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InternalMed_Harrison. assay or one of the tests for HIV RNA (discussed below). While the Western blot is an excellent confirmatory test for HIV infection in patients with a positive or indeterminate EIA, it is a poor screening test. Among individuals with a negative EIA and PCR for HIV, 20–30% may show one or more bands on Western blot. While these bands are usually faint and represent cross-reactivity, their presence creates a situation in which other diagnostic modalities (such as DNA PCR, RT-PCR, or p24 antigen capture) must be employed to ensure that the bands do not indicate early HIV infection.


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InternalMed_Harrison. A guideline for the use of these serologic tests in attempting to make a diagnosis of HIV infection is depicted in Fig. 226-30. In patients in whom HIV infection is suspected, the appropriate initial test is the EIA. If the result is negative, unless there is strong reason to suspect early HIV infection (as in a patient exposed within the previous 3 months), the diagnosis is ruled out and retesting should be performed only as clinically indicated. If the EIA is indeterminate or positive, the test should be repeated. If the repeat is negative on two occasions, one can assume that the initial positive reading was due to a technical error in the performance of the assay and that the patient is negative. If the repeat is indeterminate or positive, one should proceed to the HIV-1 Western blot. If the Western blot is positive, the diagnosis is HIV-1 Human Immunodeficiency Virus Disease: AIDS and Related Disorders 1.


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InternalMed_Harrison. Human Immunodeficiency Virus Disease: AIDS and Related Disorders 1. Virus digested: digest separated into 1. Positive HIV-1 infection components by molecular weight 2. gp 160 immunization 2. Proteins transferred to filter paper: 3. Indeterminate (HIV-2 infection) reaction with test serum 4. Indeterminate (cross-reacting antibody to p24) 3. Enzyme-conjugated antihuman antibody added 5. Negative 4. FIGuRE 226-29 Western blot assay for detection of antibodies to HIV. A. Schematic representation of how a Western blot is performed. B. Examples of patterns of Western blot reactivity. In each instance the Western blot strip contains antigens to HIV-1. The serum from the patient immunized to the HIV-1 envelope gp160 contains only antibodies to the HIV-1 envelope proteins. The serum from the patient with HIV-2 infection cross-reacts with both reverse transcriptase and gag gene products of HIV-1.


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InternalMed_Harrison. infection. If the Western blot is negative, the EIA can be assumed to there is no progression in the Western blot, a diagnosis of HIV-1 is have been a false positive for HIV-1 and the diagnosis of HIV-1 infec-ruled out. If either the p24 or HIV-1 RNA assay is positive and/or the tion is ruled out. It would also be prudent at this point to perform spe-HIV-1 Western blot shows progression, a tentative diagnosis of HIV-1 cific serologic testing for HIV-2 following the same type of algorithm. infection can be made and later confirmed with a follow-up Western If the Western blot for HIV-1 is indeterminate, it should be repeated blot demonstrating a positive pattern. In addition to these standard in 4–6 weeks; in addition, one may proceed to a p24 antigen capture laboratory-based assays for detecting antibodies to HIV, an series of assay, HIV-1 RNA assay, or HIV-1 DNA PCR and specific serologic point-of-care tests can provide results in 1–60 min. Among the most testing for HIV-2. If the p24


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InternalMed_Harrison. antibodies to HIV, an series of assay, HIV-1 RNA assay, or HIV-1 DNA PCR and specific serologic point-of-care tests can provide results in 1–60 min. Among the most testing for HIV-2. If the p24 and HIV RNA assays are negative and popular of these is the OraQuick Rapid HIV-1 antibody test that can be run on blood, plasma, or saliva. The sensitivity and specificity of this test is ~99% when run on whole blood. Specificity remains the SEROLOGIC TESTS IN THE DIAGNOSIS OF HIV-1 OR same but sensitivity drops to 98% when the test is run on saliva. While


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InternalMed_Harrison. HIV-2 INFECTION negative results from this test are adequate to rule out a diagnosis of HIV infection, a positive finding should be considered preliminary and confirmed with standard serologic testing, as described above. Two rapid test kits are licensed for home use. They are the OraQuick In-Home HIV test and the Home Access HIV-1 test system.


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InternalMed_Harrison. A variety of laboratory tests are available for the direct detection of HIV or its components (Table 226-8). These tests may be of considerable help in making a diagnosis of HIV infection when the Western blot results are indeterminate. In addition, the tests detecting levels of HIV RNA can be used to determine prognosis and to assess the response to antiretroviral therapies. The simplest of the direct detection tests is the p24 antigen capture assay. This is an EIA-type assay in which the solid phase consists of antibodies to the p24 antigen of HIV. It detects the viral protein p24 in the blood of HIV-infected individuals where it exists either as free antigen or complexed to anti-p24 antibodies. Overall, ~30% of individuals with untreated HIV infection have detectable levels of free p24 antigen. This increases to ~50% when samples are treated with a weak acid to dissociate antigen-antibody FIGuRE 226-30 Algorithm for the use of serologic tests in the complexes. Throughout the course


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InternalMed_Harrison. antigen. This increases to ~50% when samples are treated with a weak acid to dissociate antigen-antibody FIGuRE 226-30 Algorithm for the use of serologic tests in the complexes. Throughout the course of HIV infection, an equilibrium diagnosis of HIV-1 or HIV-2 infection. *Stable indeterminate exists between p24 antigen and anti-p24 antibodies. During the first Western blot 4–6 weeks later makes HIV infection unlikely. However, few weeks of infection, before an immune response develops, there it should be repeated twice at 3-month intervals to rule out HIV infec-is a brisk rise in p24 antigen levels (Fig. 226-27). After the develoption. Alternatively, one may test for HIV-1 p24 antigen or HIV RNA. EIA, ment of anti-p24 antibodies, these levels decline. Late in the course of enzyme immunoassay. infection, when circulating levels of virus are high, p24 antigen levels aSensitivity figures refer to those approved by the U.S. Food and Drug Administration. bPrices may be lower in


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InternalMed_Harrison. immunoassay. infection, when circulating levels of virus are high, p24 antigen levels aSensitivity figures refer to those approved by the U.S. Food and Drug Administration. bPrices may be lower in large-volume settings. Abbreviations: bDNA, branched DNA; cDNA, complementary DNA; EIA, enzyme immunoassay; TMA, transcription-mediated amplification; NASBA, nucleic acid sequence–based amplifi cation; PCR, polymerase chain reaction.


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InternalMed_Harrison. also increase, particularly when detected by techniques involving dissociation of antigen-antibody complexes. The p24 antigen capture assay has its greatest use as a screening test for HIV infection in patients suspected of having the acute HIV syndrome, as high levels of p24 antigen are present prior to the development of antibodies. Its use as a stand-alone test for routine blood donor screening for HIV infection has been replaced by use of NAT or “fourth-generation” assays that combine antigen and antibody testing. The ability to measure and monitor levels of HIV RNA in the plasma of patients with HIV infection has been of extraordinary value in furthering our understanding of the pathogenesis of HIV infection, in monitoring the response to cART, and in providing a diagnostic tool in settings where measurements of anti-HIV antibodies may be misleading, such as in acute infection and neonatal infection. Four assays are predominantly used for this purpose. They are reverse


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InternalMed_Harrison. tool in settings where measurements of anti-HIV antibodies may be misleading, such as in acute infection and neonatal infection. Four assays are predominantly used for this purpose. They are reverse transcriptase PCR (RT-PCR; Amplicor); branched DNA (bDNA; VERSANT); transcription-mediated amplification (TMA; APTIMA); and nucleic acid sequence–based amplification (NASBA; NucliSENS). These tests are of value in making a diagnosis of HIV infection, in establishing initial prognosis, and in monitoring the effects of therapy. In addition to these four commercially available tests, the DNA PCR also is employed by research laboratories for making a diagnosis of HIV infection by amplifying HIV proviral DNA from peripheral blood mononuclear cells. The commercially available RNA detection tests have a sensitivity of 40–8100 copies of HIV RNA per milliliter of plasma. Research laboratory–based RNA assays can detect as few as one HIV RNA copy per milliliter, while the DNA PCR tests can detect


InternalMed_Harrison

InternalMed_Harrison. have a sensitivity of 40–8100 copies of HIV RNA per milliliter of plasma. Research laboratory–based RNA assays can detect as few as one HIV RNA copy per milliliter, while the DNA PCR tests can detect proviral DNA at a frequency of one copy per 10,000–100,000 cells. Thus, these tests are extremely sensitive. One frequent consequence of a high degree of sensitivity is some loss of specificity, and false-positive results have been reported with each of these techniques. For this reason, a positive EIA with a confirmatory Western blot remains the “gold standard” for a diagnosis of HIV infection, and the interpretation of other test results must be done with this in mind.


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InternalMed_Harrison. In the RT-PCR technique, following DNAse treatment, a cDNA copy is made of all RNA species present in plasma. Because HIV is an RNA virus, this will result in the production of DNA copies of the HIV genome in amounts proportional to the amount of HIV RNA present in plasma. This cDNA is then amplified and characterized using standard PCR techniques, employing primer pairs that can distinguish genomic cDNA from messenger cDNA. The bDNA assay involves the use of a solid-phase nucleic acid capture system and signal amplification through successive nucleic acid hybridizations to detect small quantities of HIV RNA. Both tests can achieve a tenfold increase in sensitivity to 40–50 copies of HIV RNA per milliliter with a preconcentration step in which plasma undergoes ultracentrifugation to pellet the viral particles. In the TMA assay, a cDNA copy of viral RNA is made using primers that contain a promoter sequence for T7 RNA polymerase. T7 polymerase is then added to produce multiple copies


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InternalMed_Harrison. the viral particles. In the TMA assay, a cDNA copy of viral RNA is made using primers that contain a promoter sequence for T7 RNA polymerase. T7 polymerase is then added to produce multiple copies of RNA amplicon from the DNA template. It is qualified at 100 copies/mL. The NASBA technique involves the isothermal amplification of a sequence within the gag region of HIV in the presence of internal standards and employs the production of multiple RNA copies through the action of T7-RNA polymerase. The resulting RNA species are quantitated through hybridization with a molecular beacon DNA probe that is quenched in the absence of hybridization. The lower limit of detection for the NucliSENS assay is 80 copies/mL.


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InternalMed_Harrison. In addition to being a diagnostic and prognostic tool, RT-PCR and DNA-PCR are also useful for amplifying defined areas of the HIV genome for sequence analysis and have become an important technique for studies of sequence diversity and microbial resistance to antiretroviral agents. In patients with a positive or indeterminate EIA test and an indeterminate Western blot, and in patients in whom serologic testing may be unreliable (such as patients with hypogammaglobulinemia or advanced HIV disease), these tests for quantitating HIV RNA in plasma or detecting proviral DNA in peripheral blood mononuclear cells are valuable tools for making a diagnosis of HIV infection; however, they should be used for diagnosis only when standard serologic testing has failed to provide a definitive result.


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InternalMed_Harrison. The epidemic of HIV infection and AIDS has provided the clinician with new challenges for integrating clinical and laboratory data to effect optimal patient management. The close relationship between clinical manifestations of HIV infection and CD4+ T cell count has made measurement of CD4+ T cell numbers a routine part of the evaluation of HIV-infected individuals. The discovery of HIV as the cause of AIDS led to the development of sensitive tests that allow one to monitor the levels of HIV in the blood. Determinations of peripheral blood CD4+ T cell counts and measurements of the plasma levels of HIV RNA provide a powerful set of tools for determining prognosis and monitoring response to therapy.


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InternalMed_Harrison. CD4+ T Cell Counts The CD4+ T cell count is the laboratory test generally accepted as the best indicator of the immediate state of immunologic competence of the patient with HIV infection. This measurement, which can be made directly or calculated as the product of the percentage of CD4+ T cells (determined by flow cytometry) and the total lymphocyte count (determined by the white blood cell count [WBC] multiplied by the lymphocyte differential percentage), has been shown to correlate very well with the level of immunologic competence. Patients with CD4+ T cell counts <200/μL are at high risk of disease from P. jiroveci, while patients with CD4+ T cell counts <50/ μL are at high risk of disease from CMV, mycobacteria of the M. avium complex (MAC), and/or T. gondii (Fig. 226-31). Once the CD4+ T cell count is <200/μL, patients should be placed on a regimen for P. jiroveci prophylaxis, and once the count is <50/μL, primary prophylaxis for MAC infection is indicated. As with any


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InternalMed_Harrison. the CD4+ T cell count is <200/μL, patients should be placed on a regimen for P. jiroveci prophylaxis, and once the count is <50/μL, primary prophylaxis for MAC infection is indicated. As with any laboratory measurement, one may wish to obtain two determinations prior to any significant changes in patient management based on CD4+ T cell count alone. Patients with HIV infection should have CD4+ T cell measurements performed at the time of diagnosis and every 3–6 months thereafter. More frequent measurements should be made if a declining trend is noted. For patients who have been on cART for at least 2 years


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InternalMed_Harrison. Human Immunodeficiency Virus Disease: AIDS and Related Disorders


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InternalMed_Harrison. FIGuRE 226-31 Relationship between CD4+ T cell counts and the development of opportunistic diseases. Boxplot of the median (line inside the box), first quartile (bottom of the box), third quartile (top of the box), and mean (asterisk) CD4+ lymphocyte count at the time of the development of opportunistic disease. Can, candidal esophagitis; CMV, cytomegalovirus infection; Crp, cryptosporidiosis; Cry, cryptococcal meningitis; DEM, AIDS dementia complex; HSV, herpes simplex virus infection; HZos, herpes zoster; KS, Kaposi’s sarcoma; MAC, Mycobacterium avium complex bacteremia; NHL, non-Hodgkin’s lymphoma; PCP, primary Pneumocystis jiroveci pneumonia; PCP2, secondary P. jiroveci untreated patient. Following the initiation of therapy or any change in therapy, plasma HIV RNA levels should be monitored approximately every 4 weeks until the effectiveness of the therapeutic regimen is determined by the development of a new steady-state level of HIV RNA. In most instances of effective


InternalMed_Harrison

InternalMed_Harrison. be monitored approximately every 4 weeks until the effectiveness of the therapeutic regimen is determined by the development of a new steady-state level of HIV RNA. In most instances of effective antiretroviral therapy the plasma level of HIV RNA will drop to <50 copies/mL within 6 months of the initiation of treatment. During therapy, levels of HIV RNA should be monitored every 3–6 months to evaluate the continuing effectiveness of therapy.


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InternalMed_Harrison. HIV Resistance Testing The availability of multiple antiretroviral drugs as treatment options has generated a great deal of interest in the potential for measuring the sensitivity of an individual’s HIV virus(es) to different antiretroviral agents. HIV resistance testing can be done through either genotypic pneumonia; PML, progressive multifocal leukoencephalopathy; Tox, Toxoplasma gondii encephalitis; or phenotypic measurements. In the WS, wasting syndrome. (From RD Moore, RE Chaisson: Ann Intern Med 124:633, 1996.) genotypic assays, sequence analyses with HIV RNA levels persistently <50 copies/mL, the monitoring of the CD4 count is felt by many to be optional. There are a handful of clinical situations in which the CD4+ T cell count may be misleading. Patients with HTLV-1/HIV co-infection may have elevated CD4+ T cell counts that do not accurately reflect their degree of immune competence. In patients with hypersplenism or those who have undergone splenectomy, and in patients


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InternalMed_Harrison. may have elevated CD4+ T cell counts that do not accurately reflect their degree of immune competence. In patients with hypersplenism or those who have undergone splenectomy, and in patients receiving medications that suppress the bone marrow such as IFN-α, the CD4+ T cell percentage may be a more reliable indication of immune function than the CD4+ T cell count. A CD4+ T cell percentage of 15 is comparable to a CD4+ T cell count of 200/μL.


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InternalMed_Harrison. HIV RNA Determinations Facilitated by highly sensitive techniques for the precise quantitation of small amounts of nucleic acids, the measurement of serum or plasma levels of HIV RNA has become an essential component in the monitoring of patients with HIV infection. As discussed in “Diagnosis of HIV Infection,” above, the most commonly used technique is the RT-PCR assay. This assay generates data in the form of number of copies of HIV RNA per milliliter of serum or plasma and can reliably detect as few as 40 copies of HIV RNA per milliliter of plasma. Research-based assays can detect down to one copy per milliliter. While it is common practice to describe levels of HIV RNA below these cut-offs as “undetectable,” this is a term that should be avoided as it is imprecise and leaves the false impression that the level of virus is 0. By utilizing more sensitive, nested PCR techniques and by studying tissue levels of virus as well as plasma levels, HIV RNA can be detected in virtually every


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InternalMed_Harrison. impression that the level of virus is 0. By utilizing more sensitive, nested PCR techniques and by studying tissue levels of virus as well as plasma levels, HIV RNA can be detected in virtually every patient with HIV infection. The one notable exception to this is a patient who underwent cytoreductive therapy followed by a bone marrow transplant from a CCR5Δ32 homozygous donor.


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InternalMed_Harrison. Measurements of changes in HIV RNA levels over time have been of great value in delineating the relationship between levels of virus and rates of disease progression (Fig. 226-22), the rates of viral turnover, the relationship between immune system activation and viral replication, and the time to development of drug resistance. HIV RNA measurements are greatly influenced by the state of activation of the immune system and may fluctuate greatly in the setting of secondary infections or immunization. For these reasons, decisions based on HIV RNA levels should never be made on a single determination. Measurements of plasma HIV RNA levels should be made at the time of HIV diagnosis and every 3–6 months thereafter in the of the HIV genomes obtained from patients are compared with sequences of viruses with known antiretroviral resistance profiles. In the phenotypic assays, the in vivo growth of viral isolates obtained from the patient is compared to the growth of reference strains of the


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InternalMed_Harrison. viruses with known antiretroviral resistance profiles. In the phenotypic assays, the in vivo growth of viral isolates obtained from the patient is compared to the growth of reference strains of the virus in the presence or absence of different antiretroviral drugs. A modification of this phenotypic approach utilizes a comparison of the enzymatic activities of the reverse transcriptase, protease, or integrase genes obtained by molecular cloning of patients’ isolates to the enzymatic activities of genes obtained from reference strains of HIV in the presence or absence of different drugs targeted to these genes. These tests are quite good in identifying those antiretroviral agents that have been utilized in the past and suggesting agents that may be of future value in a given patient. Resistance testing is recommended at the time of initial diagnosis and, if therapy is not initiated at that time, at the time of initiation of cART. Drug resistance testing is also indicated in the setting


InternalMed_Harrison

InternalMed_Harrison. testing is recommended at the time of initial diagnosis and, if therapy is not initiated at that time, at the time of initiation of cART. Drug resistance testing is also indicated in the setting of virologic failure and should be performed while the patient is still on the failing regimen because of the propensity for the pool of HIV quasispecies to rapidly revert to wild-type in the absence of the selective pressures of cART. In the hands of experts, resistance testing enhances the short-term ability to decrease viral load by ~0.5 log compared with changing drugs merely on the basis of drug history. In addition to the use of resistance testing to help in the selection of new drugs in patients with virologic failure, it may also be of value in selecting an initial regimen for treatment of therapy-naïve individuals. This is particularly true in geographic areas with a high level of background resistance. The patient needs to have an HIV-1 RNA level above 500– 1000 copies/mL for an


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InternalMed_Harrison. of therapy-naïve individuals. This is particularly true in geographic areas with a high level of background resistance. The patient needs to have an HIV-1 RNA level above 500– 1000 copies/mL for an accurate resistance determination. Resistance assays lose their consistency at lower levels of plasma viremia.


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InternalMed_Harrison. Co-Receptor Tropism Assays Following the licensure of maraviroc as the first CCR5 antagonist for the treatment of HIV infection (see below), it became necessary to be able to determine whether a patient’s virus was likely to respond to this treatment. Patients tend to have CCR5tropic virus early in the course of infection, with a trend toward CXCR4 viruses later in disease. The antiretroviral agent maraviroc is effective only against CCR5-tropic viruses. Because the genotypic determinants of cellular tropism are poorly defined, a phenotypic assay is necessary to determine this property of HIV. Two commercial assays, the Trofile assay (Monogram Biosciences) and the Phenoscript assay (VIRalliance), are available to make this determination. These assays clone the envelope regions of the patient’s virus into an indicator virus that is then used to infect target cells expressing either CCR5 or CXCR4 as their


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InternalMed_Harrison. TABLE 226-9 AssOCIATIOn BETwEEn HIgH-sEnsITIvITy CRP, IL-6, And D-dIMER wITH ALL-CAusE MORTALITy In PATIEnTs wITH HIv InFECTIOn IL-6 8.3 <.0001 11.8 <.0001 D-dimer 12.4 <.0001 26.5 <.0001 Abbreviations: Hs-CRP, high-sensitivity C-reactive protein; IL-6, interleukin 6. Source: From LH Kuller et al: PLoS Med 5:e203, 2008. co-receptor. These assays take weeks to perform and are expensive. Another, less costly option is to obtain a genotypic assay of the V3 region of HIV-1 and then employ a computer algorithm to predict viral tropism from the sequence. While this approach is less expensive than the classic phenotypic assay, there are fewer data to validate its predictive value.


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InternalMed_Harrison. Other Tests A variety of other laboratory tests have been studied as potential markers of HIV disease activity. Among these are quantitative culture of replication-competent HIV from plasma, peripheral blood mononuclear cells, or resting CD4+ T cells; circulating levels of β2-microglobulin, soluble IL-2 receptor, IgA, acid-labile endogenous IFN, or TNF-α; and the presence or absence of activation markers such as CD38, HLA-DR, and PD-1 on CD4+ or CD8+ T cells. Nonspecific serologic markers of inflammation and/or coagulation such as IL-6, d-dimer, and sCD14 have been shown to have a high correlation with all-cause mortality (Table 226-9). While these measurements have value as markers of disease activity and help to increase our understanding of the pathogenesis of HIV disease, they do not currently play a major role in the monitoring of patients with HIV infection.


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InternalMed_Harrison. The clinical consequences of HIV infection encompass a spectrum ranging from an acute syndrome associated with primary infection to a prolonged asymptomatic state to advanced disease. It is best to regard HIV disease as beginning at the time of primary infection and progressing through various stages. As mentioned above, active virus replication and progressive immunologic impairment occur throughout the course of HIV infection in most patients. With the exception of the rare, true, “elite” virus controllers or long-term nonprogressors (see “Long-Term Survivors and Long-Term Nonprogressors,” above), HIV disease in untreated patients inexorably progresses even during the clinically latent stage. Since the mid-1990s, cART has had a major impact on preventing and reversing the progression of disease over extended periods of time in a substantial proportion of adequately treated patients.


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InternalMed_Harrison. It is estimated that 50–70% of individuals with HIV infection experience an acute clinical syndrome ~3–6 weeks after primary infection (Fig. 226-32). Varying degrees of clinical severity have been reported, and although it has been suggested that symptomatic seroconversion leading to the seeking of medical attention indicates an increased risk for an accelerated course of disease, there does not appear to be a correlation between the level of the initial burst of viremia in acute HIV infection and the subsequent course of disease. The typical clinical findings in the acute HIV syndrome are listed in Table 226-10; they occur along with a burst of plasma viremia. It has been reported that several symptoms of the acute HIV syndrome (fever, skin rash, pharyngitis, and myalgia) occur less frequently in those infected by injection drug use compared with those infected by sexual contact. The syndrome is typical of an acute viral syndrome and has been likened to acute infectious


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InternalMed_Harrison. less frequently in those infected by injection drug use compared with those infected by sexual contact. The syndrome is typical of an acute viral syndrome and has been likened to acute infectious mononucleosis. Symptoms usually persist for one to several weeks and gradually subside as an immune response to HIV develops and the levels of plasma viremia decrease. Opportunistic infections have been reported during this stage of infection, reflecting the immunodeficiency that results from reduced numbers of CD4+


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InternalMed_Harrison. Plasma viremia (wide dissemination of virus) Acute syndrome Retrafficking of lymphocytes 1 week–3 months 1–2 weeks 3–6 weeks Immune response to HIV Curtailment of plasma viremia Primary Infection Establishment of chronic, persistent infection in lymphoid tissue Clinical latency FIGuRE 226-32 The acute HIV syndrome. See text for detailed description. (Adapted from G Pantaleo et al: N Engl J Med 328:327, 1993. Copyright 1993 Massachusetts Medical Society. All rights reserved.)


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InternalMed_Harrison. T cells and likely also from the dysfunction of CD4+ T cells owing to viral protein and endogenous cytokine-induced perturbations of cells (Table 226-5) associated with the extremely high levels of plasma viremia. A number of immunologic abnormalities accompany the acute HIV syndrome, including multiphasic perturbations of the numbers of circulating lymphocyte subsets. The number of total lymphocytes and T cell subsets (CD4+ and CD8+) are initially reduced. An inversion of the CD4+/CD8+ T cell ratio occurs later because of a rise in the number of CD8+ T cells. In fact, there may be a selective and transient expansion of CD8+ T cell subsets, as determined by T cell receptor analysis (see above). The total circulating CD8+ T cell count may remain elevated or return to normal; however, CD4+ T cell levels usually remain somewhat depressed, although there may be a slight rebound toward normal. Lymphadenopathy occurs in ~70% of individuals with primary HIV infection. Most patients recover


InternalMed_Harrison

InternalMed_Harrison. T cell levels usually remain somewhat depressed, although there may be a slight rebound toward normal. Lymphadenopathy occurs in ~70% of individuals with primary HIV infection. Most patients recover spontaneously from this syndrome and many are left with only a mildly depressed CD4+ T cell count that remains stable for a variable period before beginning its progressive decline; in some individuals, the CD4+ T cell count returns to the normal range. Approximately 10% of patients manifest a fulminant course of immunologic and clinical deterioration after primary infection, even after the disappearance of initial symptoms. In most patients, primary infection with or without the acute syndrome is followed by a prolonged period of clinical latency or smoldering low disease activity.


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InternalMed_Harrison. Although the length of time from initial infection to the development of clinical disease varies greatly, the median time for untreated patients is ~10 years. As emphasized above, HIV disease with active virus replication is ongoing and progressive during this asymptomatic period. The rate of disease progression is directly correlated with HIV Source: From B Tindall, DA Cooper: AIDS 5:1, 1991.


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InternalMed_Harrison. Human Immunodeficiency Virus Disease: AIDS and Related Disorders 1250 RNA levels. Patients with high levels of HIV RNA in plasma progress to symptomatic disease faster than do patients with low levels of HIV RNA (Fig. 226-22). Some patients referred to as long-term nonprogressors show little if any decline in CD4+ T cell counts over extended periods of time. These patients generally have extremely low levels of HIV RNA; a subset, referred to as elite nonprogressors, exhibits HIV RNA levels <50 copies/mL. Certain other patients remain entirely asymptomatic despite the fact that their CD4+ T cell counts show a steady progressive decline to extremely low levels. In these patients, the appearance of an opportunistic disease may be the first manifestation of HIV infection. During the asymptomatic period of HIV infection, the average rate of CD4+ T cell decline is ~50/μL per year. When the CD4+ T cell count falls to <200/μL, the resulting state of immunodeficiency is severe enough to place


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InternalMed_Harrison. period of HIV infection, the average rate of CD4+ T cell decline is ~50/μL per year. When the CD4+ T cell count falls to <200/μL, the resulting state of immunodeficiency is severe enough to place the patient at high risk for opportunistic infection and neoplasms and, hence, for clinically apparent disease.


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InternalMed_Harrison. Symptoms of HIV disease can appear at any time during the course of HIV infection. Generally speaking, the spectrum of illnesses that one observes changes as the CD4+ T cell count declines. The more severe and life-threatening complications of HIV infection occur in patients with CD4+ T cell counts <200/μL. A diagnosis of AIDS is made in individuals age 6 years and older with HIV infection and a CD4+ T cell count <200/μL (Stage 3, Table 226-2) and in anyone with HIV infection who develops one of the HIV-associated diseases considered to be indicative of a severe defect in cell-mediated immunity (Table 226-1). While the causative agents of the secondary infections are characteristically opportunistic organisms such as P. jiroveci, atypical mycobacteria, CMV, and other organisms that do not ordinarily cause disease in the absence of a compromised immune system, they also include common bacterial and mycobacterial pathogens. Following the widespread use of cART and implementation of


InternalMed_Harrison

InternalMed_Harrison. not ordinarily cause disease in the absence of a compromised immune system, they also include common bacterial and mycobacterial pathogens. Following the widespread use of cART and implementation of guidelines for the prevention of opportunistic infections (Table 226-11), the incidence of these secondary infections has decreased dramatically (Fig. 226-33). Overall, the clinical spectrum of HIV disease is constantly changing as patients live longer and new and better approaches to treatment and prophylaxis are developed. In addition to the classic AIDS-defining illnesses, patients with HIV infection also have an increase in serious non-AIDS illnesses, including non-AIDS related cancers and cardiovascular, renal, and hepatic disease. Non-AIDS events dominate the disease burden for patients with HIV infection receiving cART (Table 226-4). While AIDS-related illnesses are the leading cause of death in patients with HIV infection, they account for fewer than 50% of deaths.


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InternalMed_Harrison. for patients with HIV infection receiving cART (Table 226-4). While AIDS-related illnesses are the leading cause of death in patients with HIV infection, they account for fewer than 50% of deaths. Non-AIDS-defining malignancies, liver disease, and cardiovascular disease each account for 10–15% of deaths in patients with HIV infection. The physician providing care to a patient with HIV infection must be well versed in general internal medicine as well as HIV-related opportunistic diseases. In general, it should be stressed that a key element of treatment of symptomatic complications of HIV disease, whether they are primary or secondary, is achieving good control of HIV replication through the use of cART and instituting primary and secondary prophylaxis for opportunistic infections as indicated.


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InternalMed_Harrison. Diseases of the Respiratory System Acute bronchitis and sinusitis are prevalent during all stages of HIV infection. The most severe cases tend to occur in patients with lower CD4+ T cell counts. Sinusitis presents as fever, nasal congestion, and headache. The diagnosis is made by CT or MRI. The maxillary sinuses are most commonly involved; however, disease is also frequently seen in the ethmoid, sphenoid, and frontal sinuses. While some patients may improve without antibiotic therapy, radiographic improvement is quicker and more pronounced in patients who have received antimicrobial therapy. It is postulated that this high incidence of sinusitis results from an increased frequency of infection with encapsulated organisms such as H. influenzae and Streptococcus pneumoniae. In patients with low CD4+ T cell counts one may see mucormycosis infections of the sinuses. In contrast to the course of this infection in other patient populations, mucormycosis of the sinuses in patients with HIV


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InternalMed_Harrison. low CD4+ T cell counts one may see mucormycosis infections of the sinuses. In contrast to the course of this infection in other patient populations, mucormycosis of the sinuses in patients with HIV infection may progress more slowly. In this setting aggressive, frequent local debridement in addition to local and systemic amphotericin B may result in effective treatment.


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InternalMed_Harrison. Pulmonary disease is one of the most frequent complications of HIV infection. The most common manifestation of pulmonary disease is pneumonia. Three of the 10 most common AIDS-defining illnesses are recurrent bacterial pneumonia, tuberculosis, and pneumonia due to the unicellular fungus P. jiroveci. Other major causes of pulmonary infiltrates include other mycobacterial infections, other fungal infections, nonspecific interstitial pneumonitis, KS, and lymphoma.


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InternalMed_Harrison. Bacterial pneumonia is seen with an increased frequency in patients with HIV infection, with 0.8–2.0 cases per 100 person-years. Patients with HIV infection are particularly prone to infections with encapsulated organisms. S. pneumoniae (Chap. 171) and H. influenzae (Chap. 182) are responsible for most cases of bacterial pneumonia in patients with AIDS. This may be a consequence of altered B cell function and/or defects in neutrophil function that may be secondary to HIV disease (see above). Pneumonias due to S. aureus (Chap. 172) and P. aeruginosa (Chap. 189) also are reported to occur with an increased frequency in patients with HIV infection.


InternalMed_Harrison

InternalMed_Harrison. S. pneumoniae (pneumococcal) infection may be the earliest serious infection to occur in patients with HIV disease. This can present as pneumonia, sinusitis, and/or bacteremia. Patients with untreated HIV infection have a sixfold increase in the incidence of pneumococcal pneumonia and a 100-fold increase in the incidence of pneumococcal bacteremia. Pneumococcal disease may be seen in patients with relatively intact immune systems. In one study, the baseline CD4+ T cell count at the time of a first episode of pneumococcal pneumonia was ~300/μL. Of interest is the fact that the inflammatory response to pneumococcal infection appears proportional to the CD4+ T cell count. Due to this high risk of pneumococcal disease, immunization with the conjugated pneumococcal vaccine followed by booster immunization with the 23-valent pneumococcal polysaccharide vaccine is one of the generally recommended prophylactic measures for patients with HIV infection. This is likely most effective if given


InternalMed_Harrison

InternalMed_Harrison. immunization with the 23-valent pneumococcal polysaccharide vaccine is one of the generally recommended prophylactic measures for patients with HIV infection. This is likely most effective if given while the CD4+ T cell count is >200/μL and, if given to patients with lower CD4+ T cell counts, should be repeated once the count has been above 200 for 6 months. Although clear guidelines do not exist, it also makes sense to repeat immunization every 5 years. The incidence of bacterial pneumonia is cut in half when patients quit smoking.


InternalMed_Harrison

InternalMed_Harrison. Pneumocystis pneumonia (PCP), once the hallmark of AIDS, has dramatically declined in incidence following the development of effective prophylactic regimens and the widespread use of cART. It is, however, still the single most common cause of pneumonia in patients with HIV infection in the United States and can be identified as a likely etiologic agent in 25% of cases of pneumonia in patients with HIV infection, with an incidence in the range of 2–3 cases per 100 person-years. Approximately 50% of cases of HIV-associated PCP occur in patients who are unaware of their HIV status. The risk of PCP is greatest among those who have experienced a previous bout of PCP and those who have CD4+ T cell counts of <200/μL. Overall, 79% of patients with PCP have CD4+ T cell counts <100/μL and 95% of patients have CD4+ T cell counts <200/μL. Recurrent fever, night sweats, thrush, and unexplained weight loss also are associated with an increased incidence of PCP. For these reasons, it is strongly


InternalMed_Harrison

InternalMed_Harrison. patients have CD4+ T cell counts <200/μL. Recurrent fever, night sweats, thrush, and unexplained weight loss also are associated with an increased incidence of PCP. For these reasons, it is strongly recommended that all patients with CD4+ T cell counts <200/μL (or a CD4 percentage <15) receive some form of PCP prophylaxis. The incidence of PCP is approaching zero in patients with known HIV infection receiving appropriate cART and prophylaxis. In the United States, primary PCP is now occurring at a median CD4+ T cell count of 36/ μL, while secondary PCP is occurring at a median CD4+ T cell count of 10/μL. Patients with PCP generally present with fever and a cough that is usually nonproductive or productive of only scant amounts of white sputum. They may complain of a characteristic retrosternal chest pain that is worse on inspiration and is described as sharp or burning. HIV-associated PCP may have an indolent course characterized by weeks of vague symptoms and should be included in


InternalMed_Harrison

InternalMed_Harrison. chest pain that is worse on inspiration and is described as sharp or burning. HIV-associated PCP may have an indolent course characterized by weeks of vague symptoms and should be included in the differential diagnosis of fever, pulmonary complaints, or unexplained weight loss in any patient with HIV infection and <200 CD4+ T cells/μL. The most


InternalMed_Harrison

InternalMed_Harrison. Recommended as Standard of Care for Primary and Secondary Prophylaxis Prior bout of PCP Close contact with case of active pulmonary TB Drug resistant Same with high probability of exposure to drug-resistant TB Trimethoprim/sulfamethoxazole (TMP/SMX), 1 DS tablet qd PO TMP/SMX, 1 SS tablet qd PO Aerosolized pentamidine, 300 mg via Respirgard II nebulizer every month TMP/SMX, 1 SS PO daily Human Immunodeficiency Virus Disease: AIDS and Related Disorders All patients, preferably before CD4+ T cell count ≤200/μL Hepatitis B vaccine: 3 doses Hepatitis A vaccine: 2 doses (13) 0.5 mL IM × 1 followed in 8 weeks or more by pneumococcal polysaccharide vaccine (23) if CD4+ T cell count >200/μL Oseltamivir 75 mg PO qd Streptococcus pneumoniae Reimmunize patients initially immunized at a CD4+ T cell count <100/μL whose CD4+ T cell count then increases to >200/μL Human papillomavirus All patients 13–26 years of age HPV vaccine; 3 doses


InternalMed_Harrison

InternalMed_Harrison. Human papillomavirus All patients 13–26 years of age HPV vaccine; 3 doses Recommended for Prevention of Severe or Frequent Recurrences Abbreviations: ARV, antiretroviral; bid, twice daily; DS, double-strength; PCP, Pneumocystis jiroveci pneumonia; PO, by mouth; SS, single-strength; TB, tuberculosis.


InternalMed_Harrison

InternalMed_Harrison. common finding on chest x-ray is either a normal film, if the disease may demonstrate a patchy ground-glass appearance. Routine laborais suspected early, or a faint bilateral interstitial infiltrate. The classic tory evaluation is usually of little help in the differential diagnosis finding of a dense perihilar infiltrate is unusual in patients with AIDS. of PCP. A mild leukocytosis is common, although this may not be In patients with PCP who have been receiving aerosolized pentamidine obvious in patients with prior neutropenia. Elevation of lactate dehyfor prophylaxis, one may see an x-ray picture of upper lobe cavitary drogenase is common. Arterial blood-gases may indicate hypoxemia disease, reminiscent of TB. Other less common findings on chest with a decline in Pao and an increase in the arterial-alveolar (a–a) x-ray include lobar infiltrates and pleural effusions. Thin-section CT gradient. Arterial blood-gas measurements not only aid in making the diagnosis of PCP but also


InternalMed_Harrison

InternalMed_Harrison. in the arterial-alveolar (a–a) x-ray include lobar infiltrates and pleural effusions. Thin-section CT gradient. Arterial blood-gas measurements not only aid in making the diagnosis of PCP but also provide important information for staging the severity of the disease and directing treatment (see below). A definitive diagnosis of PCP requires demonstration of the organism in samples obtained from induced sputum, bronchoalveolar lavage, transbronchial biopsy, or open-lung biopsy. PCR has been used to10 detect specific DNA sequences for P. jiroveci in clinical specimens where histologic examinations have failed to make a diagnosis.


InternalMed_Harrison

InternalMed_Harrison. In addition to pneumonia, a number of other clinical problems have been reported in HIV-infected patients as a result of infection with P. jiroveci. Otic involvement may be seen as a primary infection, presenting as a polypoid mass involving the external auditory canal. PCP, one may see a variety of extrapulmonary manifestations of P. jiroveci. These include ophthalmic lesions of the choroid, a necrotiz ing vasculitis that resembles Burger’s disease, bone marrow hypopla sia, and intestinal obstruction. Other organs that have been involved include lymph nodes, spleen, liver, kidney, pancreas, pericardium, heart, thyroid, and adrenals. Organ infection may be associated with Human Immunodeficiency Virus Disease: AIDS and Related Disorders cystic lesions that may appear calcified on CT or ultrasound. The standard treatment for PCP or disseminated pneumocystosis


InternalMed_Harrison

InternalMed_Harrison. Human Immunodeficiency Virus Disease: AIDS and Related Disorders cystic lesions that may appear calcified on CT or ultrasound. The standard treatment for PCP or disseminated pneumocystosis No. of opportunistic infectionsper 100 person-years is trimethoprim/sulfamethoxazole (TMP/SMX). A high (20–85%) incidence of side effects, particularly skin rash and bone marrow suppression, is seen with TMP/SMX in patients with HIV infection.


InternalMed_Harrison

InternalMed_Harrison. 12 Alternative treatments for mild to moderate PCP include dapsone/ trimethoprim, clindamycin/primaquine, and atovaquone. IV pentami dine is the treatment of choice for severe disease in the patient unable 8 to tolerate TMP/SMX. For patients with a Pao <70 mmHg or with an 6 a–a gradient >35 mmHg, adjunct glucocorticoid therapy should be used in addition to specific antimicrobials. Overall, treatment should be continued for 21 days and followed by secondary prophylaxis. 2 Prophylaxis for PCP is indicated for any HIV-infected individual who 0 has experienced a prior bout of PCP, any patient with a CD4+ T cell count of <200/μL or a CD4 percentage <15, any patient with unex-


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InternalMed_Harrison. FIGuRE 226-33 A. Decrease in the incidence of opportunistic infections and Kaposi’s sarcoma in HIV-infected individuals with CD4+ T cell counts <100/μL from 1992 through 1998. (Adapted and updated from FJ Palella et al: N Engl J Med 338:853, 1998, and JE Kaplan et al: Clin Infect Dis 30[S1]:S5, 2000, with permission.) B. Quarterly incidence rates of cytomegalovirus (CMV), Pneumocystis jiroveci pneumonia (PCP), and Mycobacterium avium complex (MAC) from 1995 to 2001. (From FJ Palella et al: AIDS 16:1617, 2002.) plained fever for >2 weeks, and any patient with a recent history of oropharyngeal candidiasis. The preferred regimen for prophylaxis is TMP/SMX, one double-strength tablet daily. This regimen also provides protection against toxoplasmosis and some bacterial respiratory pathogens. For patients who cannot tolerate TMP/SMX, alternatives for prophylaxis include dapsone plus pyrimethamine plus leucovorin, aerosolized pentamidine administered by the Respirgard II nebulizer, and


InternalMed_Harrison

InternalMed_Harrison. For patients who cannot tolerate TMP/SMX, alternatives for prophylaxis include dapsone plus pyrimethamine plus leucovorin, aerosolized pentamidine administered by the Respirgard II nebulizer, and atovaquone. Primary or secondary prophylaxis for PCP can be 1254 discontinued in those patients treated with cART who maintain good suppression of HIV (<50 copies/mL) and CD4+ T cell counts >200/μL for at least 3 months.


InternalMed_Harrison

InternalMed_Harrison. M. tuberculosis, once thought to be on its way to extinction in the United States, experienced a resurgence associated with the HIV epidemic (Chap. 202). Worldwide, approximately one-third of all AIDS-related deaths are associated with TB, and TB is the primary cause of death for 10–15% of patients with HIV infection. In the United States ~5% of AIDS patients have active TB. Patients with HIV infection are more likely to have active TB by a factor of 100 when compared with an HIV-negative population. For an asymptomatic HIV-negative person with a positive purified protein derivative (PPD) skin test, the risk of reactivation TB is around 1% per year. For the patient with untreated HIV infection, a positive PPD skin test, and no signs or symptoms of TB, the rate of reactivation TB is 7–10% per year. Untreated TB can accelerate the course of HIV infection. Levels of plasma HIV RNA increase in the setting of active TB and decline in the setting of successful TB treatment. Active TB is


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InternalMed_Harrison. per year. Untreated TB can accelerate the course of HIV infection. Levels of plasma HIV RNA increase in the setting of active TB and decline in the setting of successful TB treatment. Active TB is most common in patients 25–44 years of age, in African Americans and Hispanics, in patients in New York City and Miami, and in patients in developing countries. In these demographic groups, 20–70% of the new cases of active TB are in patients with HIV infection. The epidemic of TB embedded in the epidemic of HIV infection probably represents the greatest health risk to the general public and the health care profession associated with the HIV epidemic. In contrast to infection with atypical mycobacteria such as MAC, active TB often develops relatively early in the course of HIV infection and may be an early clinical sign of HIV disease. In one study, the median CD4+ T cell count at presentation of TB was 326/μL. The clinical manifestations of TB in HIV-infected patients are quite varied and


InternalMed_Harrison

InternalMed_Harrison. be an early clinical sign of HIV disease. In one study, the median CD4+ T cell count at presentation of TB was 326/μL. The clinical manifestations of TB in HIV-infected patients are quite varied and generally show different patterns as a function of the CD4+ T cell count. In patients with relatively high CD4+ T cell counts, the typical pattern of pulmonary reactivation occurs: patients present with fever, cough, dyspnea on exertion, weight loss, night sweats, and a chest x-ray revealing cavitary apical disease of the upper lobes. In patients with lower CD4+ T cell counts, disseminated disease is more common. In these patients the chest x-ray may reveal diffuse or lower-lobe bilateral reticulonodular infiltrates consistent with miliary spread, pleural effusions, and hilar and/or mediastinal adenopathy. Infection may be present in bone, brain, meninges, GI tract, lymph nodes (particularly cervical lymph nodes), and viscera. Some patients with advanced HIV infection and active TB may


InternalMed_Harrison

InternalMed_Harrison. adenopathy. Infection may be present in bone, brain, meninges, GI tract, lymph nodes (particularly cervical lymph nodes), and viscera. Some patients with advanced HIV infection and active TB may have no symptoms of illness, and thus screening for TB should be part of the initial evaluation of every patient with HIV infection. Approximately 60–80% of HIV-infected patients with TB have pulmonary disease, and 30–40% have extrapulmonary disease. Respiratory isolation and a negative-pressure room should be used for patients in whom a diagnosis of pulmonary TB is being considered. This approach is critical to limit nosocomial and community spread of infection. Culture of the organism from an involved site provides a definitive diagnosis. Blood cultures are positive in 15% of patients. This figure is higher in patients with lower CD4 +T cell counts. In the setting of fulminant disease one cannot rely on the accuracy of a negative PPD skin test to rule out a diagnosis of TB. In addition,


InternalMed_Harrison

InternalMed_Harrison. figure is higher in patients with lower CD4 +T cell counts. In the setting of fulminant disease one cannot rely on the accuracy of a negative PPD skin test to rule out a diagnosis of TB. In addition, IFN-γ release assays may be difficult to interpret due to high backgrounds as a consequence of HIV-associated immune activation. TB is one of the conditions associated with HIV infection for which cure is possible with appropriate therapy. Therapy for TB is generally the same in the HIV-infected patient as in the HIV-negative patient (Chap. 202). Due to the possibility of multidrug-resistant or extensively drug-resistant TB, drug susceptibility testing should be performed to guide therapy. Due to pharmacokinetic interactions, adjusted doses of rifabutin should be substituted for rifampin in patients receiving the HIV protease inhibitors or nonnucleoside reverse transcriptase inhibitors. Treatment is most effective in programs that involve directly observed therapy. Initiation of cART


InternalMed_Harrison

InternalMed_Harrison. in patients receiving the HIV protease inhibitors or nonnucleoside reverse transcriptase inhibitors. Treatment is most effective in programs that involve directly observed therapy. Initiation of cART and/or anti-TB therapy may be associated with clinical deterioration due to immune reconstitution inflammatory syndrome (IRIS) reactions. These are most common in patients initiating both treatments at the same time, may occur as early as 1 week after initiation of cART therapy, and are seen more frequently in patients with advanced HIV disease. For these reasons it is recommended that initiation of cART be delayed in antiretroviral-naïve patients with CD4 counts >50 cells/μL until 2–4 weeks following the initiation of treatment for TB. For patients with lower CD4 counts the benefits of more immediate cART outweigh the risks of IRIS, and cART should be started as soon as possible in those patients. Effective prevention of active TB can be a reality if the health care professional is


InternalMed_Harrison

InternalMed_Harrison. more immediate cART outweigh the risks of IRIS, and cART should be started as soon as possible in those patients. Effective prevention of active TB can be a reality if the health care professional is aggressive in looking for evidence of latent or active TB by making sure that all patients with HIV infection receive a PPD skin test or evaluation with an IFN-γ release assay. Anergy testing is not of value in this setting. Since these tests rely on the host mounting an immune response to


InternalMed_Harrison

InternalMed_Harrison. M. tuberculosis, patients with CD4+ T cell counts <200 cells/μL should be retested if their CD4+ T cell counts rise to persistently above 200. Patients at risk of continued exposure to TB should be tested annually. HIV-infected individuals with a skin-test reaction of >5 mm, those with a positive IFN-γ release assay, or those who are close household contacts of persons with active TB should receive treatment with 9 months of isoniazid and pyridoxine.


InternalMed_Harrison

InternalMed_Harrison. Atypical mycobacterial infections are also seen with an increased frequency in patients with HIV infection. Infections with at least 12 different mycobacteria have been reported, including M. bovis and representatives of all four Runyon groups. The most common atypical mycobacterial infection is with M. avium or M. intracellulare species— the Mycobacterium avium complex (MAC). Infections with MAC are seen mainly in patients in the United States and are rare in Africa. It has been suggested that prior infection with M. tuberculosis decreases the risk of MAC infection. MAC infections probably arise from organisms that are ubiquitous in the environment, including both soil and water. There is little evidence for person-to-person transmission of MAC infection. The presumed portals of entry are the respiratory and GI tracts. MAC infection is a late complication of HIV infection, occurring predominantly in patients with CD4+ T cell counts of <50/μL. The average CD4+ T cell count at the time


InternalMed_Harrison

InternalMed_Harrison. the respiratory and GI tracts. MAC infection is a late complication of HIV infection, occurring predominantly in patients with CD4+ T cell counts of <50/μL. The average CD4+ T cell count at the time of diagnosis is 10/μL. The most common presentation is disseminated disease with fever, weight loss, and night sweats. At least 85% of patients with MAC infection are mycobacteremic, and large numbers of organisms can often be demonstrated on bone marrow biopsy. The chest x-ray is abnormal in ~25% of patients, with the most common pattern being that of a bilateral, lower-lobe infiltrate suggestive of miliary spread. Alveolar or nodular infiltrates and hilar and/or mediastinal adenopathy can also occur. Other clinical findings include endobronchial lesions, abdominal pain, diarrhea, and lymphadenopathy. Anemia and elevated liver alkaline phosphatase are common. The diagnosis is made by the culture of blood or involved tissue. The finding of two consecutive sputum samples positive for MAC is


InternalMed_Harrison

InternalMed_Harrison. Anemia and elevated liver alkaline phosphatase are common. The diagnosis is made by the culture of blood or involved tissue. The finding of two consecutive sputum samples positive for MAC is highly suggestive of pulmonary infection. Cultures may take 2 weeks to turn positive. Therapy consists of a macrolide, usually clarithromycin, with ethambutol. Some physicians elect to add a third drug from among rifabutin, ciprofloxacin, or amikacin in patients with extensive disease. Therapy was generally for life; however, with the use of cART it is possible to discontinue therapy in patients with sustained suppression of HIV replication and CD4+ T cell counts >100/μL for 3–6 months. Primary prophylaxis for MAC is indicated in patients with HIV infection and CD4+ T cell counts <50/μL (Table 226-11). This may be discontinued in patients in whom cART induces a sustained suppression of viral replication and an increase in CD4+ T cell count to >100/μL for ≥6 months.


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InternalMed_Harrison. Rhodococcus equi is a gram-positive, pleomorphic, acid-fast, nonspore-forming bacillus that can cause pulmonary and/or disseminated infection in patients with advanced HIV infection. Fever and cough are the most common presenting signs. Radiographically one may see cavitary lesions and consolidation. Blood cultures are often positive. Treatment is based on antimicrobial sensitivity testing.


InternalMed_Harrison

InternalMed_Harrison. Fungal infections of the lung, in addition to PCP, can be seen in patients with AIDS. Patients with pulmonary cryptococcal disease present with fever, cough, dyspnea, and, in some cases, hemoptysis. A focal or diffuse interstitial infiltrate is seen on chest x-ray in >90% of patients. In addition, one may see lobar disease, cavitary disease, pleural effusions, and hilar or mediastinal adenopathy. More than half of patients are fungemic, and 90% of patients have concomitant CNS infection. Coccidioides immitis is a mold that is endemic in the southwest United States. It can cause a reactivation pulmonary syndrome in patients with HIV infection. Most patients with this condition will have CD4+ T cell counts <250/μL. Patients present with fever, weight loss, cough, and extensive, diffuse reticulonodular infiltrates on chest x-ray. One may also see nodules, cavities, pleural effusions, and hilar adenopathy. While serologic testing is of value in the immunocompetent host, serologies are


InternalMed_Harrison

InternalMed_Harrison. infiltrates on chest x-ray. One may also see nodules, cavities, pleural effusions, and hilar adenopathy. While serologic testing is of value in the immunocompetent host, serologies are negative in 25% of HIV-infected patients with coccidioidal infection. Invasive aspergillosis is not an AIDS-defining illness and is generally not seen in patients with AIDS in the absence of neutropenia or administration of glucocorticoids. When it does occur, Aspergillus infection may have an unusual presentation in the respiratory tract of patients with AIDS, where it gives the appearance of a pseudomembranous tracheobronchitis. Primary pulmonary infection of the lung may be seen with histoplasmosis. The most common pulmonary manifestation of histoplasmosis, however, is in the setting of disseminated disease, presumably due to reactivation. In this setting respiratory symptoms are usually minimal, with cough and dyspnea occurring in 10–30% of patients. The chest x-ray is abnormal in ~50% of patients,


InternalMed_Harrison

InternalMed_Harrison. presumably due to reactivation. In this setting respiratory symptoms are usually minimal, with cough and dyspnea occurring in 10–30% of patients. The chest x-ray is abnormal in ~50% of patients, showing either a diffuse interstitial infiltrate or diffuse small nodules, and the urine will often be positive for Histoplasma antigen.


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InternalMed_Harrison. Two forms of idiopathic interstitial pneumonia have been identified in patients with HIV infection: lymphoid interstitial pneumonitis (LIP) and nonspecific interstitial pneumonitis (NIP). LIP, a common finding in children, is seen in about 1% of adult patients with untreated HIV infection. This disorder is characterized by a benign infiltrate of the lung and is thought to be part of the polyclonal activation of lymphocytes seen in the context of HIV and EBV infections. Transbronchial biopsy is diagnostic in 50% of the cases, with an open-lung biopsy required for diagnosis in the remainder of cases. This condition is generally self-limited and no specific treatment is necessary. Severe cases have been managed with brief courses of glucocorticoids. Although rarely a clinical problem since the use of cART, evidence of NIP may be seen in up to half of all patients with untreated HIV infection. Histologically, interstitial infiltrates of lymphocytes and plasma cells in a perivascular and


InternalMed_Harrison

InternalMed_Harrison. the use of cART, evidence of NIP may be seen in up to half of all patients with untreated HIV infection. Histologically, interstitial infiltrates of lymphocytes and plasma cells in a perivascular and peribronchial distribution are present. When symptomatic, patients present with fever and nonproductive cough occasionally accompanied by mild chest discomfort. Chest x-ray is usually normal or may reveal a faint interstitial pattern. Similar to LIP, NIP is a self-limited process for which no therapy is indicated other than appropriate management of the underlying HIV infection. HIV-related pulmonary arterial hypertension (HIV-PAH) is seen in ~0.5% of HIV-infected individuals. Patients may present with an array of symptoms including shortness of breath, fatigue, syncope, chest pain, and signs of right-sided heart failure. Chest x-ray reveals dilated pulmonary vessels and right-sided cardiomegaly with right ventricular hypertrophy seen on electrocardiogram. cART does not appear to be of


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InternalMed_Harrison. of right-sided heart failure. Chest x-ray reveals dilated pulmonary vessels and right-sided cardiomegaly with right ventricular hypertrophy seen on electrocardiogram. cART does not appear to be of clear benefit, and the prognosis is quite poor with a median survival in the range of 2 years.


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InternalMed_Harrison. Neoplastic diseases of the lung including KS and lymphoma are discussed below in the section on neoplastic diseases.


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InternalMed_Harrison. Diseases of the Cardiovascular System Heart disease is a relatively common postmortem finding in HIV-infected patients (25–75% in autopsy series). The most common form of heart disease is coronary heart disease. In one large series the overall rate of myocardial infarction (MI) was 3.5/1000 patient-years, 28% of these events were fatal, and MI was responsible for 7% of all deaths in the cohort. In patients with HIV infection, cardiovascular disease may be associated with classic risk factors such as smoking, a direct consequence of HIV infection, or a complication of cART. Patients with HIV infection have higher levels of triglycerides, lower levels of high-density lipoprotein cholesterol, and a higher prevalence of smoking than cohorts of individuals without HIV infection. The finding that the rate of cardiovascular disease events was lower in patients on antiretroviral therapy than in those randomized to undergo a treatment interruption identified a clear association between HIV


InternalMed_Harrison

InternalMed_Harrison. that the rate of cardiovascular disease events was lower in patients on antiretroviral therapy than in those randomized to undergo a treatment interruption identified a clear association between HIV replication and risk of cardiovascular disease. In one study, a baseline CD4+ T cell count of <500/μL was found to be an independent risk factor for cardiovascular disease comparable in 1255 magnitude to that attributable to smoking. While the precise pathogenesis of this association remains unclear, it is likely related to the immune activation and increased propensity for coagulation seen as a consequence of HIV replication. Exposure to HIV protease inhibitors and certain reverse transcriptase inhibitors has been associated with increases in total cholesterol and/or risk of MI. Any increases in the risk of death from MI resulting from the use of certain antiretrovirals must be balanced against the marked increases in overall survival brought about by these drugs.


InternalMed_Harrison

InternalMed_Harrison. Another form of heart disease associated with HIV infection is a dilated cardiomyopathy associated with congestive heart failure (CHF) referred to as HIV-associated cardiomyopathy. This generally occurs as a late complication of HIV infection and, histologically, displays elements of myocarditis. For this reason some have advocated treatment with IV immunoglobulin (IVIg). HIV can be directly demonstrated in cardiac tissue in this setting, and there is debate over whether it plays a direct role in this condition. Patients present with typical findings of CHF including edema and shortness of breath. Patients with HIV infection may also develop cardiomyopathy as side effects of IFN-α or nucleoside analogue therapy. These are reversible once therapy is stopped. KS, cryptococcosis, Chagas’ disease, and toxoplasmosis can involve the myocardium, leading to cardiomyopathy. In one series, most patients with HIV infection and a treatable myocarditis were found to have myocarditis associated


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InternalMed_Harrison. disease, and toxoplasmosis can involve the myocardium, leading to cardiomyopathy. In one series, most patients with HIV infection and a treatable myocarditis were found to have myocarditis associated with toxoplasmosis. Most of these patients also had evidence of CNS toxoplasmosis. Thus, MRI or double-dose contrast CT scan of the brain should be included in the workup of any patient with advanced HIV infection and cardiomyopathy.


InternalMed_Harrison

InternalMed_Harrison. A variety of other cardiovascular problems are found in patients with HIV infection. Pericardial effusions may be seen in the setting of advanced HIV infection. Predisposing factors include TB, CHF, mycobacterial infection, cryptococcal infection, pulmonary infection, lymphoma, and KS. While pericarditis is quite rare, in one series 5% of patients with HIV disease had pericardial effusions that were considered to be moderate or severe. Tamponade and death have occurred in association with pericardial KS, presumably owing to acute hemorrhage. Nonbacterial thrombotic endocarditis has been reported and should be considered in patients with unexplained embolic phenomena. IV pentamidine, when given rapidly, can result in hypotension as a consequence of cardiovascular collapse.


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InternalMed_Harrison. Diseases of the Oropharynx and Gastrointestinal System Oropharyngeal and GI diseases are common features of HIV infection. They are most frequently due to secondary infections. In addition, oral and GI lesions may occur with KS and lymphoma.


InternalMed_Harrison

InternalMed_Harrison. Oral lesions, including thrush, hairy leukoplakia, and aphthous ulcers (Fig. 226-34), are particularly common in patients with untreated HIV infection. Thrush, due to Candida infection, and oral hairy leukoplakia, presumed due to EBV, are usually indicative of fairly advanced immunologic decline; they generally occur in patients with CD4+ T cell counts of <300/μL. In one study, 59% of patients with oral candidiasis went on to develop AIDS in the next year. Thrush appears as a white, cheesy exudate, often on an erythematous mucosa in the posterior oropharynx. While most commonly seen on the soft palate, early lesions are often found along the gingival border. The diagnosis is made by direct examination of a scraping for pseudohyphal elements. Culturing is of no diagnostic value, as patients with HIV infection may have a positive throat culture for Candida in the absence of thrush. Oral hairy leukoplakia presents as white, frondlike lesions, generally along the lateral borders of the


InternalMed_Harrison

InternalMed_Harrison. with HIV infection may have a positive throat culture for Candida in the absence of thrush. Oral hairy leukoplakia presents as white, frondlike lesions, generally along the lateral borders of the tongue and sometimes on the adjacent buccal mucosa (Fig. 226-34). Despite its name, oral hairy leukoplakia is not considered a premalignant condition. Lesions are associated with florid replication of EBV. While usually more disconcerting as a sign of HIV-associated immunodeficiency than a clinical problem in need of treatment, severe cases have been reported to respond to topical podophyllin or systemic therapy with anti-herpesvirus agents. Aphthous ulcers of the posterior oropharynx also are seen with regularity in patients with untreated HIV infection


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InternalMed_Harrison. Human Immunodeficiency Virus Disease: AIDS and Related Disorders FIGuRE 226-34 Various oral lesions in HIV-infected individuals. A. Thrush. B. Hairy leukoplakia. C. Aphthous ulcer. D. Kaposi’s sarcoma. (Fig. 226-34). These lesions are of unknown etiology and can be quite painful and interfere with swallowing. Topical anesthetics provide immediate symptomatic relief of short duration. The fact that thalidomide is an effective treatment for this condition suggests that the pathogenesis may involve the action of tissue-destructive cytokines. Palatal, glossal, or gingival ulcers may also result from cryptococcal disease or histoplasmosis.


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InternalMed_Harrison. Esophagitis (Fig. 226-35) may present with odynophagia and retrosternal pain. Upper endoscopy is generally required to make an accurate diagnosis. Esophagitis may be due to Candida, CMV, or HSV. While CMV tends to be associated with a single large ulcer, HSV infection is more often associated with multiple small ulcers. The esophagus may also be the site of KS and lymphoma. Like the oral mucosa, the esophageal mucosa may have large, painful ulcers of unclear etiology that may respond to thalidomide. While achlorhydria is a common problem in patients with HIV infection, other gastric problems are generally rare. Among the neoplastic conditions involving the stomach are KS and lymphoma. Infections of the small and large intestine leading to diarrhea, abdominal pain, and occasionally fever are among the most significant GI problems in HIV-infected patients. They include infections with bacteria, protozoa, and viruses.


InternalMed_Harrison

InternalMed_Harrison. Bacteria may be responsible for secondary infections of the GI tract. Infections with enteric pathogens such as Salmonella, Shigella, and Campylobacter are more common in men who have sex with men and are often more severe and more apt to relapse in patients with HIV infection. Patients with untreated HIV have approximately a 20-fold increased risk of infection with S. typhimurium. FIGuRE 226-35 Barium swallow of a patient with Candida esophagitis. The flow of barium along the mucosal surface is grossly irregular.


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InternalMed_Harrison. FIGuRE 226-35 Barium swallow of a patient with Candida esophagitis. The flow of barium along the mucosal surface is grossly irregular. They may present with a variety of nonspecific symptoms including fever, anorexia, fatigue, and malaise of several weeks’ duration. Diarrhea is common but may be absent. Diagnosis is made by culture of blood and stool. Long-term therapy with ciprofloxacin is the recommended treatment. HIV-infected patients also have an increased incidence of S. typhi infection in areas of the world where typhoid is a problem. Shigella spp., particularly S. flexneri, can cause severe intestinal disease in HIV-infected individuals. Up to 50% of patients will develop bacteremia. Campylobacter infections occur with an increased frequency in patients with HIV infection. While


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InternalMed_Harrison. C. jejuni is the strain most frequently isolated, infections with many other strains have been reported. Patients usually present with crampy abdominal pain, fever, and bloody diarrhea. Infection may also present as proctitis. Stool examination reveals the presence of fecal leukocytes. Systemic infection can occur, with up to 10% of infected patients exhibiting bacteremia. Most strains are sensitive to erythromycin. Abdominal pain and diarrhea may be seen with MAC infection. Fungal infections may also be a cause of diarrhea in patients with HIV infection. Histoplasmosis, coccidioidomycosis, and penicilliosis have all been identified as a cause of fever and diarrhea in patients with HIV infection. Peritonitis has been seen with C. immitis.


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InternalMed_Harrison. Cryptosporidia, microsporidia, and Isospora belli (Chap. 254) are the most common opportunistic protozoa that infect the GI tract and cause diarrhea in HIV-infected patients. Cryptosporidial infection may present in a variety of ways, ranging from a self-limited or intermittent diarrheal illness in patients in the early stages of HIV infection to a severe, life-threatening diarrhea in severely immunodeficient individuals. In patients with untreated HIV infection and CD4+ T cell counts of <300/μL, the incidence of cryptosporidiosis is ~1% per year. In 75% of cases the diarrhea is accompanied by crampy abdominal pain, and 25% of patients have nausea and/or vomiting. Cryptosporidia may also cause biliary tract disease in the HIV-infected patient, leading to cholecystitis with or without accompanying cholangitis and pancreatitis secondary to papillary stenosis. The diagnosis of cryptosporidial diarrhea is made by stool examination or biopsy of the small intestine. The diarrhea is


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InternalMed_Harrison. accompanying cholangitis and pancreatitis secondary to papillary stenosis. The diagnosis of cryptosporidial diarrhea is made by stool examination or biopsy of the small intestine. The diarrhea is noninflammatory, and the characteristic finding is the presence of oocysts that stain with acid-fast dyes. Therapy is predominantly supportive, and marked improvements have been reported in the setting of effective cART. Treatment with up to 2000 mg/d of nitazoxanide (NTZ) is associated with improvement in symptoms or a decrease in shedding of organisms in about half of patients. Its overall role in the management of this condition remains unclear. Patients can minimize their risk of developing cryptosporidiosis by avoiding contact with human and animal feces, by not drinking untreated water from lakes or rivers, and by not eating raw shellfish.


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InternalMed_Harrison. Microsporidia are small, unicellular, obligate intracellular parasites that reside in the cytoplasm of enteric cells (Chap. 254). The main species causing disease in humans is Enterocytozoon bieneusi. The clinical manifestations are similar to those described for cryptosporidia and include abdominal pain, malabsorption, diarrhea, and cholangitis. The small size of the organism may make it difficult to detect; however, with the use of chromotrope-based stains, organisms can be identified in stool samples by light microscopy. Definitive diagnosis generally depends on electron-microscopic examination of a stool specimen, intestinal aspirate, or intestinal biopsy specimen. In contrast to cryptosporidia, microsporidia have been noted in a variety of extraintestinal locations, including the eye, brain, sinuses, muscle, and liver, and they have been associated with conjunctivitis and hepatitis. The most effective way to deal with microsporidia in a patient with HIV infection is to restore


InternalMed_Harrison

InternalMed_Harrison. brain, sinuses, muscle, and liver, and they have been associated with conjunctivitis and hepatitis. The most effective way to deal with microsporidia in a patient with HIV infection is to restore the immune system by treating the HIV infection with cART. Albendazole, 400 mg bid, has been reported to be of benefit in some patients.


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InternalMed_Harrison. I. belli is a coccidian parasite (Chap. 254) most commonly found as a cause of diarrhea in patients from tropical and subtropical regions. Its cysts appear in the stool as large, acid-fast structures that can be differentiated from those of cryptosporidia on the basis of size, shape, and number of sporocysts. The clinical syndromes of Isospora infection are identical to those caused by cryptosporidia. The important distinction is that infection with Isospora is generally relatively easy to treat with 1257 TMP/SMX. While relapses are common, a thrice-weekly regimen of TMP/SMX appears adequate to prevent recurrence.


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InternalMed_Harrison. CMV colitis was once seen as a consequence of advanced immunodeficiency in 5–10% of patients with AIDS. It is much less common with the advent of cART. CMV colitis presents as diarrhea, abdominal pain, weight loss, and anorexia. The diarrhea is usually nonbloody, and the diagnosis is achieved through endoscopy and biopsy. Multiple mucosal ulcerations are seen at endoscopy, and biopsies reveal characteristic intranuclear and cytoplasmic inclusion bodies. Secondary bacteremias may result as a consequence of thinning of the bowel wall. Treatment is with either ganciclovir or foscarnet for 3–6 weeks. Relapses are common, and maintenance therapy is typically necessary in patients whose HIV infection is poorly controlled. Patients with CMV disease of the GI tract should be carefully monitored for evidence of CMV retinitis.


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InternalMed_Harrison. In addition to disease caused by specific secondary infections, patients with HIV infection may also experience a chronic diarrheal syndrome for which no etiologic agent other than HIV can be identified. This entity is referred to as AIDS enteropathy or HIV enteropathy. It is most likely a direct result of HIV infection in the GI tract. Histologic examination of the small bowel in these patients reveals low-grade mucosal atrophy with a decrease in mitotic figures, suggesting a hyporegenerative state. Patients often have decreased or absent small-bowel lactase and malabsorption with accompanying weight loss.


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InternalMed_Harrison. The initial evaluation of a patient with HIV infection and diarrhea should include a set of stool examinations, including culture, exami nation for ova and parasites, and examination for Clostridium difficile toxin. Approximately 50% of the time this workup will demonstrate infection with pathogenic bacteria, mycobacteria, or protozoa. If the initial stool examinations are negative, additional evaluation, including upper and/or lower endoscopy with biopsy, will yield a diagnosis of microsporidial or mycobacterial infection of the small intestine ~30% of the time. In patients for whom this diagnostic evaluation is nonrevealing, a presumptive diagnosis of HIV enteropathy can be made if the diarrhea has persisted for >1 month. An algorithm for the evalua tion of diarrhea in patients with HIV infection is given in Fig. 226-36. Rectal lesions are common in HIV-infected patients, particularly the perirectal ulcers and erosions due to the reactivation of HSV


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InternalMed_Harrison. FIGuRE 226-36 Algorithm for the evaluation of diarrhea in a patient with HIV infection. HIV-associated enteropathy is a diagnosis of exclusion and can be made only after other, generally treatable, forms of diarrheal illness have been ruled out. Human Immunodeficiency Virus Disease: AIDS and Related Disorders FIGuRE 226-37 Severe, erosive perirectal herpes simplex in a patient with AIDS. (Fig. 226-37). These lesions may appear quite atypical, as denuded skin without vesicles. They typically respond well to treatment with acyclovir, famciclovir, or foscarnet. Other rectal lesions encountered in patients with HIV infection include condylomata acuminata, KS, and intraepithelial neoplasia (see below).


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InternalMed_Harrison. Hepatobiliary Diseases Diseases of the hepatobiliary system are a major problem in patients with HIV infection. It has been estimated that approximately 15% of the deaths of patients with HIV infection are related to liver disease. While this is predominantly a reflection of the problems encountered in the setting of co-infection with hepatitis B or C, it is also a reflection of the hepatic injury, ranging from hepatic steatosis to hypersensitivity reactions to immune reconstitution, that can be seen in the context of cART.


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InternalMed_Harrison. The prevalence of co-infection with HIV and hepatitis viruses varies by geographic region. In the United States, ~90% of HIV-infected individuals have evidence of infection with HBV; 6–14% have chronic HBV infection; 5–50% of patients are co-infected with HCV; and co-infections with hepatitis D, E, and/or G viruses are common. Among IV drug users with HIV infection, rates of HCV infection range from 70% to 95%. HIV infection has a significant impact on the course of hepatitis virus infection. It is associated with approximately a threefold increase in the development of persistent hepatitis B surface antigenemia. Patients infected with both HBV and HIV have decreased evidence of inflammatory liver disease. The presumption that this is due to the immunosuppressive effects of HIV infection is supported by the observations that this situation can be reversed, and one may see the development of more severe hepatitis following the initiation of effective cART. In studies of the impact of


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InternalMed_Harrison. is supported by the observations that this situation can be reversed, and one may see the development of more severe hepatitis following the initiation of effective cART. In studies of the impact of HIV on HBV infection, fourto tenfold increases in liver-related mortality rates have been noted in patients with HIV and active HBV infection compared to rates in patients with either infection alone. There is, however, only a slight increase in overall mortality rate in HIV-infected individuals who are also hepatitis B surface antigen (HBsAg)–positive. IFN-α is less successful as treatment for HBV in patients with HIV co-infection. Lamivudine, emtricitabine, adefovir/tenofovir/ entecavir, and telbivudine alone or in combination are useful in the treatment of hepatitis B in patients with HIV infection. It is important to remember that all the above-mentioned drugs also have activity against HIV and should not be used alone in patients with HIV infection, in order to avoid the emergence of


InternalMed_Harrison

InternalMed_Harrison. It is important to remember that all the above-mentioned drugs also have activity against HIV and should not be used alone in patients with HIV infection, in order to avoid the emergence of quasispecies of HIV resistant to these drugs. For this reason, the need to treat hepatitis B infection in a patient with HIV infection is an indication to treat HIV infection in that same patient, regardless of CD4+ T cell count. HCV infection is more severe in the patient with HIV infection; it does not appear to affect overall mortality rates in HIV-infected individuals when other variables such as age, baseline CD4+ T cell count, and use of cART are taken into account. In the setting of HIV and HCV co-infection, levels of HCV are approximately tenfold higher than in the HIV-negative patient with HCV infection. There is a 50% higher overall mortality rate with a five-fold increased risk of death due to liver disease in patients chronically infected with both HCV and HIV. Use of directly acting


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InternalMed_Harrison. infection. There is a 50% higher overall mortality rate with a five-fold increased risk of death due to liver disease in patients chronically infected with both HCV and HIV. Use of directly acting agents for the treatment for HCV leads to cure rates approaching 100%, even in patients with HIV co-infection. Successful treatment of HCV in HIV-infected patients decreases mortality. Hepatitis A virus infection is not seen with an increased frequency in patients with HIV infection. It is recommended that all patients with HIV infection who have not experienced natural infection be immunized with hepatitis A and/or hepatitis B vaccines. Infection with hepatitis G virus, also known as GB virus C, is seen in ~50% of patients with HIV infection. For reasons that are currently unclear, there are data to suggest that patients with HIV infection co-infected with this virus have a decreased rate of progression to AIDS.


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InternalMed_Harrison. A variety of other infections also may involve the liver. Granulomatous hepatitis may be seen as a consequence of mycobacterial or fungal infections, particularly MAC infection. Hepatic masses may be seen in the context of TB, peliosis hepatis, or fungal infection. Among the fungal opportunistic infections, C. immitis and Histoplasma capsulatum are those most likely to involve the liver. Biliary tract disease in the form of papillary stenosis or sclerosing cholangitis has been reported in the context of cryptosporidiosis, CMV infection, and KS. When no diagnosis can be made, the term AIDS cholangiopathy is used. Hemophagocytic lymphohistiocytosis of the liver has been seen in the setting of Hodgkin’s disease.


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InternalMed_Harrison. Many of the drugs used to treat HIV infection are metabolized by the liver and can cause liver injury. Fatal hepatic reactions have been reported with a wide array of antiretrovirals including nucleoside analogues, nonnucleoside analogues, and protease inhibitors. Nucleoside analogues work by inhibiting DNA synthesis. This can result in toxicity to mitochondria, which can lead to disturbances in oxidative metabolism. This may manifest as hepatic steatosis and, in severe cases, lactic acidosis and fulminant liver failure. It is important to be aware of this condition and to watch for it in patients with HIV infection receiving nucleoside analogues. It is reversible if diagnosed early and the offending agent(s) discontinued. Nevirapine has been associated with at times fatal fulminant and cholestatic hepatitis, hepatic necrosis, and hepatic failure. Indinavir may cause mild to moderate elevations in serum bilirubin in 10–15% of patients in a syndrome similar to Gilbert’s syndrome. A


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InternalMed_Harrison. cholestatic hepatitis, hepatic necrosis, and hepatic failure. Indinavir may cause mild to moderate elevations in serum bilirubin in 10–15% of patients in a syndrome similar to Gilbert’s syndrome. A similar pattern of hepatic injury may be seen with atazanavir. In the patient receiving cART with an unexplained increase in hepatic transaminases, strong consideration should be given to drug toxicity.


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InternalMed_Harrison. Pancreatic injury is most commonly a consequence of drug toxicity, notably that secondary to pentamidine or dideoxynucleosides. While up to half of patients in some series have biochemical evidence of pancreatic injury, <5% of patients show any clinical evidence of pancreatitis that is not linked to a drug toxicity.


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InternalMed_Harrison. Diseases of the Kidney and Genitourinary Tract Diseases of the kidney or genitourinary tract may be a direct consequence of HIV infection, due to an opportunistic infection or neoplasm, or related to drug toxicity. Overall, microalbuminuria is seen in ~20% of untreated HIV-infected patients; significant proteinuria is seen in closer to 2%. The presence of microalbuminuria has been associated with an increase in all-cause mortality rate. HIV-associated nephropathy (HIVAN) was first described in IDUs and was initially thought to be IDU nephropathy in patients with HIV infection; it is now recognized as a true direct complication of HIV infection. Although the majority of patients with this condition have CD4+ T cell counts <200/μL, HIV-associated nephropathy can be an early manifestation of HIV infection and is also seen in children. Over 90% of reported cases have been in African-American or Hispanic individuals; the disease is not only more prevalent in these populations but also more


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InternalMed_Harrison. HIV infection and is also seen in children. Over 90% of reported cases have been in African-American or Hispanic individuals; the disease is not only more prevalent in these populations but also more severe and is the third leading cause of end-stage renal failure among African Americans age 20–64 in the United States. Proteinuria is the hallmark of this disorder. Edema and hypertension are rare. Ultrasound examination reveals enlarged, hyperechogenic kidneys. A definitive diagnosis is obtained through renal biopsy. Histologically, focal segmental glomerulosclerosis is present in 80%, and mesangial proliferation in 10–15% of cases. Prior to effective antiretroviral therapy, this disease was characterized by relatively rapid progression to end-stage renal disease. Patients with HIV-associated nephropathy should be treated for their HIV infection regardless of CD4+ T cell count. Treatment with angiotensin-converting enzyme (ACE) inhibitors and/or prednisone, 60 mg/d, also has been


InternalMed_Harrison

InternalMed_Harrison. nephropathy should be treated for their HIV infection regardless of CD4+ T cell count. Treatment with angiotensin-converting enzyme (ACE) inhibitors and/or prednisone, 60 mg/d, also has been reported to be of benefit in some cases. The incidence of this disease in patients receiving adequate cART has not been well defined; however, the impression is that it has decreased in frequency and severity. It is the leading cause of end-stage renal disease in patients with HIV infection.


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InternalMed_Harrison. Among the drugs commonly associated with renal damage in patients with HIV disease are pentamidine, amphotericin, adefovir, cidofovir, tenofovir, and foscarnet. TMP/SMX may compete for tubular secretion with creatinine and cause an increase in the serum creatinine level. Sulfadiazine may crystallize in the kidney and result in an easily reversible form of renal shutdown, while indinavir or atazanavir may form renal calculi. Adequate hydration is the mainstay of treatment and prevention for these latter two conditions.


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InternalMed_Harrison. Genitourinary tract infections are seen with a high frequency in patients with HIV infection; they present with skin lesions, dysuria, hematuria, and/or pyuria and are managed in the same fashion as in patients without HIV infection. Infections with HSV are covered below (“Dermatologic Diseases”). Infections with T. pallidum, the etiologic agent of syphilis, play an important role in the HIV epidemic. In HIV-negative individuals, genital syphilitic ulcers as well as the ulcers of chancroid are major predisposing factors for heterosexual transmission of HIV infection. While most HIV-infected individuals with syphilis have a typical presentation, a variety of formerly rare clinical problems may be encountered in the setting of dual infection. Among them are lues maligna, an ulcerating lesion of the skin due to a necrotizing vasculitis; unexplained fever; nephrotic syndrome; and neurosyphilis. The most common presentation of syphilis in the HIV-infected patient is that of condylomata


InternalMed_Harrison

InternalMed_Harrison. of the skin due to a necrotizing vasculitis; unexplained fever; nephrotic syndrome; and neurosyphilis. The most common presentation of syphilis in the HIV-infected patient is that of condylomata lata,a form of secondary syphilis. Neurosyphilis may be asymptomatic or may present as acute meningitis, neuroretinitis, deafness, or stroke. The rate of neurosyphilis may be as high as 1% in patients with HIV infection, and one should consider a lumbar puncture to look for neurosyphilis in all patients with HIV infection and secondary syphilis. As a consequence of the immunologic abnormalities seen in the setting of HIV infection, diagnosis of syphilis through standard serologic testing may be challenging. On the one hand, a significant number of patients have false-positive Venereal Disease Research Laboratory (VDRL) tests due to polyclonal B cell activation. On the other hand, the development of a new positive VDRL may be delayed in patients with new infections, and the anti–fluorescent


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InternalMed_Harrison. Laboratory (VDRL) tests due to polyclonal B cell activation. On the other hand, the development of a new positive VDRL may be delayed in patients with new infections, and the anti–fluorescent treponemal antibody (anti-FTA) test may be negative due to immunodeficiency. Thus, dark-field examination of appropriate specimens should be performed in any patient in whom syphilis is suspected, even if the patient has a negative VDRL. Similarly, any patient with a positive serum VDRL test, neurologic findings, and an abnormal spinal fluid examination should be considered to have neurosyphilis and treated accordingly, regardless of the CSF VDRL result. In any setting, patients treated for syphilis need to be carefully monitored to ensure adequate therapy. Approximately one-third of patients with HIV infection will experience a Jarisch-Herxheimer reaction upon initiation of therapy for syphilis.


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InternalMed_Harrison. Vulvovaginal candidiasis is a common problem in women with HIV infection. Symptoms include pruritus, discomfort, dyspareunia, and dysuria. Vulvar infection may present as a morbilliform rash that may extend to the thighs. Vaginal infection is usually associated with 1259 a white discharge, and plaques may be seen along an erythematous vaginal wall. Diagnosis is made by microscopic examination of the discharge for pseudohyphal elements in a 10% potassium hydroxide solution. Mild disease can be treated with topical therapy. More serious disease can be treated with fluconazole. Other causes of vaginitis include Trichomonas and mixed bacteria.


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InternalMed_Harrison. Diseases of the Endocrine System and Metabolic Disorders A variety of endocrine and metabolic disorders are seen in the context of HIV infection. These may be a direct consequence of HIV infection, secondary to opportunistic infections or neoplasms, or related to medication side effects. Between 33% and 75% of patients with HIV infection receiving thymidine analogues or protease inhibitors as a component of cART develop a syndrome often referred to as lipodystrophy, consisting of elevations in plasma triglycerides, total cholesterol, and apolipoprotein B, as well as hyperinsulinemia and hyperglycemia. Many of the patients have been noted to have a characteristic set of body habitus changes associated with fat redistribution, consisting of truncal obesity coupled with peripheral wasting (Fig. 226-38). Truncal obesity is apparent as an increase in abdominal girth related to increases in mesenteric fat, a dorsocervical fat pad (“buffalo hump”) reminiscent of patients with Cushing’s


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InternalMed_Harrison. (Fig. 226-38). Truncal obesity is apparent as an increase in abdominal girth related to increases in mesenteric fat, a dorsocervical fat pad (“buffalo hump”) reminiscent of patients with Cushing’s syndrome, and enlargement of the breasts. The peripheral wasting, or lipoatrophy, is particularly noticeable in the face and buttocks and by the prominence of the veins in the legs. These changes may develop at any time ranging from ~6 weeks to several years following the initiation of cART.


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InternalMed_Harrison. Approximately 20% of the patients with HIV-associated lipodystrophy meet the criteria for the metabolic syndrome as defined by The International Diabetes Federation or The U.S. National Cholesterol Education Program Adult Treatment Panel III. The lipodystrophy syndrome has been reported in association with regimens containing a variety of different drugs, and while initially reported in the setting of protease inhibitor therapy, it appears that similar changes can also be induced by protease-sparing regimens. It has been suggested that the lipoatrophy changes are particularly severe in patients receiv ing the thymidine analogues stavudine and zidovudine. National Cholesterol Education Program (NCEP) guidelines should be followed in the management of these lipid abnormalities (Chap. 291e), and consideration should be given to changing the components of cART with avoidance of thymidine analogues (azidothymidine and stavudine) and protease inhibitors. Due to concerns regarding drug


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InternalMed_Harrison. and consideration should be given to changing the components of cART with avoidance of thymidine analogues (azidothymidine and stavudine) and protease inhibitors. Due to concerns regarding drug interactions, the most commonly utilized lipid-lowering agents in this setting are gemfibrozil and atorvastatin. In addition, lactic acidosis is associated with cART. This is most commonly seen with nucleoside analogue reverse transcriptase inhibitors and can be fatal (see below).