Joseph A. DeSimone

Inflammatory Reactions in HIV-1–Infected Persons after Initiation of Highly Active Antiretroviral Therapy

Highly active antiretroviral therapy (HAART)combination antiretroviral therapy that has potent in vivo effects on HIV-1 replicationhas led to significant decreases in AIDS-associated morbidity and mortality (1). Although patients receiving HAART have reduced plasma HIV-1 viral load and increased CD4+ T-lymphocyte counts, they still develop AIDS-defining events, particularly in the first 2 months of treatment (2, 3). A delay in restoration of immune function may account for the development of opportunistic infections. It is possible, however, that HAART may actually promote the clinical expression and development of such infections, as well as AIDS-related malignant conditions and other noninfectious diseases. Several authors have recently reported cases that may represent progression of previously quiescent disorders to symptomatic diseases after initiation of HAART. We searched MEDLINE for studies of such cases, which some authors have referred to as immune restoration disorders (4-8). Bibliographies of relevant studies were also reviewed. In this paper, we summarize clinical presentations (Table 1) and potential mechanisms of these conditions and describe therapeutic methods (Table 2). Table 1. Clinical Presentation of Specific Opportunistic Infections in HIV-1Infected Patients with and without Highly Active Antiretroviral Therapy Table 2. Successful Treatments Used for Opportunistic Infections in HIV-1Infected Patients after Highly Active Antiretroviral Therapy For the cases reported in this review, HAART refers to the initiation of a regimen that involves nucleoside reverse transcriptase inhibitors with one or more protease inhibitors or the addition of a protease inhibitor to a regimen of nucleoside reverse transcriptase inhibitors. Similarly, the usual response to HAART in the following cases involves marked reductions in plasma HIV-1 RNA levels and increases in CD4+ T-lymphocyte counts. It should be noted, however, that degrees of response to HAART varied. Mycobacterium avium Complex Several case reports have discussed the development of Mycobacterium avium complex and other nontuberculous mycobacterial infections in patients receiving HAART (6, 9-16). Many affected patients presented with focal or diffuse lymphadenitis within 2 months of initiating HAART. Mycobacteremia was rarely demonstrated, but the lymph nodes (some of which were suppurative) were usually culture positive for M. avium complex. In a retrospective chart review, Phillips and colleagues (17) found that patients who developed M. avium complex lymphadenitis within 12 weeks of starting HAART had higher CD4+ T-lymphocyte counts, were more likely to develop a localized draining sinus, and were less likely to have weight loss and disseminated M. avium complex disease than patients who had been receiving HAART for more than 12 weeks. Of interest, a case of recurrent leprosy, in the tuberculoid form secondary to increased antiM. leprae immunity, has been reported in an HIV-1infected person after initiation of HAART (18). Uncommon presentations of M. avium complex, such as granulomatous masses, osteomyelitis, bursitis, Addison disease, and skin nodules, were also seen after HAART (6, 11). Of note, similar focal M. avium complex disease was noted as early as 1988 in patients receiving zidovudine monotherapy (19, 20). In the above cases, antimycobacterial therapy, corticosteroids, or local surgical drainage alone was successful, usually in conjunction with HAART. Mycobacterium tuberculosis Inflammatory reactions in HIV-1infected patients receiving antituberculous therapy and HAART have been well documented (21-27). Affected patients had pansensitive pulmonary or extrapulmonary tuberculosis and developed inflammatory reactions several weeks after initiation of HAART despite initial response to antituberculous therapy. Examples of such reactions included fever, worsening pulmonary infiltrates, lymphadenopathy, and in some cases intracranial tuberculomas. Cultures of sputum and lymph nodes usually did not reveal acid-fast bacilli. All patients improved when anti-inflammatory agents were added to HAART. A case of regional lymphadenitis secondary to CalmetteGurin bacillus has also been reported in an HIV-1infected child after initiation of antiretroviral therapy (16). Narita and coworkers (24) noted that HIV-1infected patients treated with antituberculous therapy and HAART had a higher incidence of paradoxical reactions (new fever; worsening or emergence of lymphadenopathy, pulmonary infiltrates, or pleural effusion; or worsening of other tuberculous lesions) than HIV-1infected patients not treated with HAART. Patients in the former group developed paradoxical reactions a mean of 11 to 15 days after initiation of HAART and had a larger decrease in plasma HIV-1 viral load than those in the latter group. Cytomegalovirus Both ocular and extraocular cytomegalovirus infections have been reported after HAART. One of the earliest reports described five HIV-1infected patients with no history of ocular disease who received a first diagnosis of cytomegalovirus retinitis after CD4+ T-lymphocyte counts increased from less than 0.085 109 cells/L to more than 0.195 109 cells/L with HAART (28). Similarly, cytomegalovirus viremia, colitis, pancreatitis, and submandibular inflammation have also been reported after HAART in patients with no history of cytomegalovirus infection (29). Other authors have described the development of vitritis in patients treated with HAART who previously had active or inactive cytomegalovirus retinitis (30-35). Patients with a history of unilateral cytomegalovirus retinitis developed vitritis in the same eye after HAART. In one patient with vitritis, anterior chamber paracentesis showed no evidence of cytomegalovirus by polymerase chain reaction or antibody titer and no evidence of other infectious agents. Most cases improved without evidence of relapse, regardless of therapy (topical medications, periocular injection of steroids, or anticytomegalovirus agents). Karavellas and colleagues (36) conducted a cohort study of 30 patients with cytomegalovirus retinitis who responded to HAART. Nineteen patients (63%) developed immune recovery vitritis after a median of 43 weeks. All affected patients reported floaters, and 17 of 19 had decreased visual acuity. All patients had inactive cytomegalovirus retinitis in the affected eye when vitritis was diagnosed. In a retrospective review by Jabs and coworkers (37), this disorder was observed in only 6 of 33 patients, perhaps because of previous therapy with ganciclovir implants for cytomegalovirus retinitis. Hepatitis C Virus Several patients with previously quiescent hepatitis C virus (HCV) infection developed acute hepatitis, cirrhosis, or an HCV-associated disorder, such as cryoglobulinemia, within 1 to 9 months after initiation of HAART (5, 38-41). Hepatitis C virus was implicated because HCV IgG antibody developed or plasma HCV RNA level increased after introduction of HAART, although this was not observed in all cases. Some patients improved with interferon- therapy; however, in other patients, protease inhibitor therapy had to be discontinued. The response of plasma HCV RNA to HAART in patients co-infected with HIV-1 has been evaluated (40, 42-46). One study found that mean plasma HCV RNA level initially increased 6 weeks after addition of HAART and later decreased to below baseline, with minimal changes in serum aminotransferase levels (42). Other studies, however, noted a moderate increase in plasma HCV RNA level after HAART, and liver biopsy showed associated lobular necrosis and inflammation in some patients (40, 43, 46). Hepatitis B Virus Some studies have attributed acute hepatitis in the setting of HAART to hepatitis B virus (HBV) (47-51). Affected patients had previous HBV infection and developed clinical hepatitis 5 to 12 weeks after beginning HAART. Most of these patients demonstrated newly detectable plasma HBV RNA or increased levels of HBV RNA during acute hepatitis. In some cases, serologic tests for HBV also showed active HBV infection. Researchers discontinued HAART in one patient (51), but most other patients improved without changes in therapy. Cryptococcus and Histoplasma Species A case report of Histoplasma capsulatum infection and a retrospective review of cryptococcal infection occurring after HAART have been described. Bottaro and coworkers (52) described a 35-year-old South American HIV-1infected man with a CD4+ T-lymphocyte count of 0.005 109 cells/L who received a diagnosis of disseminated histoplasmosis on the basis of blood culture results. Successful treatment with amphotericin B was followed by itraconazole therapy. Three weeks after initiation of HAART, the patients inguinal lymph node became enlarged; excisional biopsy revealed a granulomatous reaction and H. capsulatum by culture. The CD4+ T-lymphocyte count had increased to 0.066 109 cells/L. Itraconazole therapy and HAART were continued, and the patients symptoms improved. A retrospective review of all HIV-1infected patients with culture-proven cryptococcal meningitis between 1996 and 1999 identified three patients who developed cryptococcal meningitis in temporal association with initiation of HAART (53). Two patients developed clinical meningitis within 1 to 6 weeks after introduction of HAART. Studies of cerebrospinal fluid were remarkable for leukocytosis (leukocyte count 14 109 cells/L) and the presence of Cryptococcus neoformans by culture. A third patient developed recrudescence of previously suppressed C. neoformans meningitis, also marked by cerebrospinal fluid leukocytosis (leukocyte count, 100 109 cells/L) and an elevated cerebrospinal fluid C. neoformans antigen titer within 10 days of beginning HAART. Therapy was not changed in this patient, and meningeal signs and symptoms resolved over 2 weeks. Herpes Zoster Several studies have reported development of herpes zoster after HAART (8, 54, 55).

Central nervous system infections in individuals with HIV-1 infection

Opportunistic infections of the central nervous system (CNS) are common complications of advanced immunodeficiency in individuals with human immunodeficiency virus type 1 (HIV-1) infection. Neurological disease is the first manifestation of acquired immunodeficiency syndrome (AIDS) in 10% to 20% of symptomatic HIV-1 infection. Prompt diagnosis and treatment of such disorders is critical. Also, in the era of highly active antiretroviral therapy (HAART), these disease states have changed in presentation and epidemiology. Therefore, we review the epidemiology, pathogenesis, clinical features, diagnosis, and management of five common central nervous system disorders in individuals with HIV-1 infection: toxoplasma encephalitis, primary central nervous system lymphoma, cryptococcal meningitis, cytomegalovirus encephalitis, and progressive multifocal leukoencephalopathy.

Intensification and Stimulation Therapy for Human Immunodeficiency Virus Type 1 Reservoirs in Infected Persons Receiving Virally Suppressive Highly Active Antiretroviral Therapy

Highly active antiretroviral therapy (HAART) has led to significant changes in mortality and morbidity in the human immunodeficiency virus type 1 (HIV-1) epidemic. Nevertheless, because of molecular mechanisms of viral persistence, HAART does not eradicate HIV-1. Didanosine and hydroxyurea were added to the antiretroviral regimens of 3 HIV-1-infected men who were receiving stable HAART and who had HIV-1 RNA levels <50 copies/mL at the initiation of the study protocol, as a novel intensification to attack cryptic viral replication; low-dose OKT3 was then administered, followed by a course of interleukin-2, to stimulate latent provirus. Replication-competent virus was undetectable after treatment, and plasma viral RNA was either undetectable or <5 copies/mL. In trial periods during which no antiretroviral therapy was administered, the patients developed plasma viral rebound. This translational approach combines novel intensification and stimulation therapy to deplete residual HIV-1 reservoirs. Additional experimental approaches must be developed if HIV-1 eradication is to become possible in patients receiving virally suppressive HAART.

Sustained Bacteremia Associated with Transjugular Intrahepatic Portosystemic Shunt (TIPS)

Transjugular intrahepatic portosystemic shunt (TIPS) has become a routine procedure in patients with portal hypertension, yet there are few data concerning the incidence of bacteremia associated with this shunt. All patients who underwent TIPS placement at a university hospital from January 1992 through January 1999 were studied. Ninety-nine TIPS were placed, and 10 patients subsequently developed sustained bacteremia; 5 patients had no identifiable source of bacteremia despite rigorous evaluation and were presumed to represent TIPS infections, for an estimated annual incidence of 7 cases/1000 TIPS procedures. Case patients developed bacteremia a median of 100 days after TIPS placement (range, 6-732 days). Bacteremia resolved in all patients after treatment with appropriate intravenous antibiotics (median, 2 weeks of therapy). Although the incidence of TIPS-associated bacteremia appears low, the increasing frequency of this procedure suggests that more information is needed to define this entity and to develop appropriate treatment recommendations.

Prevalence of obstructive lung disease in HIV population: A cross sectional study

BACKGROUND Observational studies have suggested an association between HIV infection and emphysema. AIMS The primary aim of this study was to estimate the prevalence of obstructive lung disease in HIV-infected patients seen in an outpatient infectious disease clinic. The secondary aim was to estimate the prevalence of Obstructive Lung Disease (OLD) in smokers and non smokers in this population. METHODS This was a prospective cross-sectional study. Consecutive patients who were seen for routine HIV care underwent spirometry and answered the St. Georges Respiratory Questionnaire (SGRQ). Further, we collected information from the charts on demographics, co-morbidities, CD4 cell count, and HIV viral load (current, baseline, etc). RESULTS This study included 98 HIV-infected patients with mean age of 45 years, (SD: 11) and 84% male. They were seen from November 2008 to May 2009 at Thomas Jefferson University in Philadelphia. According to established criteria, spirometry results were classified as normal in 69% and obstructive in 16.3%. Among those who never smoked, the prevalence of obstructive lung disease on spirometry was 13.6%. The prevalence of obstruction in HIV patients with a history of smoking was 18.5%. Current and ever smokers comprised 21.4% and 55% of the patients respectively. The mean SGRQ total score was 7. The mean SGRQ score in active smokers was 17 and 15 in those subjects with a prior history of smoking. The mean SGRQ score among patients with obstruction in spiromerty was 27.7 in patients with obstruction on spirometry. CONCLUSION This urban population of HIV-infected persons has a relatively high prevalence of obstructive lung disease as assessed by spirometry. Furthermore, the high prevalence of obstructive lung disease in never smokers may suggest a possible association between HIV infection and emphysema. In addition the SGRQ total score was comparatively higher in patients with obstruction on spirometry. Our data suggests that potentially all patients with HIV should be screened a for OLD.

Dolutegravir: A new integrase strand transfer inhibitor for the treatment of HIV

The first two integrase strand transfer inhibitors (INSTIs) approved for treatment of patients infected with human immunodeficiency virus (HIV) were raltegravir and elvitegravir. Both raltegravir and elvitegravir are now guideline‐preferred agents as part of an antiretroviral regimen for treatment‐naive patients. However, raltegravir is dosed twice/day. Elvitegravir is available in a single‐tablet regimen and dosed once/day because it is administered with the pharmacokinetic booster cobicistat, a potent CYP3A4 inhibitor that can lead to clinically significant drug–drug interactions. In addition, raltegravir and elvitegravir have a low genetic barrier to resistance and are associated with cross‐resistance. Dolutegravir is a new‐generation INSTI administered once/day without a pharmacokinetic booster and can be coformulated in a single‐tablet regimen. Phase III studies have demonstrated the efficacy and safety of dolutegravir for treatment‐naive and treatment‐experienced patients. Compared with other INSTIs, dolutegravir has a higher genetic barrier to resistance. Dolutegravir was approved by the U.S. Food and Drug Administration in August 2013 and joins raltegravir and elvitegravir as guideline‐preferred agents for the management for HIV‐infected treatment‐naive patients.

Attenuation of HIV-1 Infection by Other Microbial Agents

Although potentiation of human immunodeficiency virus (HIV) type 1 (HIV-1) infection has been known to occur in coinfection with a variety of pathogens and types of vaccination, there are emerging data on specific infectious agents that may attenuate HIV-1 infection. New literature suggests that certain pathogens are capable of inhibiting HIV-1 replication. These include GB virus C, measles virus, Orientia tsutsugamushi, and human T lymphotropic virus types 1 and 2. In addition, there are conflicting data on the effects of Mycobacterium tuberculosis on the replication of HIV-1, with some suggesting that this organism may inhibit HIV-1 replication. Also remaining controversial are the possible protective effects of HIV type 2 against HIV-1 infection. In this review, we summarize and critically discuss the body of emerging literature concerning infections that may have the ability to attenuate HIV-1 infection.

Candidemia complicated by endophthalmitis: a prospective analysis

Endogenous fungal endophthalmitis, including chorioretinitis or vitreal involvement, is a known complication of disseminated candidal infection. The incidence rate of candidal eye infection as a complication of candidemia is unclear. Some studies of ocular candidiasis, many of which were performed retrospectively, report rates varying from 2% to 40% [1–7]. This variability in incidence may relate to the retrospective nature of these reports, a difference in definition of ocular candidiasis, or other differences in methodology. A few prospective studies report similar rates ranging from approximately 2% to 40% [1–4, 6, 8–10]. Therefore, to demonstrate the current incidence of ocular candidiasis, we undertook a prospective study of fungal endophthalmitis as a complication of candidemia in hospitalized patients. After the institutional review board approval was obtained, we prospectively identified all inpatients at Thomas Jefferson University Hospital (Philadelphia, PA) with candidemia, diagnosed by at least one positive blood culture, for the period from August 2004 to April 2005. After informed consent, indirect ophthalmoscopy was performed by a Wills Eye Hospital ophthalmologist within 72 h from the time that the laboratory reported a positive blood culture. Blood cultures were obtained using the Bactec blood culture system (Becton Dickinson, Franklin Lakes, NJ). The ophthalmologist rated the funduscopic examination into one or more of the following groups: candidal chorioretinitis, candidal endophthalmitis (chorioretinitis plus vitreitis), normal examination, or non-specific findings. A similar ophthalmologic examination was performed two weeks later, if feasible. Patients with prior candidemia or life expectancy <72 h were excluded. There were 97 patients with candidal bloodstream infections identified during the study period. Forty-six patients were enrolled. Of the patients not enrolled, 42 refused to participate, five expired prior to enrollment, three had prior fungemia, and one had life expectancy <72 h. Bloodstream isolates for the 46 study patients were as follows: C. albicans 24 (52%), C. glabrata 12 (26%), C. parapsilosis 8 (17%), C. tropicalis 1 (2%), and C. krusei 1 (2%). The patient characteristics, including demographics and risk factors for candidemia, are displayed in Table 1. The group of patients not included in the study was similar to the study population with respect to demographics and risk factors for candidemia. Only one episode of candidal chorioretinitis was identified during the study period: incidence 2.2% (95% confidence interval: 0.06% to 11.5%) [11]. This single case of fungal chorioretinitis, diagnosed at initial ophthalmologic examination, was due to C. albicans infection. Of the 46 patients enrolled, all patients received an initial eye examination at the onset of candidemia, and 22 patients completed an eye examination at two weeks follow-up. No new subjective complaints or changes in ophthalmologic examination were demonstrated Eur J Clin Microbiol Infect Dis (2007) 26:839–841 DOI 10.1007/s10096-007-0372-7

Successful Desensitization to Enfuvirtide after a Hypersensitivity Reaction in an HIV-1-Infected Man

We report a case of successful, rapid desensitization to enfuvirtide after a hypersensitivity reaction in a man with highly drug-resistant human immunodeficiency virus type 1 infection. The patient was desensitized in a monitored intensive care unit and tolerated the rapid desensitization protocol without any serious adverse effects. This case illustrates the ability to safely desensitize patients with limited treatment options who require enfuvirtide therapy.

Rothia mucilaginosa Prosthetic Device Infections: a Case of Prosthetic Valve Endocarditis

ABSTRACT Rothia mucilaginosa is increasingly recognized as an emerging opportunistic pathogen associated with prosthetic device infections. Infective endocarditis is one of the most common clinical presentations. We report a case of R. mucilaginosa prosthetic valve endocarditis and review the literature of prosthetic device infections caused by this organism.