997;126:946-954.
levels that provide adequate protection from the development of opportunistic disease. These individuals generally have gradual loss of CD4+ lymphocytes, however, and eventually progress to advanced immunodeficiency. A much smaller group of individuals are so-called elite controllers, who have undetectable HIV viral loads and maintain normal CD4+ lymphocyte counts.44 This group is of considerable interest because of their ability to contain viral replication. Understanding of the mechanisms whereby they control HIV is of potential value for the development and evaluation of HIV vaccines. Before the availability of effective antiretroviral therapy, the rate of progression from primary HIV infection to AIDS and from AIDS to death was estimated in a number of studies. Among homosexual men in San Francisco, the median time from seroconversion to AIDS by the 1987 CDC case definition was 9.8 years.45 Other studies estimated the period from infection to AIDS (1987 definition) to be 7 years for transfusion recipients, 10 years for hemophiliacs, 10 years for injection drug users, and 8 to 12 years for homosexual men.46 An important study of the natural history of HIV infection was the study of a cohort of homosexual and bisexual men by the San Francisco Department of Public Health and the CDC beginning early in the AIDS epidemic.47 These subjects were originally enrolled in a study of hepatitis B vaccine in 1978 and had serologic studies and clinical evaluations that dated from that time. Of the 489 men for whom the time of HIV seroconversion could be reliably estimated, 13% developed AIDS within 5 years, 51% within 10 years, and 54% at 11 years. In addition, of those who had not developed AIDS within 11 years of seroconversion, 19% had symptomatic disease and another 29% had CD4+ cell counts less than 200/mm3. Thus, after 11 years of follow-up, more than three quarters of HIV-infected homosexual men had severe immunodeficiency, had AIDS, or had died. A number of laboratory tests have been correlated with progressive immunodeficiency, the development of AIDS, and mortality. Taken together, however, the CD4+ lymphocyte count and plasma viral load are the best prognostic markers for subsequent disease course in an HIV-infected individual. The CD4+ lymphocyte count, a specific test for cellular immunocompetence, is a sensitive predictor of the development of symptomatic HIV infection and AIDS in the near term, because it reflects current immunologic capacity.48-52 Conversely, the plasma viral load (HIV-1 RNA) is an extremely useful predictor of disease course over a more extended period and is strongly associated with the rate of subsequent CD4+ cell count decline.53-61 A more rapid decline in CD4+ count, faster clinical progression, and decreased survival are all associated with a higher baseline viral load. In a study of HIV-infected gay or bisexual men enrolled in the Multicenter AIDS Cohort Study, the risk of progression to AIDS and death was highly correlated with plasma viral load at study entry, indepen-
dent of CD4+ cell count.56,57 Baseline plasma viral load was a stronger predictor of progression and mortality than CD4+ count. In addition, the average annual decline in the CD4+ count of HIV-infected men varied according to their initial viral load, decreasing by 36 CD4+ cells/ year in men with baseline HIV-1 RNA less than 500 copies/mL, and by 77 CD4+ cells/year in men with baseline HIV-1 RNA higher than 30,000 copies/mL.57 Using the viral load and CD4+ count together, however, provides the best prognostic estimate of subsequent clinical course (Table 121-6; Fig. 121-2). Put in the context of HIV pathogenPre-HAART era 100 80 60 3year probability of AIDS (%) 40 20 0 >55 2055 720 1.57 <1.5 <200 201350 351500 501750 >750 CD4 count (cells/L)
HIV-1 RNA concentration ( 103 copies /mL) HAART era 100 80 60 40 20 0 >55 2055 720 1.57 <1.5
HIV-1 RNA concentration ( 103 copies /mL)
<200 201350 351500 501750 >750 CD4 count (cells/L)
Figure 121-2 Prognosis according to CD4+ cell count and viral load in the pre-Haart and Haart eras. These data were from 12,574 adult patients starting HAART with a combination of at least three drugs. Kaplan-Meier estimates of the probability of AIDS at 3 years are shown. HAART, highly active antiretroviral therapy. (From Egger M, May M, Chene G, et al. Prognosis of HIV-1-infected patients starting highly active antiretrovival therapy: a collaborative analysis of prospective studies. Lancet. 2002;360:119-129.)
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esis, the viral load measures the replicative rate of the infection and its destructive potential for the cellular immune system, and the CD4+ count gauges the extent of immune compromise and the present risk of opportunistic disease. In the absence of treatment, survival is short after the diagnosis of clinically defined AIDS. A study of survival of the first 505 patients with AIDS in San Francisco found a median survival of 9 months, with most patients dead within 2 years.62 Patients diagnosed with an opportunistic infection had the most rapid mortality, whereas survival was significantly longer in patients initially diagnosed with KS. Similar results were noted in AIDS patients in New York City, although overall survival was slightly longer (median survival, 12 months).63 Subsequent studies revealed that survival after diagnosis of AIDS was directly related to the CD4+ count at diagnosis. In most studies before the availability of combination antiretroviral therapy, median survival after the diagnosis of AIDS was estimated to be between 12 and 18 months.64 The mean survival time after a CD4+ count of 200/mm3 was 38 to 40 months.65,66 The rate of progression of HIV infection in population-based studies varies depending on age, with older individuals generally having a more rapidly progressive course.67-71 Whether age differences in the pace of progression of HIV infection are the result of differences in viral set points, host immune responses, or both is unclear. Patients who experience more severe or long-lasting symptoms during the acute retroviral syndrome tend to have higher viral loads after seroconversion and progress more rapidly than those who seroconvert without symptoms.72 Women have approximately half-log10 lower HIV-1 RNA than men after seroconversion, but this difference diminishes with time from seroconversion.73-75 Although HIV-1 RNA is an important predictor of subsequent disease progression in both women and men,57,76,77 there is no gender difference in HIV disease progression, particularly when women and men have equal access to care.78-80 There do not appear to be racial differences in HIV-1 RNA levels81 or the natural history of HIV disease progression.79,82 Other laboratory studies that predict the development of AIDS in a seropositive individual include a total lymphocyte count less than 1000/mm3, a total white blood cell count less than 4000/mm3, a hematocrit less than 40 mL/dL, and a low percentage of CD4+ lymphocytes. Because the CD4+ percentage has a narrower range of variation in most clinical laboratories than the absolute CD4+ cell count, many clinicians favor using this measure for staging and monitoring of patients.83 Other markers of HIV disease progression that have been validated in clinical studies include the HIV p24 antigen, serum 2-microglobulin, neopterin, acid-labile interferon-, anti-p24 antibody, and soluble CD8. These so-called surrogate markers are measures of viral markers or host immune responses to HIV. Many of these measures do not provide prognostic information independent of the viral load and have therefore been supplanted by quantitative plasma HIV-1 RNA monitoring in developed countries. Heat-denatured p24 antigen assay provides prognostic information independent of HIV-1 RNA84,85 but is unlikely to supplant the CD4+ count or HIV viral load as a clinical monitoring tool. Low-cost alternatives to flow cytometric quantification of CD4+ lymphocytes for application in resource-poor settings are currently under development and include manual assays that use enzyme-linked immunosorbent assay (ELISA) or bead-based formats.86 Other low-cost predictors of disease progression include total lymphocyte count and hemoglobin, although these are relatively nonspecific.87-89 Of note, coinfection with GB virus C, a close relative of hepatitis C virus, may be associated with a decreased risk of HIV disease progression.90-92 The probability of an HIV-infected individual developing opportunistic disease is influenced by several factors. First, immunocompetence is a critical determinant of whether an infected individual can contain a potential pathogen. As discussed later, the CD4+ cell count appears to be the most clinically useful measure of host cellular immunocompetence and plays a central role in the staging of HIV disease. Second, exposure to potential pathogens is required before disease can result. Although some opportunistic pathogens are ubiquitous, result-
ing in latent or continuous infection in a large proportion of HIVinfected persons (e.g., Pneumocystis jirovecii, CMV), others are prevalent in a smaller proportion of individuals and cause disease less often (e.g., Toxoplasma gondii). Other opportunistic pathogens do not appear to be associated with latent reactivation but rather cause disease when a sufficiently immunocompromised host acquires new infection (e.g., Cryptococcus neoformans, M. avium complex). Third, the relative virulence of a potential pathogen is a factor that may determine which disease is likely to occur. For example, more virulent organisms such as Mycobacterium tuberculosis or Streptococcus pneumoniae cause clinical illness in patients with less severe immunodeficiency, whereas less virulent organisms such as P. jirovecii or CMV cause illness in those with more severe immunodeficiency.93-95 Finally, whether a patient is taking chemoprophylactic agents with activity against specific pathogens influences the risk of disease. Figure 121-3 shows CD4+ cell counts at the time of diagnosis of opportunistic diseases in patients with CD4+ cell counts of 300/mm3 or less before 1996.96,97 Although the range of CD4+ cell counts for some conditions is broad, most patients with truly opportunistic infections had CD4+ counts less than 100/mm3. Although the clinical manifestations of HIV infection do not vary according to HIV subtype, the incidence of specific opportunistic infections is profoundly influenced by geography and the prevalence of infectious diseases in particular regions. HIV-1 infection increases susceptibility to tuberculosis, and the incidence of tuberculosis in HIV-infected persons is extremely high in sub-Saharan Africa, where tuberculosis is endemic.98 Malaria is also endemic in many developing countries and occurs with increased frequency and severity in HIVinfected persons, particularly during pregnancy.99 Opportunistic infections such as P. jirovecii pneumonia, M. avium complex disease, CMV retinitis, non-Hodgkins lymphoma, and HIV encephalopathy, which are relatively common in developed countries, are uncommon in developing countries, such as those in West Africa.100 In regions in which it is endemic (e.g., the Mediterranean, Central America, South America, Africa, and Asia), leishmania occurs with increased frequency among HIV-infected persons. Similarly, Trypanosoma cruzi (South America), histoplasmosis (Ohio and Mississippi River Valleys), and Penicillium marneffei (Thailand, China, Hong Kong) occur with increased frequency in certain regions.
400
CD4 (cells/mm3)
300
200
* *
100
HSV HZos Crp KS Cry Can PCP NHL Enc PML WS Tox CMVPCP2MAC
Opportunistic illness
Figure 121-3 range of CD4 lymphocyte counts at the time of diagnosis of opportunistic diseases in patients with human immunodeficiency virus (HIV) infection. Boxes represent the 25th to 75th percentiles, bars represent medians, and asterisks represent means. Can, Candida esophagitis; CMV, cytomegalovirus; Crp, cryptosporidiosis; Cry, cryptococcosis; Enc, HIV encephalopathy; HSV, herpes simplex virus; HZos, herpes zoster; KS, Kaposis sarcoma; MAC, Mycobacterium avium complex; NHL, non-Hodgkins lymphoma; PCP, first episodes of Pneumocystis jirovecii pneumonia; PCP2, recurrent P. jirovecii pneumonia; PML, progressive multifocal leukoencephalopathy; Tox, toxoplasmosis; WS, wasting syndrome. (From Moore RD, Chaisson RE. Natural history of opportunistic disease in an HIV-infected urban cohort. Ann Intern Med. 1996;124:633-642.)
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The incidence of specific opportunistic diseases has been determined for several large cohorts of HIV-infected individuals. In a cohort of more than 1200 patients with CD4+ cell counts less than 300/ mm3 prior to the availability of highly active antiretroviral therapy (HAART), the most common opportunistic infection was Candida esophagitis (13.3 cases/100 person-years). P. jirovecii pneumonia, disseminated M. avium complex, CMV disease, and the AIDS dementia complex occurred at rates of 5 to 9 cases/100 person-years. The relatively lower incidence of P. jirovecii pneumonia reflects the use of specific prophylaxis with trimethoprim-sulfamethoxazole or aerosolized pentamidine, which dramatically lowers the risk of this infection, even in the absence of HAART.70,96 Less common were toxoplasmosis, cryptococcal meningitis, herpes zoster, the wasting syndrome, and KS (2 to 4 cases/100 person-years). The least common complications were non-Hodgkins lymphoma, tuberculosis, progressive multifocal leukoencephalopathy, and cryptosporidiosis (1 to 2 cases/100 person-years). Similar results have been found in other cohorts of patients in developed country settings.101 Considerably less information is available on the natural history of HIV infection in developing countries, but the spectrum of disease in patients presenting with HIV-related illnesses is different, with tuberculosis, cryptococcosis, bacterial sepsis and pneumonia, herpes zoster, and gastroenteritis predominating.102 Early clinical findings may also predict disease progression in HIVinfected individuals who have not developed opportunistic disease. Oral candidiasis and oral hairy leukoplakia are markers of immunosuppression and herald the development of AIDS in many patients.103-105 Generalized lymphadenopathy is a common clinical finding in early HIV infection but does not predict progression to AIDS.106 The occurrence of an opportunistic disease increases the risk of death independently of the CD4+ cell count.107,108 This may be caused not only by morbidity related to the complication itself, but also by an increase in immune activation and inflammatory responses leading to upregulation of HIV replication, with acceleration of HIV disease progression. A number of studies have demonstrated increases in HIV viral load in patients with acute opportunistic infections.109-112 Although viral load generally decreases somewhat after the acute illness, it generally does not return to premorbid levels. EFFECt OF HIGHLY aCtIVE aNtIrEtrOVIraL tHEraPY ON NatUraL HIStOrY OF HUMaN IMMUNODEFICIENCY VIrUS INFECtION Even before the era of HAART, it was clear that antiretroviral therapy and prophylaxis against P. jirovecii pneumonia had substantially altered the natural history of AIDS, prolonging the median survival of treated AIDS patients to 2 to 3 years.113-117 Antiretroviral therapy and prophylaxis against P. jirovecii pneumonia and M. avium complex also prolonged the time from HIV infection to AIDS, decreased the incidence of opportunistic complications, and improved overall survival.118-125 Changes in plasma HIV-1 RNA and CD4+ lymphocyte counts resulting from antiretroviral drug treatment have been shown to be strong predictors of clinical progression (or regression) of HIV disease.126-128 The use of combination antiretroviral therapy and the introduction of protease inhibitors in 1995 and 1996 led to a dramatic change in the natural history of treated HIV disease.129-133 In the HIV Outpatient Study, mortality declined from 29.4 deaths/100 person-years in 1995 to 8.8 deaths/100 person-years in the second quarter of 1997 (Fig. 121-4).134 This decline in mortality was accompanied by marked decreases in the incidence of P. jirovecii pneumonia, M. avium complex disease, and CMV retinitis; the incidence of any one of those three infections declined from 21.9/100 person-years in 1994 to 3.7/100 person-years by mid-1997 (Fig. 121-5). The degree of benefit was associated with the intensity of antiretroviral therapy; combination therapy resulted in an improved prognosis compared with monotherapy, and the use of a protease inhibitor in a combination regimen was associated with the greatest benefit. In the United States as a whole, deaths attributed to AIDS decreased by 23% in 1996 and by 44% in 1997.130,131 Subsequent studies among cohorts of HIV-infected persons
40 Deaths Deaths per 100 person-years 30
100 90 80 70 60
20
50 40 30
10
Use of protease inhibitors
20 10
1994
1995
1996
1997
Figure 121-4 Incidence of death and use of protease inhibitors in patients with human immunodeficiency virus (HIV) infection and a CD4+ count lower than 100/mm3 in the HIV Outpatient Study. (From Palella FJ, Delaney KM, Moorman AC, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. N Engl J Med. 1998:338:853-860. 1998 Massachusetts Medical Society.)
have continued to demonstrate the beneficial effect of HAART on clinical disease progression and death (Fig. 121-6).135 Improvements in survival have also been documented in patients receiving HAART in resource-poor settings, although the incidence of death remains higher in these areas than in developed countries.136,137 In developed countries in particular, death among persons with AIDS or advanced HIV infection is now more frequently caused by chronic diseases not traditionally classified as related to HIV infection. In a study of persons with AIDS in San Francisco, the proportion of deaths associated with septicemia, nonAIDS-defining malignancies, chronic liver disease,
Number of opportunistic infections per 100 person-years
20 M. avium complex 15 Cytomegalovirus
10
P. jirovecii pneumonia
1994
1995
1996
1997
Figure 121-5 Incidence of selected opportunistic infections in patients with human immunodeficiency virus (HIV) infection and a CD4+ count lower than 100/mm3 in the HIV Outpatient Study in the era before and after the introduction of protease inhibitors. (From Palella FJ, Delaney KM, Moorman AC, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. N Engl J Med. 1998:338:853-860. 1998 Massachusetts Medical Society.)
Therapy with a protease inhibitor (% of patient days)
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100
Relative risk of AIDS and death
10
0.1 Sept, 1994 March, 1995 March, 1995 Sept, 1995 Sept, 1995 March, 1996 March, 1996 Sept, 1996 Sept, 1996 March, 1997 March, 1997 Sept, 1997 Sept, 1997 March, 1998 March, 1998 Sept, 1998 Sept, 1998 March, 1999 March, 1999 Sept, 1999 Sept, 1999 March, 2000 March, 2000 Sept, 2000 Sept, 2000 March, 2001 March, 2001 Sept, 2001 Sept, 2001, onwards
Time Figure 121-6 relative risk of acquired immunodeficiency syndrome (aIDS) or death since the introduction of highly active antiretroviral therapy (Haart) adjusted for CD4+ count at recruitment, age, previous Haart treatment, and aIDS status. Data are from 9803 HIV-infected patients seen at 70 treatment centers in Europe, Israel, and Argentina. Vertical bars represent 95% confidence intervals. (From Mocroft A, Ledergerber B, Katlama C, et al. Decline in the AIDS and death rates in the EuroSIDA study: An observational study. Lancet. 2003;362:22-29.)
viral hepatitis, overdose, obstructive lung disease, coronary artery disease, and pancreatitis increased between 1994 and 1998.138 In a study from Cleveland, 20% to 25% of HIV-infected persons who died between 1997 and 1999 had an undetectable viral load.139 A study from Switzerland has indicated that patients receiving effective antiretroviral treatment have a risk of death similar to that in patients with cured cancer.140 Interruption of HAART increases the risk of opportunistic disease and death from any cause, as well as major cardiovascular, renal, and hepatic disease.141,142 This suggests that lower counts of CD4+ lymphocytes and higher HIV-1 RNA increase the risk of non-AIDS events as well as AIDS-related events in HIV-infected persons.143 Effective therapy has not only decreased the incidence of new opportunistic infections but has also led to the resolution of preexisting conditions.144 In some cases, the immune restoration resulting from HAART can alter the clinical presentation of specific opportunistic infections, as in the case of focal mycobacterial lymphadenitis or CMV vitritis.145 It may also unmask opportunistic infections that were not evident prior to HAART initiation, such as tuberculosis.146,147 It is becoming increasingly clear that the immunologic changes resulting from HAART represent at least a partial immune reconstitution, although the recovery of antigen-specific immunity appears to lag behind CD4+ cell count increases.148-151 The clinical manifestations of immune reconstitution syndromes are discussed at the end of this chapter. The incidence of new opportunistic infections in patients who have had satisfactory virologic and immunologic responses to HAART is extremely low, even when primary prophylaxis has been discontinued.152,153 Moreover, reactivation of previously diagnosed opportunistic infections, such as M. avium complex infections and CMV retinitis, appears to be uncommon in patients with immune recovery who discontinue maintenance therapy.154,155 Thus, over the past 3 decades, the natural history of HIV infection has undergone considerable change, as has our understanding of it. The clinical course of HIV disease in those receiving antiretroviral
therapy is likely to evolve further in the coming years, with additional manifestations and disease trajectories becoming apparent as larger numbers of patients are treated for longer periods of time.
Clinical Presentation and Findings

HIV infection causes disease manifestations of three principal types: (1) an acute viral illness seen in the initial weeks of infection and associated with a high viral load and an intense host immune response; (2) immunologically mediated processes related to host responses to chronic viral infection (e.g., lymphadenopathy, thrombocytopenia, HIV-related dementia); and (3) opportunistic diseases resulting from impaired host responses as the cellular immune system is damaged or ablated. The major clinical syndromes most frequently seen in HIVinfected individuals fall into the last categorythat is, opportunistic diseases that arise as a consequence of impaired cellular immunity in late-stage HIV infection. Potent antiretroviral therapy has added two new categories of clinical manifestations that may be commonly encountered in patients with HIV infection, immune reconstitution syndromes with exacerbations of previously silent or adequately treated infections, especially mycobacterial infections,156,157 and a syndrome of lipodystrophy with fat loss and redistribution, elevated serum triglyceride and cholesterol levels, and insulin resistance seen in patients receiving HAART, especially with protease inhibitors.158,159 The clinical features of immune reconstitution syndromes are discussed later in this chapter, and the manifestations of drug toxicity related to the treatment of HIV are discussed in Chapter 128. aCUtE rEtrOVIraL SYNDrOME The initial manifestation of HIV infection in one half to two thirds of recently infected individuals is a mononucleosis-like illness referred to as the acute retroviral syndrome. The syndrome was first described in
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1985 by Cooper and colleagues160 as an acute mononucleosis-like syndrome in 11 of 12 homosexual men who seroconverted for HIV antibodies. In a follow-up study, 36 of 39 (92%) homosexual men with recent HIV infection recalled an illness consistent with the acute retroviral syndrome during the time when their tests showed seroconversion,161 but 40% of a seronegative control group also reported a mononucleosis-like illness. Similar descriptions of a characteristic syndrome have been reported in people infected with HIV through parenteral exposures, including health care workers exposed to accidental parenteral inoculation of HIV.162 The incidence of the acute retroviral syndrome is not precisely known. Retrospective studies of homosexual men infected with HIV found a low frequency of seroconversion illness.163,164 A prospective study of homosexual men showed a 55% incidence of a mononucleosis-like illness in 22 subjects who became antibody-positive compared with 21% in 44 nonconverting control subjects.165 In one study of 378 persons with acute retroviral syndrome, injection drug users had or reported symptoms less frequently than persons who acquired HIV through sexual transmission.166 Most health care workers with occupationally acquired HIV had the acute retroviral syndrome after exposure.162,167 Overall, this syndrome is probably underreported and underdiagnosed, as noted in two series of patients, most of whom were not initially thought to have acute HIV infection.168,169 The clinical features of the acute retroviral syndrome are nonspecific and variable.170-172 The onset of the illness ranges from 1 to 6 weeks after exposure to the virus but peaks at 3 weeks. Table 121-7 shows the signs and symptoms of the acute retroviral syndrome reported in 209 cases, reviewed by Niu and co-workers.173 Fever, sweats, malaise, myalgias, anorexia, nausea, diarrhea, and a nonexudative pharyngitis are prominent symptoms.173-180 Many patients report headaches, photophobia, and meningismus. Two thirds of patients may have a truncal exanthem that may be maculopapular, roseola-like, or urticarial. Skin biopsies are nonspecific, with perivascular lymphocytic infiltrates and dermal mononuclear cell infiltrates.181 In addition to aseptic meningitis, neurologic symptoms occur in a minority of patients and may include encephalitis, peripheral neuropathy, and an acute ascending polyneuropathy (Guillain-Barr syndrome).182 Physical examination frequently reveals cervical, occipital, or axillary lymphadenopathy; rash and, less commonly, hepatosplenomegaly. Oral aphthous ulcerations (Fig. 121-7) have been reported in several cases; these may involve the esophagus. Oral and esophageal candidiasis during the seroconversion illness has been reported. The remainder of the physical examination is usually unremarkable. Symptoms generally resolve
Figure 121-7
aphthous ulcer. (Courtesy of Dr. Stephen Raffanti.)
121-7
taBLE
Symptoms and Signs of the Acute Retroviral Syndrome in 209 Patients Number with Finding 200 154 146 146 112 94 80 67 66 56 38 30 24 13 12 Frequency (%) 96 74 70 70 54 45 38 32 32 27 21 14 12 6 6
Symptom or Sign Fever Adenopathy Pharyngitis Rash Myalgia or arthralgia Thrombocytopenia Leukopenia Diarrhea Headache Nausea, vomiting Elevated transaminase levels* Hepatosplenomegaly Thrush Neuropathy Encephalopathy
*Based on 178 subjects. Adapted from Niu MT, Stein DS, Schnittman SM. Primary human immunodeficiency virus type 1 infection: Review of pathogenesis and early treatment intervention in human and animal retrovirus infections. J Infect Dis. 1993;168:1490-1501.
in 10 to 15 days. A wide range of acute opportunistic infections have been reported in patients with the acute retroviral syndrome, including P. jirovecii pneumonia, cryptococcal meningitis, and Candida esophagitis. Their occurrence is probably caused by the depression of the CD4+ cell count that generally accompanies acute HIV infection. Laboratory evaluation of patients with the syndrome reveals a reduced total lymphocyte count, elevated sedimentation rate, negative heterophile antibody test, and elevated transaminase and alkaline phosphatase levels.173 When lymphocyte phenotyping is performed, a characteristic pattern is observed.183 Initially, the total lymphocyte count, including both CD4+ and CD8+ T lymphocytes, decreases, with a normal ratio of CD4+ to CD8+ cells. Within several weeks, both the CD4+ and CD8+ cell populations begin to increase. The rise in CD8+ cell numbers is relatively greater than that in CD4+ cells, and the CD4/ CD8 ratio is inverted. In the weeks that follow, the CD8+ cell population increases rather markedly because of HIV-specific CD8+ T lymphocytes. The ratio of CD4+ to CD8+ cells usually remains inverted as the acute illness resolves, primarily because of excess numbers of CD8+ cells. In patients with neurologic symptoms, cerebrospinal fluid may show a lymphocytic pleocytosis with normal levels of protein and glucose.184 HIV p24 antigen may be detected in the serum and cerebrospinal fluid in about 75% of patients with primary HIV infection within 2 weeks of exposure, often coincidentally with the onset of symptoms.184,185 Antigenemia can persist for several weeks or months and generally resolves when antibodies to p24 are produced in sufficient quantity to form complexes with free antigen. The most sensitive marker for acute HIV infection, however, is plasma HIV RNA, which is markedly elevated in most patients.186 Typical RNA levels range from 105 to more than 106 copies/mL of plasma, and the titers decline as the CD8+ cytotoxic T-cell and antibody responses increase subsequently. Low-level (less than 104) false-positive HIV RNA tests may occur, but high-level viremia is almost diagnostic of acute infection in the absence of anti-HIV antibodies. The enzyme immunoassay for HIV antibodies remains negative for an average of 2 to 6 weeks after the onset of symptoms, despite the appearance of specific antibodies on a Western blot of the patients serum. Anti-p24 appears on the Western blot shortly before seroconversion is detected by ELISA and by the appearance of antibodies to other antigens. To increase sensitivity among antibody-negative persons, and to overcome the costs, labor, and falsepositive results of HIV-1 RNA tests, pooled-sample group testing can be used.187,188 The differential diagnosis of the acute retroviral syndrome includes a number of other illnessesinfectious mononucleosis and other viral infections such as influenza, viral hepatitis, measles, rubella, primary herpes simplex virus (HSV) infection, cytomegalovirus, and secondary syphilis. Evaluation of patients presenting with an illness consistent
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with acute retroviral infection should include a careful history to elicit risks for HIV infection, laboratory tests to rule out mononucleosis, cytomegalovirus, and syphilis, HIV antibody and plasma RNA tests, and complete blood counts and differential. There is potential benefit in treating acute HIV with combination antiretroviral therapy, because there is evidence that this may lower the viral set point and lead to enhanced CD4+ and CD8+ HIV-specific responses.189 However, early treatment does not appear to prevent establishment of reservoirs of latently infected resting CD4+ cells and may not provide any long-term benefit.190 There are also concerns about the potential toxicity of longterm therapy and the risk of developing drug resistance. Thus, treatment of acute HIV infection is currently considered optional191 (also see Chapter 128). PErSIStENt GENEraLIZED LYMPHaDENOPatHY Infection with HIV is associated with a high prevalence of generalized lymphadenopathy, often beginning with the acute retroviral syndrome. In the early 1980s, PGL was recognized as a prodromal state to the development of AIDS in homosexual men who were otherwise healthy.15,17 The pathogenesis of generalized lymphadenopathy is related to the rapid infection of CD4+ cells in lymph nodes by HIV after initial infection. The syndrome of PGL is defined as the presence of two or more extrainguinal sites of lymphadenopathy for a minimum of 3 to 6 months for which no other explanation can be found. Biopsy specimens of lymph nodes from such patients usually reveal a follicular hyperplasia without specific pathogens. Approximately 50% to 70% of HIV-infected individuals develop PGL. The most frequently involved node groups are the posterior and anterior cervical, submandibular, occipital, and axillary chains; epitrochlear and femoral nodes may also be enlarged. Physical examination usually reveals symmetrical, mobile, rubbery lymph nodes ranging from 0.5 to 2 cm in size. Pain and tenderness are uncommon. Localized (i.e., asymmetrical) adenopathy and rapid nodal enlargement are not characteristic and suggest an infectious or malignant process. The remainder of the physical examination is often unremarkable, although other complications of HIV infection may be found, such as thrush or hairy leukoplakia. Mediastinal and hilar adenopathy is not characteristic of the syndrome; however, abdominal computed tomography (CT) often reveals enlarged mesenteric and retroperitoneal adenopathy in HIV-infected persons. The natural history of HIV infection in those with PGL does not differ significantly from that of HIV infection without PGL.106,192 Involution of enlarged lymph nodes, with degeneration of follicular germinal centers and loss of hyperplasia, often accompanies progression of HIV infection to advanced disease. In patients treated with HAART, previously involuted lymph nodes may again enlarge as HIV-specific and other T cells are replenished. In addition, focal lymphadenitis with constitutional symptoms may occur in patients with previously silent mycobacterial infections 1 to 2 months after starting HAART. These reversal or unmasking reactions, or immune reconstitution syndromes, are reminiscent of reversal reactions seen in multibacillary forms of leprosy, heralding a return of pathogen-specific T-cell responses. The differential diagnosis of PGL includes HIV infection and a wide variety of other processes associated with generalized lymphadenopathy, such as sarcoid, secondary syphilis, and Hodgkins disease. In patients with HIV infection, lymphadenopathy may also be caused by mycobacterial infections, KS, and lymphoma.193 An unusual cause of lymphadenopathy in patients with HIV infection is multicentric Castlemans disease.194,195 Castlemans disease is an angioproliferative, hyperplastic process of lymph nodes and other lymphoid tissues showing characteristic histologic findings, with either hyaline vascular or plasma cell variants. In patients with HIV in particular, multicentric Castlemans disease is the most common presentation, with involvement of lymph nodes, liver, spleen, and other organs. Although the pathogenesis of Castlemans disease is not fully understood, infection with Kaposis sarcoma-associated herpesvirus (human herpesvirus type 8) is thought to underlie a large proportion of cases.196,197 Unlike
PGL, multicentric Castlemans disease is associated with constitutional symptoms and multiorgan involvement in most HIV-infected patients. The diagnosis is established histopathologically. Treatment with the anti-CD20 monoclonal antibody rituximab has shown promise.198 In patients with clinical findings suggesting opportunistic disease, needle aspiration of lymph nodes may help establish a specific diagnosis.199 Examination of aspirates with cytologic, acid-fast, and Gram stains is valuable in identifying infection or malignancy. If a specific diagnosis is not determined after staining and culture of node aspirates, lymph node biopsy is indicated. Aspiration of lymph nodes in patients with PGL usually reveals benign cells. Biopsy specimens show follicular hyperplasia, with the normal architecture distorted by greatly expanded germinal centers composed of B lymphocytes. It is now known that active viral replication is occurring in these follicular cells and that virus is trapped in dendritic cells, although the patient may appear well clinically.200 Most patients with PGL require no invasive evaluation and can be managed according to standard guidelines for HIV infection. CONStItUtIONaL DISEaSE aND WaStING HIV infection is often completely asymptomatic; however, some patients complain of nonspecific constitutional symptoms in the months or years after primary infection but before opportunistic disease is diagnosed. Patients commonly complain of being easily fatigued and report the need to reduce their normal activities somewhat. Debilitating fatigue is uncommon in the early years of infection. Low-grade fevers (temperature lower than 38C), occasional night sweats, and intermittent diarrhea are also reported. Severe wasting, with loss of more than 10% of body weight, is generally a finding of advanced HIV disease. The exact incidence of constitutional symptoms, fatigue, and weight loss is not known, and the cause is varied and often multifactorial. The differential diagnosis of these findings includes intercurrent minor illnesses, endocrinologic abnormalities, anemia, and psychological or psychiatric disorders. Anxiety disorders and depression are common in populations of patients with HIV infection,201-203 and studies have suggested an increased prevalence of affective disorders among HIV-infected individuals. Injection drug users, in particular, have a high prevalence of affective disorders that may result in somatic complaints. Moreover, the physical effects of opiates and withdrawal from stimulants such as cocaine and amphetamines cause fatigue and other constitutional symptoms. MEtaBOLIC aND ENDOCrINE aBNOrMaLItIES A number of metabolic and endocrinologic disturbances have been identified in patients with HIV.204-206 Hypogonadism, particularly depression of testosterone or dihydrotestosterone levels, has been reported in men and women with HIV infection and weight loss or wasting.207,208 Elevated levels of myostatin-immunoreactive protein, a muscle catabolic agent, have been found in men with HIV and wasting.209 In most clinical studies, however, wasting has been found in association with decreased caloric intake, elevated catabolism caused by opportunistic infections, or chronic diarrhea.210-213 In advanced HIV, severe wasting, whatever the cause, is strongly associated with the risk of dying.214 Weight loss has remained an important predictor of mortality, even in the era of HAART.215 In patients with more advanced HIV disease with high viral loads and severe depletion of CD4+ cells, constitutional disease (fatigue, weight loss, malaise, fever) usually heralds the onset of opportunistic infections or malignancies. In one study of HIV-infected outpatients with fever, a specific cause could be identified for 83%.216 Common causes of fever in these patients included P. jirovecii pneumonia, M. avium complex bacteremia, catheter-related bacteremia, bacterial pneumonia, sinusitis, lymphoma, and drug reactions. Fever of longer than 2 weeks duration was more often associated with AIDS-defining illnesses.
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In African patients with HIV infection, a wasting illness, termed slim disease, has been described.217 These patients have debilitating fatigue, fevers, sweats, protracted diarrhea, and severe weight loss. Opportunistic or conventional pathogens are not found, but the patients waste away and die of severe malnutrition and terminal secondary infections. This illness has been encountered in developed countries as well but far less commonly than in Africaa pattern that suggests underdiagnosis of opportunistic diseases in Africa. Several studies of African patients with enteropathic slim disease have found that most had enteric pathogens or microsporidia when a thorough evaluation was performed.218,219 In Abidjan, Cte dIvoire, 37% of patients who died with a diagnosis of slim disease were found at autopsy to have disseminated tuberculosis,220 and the presence of tuberculosis at autopsy was strongly associated with the degree of wasting.221 The definition of wasting syndrome in the United States is the presence of unexplained constitutional disease for longer than 1 month with a temperature higher than 38.3C, diarrhea, and loss of more than 10% of baseline body weight. A thorough evaluation to identify specific pathogens that would explain the symptoms and that might be amenable to treatment is essential before wasting syndrome is diagnosed, and usually a specific cause can be implicated. In contrast to the wasting illness seen in advanced untreated HIV, persons receiving antiretroviral therapy may have lipid abnormalities, including hypertriglyceridemia and high low-density lipoprotein (LDL) cholesterol and low high-density lipoprotein (HDL) cholesterol levels. They may also have lipodystrophy, obesity, and insulin resistance.159,222 These abnormalities are seen more commonly with protease inhibitorbased therapy, but they also occur with non-nucleoside reverse transcriptase inhibitor therapy. The lipid and glucose abnormalities may contribute to an increased risk of cardiovascular disease, including myocardial infarction.223 OraL DISEaSE Abnormalities of the oral cavity occur throughout the course of HIV infection. Primary HIV infection has been associated with severe aphthous stomatitis and with oropharyngeal and esophageal candidiasis. As the infection progresses and immunologic impairment proceeds, numerous oral complications arise. In the late stages of disease, oral manifestations are highly prevalent and frequently severe.224-226 A number of studies have demonstrated that the occurrence of oral lesions such as candidiasis and hairy leukoplakia is associated with an increased risk of progression to AIDS.227-229 Oral Candidiasis Candida infections of the hard and soft palates, buccal mucosa, tongue, pharynx, and hypopharynx are observed frequently. Candida albicans is the species most commonly identified, but Candida tropicalis, Candida glabrata, and Candida krusei infections also occur. Contrary to systemic Candida infections, which appear to result from defects in phagocyte function and number, mucosal Candida infections result from impaired cellular immunity. The incidence of candidiasis increases with progressive cellular immunodeficiency, particularly as CD4+ lymphocyte counts fall below 200 to 300/mm3.230 Because oral candidiasis itself is an opportunistic infection, it is predictive of the disease progression and development of other AIDS-related infections. Several clinical manifestations of candidiasis have been described in HIV-infected patients. The most common form is thrush, pseudomembranous candidiasis. Characteristic cottage cheese plaques that can be removed with a tongue blade are seen on the soft palate, tonsils, and buccal mucosa (Fig. 121-8). Less often, thrush involves the lateral and posterior aspects of the tongue, the hard palate, and the hypopharynx. Candida infection can produce flat erythematous plaques distributed in the same way as the pseudomembranous form of the disease but without the characteristic white exudate. This atrophic form of candidiasis is underdiagnosed because many clinicians are unfamiliar with its appearance. Atrophic candidiasis of the tongue also occurs.
Figure 121-8 Raffanti.)
Oral candidiasis (thrush). (Courtesy of Dr. Stephen
Less frequently, Candida can cause a nonscrapeable white plaque similar to that in hairy leukoplakia (see next section). Unlike the corrugated lesions and hairlike projections seen in oral hairy leukoplakia (OHL), candidal lesions are smooth. This hypertrophic form of disease may involve the lateral border of the tongue, palate, and buccal mucosa. Candida infection of the lateral lip (angular cheilitis) is another common complication. Angular cheilitis can cause pain, fissures, erythema, and difficulty opening the mouth (Fig. 121-9). Physical examination, potassium hydroxide (KOH) preparation, and the response to antifungal therapy establish the diagnosis. The diagnosis of candidiasis is frequently made on the basis of physical examination alone. A KOH preparation of scraped material from a plaque is diagnostic and can be performed easily in most clinical settings. Cultures for Candida are rarely necessary. A biopsy specimen of oral lesions can be used to distinguish various forms of leukoplakia. A therapeutic trial of antifungal agents can also help establish a diagnosis. The widespread use of oral triazole antifungal agents has been accompanied by the emergence of disease caused by drug-resistant fungi.231 Risk factors for fluconazole-resistant candidiasis include an extended duration of prior antifungal therapy and low
Figure 121-9
angular cheilitis. (Courtesy of Dr. Stephen Raffanti.)
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CD4+ count.232 Of note, in patients treated with HAART, rates of fluconazole resistance were relatively low, even though many had received several previous courses of fluconazole, suggesting that advanced immunosuppression is the most important risk factor for resistance.233 In addition, some species of Candida, such as C. krusei and C. glabrata, are frequently less sensitive to fluconazole. Oral Hairy Leukoplakia Originally described in 1984 by Greenspan and colleagues,234 OHL is a raised white lesion of the oral mucosa that is usually seen on the lateral margin of the tongue. The frequency of occurrence of OHL increases as the CD4+ count decreases.230 OHL appears to be caused by the replication of Epstein-Barr virus in the epithelium of keratinized cells on the surface of the tongue and buccal mucosa.235 Other herpesviruses have also been isolated from cultures of biopsy specimens of lesions; however, their role in the pathogenesis of OHL is unclear. HIV is not routinely cultured from specimens and is not found with DNA probes. The diagnosis of OHL is established by visual inspection, failure to scrape off the lesion with a tongue blade, failure of the lesion to respond to antifungal therapy, and biopsy material or scrapings in which Epstein-Barr virus can be identified. Hairy leukoplakia is usually asymptomatic, although large lesions may impair taste, hinder eating, and cause discomfort. Lesions respond to high-dose acyclovir or ganciclovir, foscarnet, podophyllin, and isotretinoin, but only temporarily. There may be clinical improvement on antiretroviral therapy. Gingivitis and Periodontitis Severe gingivitis (linear gingival erythema) and periodontitis (necrotizing ulcerative periodontitis) have been observed in patients with HIV disease.236 The onset of symptoms is often insidious but may be abrupt. Pain is often severe; patients may note foul breath, bleeding gums, and loosening of teeth. Physical examination may reveal a bright red marginal line on the gingiva, necrosis and ulceration of interdental papillae, gingival erosion, exfoliation of enamel, and loose teeth. The cause of gingivitis and periodontitis is unclear. Cigarette smoking may be an important cofactor in the pathogenesis of periodontitis. Mixed cultures of aerobic and anaerobic flora have been obtained from gingival biopsy samples. More severe, ulcerating gingivitis can be caused by infections with gram-negative bacilli, particularly Klebsiella pneumoniae and Enterobacter cloacae. Infections tend to be chronic, but dbridement, irrigation, and topical antiseptic agents or metronidazole therapy may control some cases. Oral Ulcers A number of ulcerative lesions may occur in the oral cavity of patients with HIV infection. Herpes simplex virus (HSV) types 1 and 2 may cause primary or recurrent oral ulcers. These lesions generally appear as small smooth ulcers on an erythematous base on the lips, buccal mucosa, hard palate, or gums. The ulcers may be single or multiple and are often painful. Episodes may last for several weeks; acyclovir may be beneficial. CMV may rarely cause solitary large ulcers in those with disseminated CMV infection. Aphthous stomatitis is manifested by single or multiple painful ulcers, often with exudate or necrosis, that may appear on the buccal and labial mucosa and lateral margin of the tongue (see Fig. 121-7). These ulcers do not occur more commonly than in HIV-seronegative persons, but episodes are more severe and prolonged.237 They may be treated with topical steroids or thalidomide if persistent.238-240 The cause of oral ulcers is best determined by biopsy and viral culture, although minor lesions may be observed without specific therapy in many cases. Several drugs have been reported to cause oral and gastrointestinal ulcers, including zalcitabine, zidovudine, and dapsone. Other Oral Lesions The purple-red lesions of KS may occur at any site in the mouth, but the palate is most common. Lesions may become large and nodular. Non-Hodgkins lymphoma may arise in the mouth as a swelling or ulcers; biopsy is required for diagnosis. Oral warts caused by human
papillomavirus infection may be seen but they are not malignant precursors. Ketoconazole and zidovudine can cause brown oral pigmentation. Salivary glands such as the parotid gland may be enlarged by infiltration with CD8+ lymphocytes or benign lymphoepithelial cysts. These cysts often respond to antiretroviral therapy.241 MUSCULOSKELEtaL COMPLICatIONS Polymyositis complicates HIV infection in a small number of patients and can occur at any stage of HIV infection.242 Clinical features include myalgias, weakness of the proximal muscles, muscle tenderness, wasting, and fatigue.243 Creatine kinase and other muscle enzyme concentrations are usually elevated, although they do not correlate with disease severity; electrophysiologic studies are consistent with a myopathy.244,245 The pathogenesis is unknown; most patients respond clinically to a course of corticosteroids. Nucleoside reverse transcriptase inhibitors have been associated with a polymyositis-like clinical picture in a small proportion of patients who receive this drug class. Although initially described with zidovudine, it can occur with other drugs in this class. The mechanism of this myopathy is inhibition of mitochondrial DNA, which is distinguished on electron microscopy by ragged red fibers.246 Pyomyositis has been reported in patients with advanced HIV. Skin flora, particularly Staphylococcus aureus, are usually recovered from wound cultures, and preexisting skin diseases such as prurigo nodularis are a risk factor.247,248 Although rheumatologic findings in patients with HIV disease are not unusual, the extent to which HIV infection is associated with these disorders is not always clear. Defining a specific arthropathy caused by HIV is difficult because many patients with HIV infection are already at increased risk for inflammatory joint disease. Injection drug users, for example, may develop septic arthritis caused by pyogenic bacteria, particularly S. aureus. Homosexual men may have an increased risk for gonococcal arthritis or postinfectious reactive arthritis associated with genital or gastrointestinal tract infections (Reiters syndrome). Immune complex deposition related to hepatitis B or C infection may also be associated with arthritis in patients with HIV infection. Thus, although some animal retroviruses are clearly associated with arthropathies, the situation with HIV remains somewhat clouded. Data from three large cohort studies have demonstrated that Reiters syndrome does not occur with increased frequency in HIV-infected persons.249,250 The clinical course of Reiters syndrome in HIV-infected individuals may be prolonged and severe, however.251 Patients with this syndrome are usually human leukocyte antigen (HLA)B27 positive and present with an asymmetrical oligoarticular arthritis, primarily of the large joints of the lower extremities, and sacroiliitis. Urethritis, conjunctivitis, keratoderma blennorrhagicum, and circinate balanitis may also be present. An enthesopathy of the Achilles tendon and plantar fascia can result in a characteristic gait in which weight is distributed to the lateral portion of the feet.252 Aspirated synovial fluid is generally unremarkable, and synovial biopsy specimens show mononuclear cell infiltrates. Management is difficult, because the response to nonsteroidal anti-inflammatory drugs (NSAIDs) is limited and the use of the high doses of steroids often required further increases the risk of opportunistic infections. Methotrexate and azathioprine should also be avoided because of the resultant exacerbation of immune suppression. Osteopenia and avascular necrosis of bone occur at a higher frequency in HIV-infected persons than in HIV-seronegative persons in the general population,253-255 and the incidence of avascular necrosis appears to be increasing.256 Risk factors for avascular necrosis include corticosteroid therapy, lipid-lowering agents, and testosterone.254 Although avascular necrosis has been described in persons receiving HAART,257 such therapy does not appear to affect the risk of avascular necrosis.258 Bone mineral density decreases modestly shortly after HAART initiation but does not appear to decrease with time on HAART, and in some studies it has increased.255
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CUtaNEOUS MaNIFEStatIONS Dermatologic consequences of HIV infection include primary cutaneous opportunistic infections and malignancies, which may also disseminate to the viscera, and systemic opportunistic diseases with skin involvement.259,260 Viral Infections of the Skin and Mucous Membranes A wide range of viruses involve the skin in HIV-immunosuppressed patients. The exanthem of acute HIV infection is an erythematous morbilliform eruption of the trunk and upper arms that occurs 2 to 4 weeks after infection and is usually associated with fever, headache, arthralgias, night sweats, pharyngitis, or thrush.169,261,262 The rash resolves within 5 to 7 days. HSVs (see Chapter 136) frequently cause morbidity in patients with advanced HIV disease.263 Serology shows previous infection with HSV-2 in more than 90% of homosexual men with HIV infection; it is less prevalent in other groups. Although HSV-2 recurs frequently even in nonimmunosuppressed hosts, it recurs more frequently and for prolonged periods in patients with HIV infection. HSV-2, a common pathogen of the sacral root dermatomes, often causes outbreaks in the buttocks, perineum, scrotum (or vulva), and shaft and glans of the penis. Characteristic lesions of herpes simplex appear first as painful erythematous papules; later they vesiculate and ulcerate, and pustules may form. Chronic ulcers may become granulated, verrucous, or bloody (Fig. 121-10). Herpes simplex proctitis is associated with severe rectal pain, fever, tenesmus, and obstipation. External lesions may be absent, and the diagnosis is established by anoscopic or sigmoidoscopic examination and cultures. Giant perirectal ulcers and lesions at other sites that yield thymidine kinase resistant strains of HSV-2 have occurred in patients who were previously treated with acyclovir. HSV infections are diagnosed by the typical appearance and distribution of the lesions and culture. Tzanck preparations may show giant cells, which suggest HSV infection. Some physicians base their diagnosis on how patients respond to an empirical trial of acyclovir. Orolabial HSV infections in HIV-infected persons may be caused by HSV-1 or HSV-2. Although primary infections may occur after patients acquire HIV, recurrences are the more common manifestation of HSV infection. Often, a prodrome of tingling and pain precedes the appearance of painful vesicles and ulcers. Lesions may be found on the lips, buccal mucosa, gingiva, soft palate, uvula, and tongue. HSV disease may recur chronically in patients with advanced immunosuppression. In persons with HIV infection, varicella-zoster virus (shingles) is often reactivated264 (see Chapter 137), typically when the CD4+ level is 200 to 500 cells/mm3. There have been reports of herpes zoster after initiation of HAART,265 suggesting a role of the host immune response in this clinical manifestation. Herpes zoster may occur early in the course of HIV infection, but the incidence in late HIV disease is 5% to 10% annually.266-270 Dermatomal outbreaks are most common, and a substantial proportion of patients may have several dermatomes
Figure 121-11 Herpes zoster in dermatomal distribution. (Courtesy of Dr. Stephen Raffanti.)
involved (Fig. 121-11). Recurrent episodes at the same or different sites, chronic (nonremitting) zoster, and dissemination are often seen.271 Shingles is often characterized by radicular pain and itching several days before erythematous papules appear, and vesiculation occurs within several days. Lesions are often extremely pruritic, and excoriation with secondary bacterial infection commonly occurs. Over a period of 4 to 7 days, lesions form bullae and crusts and begin to heal, although some patients have zoster chronically. Cranial and thoracic dermatomes, followed by lumbar and sacral roots, are most often involved. Outbreaks along the ophthalmic branch of the trigeminal nerve may result in corneal involvement and lead to scarring and opacification that impair vision. A substantial proportion of patients may experience postherpetic scarring and pain. In patients with HIV infection who acquire primary varicella (chickenpox), the acute infection may progress to a chronic form in a period of weeks to months. Despite the frequency of disseminated CMV disease in late-stage AIDS, cutaneous manifestations are unusual. Vesicles, bullae, and hyperpigmented indurated plaques have all been described, however. Infections with human papillomavirus, the causative agent of condylomata acuminata, are more prevalent in HIV-infected persons than in the general population. In addition to genital lesions (see Chapter 144), warts are often seen in periungual locations, on the feet (plantar warts), and in bearded areas of the face. Molluscum contagiosum, a cutaneous poxvirus infection, is seen more often in HIV-infected persons than in other populations (see Chapter 134). Most patients have CD4+ cell counts less than 200/mm3. The agent is transmitted by sexual or other close contact; reactivation of remote infection may cause outbreaks in immunosuppressed hosts. Molluscum lesions are small firm papules with a pearly white umbilicated surface distributed on the face, trunk, or genital areas. The lesions are usually painless and can be differentiated from herpetic lesions by the absence of erythema, smaller size, and resolution of lesions without ulcerating or crusting (Fig. 121-12). Biopsy may be necessary to exclude more serious causes of cutaneous lesions, such as cryptococcosis, pyogenic granuloma, and basal cell carcinoma. Liquid nitrogen is used effectively to treat this condition. Lesions may also resolve after initiation of HAART, with a resultant increase in CD4+ level.272 Bacillary Angiomatosis Bacillary angiomatosis is associated with cutaneous and visceral involvement that produces lesions characterized by vascular proliferation, hemorrhage, and necrosis.273-277 The disease was first described in 1983 in an AIDS patient with subcutaneous nodules with vascular proliferation and evidence of bacterial involvement by electron microscopy.277 Subsequently, the cause of bacillary angiomatosis was attributed to the organisms Bartonella henselae and Bartonella quin-
Figure 121-10 Herpes simplex. (Courtesy of Dr. Stephen Raffanti.)
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Molluscum contagiosum. (Courtesy of Dr. Stephen
Kaposis
sarcoma.
(Courtesy of Dr. Stephen
tana (see Chapter 235). B. henselae infection has been associated with cat and flea exposure and B. quintana infection with low socioeconomic status, homelessness, and exposure to lice.278 Bartonella organisms have been cultured from skin lesions, blood, liver, bone, and other sites.273-276 Patients with bacillary angiomatosis usually present with one or several cutaneous lesions, although disseminated disease is common. The typical skin lesions are purple-red nodules or plaques that can ulcerate and crust. Lesions may be mistaken for cutaneous KS, skin tags, or basal cell carcinoma. Visceral disease may include hepatitis (bacillary peliosis), splenic or osseous lesions, bacillemia, pneumonitis or, less often, involvement of other organs.279 Bacillary peliosis is a characteristic illness in which patients present with fever, right upper quadrant pain, hepatomegaly, and elevation of liver enzyme levels, particularly alkaline phosphatase.280,281 Imaging studies of the liver may reveal echogenic defects; histologically, lesions have a cystic appearance, with vascular proliferation, hemorrhage, and necrosis. The diagnosis of bacillary angiomatosis is best made by biopsy of involved sites. Hematoxylin and eosin stains of biopsy specimens from skin lesions show proliferation of small blood vessels in the dermis or cutis, enlarged endothelial cells with abundant cytoplasm, and necrotic and granulomatous changes. Warthin-Starry stains show perivascular accumulations of bacilli; these findings may be confirmed by electron microscopy, although this is not usually necessary. The diagnosis can also be established by culture of the organism in several special media or by detection of Bartonella DNA by polymerase chain reaction (PCR) assay.282 Serologic assays for anti-Bartonella antibodies are available through the Special Pathogens Branch of the CDC. The natural history of the infection in patients with HIV is for relapses to occur in the absence of prolonged therapy with erythromycin or doxycycline. Fluoroquinolones, other macrolides, and trimethoprim-sulfamethoxazole also have activity against Bartonella. Kaposis Sarcoma KS is a vascular neoplastic disorder that in the United States is seen predominantly in HIV-infected homosexual men. Human herpesvirus type 8, which is transmitted sexually, has been implicated in the pathogenesis of KS (see Chapters 125 and 141).283-286 Although KS also affects visceral organs, the characteristic findings are cutaneous red-purple nodules or plaques (Fig. 121-13). Sites commonly involved include the legs, feet, mucous membranes, hard palate, nose, trunk, and scalp.287 Lesions of KS are often difficult to distinguish from those of bacillary angiomatosis; biopsy is required for diagnosis. Other Cutaneous Manifestations Various other skin disorders have been described in HIV-infected patients. Seborrheic dermatitis, an inflammatory condition of seba-
ceous glands that may be associated with dermatophytic superinfection, is an early complication (Fig. 121-14). Erythema and scaling of midline areas of the forehead, face, and groin are typical findings. Psoriasis occurs in 5% of HIV-infected persons, with scaly reddish plaques, onycholysis, nail pitting, and subungual hyperkeratosis. Associated psoriatic arthritis occurs more frequently than in HIVseronegative persons with psoriasis. Tinea infections of the scalp, trunk, inguinal and perineal areas, extremities, and feet are also common. Onychomycoses, or fungal infections of the fingernails and toenails, are common, although usually asymptomatic, causing only cosmetic changes. Bacterial folliculitis may be localized or disseminated in patients with HIV infection, and relapses frequently occur. S. aureus is the most common causative pathogen. Community-acquired methicillin-resistant S. aureus (MRSA) skin infections occur with increasing frequency in HIV-infected persons; risk factors include high-risk sex, drug-using behavior, and environmental exposure, but not immune status.288 Eosinophilic folliculitis (Fig. 121-15) is an inflammatory condition associated with raised pruritic nodules with a pustular head on an erythematous base; it is similar to bacterial folliculitis. Biopsy specimens of these lesions reveal intense infiltration of eosinophils and absence of polymorphonuclear cells and organisms. Xerosis and ichthyosis are also common in patients with advanced HIV disease and may be refractory to therapy with emollients and anti-inflammatory agents; antihistamines may provide symptomatic relief. Prurigo nodularis appears as nodules and papules caused by
Seborrheic dermatitis. (Courtesy of Dr. Stephen
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Figure 121-15 Eosinophilic dermatitis. (Courtesy of Dr. Stephen Raffanti.)
Figure 121-17
Histoplasmosis. (Courtesy of Dr. Stephen Raffanti.)
chronic rubbing and scratching. This is precipitated by one of the many causes of pruritus in HIV-infected persons, such as xerosis, eosinophilic folliculitis, and atopic dermatitis. Disseminated cryptococcosis and histoplasmosis may cause mucocutaneous papules, nodules, pustules, or ulcers (Figs. 121-16 and 12117). Biopsy and culture establish the diagnosis. In Thailand and southern China, P. marneffei is a common opportunistic fungal infectious agent in AIDS patients.289 Patients can present with umbilicated papules, subcutaneous nodules, or morbilliform eruptions. Diagnosis is established by identifying the elliptic organism with central septation and characteristic red pigment production when grown in culture. Nontuberculous mycobacteria such as M. avium complex and Mycobacterium haemophilum may cause cutaneous papules, pustules, abscesses, lymphadenitis, or ulcerations. Culture is required for diagnosis. Scabies Sarcoptes scabiei var. humanus is the mite responsible for this common ectoparasitic infestation in HIV-infected persons. Scaly pruritic papules or hyperkeratotic plaques may occur on the palms, soles, trunk, or extremities. Characteristic burrows between the fingers and on the wrists are not always seen. Norwegian (crusted) scabies (Fig. 121-18) is a severe and highly contagious manifestation of this disease, seen particularly with advanced immunosuppression.290 Permethrin 5% cream and ivermectin are effective therapies.291
rENaL DISEaSE A number of renal abnormalities have been described in patients with HIV infection, including a specific HIV-related nephropathy.292-294 Ascribing renal dysfunction to HIV infection is problematic, however, because some patients with HIV have a high risk for renal disease of other causes. Intravenous drug use, hepatitis B and C infection, hypertension, fluid and electrolyte disorders, and concomitant opportunistic infections and malignancies are all associated with renal dysfunction. In addition, many drugs used to treat HIV infection and its associated opportunistic infections are nephrotoxic.295 Tenofovir can cause Fanconis syndrome. Pentamidine, foscarnet, and the aminoglycosides can cause acute tubular necrosis, and indinavir, sulfadiazine, and intravenous acyclovir can cause intratubular obstruction by crystal formation. Thrombotic thrombocytopenic purpurahemolytic uremic syndrome has been reported in HIV-infected persons. Hypertension may be a prominent feature, and the prognosis is poor.296 Immune complex mediated glomerular diseases, such as those associated with immunoglobulin A nephropathy297 and hepatitis C virus infection,298 have also been reported. The incidence of acute renal failure is increased in persons with advanced HIV, particularly among persons in care less than 3 months.299
Figure 121-16 Cryptococcosis. (Courtesy of Dr. Stephen Raffanti.)
Figure 121-18 Norwegian scabies (in a patient with wasting syndrome). (Courtesy of Dr. Stephen Raffanti.)
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HIV-associated nephropathy was first reported in 1984 and occurs in 2% to 10% of HIV-infected persons.292 Manifestations include proteinuria, mildly elevated serum creatinine levels, and focal and segmental glomerulosclerosis on histopathology. Although this entity is similar to heroin-associated nephropathy, only half of patients studied had a history of intravenous drug use. In a review of 75 consecutive AIDS patients in Miami, 43% of the patients had proteinuria with more than 0.5 g of protein/24 hours; 9% had more than 3 g of protein/24 hours.300 In 36 autopsies, 17 (47%) had renal pathology, 5 had focal glomerulosclerosis, and 12 had mesangial proliferation. A subsequent review of the same population of patients found that patients with a history of intravenous drug use had the highest incidence of renal disease; however, other nondrug-using patients, including children, can develop HIV-related nephropathy. In another series, renal disease was observed in 13 of 32 of patients and included focal glomerulosclerosis, mesangial proliferation, and glomerulonephritis.301 The pathogenesis of HIV-associated nephropathy is incompletely understood. Human and animal models have demonstrated proliferation of renal epithelial cells and apoptosis302; direct HIVinduced damage of glomerular and tubular epithelial cells may be involved. Renal biopsy is required to establish the diagnosis. HIVassociated nephropathy is more commonly reported in blacks than in other racial groups, suggesting a biologic or genetic susceptibility to this disorder.294 Renal dysfunction in patients with HIV disease is usually diagnosed incidentally when patients present with opportunistic infections and have a CD4+ cell count less than 200/mm3.303 Asymptomatic proteinuria, up to 5 g/day, is often the initial finding, and the serum creatinine level is often normal or only mildly elevated. The albumin concentration is almost always low, as is true for most AIDS patients with opportunistic infections, and the blood pressure is usually normal. Renal biopsy most often shows focal and segmental glomerulosclerosis (collapsing glomerulosclerosis) with severe tubulointerstitial disease and proliferative microcyst formation. Immunofluorescence studies often reveal deposits of immunoglobulin M and C3, and electron microscopy shows tubuloreticular inclusion bodies.294 In one study, blacks were at only slightly increased risk of chronic kidney disease compared with whites, but once chronic kidney disease developed, blacks developed end-stage renal disease 18 times faster than whites, suggesting a more aggressive natural disease history in blacks.304 The clinical course of HIV-related nephropathy progresses quickly, usually because many other opportunistic processes occur simultaneously. Rao and associates292 originally reported death with renal failure in 8 of 11 patients with HIV-related nephropathy in less than 4 months. Because nephropathy is usually diagnosed late in the course of HIV disease, it is difficult to determine the effect of renal dysfunction on survival. Some centers have reported that patients with AIDS respond poorly to maintenance by hemodialysis.305 There is no proven effective therapy for HIV-associated nephropathy, although reports have suggested a survival benefit from HAART,306,307 corticosteroids,308 angiotensin-converting enzyme inhibitors,309 and cyclosporine.310 OCULar COMPLICatIONS Ocular diseases are extremely common manifestations of HIV disease, with a wide variety of causes, ranging from a benign HIV retinopathy to sight-threatening viral opportunistic infections.311-313 As HIV disease progresses, the risk of ocular complications rises appreciably. Prior to widespread initiation of HAART, HIV retinopathy occurred in approximately one third of all patients with HIV, with the prevalence higher in those with low CD4+ counts. The most frequent finding is a cotton wool spot, a small pale lesion that is thought to represent transient focal retinal ischemia. HIV retinopathy may also produce microaneurysms and retinal hemorrhages. The condition is generally benign, although some patients have developed visual defects attributed to this condition. The most common and serious ocular complication of HIV disease is retinitis, most often caused by CMV. CMV is ubiquitous in patients
with HIV infection and causes serious morbidity in AIDS. CMV is transmitted by the same routes as HIV, and almost all patients with sexually acquired HIV infection are also infected with CMV. Like other herpesviruses, CMV may infect cells latently and be reactivated when host defenses are impaired. Asymptomatic CMV viruria and viremia may be found in one third to one half of patients with advanced HIV disease. The risk of CMV retinitis is determined largely by the CD4+ cell count and by the CMV DNA level in the peripheral blood. For patients with CD4+ cell counts less than 200/mm3, the annual risk is 4% to 12%. Further risk stratification is aided by CMV DNA measurements, with aviremic patients having less than 1% risk/year, even at low CD4+ cell counts.314 CMV has a unique predilection for the retina, with 90% of endorgan disease in patients with HIV infection being retinitis.315 Other involved sites include the colon, esophagus, stomach, adrenals, pancreas, brain, and lungs. The onset of CMV retinitis may be insidious or rapid. Patients complain of painless, progressive visual loss, blurring, and floaters. CMV retinitis usually arises unilaterally, although it may subsequently progress to the contralateral retina. Funduscopic examination of the involved eye typically reveals coalescing white exudates in a vascular pattern, with surrounding hemorrhage and edema. Often, lesions are peripheral initially, involve the fovea later, and result in visual loss. Retinal detachment may occur as a late complication. Fortunately, the advent of combination antiretroviral therapy has resulted in astonishing declines in the incidence of CMV retinitis. Several population-based studies have reported 60% to 90% reductions in the incidence of this disease. Improvement in cell-mediated immunity with antiretroviral therapy results in suppression of CMV DNA in plasma, with a subsequent fall in the risk of disease. Indeed, it appears that patients with treated CMV retinitis who receive HAART may safely discontinue anti-CMV therapy if their CD4+ count rises to more than 100 cells/mm3 for at least 3 to 6 months.316,317 For patients with CD4+ counts less than 50 cells/mm3, education regarding retinitis symptoms and regular ophthalmologic examinations are recommended. Patients complaining of ocular symptoms should undergo a thorough ophthalmologic examination. Retinal findings may include cotton wool spots or lesions of infectious retinitis. Less common retinal infections include toxoplasmosis, pneumocystosis, varicellazoster virus, and ocular syphilis, which is usually a diffuse intraocular process. Cotton wool spots are prevalent in patients with AIDS but do not appear to predict the development of other retinal disease. The cotton wool spots are distributed in a vascular pattern similar to that of CMV but do not have the irregular pattern of full retinal exudates and hemorrhages characteristic of CMV retinitis. An ophthalmologist or other highly trained observer should examine any patient with signs or symptoms of retinitis promptly, because delay in therapy can result in irreversible visual loss. Cultures of the blood and urine yield CMV in 60% and 80% of cases, respectively, although the diagnosis rarely rests entirely on these results. Patients who have had CMV retinitis frequently experience acute retinal detachment. Erosion of the retinal border at the site of a necrotic lesion allows the retina to be lifted off underlying tissues. Patients complain of sudden loss of vision, like a curtain falling in front of the affected eye. Surgical reattachment is often partially successful in restoring vision, although progressive visual loss may ensue. Treatment options include oral valganciclovir, intravenous ganciclovir, intravenous foscarnet, intravenous cidofovir, and intraocular ganciclovir implants with oral valganciclovir.317 Varicella-zoster retinitis is a severe necrotizing retinitis (progressive outer retinal necrosis [PORN]) that may occur in patients with advanced HIV disease and low CD4+ cell counts, although some cases occur at earlier stages of HIV disease.318 Patients most often note rapid visual loss. Funduscopic findings include peripheral necrosis, occlusive vasculopathy, optic neuritis, and vitreal and scleral inflammation, and the syndrome is termed acute retinal necrosis. Varicella-zoster retinitis usually occurs in the absence of zoster at other sites, but a history of varicella-zoster virus disease is common and the virus may be isolated from tissue samples in some patients.319 Blindness ensues despite
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therapy in most patients, although responses to intravenous ganciclovir and foscarnet plus intravitreal injections of ganciclovir and/or foscarnet have been reported.317 Optimization of HAART is also recommended. Ocular toxoplasmosis occurs in patients with advanced immunodeficiency, and many but not all have cerebral toxoplasmosis. Toxoplasma retinitis is characterized by discrete, rounded, pale exudates. Lesions are usually discrete foci of retinal inflammation without hemorrhage or vasculopathy. Vitreal inflammation is common. The diagnosis is made by observation by an experienced ophthalmologist. P. jirovecii may cause a choroiditis that mimics CMV retinitis.320 The lesions are typically posterior, yellow-orange in appearance, and do not cause vitreal inflammation. Choroidal pneumocystosis occurs most often in patients with previous P. jirovecii pneumonia, particularly in those taking aerosolized pentamidine for prophylaxis. CarDIaC MaNIFEStatIONS Although early clinical observations suggested that HIV infection spared the heart, subsequent experience has shown that cardiac involvement in HIV and AIDS is not unusual.321,322 Cardiac abnormalities in patients with HIV infection may include opportunistic infections or diseases of the myocardium (e.g., T. gondii, Trypanosoma cruzi) or pericardium (e.g., mycobacteria, KS), left ventricular dysfunction and dilated cardiomyopathy, cardiac autonomic abnormalities, and vascular heart disease, such as pulmonary hypertension. Infectious endocarditis may also occur in patients with HIV infection, especially injection drug users, but there is little evidence to suggest that the risk is increased after accounting for behaviors. Marantic endocarditis is a manifestation of late-stage HIV disease and is sometimes noted at autopsy. As noted, accelerated atherosclerosis with myocardial infarction has been reported in patients with HIV infection treated with protease inhibitors and with elevated serum cholesterol and triglyceride levels.323,223 Myocardial disease in HIV-infected individuals is surprisingly common, particularly in late-stage disease. Infectious myocarditis has been reported with a number of opportunistic infections, notably T. gondii. In an autopsy-based study in France, for example, 12% of AIDS patients who died were found to have cardiac toxoplasmosis.324 Most patients with cardiac toxoplasmosis also had cerebral involvement, although several patients had isolated toxoplasmic myocarditis. Myocarditis may be seen in acute T. gondii infection, and coincident toxoplasmic pneumonitis may present a clinical picture of diffuse pulmonary infiltrates and cardiac insufficiency. Other opportunistic agents causing myocardial involvement include mycobacteria and fungi. A more common and underdiagnosed disorder in HIV-infected individuals is cardiomyopathy with left ventricular dysfunction, which may result in congestive heart failure.325 Several large cohort studies in the pre-HAART era found that 8% to 12% of patients with HIV infection had echocardiographic evidence of left ventricular dysfunction, and the incidence of dilated cardiomyopathy with severe congestive heart failure (New York Heart Association Class III or IV) was 15% to 18%/year.326,327 Clinical evaluation of patients may reveal only complaints of fatigue and exertional dyspnea, and physical examination may show tachycardia without rales or overt signs of congestive heart failure. Echocardiography shows global hypokinesis and enlargement of all four chambers, with a modestly to severely reduced left ventricular ejection fraction and increased end-diastolic volume index. Chest radiography is frequently unhelpful. The cause of HIV-related cardiomyopathies is multifactorial, with conflicting data on the causative role of cardiotropic viruses, vitamin deficiencies, and cardiotoxic drugs. There is compelling evidence, however, that HIV itself is involved in the pathogenesis of cardiomyopathy in a large proportion of patients.326,327 HIV has been identified in myocardial tissue by in situ hybridization in several studies and found to be positive in one third to two thirds of patients with myocarditis. In addition, an inflammatory cellular infiltrate composed of major histocompatibility complex
class Iexpressing CD8+ cells is found in a large proportion of patients, suggesting an autoimmune mechanism in this process. Other viruses also implicated in dilated cardiomyopathy in patients with HIV infection include Epstein-Barr virus, coxsackieviruses, and CMV. Supportive treatment with digoxin, diuretics, and afterload reduction is usually of symptomatic benefit, and some patients with inflammatory myocarditis respond to corticosteroid therapy. Nonetheless, the prognosis for patients with this finding is poor,328 although combination antiretroviral therapy might change this. Pericardial effusions have been reported in varying proportions of patients in a number of studies, many of which have suffered from selection bias. In patients with more advanced illness in hospital-based settings, pericardial effusions can be common. A Portuguese study found, for example, that 41% of 181 HIV-infected patients had pericardial effusions.329 Most effusions in this setting are asymptomatic or arise with signs and symptoms of opportunistic disease at other sites. The cause of pericardial disease in patients with HIV infection is diverse, but opportunistic infections and malignancies are the agents most commonly implicated. Mycobacterial infections, especially tuberculosis, are frequently associated with pericardial involvement in areas in which coinfection with HIV and M. tuberculosis is common, and nontuberculous mycobacteria may also invade the pericardial space. Other infections seen in the pericardium include bacterial infections, fungal infections (e.g., Cryptococcus), and viral cardiopulmonary infections. KS and non-Hodgkins lymphoma may also cause pericardial effusion. Cardiac tamponade or cardiac dysfunction resulting from effusions is unusual in most series, and in most cases pericardiocentesis is not necessary as a therapeutic maneuver. One study, however, reported that 40% of patients with an HIV-related pericardial effusion had signs of tamponade.330 HEMatOLOGIC MaNIFEStatIONS HIV infection can affect all three hematologic cell linesleukocytes, red blood cells, and platelets. Although neutropenia and anemia are seen primarily in advanced disease, thrombocytopenia can occur in early-stage disease (e.g., HIV-related thrombocytopenia) or late-stage disease (thrombotic thrombocytopenic purpura [TTP]). Neutropenia may be caused by HIV infection itself or may be an adverse effect of therapy. In one study, neutropenia was an independent risk factor for bacterial infection after controlling for CD4+ count.331 In another study of 71 patients with an absolute neutrophil count less than 1000 cells/ mm3 for a median of 13 days, only 6 (8%) developed culture-proven infection.332 The risk of infection increased with decreasing CD4 counts, but most episodes were mild and self-limited. Anemia is common in advanced HIV infection and is an independent risk factor for death.333,334 HIV-related thrombocytopenia is a result of both immune-mediated platelet destruction (as is seen in idiopathic thrombocytopenic purpura) and impaired platelet production.335 Patients are usually asymptomatic, even with profound thrombocytopenia. The thrombocytopenia usually responds to antiretroviral therapy; this has been best studied with zidovudine but has also been shown with HAART.336,337 TTP in an HIV-infected person was first described by Jokela and colleagues in 1987.338 The classic diagnostic pentad includes thrombocytopenia, microangiopathic hemolytic anemia, renal failure, fever, and neurologic abnormalities, although not all patients have all these findings. In addition, given the high frequency of many of these findings in those with advanced AIDS, such a diagnosis may not always be considered. The incidence of TTP has appeared to be decreasing in the HAART era.339 IMMUNE rECONStItUtION SYNDrOMES HAARTregimens that include a HIV-1 protease inhibitor or nonnucleoside reverse transcriptase inhibitor, together with nucleoside reverse transcriptase inhibitorsis associated with dramatic reductions in HIV-1 RNA and increases in CD4+ lymphocyte counts. In addition to decreasing HIV-related mortality and the incidence of
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opportunistic infections significantly (as discussed earlier), the improvement in immune function can be associated with paradoxical worsening of underlying opportunistic infections.340,341 The clinical presentation of immune reconstitution inflammatory syndrome (IRIS) varies according to the pathogen (see later). Not every patient who has immunologic improvement with antiretroviral therapy experiences IRIS; the risk factors for the development of these syndromes are not well understood. Mycobacterium tuberculosis Paradoxical worsening of tuberculosis was initially described in HIVseronegative tuberculosis patients before the HIV era, but it appears to be more common in HIV-infected patients.156 Clinical manifestations include fever, adenopathy (e.g., cervical, thoracic, or intraabdominal), and worsening pulmonary infiltrates. Central nervous system tuberculomas, pleural effusions, and psoas abscesses have also been described.156,157,342,343 Diagnoses such as lymphoma, adverse drug reaction, and tuberculosis treatment failure related to nonadherence, malabsorption, or drug resistance must be excluded before the diagnosis of tuberculosis IRIS can be established. Treatment with HAART has been associated with an increased risk of IRIS in some but not all studies; the incidence rate ranges from 7% to 43%.156,157,342-344 Persons who experience IRIS with HAART usually do so within 2 to 3 weeks of starting therapy. Clinical management includes a continuation of antituberculosis and antiretroviral therapy and the use of NSAIDs for symptomatic relief. For severe manifestations, such as compromise of the airways or venous return to the heart, corticosteroids (e.g., prednisone 1 mg/kg/day, then taper as symptoms allow) may be given. Unmasking of previously unrecognized tuberculosis after HAART initiation has also been reported, although this may represent progression of untreated tuberculosis that is coincidental to the start of HIV therapy.146,147 Mycobacterium avium Complex Disease Focal or diffuse lymphadenitis developing within 2 to 3 months of initiation of HAART has been described in several persons with low baseline CD4+ lymphocyte counts.145,345 Mycobacteremia is generally not present, but cultures of lymph nodes usually grow M. avium. There have also been reports of focal osteomyelitis developing in persons who discontinue primary or secondary M. avium prophylaxis after sustained increases in CD4+ counts during HAART.346,347 Treatment is the same as that for M. avium infection in the absence of immune reconstitution. Cytomegalovirus CMV retinitis in the setting of immune reconstitution (immune recovery uveitis) has been described in persons with and without a history of CMV retinitis before initiation of HAART.348-350 Development of CMV disease at extraocular sites (e.g., bloodstream, colon, and pancreas) in patients without prior CMV disease has also been described.351
Among persons with a history of CMV retinitis who subsequently initiate and respond to HAART, 18% to 63% develop immune recovery uveitis.352,353 The median time of HAART until development of uveitis was 43 weeks in one study.352 The optimal management is unclear. Oral corticosteroids with or without concomitant anti-CMV therapy are often used. Varicella-Zoster Virus There have been several reports of the development of herpes zoster in persons receiving HAART. In two series, herpes zoster developed in 7% to 8% of persons receiving combination antiretroviral therapy and occurred within 17 weeks of initiation of therapy.354,355 In one report herpes zoster was associated with an increase in CD8+ lymphocytes.355 The clinical manifestations are usually not severe and respond to acyclovir or famciclovir. Viral Hepatitis Persons infected with hepatitis C virus (HCV) can develop acute hepatitis or cirrhosis during HAART.356,357 It is difficult to discern whether elevations in hepatic transaminase levels are caused by toxicity of antiretroviral therapy or immune reconstitutionthere is no reliable clinical or laboratory parameter that will distinguish between these two entities. In a study of 60 persons coinfected with HIV and HCV who completed at least 16 weeks of HAART, immune recovery was associated with a persistent increase in HCV RNA, particularly in persons with baseline CD4+ count less than 350 cells/mm3.358,359 Other studies have found that hepatotoxicity in coinfected patients who respond to HAART is associated with increased HCV-specific immune responses and T-cell activation.360 This suggests that at least in some cases, hepatotoxicity is associated with immune reconstitution. There have also been reports of acute hepatitis developing during HAART in those with prior hepatitis B virus infection, in which increased HBV RNA levels are detected.361 Patients with chronic hepatitis B infection are at increased risk of hepatotoxicity from antiretroviral therapy, and withdrawal of antiretroviral drugs that have activity against hepatitis B virus, such as tenofovir or lamivudine, may result in worsening of hepatic function and increased aminotransferase levels, which may be caused by immune mechanisms or loss of viral suppression.362 Management of patients with chronic hepatitis is discussed in Chapter 116. Other Diseases Paradoxical worsening in the setting of immune reconstitution has also been described after initiation of HAART with C. neoformans,363 P. jirovecii pneumonia,364,365 progressive multifocal leukoencephalopathy,366 and Kaposis sarcoma.367 Of particular concern is IRIS that involves the central nervous system because of the high associated morbidity and mortality. This has been seen with C. neoformans and progressive multifocal leukoencephalopathy in addition to tuberculosis.
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HIV Mandell Clinical Manifestations

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121

Human immunodeficiency virus (HIV) infection results in a wide

Classification of Human Immunodeficiency Virus Infection

Part II Major Clinical Syndromes

121-1 Stage Stage 1

WHO Clinical Staging of Established HIV Infection WHO Clinical Stage 1 2 3 4

HIV-Associated Symptoms Asymptomatic Mild symptoms Advanced symptoms Severe symptoms

None required (but no AIDS-defining condition)

Natural History of Human Immunodeficiency Virus Infection

HIV-Associated Immunodeficiency None or not significant Mild Advanced Severe

<11 mo (% CD4+) >35 30-35 25-29 <25

12-35 mo (% CD4+) >30 25-30 20-24 <20

36-59 mo (% CD4+) >25 20-25 15-19 <15

>5 yr (Absolute No./mm3 or % CD4+) >500 350-500 200-349 <200 or <15%

121 General Clinical Manifestations of Human Immunodeficiency Virus Infection

Culturable plasma viremia (dilutional titer)

HIV RNA copies per mL plasma

1 512 1 256 1 128 1 64 1 32 1 16 1 8 1 4 1 2

Part II Major Clinical Syndromes

Baseline Viral Load

501-3000 3001-10,000 10,001-30,000

HIV-1 RNA concentration ( 103 copies /mL)

<200 201350 351500 501750 >750 CD4 count (cells/L)

121 General Clinical Manifestations of Human Immunodeficiency Virus Infection

Part II Major Clinical Syndromes

40 Deaths Deaths per 100 person-years 30

Use of protease inhibitors

Number of opportunistic infections per 100 person-years

20 M. avium complex 15 Cytomegalovirus

Therapy with a protease inhibitor (% of patient days)

121 General Clinical Manifestations of Human Immunodeficiency Virus Infection

Relative risk of AIDS and death

Clinical Presentation and Findings

Part II Major Clinical Syndromes

aphthous ulcer. (Courtesy of Dr. Stephen Raffanti.)

121 General Clinical Manifestations of Human Immunodeficiency Virus Infection

Part II Major Clinical Syndromes

Figure 121-8 Raffanti.)

Oral candidiasis (thrush). (Courtesy of Dr. Stephen

angular cheilitis. (Courtesy of Dr. Stephen Raffanti.)

121 General Clinical Manifestations of Human Immunodeficiency Virus Infection

Part II Major Clinical Syndromes

Figure 121-10 Herpes simplex. (Courtesy of Dr. Stephen Raffanti.)

121 General Clinical Manifestations of Human Immunodeficiency Virus Infection

Figure 121-12 Raffanti.)

Molluscum contagiosum. (Courtesy of Dr. Stephen

Figure 121-13 Raffanti.)

(Courtesy of Dr. Stephen

Figure 121-14 Raffanti.)

Seborrheic dermatitis. (Courtesy of Dr. Stephen

Part II Major Clinical Syndromes

Figure 121-15 Eosinophilic dermatitis. (Courtesy of Dr. Stephen Raffanti.)

Histoplasmosis. (Courtesy of Dr. Stephen Raffanti.)

Figure 121-16 Cryptococcosis. (Courtesy of Dr. Stephen Raffanti.)

121 General Clinical Manifestations of Human Immunodeficiency Virus Infection

Part II Major Clinical Syndromes

121 General Clinical Manifestations of Human Immunodeficiency Virus Infection

Part II Major Clinical Syndromes

121 General Clinical Manifestations of Human Immunodeficiency Virus Infection

Part II Major Clinical Syndromes

121 General Clinical Manifestations of Human Immunodeficiency Virus Infection

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