Treatment outcomes for Mycobacterium avium complex: a systematic review and meta-analysis.

To evaluate the existing evidence regarding treatment regimens for Mycobacterium avium complex (MAC), a systematic review of the available therapeutic studies was conducted to assess treatment outcomes. A random-effects meta-analysis was used to assess treatment outcomes. Subgroup analyses were also conducted by separating studies based on each characteristic independently. Twenty-eight trials met the inclusion criteria. Our meta-analysis showed that the estimated pooled treatment success rate for patients with MAC disease was 39 % [95 % confidence interval (CI) 38-41 %]. The rates of failure, relapse, death, and default were 27 % (95 % CI 25-29 %), 6 % (95 % CI 5-7 %), 17 % (95 % CI 15-18 %), and 12 % (95 % CI 11-13 %), respectively. The proportion of patients treated successfully did not differ significantly on the basis of the study characteristics. However, studies with treatment regimens containing macrolides had significantly higher pooled success proportions (42 %, 95 % CI 40-44 %) than that of other studies (28 %, 95 % CI 24-32 %). Substantial heterogeneity in the study characteristics prevented more conclusive determination of what factors had the greatest effect on the proportion of patients that achieve treatment success and limited the validity of this analysis. This review underscored the importance of strong patient support and treatment follow-up systems to develop successful MAC treatment programs.

Non-cytomegalovirus ocular opportunistic infections in patients with acquired immunodeficiency syndrome.

PURPOSE: To report the incidence and clinical outcomes of non-cytomegalovirus (non-CMV) ocular opportunistic infections in patients with acquired immunodeficiency syndrome (AIDS) in the era of highly active antiretroviral therapy. DESIGN: Multicenter, prospective, observational study of patients with AIDS. METHODS: Medical history, ophthalmologic examination, and laboratory tests were performed at enrollment and every 6 months subsequently. Once an ocular opportunistic infection was diagnosed, patients were seen every 3 months for outcomes. RESULTS: At enrollment, 37 non-CMV ocular opportunistic infections were diagnosed: 16 patients, herpetic retinitis; 11 patients, toxoplasmic retinitis; and 10 patients, choroiditis. During the follow-up period, the estimated incidences (and 95% confidence intervals [CI]) of these were: herpetic retinitis, 0.007/100 person-years (PY) (95% CI 0.0004, 0.039); toxoplasmic retinitis, 0.007/100 PY (95% CI 0.004, 0.039); and choroiditis, 0.014/ 100 PY (95% CI 0.0025, 0.050). The mortality rates appeared higher among those patients with newly diagnosed or incident herpetic retinitis and choroiditis (rates = 21.7 deaths/100 PY [P = .02] and 12.8 deaths/100 PY [P = .04]), respectively, than those for patients with AIDS without an ocular opportunistic infection (4.1 deaths/100 PY); toxoplasmic retinitis did not appear to be associated with greater mortality (6.4/100 PY, P = .47). Eyes with newly diagnosed herpetic retinitis appeared to have a poor visual prognosis, with high rates of visual impairment (37.9/100 PY) and blindness (17.5/100 PY), whereas those outcomes in eyes with choroiditis appeared to be lower (2.3/100 PY and 0/100 PY, respectively). CONCLUSIONS: Although uncommon, non-CMV ocular opportunistic infections may be associated with high rates of visual loss and/or mortality.

Mycobacterium avium-intracellulare presenting as an endobronchial tumour due to immune reconstitution inflammatory syndrome.

Mycobacterium avium-intracellulare (MAI) infection in an HIV-positive patient can present shortly after starting antiretroviral therapy, as a result of immune reconstitution inflammatory syndrome (IRIS). We report a case of a 33-year-old woman where MAI presented as an endobronchial tumour due to IRIS. She responded well to standard anti-MAI treatment (rifamycins, macrolide and ethambutol).

Antigenic stimulation in the simian model of HIV infection yields dilated cardiomyopathy through effects of TNFalpha.

OBJECTIVE: To investigate a role for endogenous myocardial cytokine production in the development of HIV-associated cardiomyopathy. DESIGN: Cardiomyopathy is a late-stage sequela of HIV infection. Although pathogenesis of this condition in HIV infection is poorly defined, inflammatory cytokines are recognized for their detrimental effects on myocardial structure and function. HIV infection is characterized by chronic immune activation and inflammatory cytokine dysregulation. As the myocardium itself is a rich potential source of inflammatory cytokines, HIV-mediated cytokine dysregulation may be an important contributor to development of HIV cardiomyopathy. An antigenic stimulation protocol conducted in the simian immunodeficiency virus (SIV) model of HIV infection was used to study the effects of endogenous cytokine production on myocardial structure and function. METHODS: Twenty-six rhesus monkeys were assigned to treatment groups for a 35-day study. Animals were SIV-infected; SIV-infected and treated with killed Mycobacterium avium complex bacteria (MAC); SIV-infected, MAC-treated, and given the TNFalpha antagonist etanercept; or uninfected and MAC-treated. All animals were subjected to weekly echocardiographic studies. Hearts were collected for further evaluation at euthanasia. RESULTS: SIV-infected, MAC-treated animals developed significant systolic dysfunction [left ventricular ejection fraction (LVEF) decline of 19 +/- 2%] and ventricular chamber dilatation [left ventricular end-diastolic diameter (LVEDD) increase of 26 +/- 6%] not seen in other groups. Concurrent treatment with etanercept prevented development of these changes, implicating a causative role of myocardial TNFalpha. CONCLUSIONS: SIV-infected animals develop exaggerated myocardial pathology on stimulation with the ubiquitous environmental agent MAC. These responses are TNFalpha-dependent and may play a significant role in the development of cardiomyopathy in HIV infection.

Susceptibility to opportunistic infections in HIV-infected patients with increased CD4 T-cell counts on antiretroviral therapy may be predicted by markers of dysfunctional effector memory CD4 T cells and B cells.

OBJECTIVES: HIV-infected patients responding to combination antiretroviral therapy (ART) after experiencing severe immunodeficiency may exhibit persistent immune defects and occasionally experience opportunistic infections (OIs) despite increased CD4 T-cell counts. The investigation of immune defects in such patients was examined in this study. METHODS: CD4 effector memory T-cell (T(em)-cell) function [assessed by blood cytomegalovirus (CMV) interferon-gamma (IFN-gamma) enzyme-linked immunosorbent spot-forming cell assay (ELISPOT) counts] and B-cell dysregulation [assessed by serum immunoglobulin A (IgA) and IgE levels] were examined in 27 patients with increased CD4 T-cell counts after receiving ART for over 2 years. Two of these patients and one other had developed OIs on ART and are described in detail. RESULTS: Serum levels of IgA and IgE were higher than reference intervals (P<0.001) and CMV IFN-gamma ELISPOT counts were lower than those in non-HIV-infected controls (P<0.001) in the HIV-infected patients. Low CMV IFN-gamma ELISPOT counts were associated with high IgA levels (r=-0.5, P=0.01, Spearman's correlation test) and segregated with high IgE levels (P=0.06, Fisher's test). CMV IFN-gamma ELISPOT counts and serum IgA and IgE levels did not change significantly over a median time of 35 (range 8-60) months after the first measurement, whereas CD4 T-cell counts increased. All three patients who experienced OIs had repeatedly low CMV IFN-gamma ELISPOT counts and increased serum levels of IgA and/or IgE. CONCLUSION: Low CD4 T(em)-cell function and B-cell dysregulation are immune defects that may persist independently of changes in the CD4 T-cell count in HIV-1-infected patients responding to ART and are associated with an increased risk of developing an OI.

Mycobacterium avium intracellularae complex associated extrapulmonary axillary lymphadenitis in a HIV-seropositive infant--a rare case report.

Opportunistic infections by Mycobacterium avium intracellulare complex in HIV infected patients, though common in adults, are rarely seen in infants. We herewith report an interesting case of an eight month old infant presenting with isolated axillary lymphadenitis, later on diagnosed to be tubercular lymphadenitis by Mycobacterium avium intracellulare and finally proved to be seropositive for HIV infection born to previously undetected HIV seropositive parents.

Changing mortality rates and causes of death for HIV-infected individuals living in Southern Alberta, Canada from 1984 to 2003.

OBJECTIVES: To examine changes over a 2-year period in both the mortality rate and the causes of death in a geographically defined HIV-infected population. METHODS: A database search of primary care information for the dates and causes of death for all patients documented with HIV infection and living in Southern Alberta between 1984 and 2003 was undertaken. Sociodemographic and clinical characteristics were obtained. Causes of death were then individually confirmed by reviewing the patients' hospital charts, autopsy reports, or death certificates and coded using the International Classification of Diseases, 9th Revisions. AIDS deaths were reconciled with Public Health Reports. The time span was divided into pre-highly active antiretroviral therapy (HAART) (1984-1996) and current HAART (1997-2003) periods. RESULTS: Between 1984 and 2003, there were 560 deaths in the 1987 individuals living with HIV infection in Southern Alberta. Of these, 436 deaths (78%) occurred pre-HAART and 124 (22%) in the current HAART period. The crude mortality rate declined from 117 deaths per 1000 patient-years pre-HAART to 24 in the current HAART period. In the pre-HAART era, 90% of all deaths were AIDS related whereas only 67% were AIDS related in the current HAART era. The leading causes of AIDS deaths were AIDS multiple causes (31%), Mycobacterium avium complex (18%), Pneumocystis pneumonia (10%) and non-Hodgkin's lymphoma (7%). The proportion of non-AIDS related deaths increased from 7% pre-HAART to 32% in the current HAART era. Accidental deaths, including drug overdose (29%), suicide (7%) and violence (3%), hepatic disease (19%), non-AIDS related malignancies (19%), and cardiovascular disease (16%) accounted for the majority of non-AIDS related deaths. No deaths directly caused by drug toxicity were found. Overall, 21% of patients who died were antiretroviral (ARV)-naive. A total of 14% of patients dying from AIDS were ARV-naive in contrast to 35% dying from non-HIV related conditions. Of all those dying from AIDS, 23% died<3 months after their initial diagnosis, reflecting late presentation. In the current HAART era, 87% of patients who died from AIDS were extensively treated, reflecting HAART treatment failures due mostly to multiclass drug resistance (42%), inexorable disease progression despite ARV (32%), lack of ability or interest to be maintained on a lifelong HAART programme (21%) and, rarely, drug intolerance (<1%). CONCLUSIONS: Deaths from AIDS-related causes have decreased significantly, but deaths from non-AIDS related conditions have increased, both as an absolute number of deaths and as a proportion of all deaths in HIV-infected patients. The increasing age of the HIV population, and the increased mean CD4 count, increased proportion of intravenous drug users, increased hepatitis B virus and hepatitis C virus coinfection rate, and increased history of smoking seen in our population also influenced the mortality rate and causes of death. These factors must also be considered in projecting future trends in mortality of an HIV-infected population.

Viable Mycobacterium avium is required for the majority of human immunodeficiency virus-induced upregulation in monocytoid cells.

The Mycobacterium avium complex (MAC), an intracellular pathogen of cells of the macrophage lineage, often clinically coexists with human immunodeficiency virus type 1 (HIV). It was shown previously that coinfection of the monocytoid cell line U937 with HIV and MAC results in the enhancement of HIV replication. To determine whether MAC-mediated HIV upregulation is due to the exposure of intact organisms to HIV-infected cells or if actual infection with viable organisms is required for the effect, U937 cells were coinfected simultaneously with HIV and live or heat-killed MAC. Live MAC (infection) consistently increased HIV reverse transcriptase (RT) activity by more than 3-fold. Heat-killed MAC, however, failed to enhance RT activity significantly. Further investigation showed that infection of U38 cells [a U937-derived cell line containing regions of the HIV-1 long terminal repeat (LTR) linked to chloramphenicol acetyl transferase (CAT)] with live or heat-killed MAC resulted in a similar enhancement of HIV LTR-CAT transcription. In addition, transient transfection of U937 cells with a full-length wild-type HIV LTR-CAT construct revealed that heat-killed MAC stimulated LTR-mediated CAT activity to levels comparable to those of viable MAC. Finally, both live and heat-killed MAC mediated similar enhancement of NF-kappa B DNA-binding activity. Taken together, these observations confirm previous findings that MAC-induced NF-kappa B-dependent LTR-CAT activity is not a major factor in upregulating HIV expression in a coinfection model. It also indicates that MAC infection plays a significant role in the enhancement of HIV replication and suggests that viable MAC either contains or induces the production of an as-yet-unidentified factor(s) that mediates the enhancement of HIV replication.

Estudo comparativo da interação de Mycobacterium intracellulare avirulenta e virulenta com macrófagos murinos da linhagem J774 / Comparative study of the interaction of Mycobacterium intracellulare with Avirulent and virulent murine macrophage line J774

Mycobacterium sp é um microrganismo intracelular facultativo que vive em macrófagos no interior de fagossomas que restringem a fusão com lisossomas da célula hospedeira. Recentemente foi demonstrado que micobactéria patogênica reside em vacúolos não acidificados. Células J774 pré-ativadas ou não com IFN-y foram infectadas com M intracellulare avirulenta ou virulenta na proporção de lO bacilos por célula. A virulência dos bacilos foi determinada pelas características morfológicas das colônias. Neste trabalho nós avaliamos, comparativamente, a produção de NO pelas células e a viabilidade intracelular dos bacilos. Micobactérias avirulentas induziram maior produção de NO, em comparação com as virulentas. A viabilidade intracelular dos bacilos avirulentos diminuiu pelo tratamento das células com IFN-y e foi revertida pela adição de AMG, um inibidor da iNOS. A viabilidade da variante virulenta não foi alterada pelo tratamento com IFN-y ou IFN-y e AMG. Estudos em microscopia eletrônica foram realizados para avaliar a capacidade de fagossomas fusionarem com lisossomas marcados com partículas de Au-BSA. Vinte e quatro horas após a infecção, 77% de fagossomas contendo micobactéria avirulenta fusionaram com lisossomas, em contraste com 50% de fagossomas contendo micobactéria virulenta. A fusão de fagossomas com lisossomas aumentou com o tratamento por IFN-y, enquanto que a adição de AMG provocou a redução da fusão de fagossomas formados por micobactéria avirulenta ou virulenta com lisossomas. Demonstramos que a produção de NO é dependente da virulência das micobactérias e que o NO favorece a fusão de fagossomas com lisossomas e diminui a viabilidade dos bacilos.

Permissive factors for HIV-1 infection of macrophages.

Immunodeficiency, the consequence of HIV-1 infection, predisposes the host to opportunistic infections. In turn, opportunistic pathogens influence target cell susceptibility to HIV-1 infection and replication. Although the advent of highly active antiretroviral therapy (HAART) has altered these sequelae, co-infections may prevail in some parts of the world and in failed HAART regimens. Moreover, immune activation as occurs in tonsil and non-infectious mucosal inflammatory lesions may also be associated with proximal sites of viral replication. These connections between enhancement of HIV-1 infection and activation/inflammation warrant further elucidation of the factors promoting permissiveness to HIV-1 infection. Using the opportunistic pathogen Mycobacterium avium as an in vitro model, we demonstrated that co-infection facilitated HIV-1 infection of monocyte-macrophages by multiple pathways. M. avium activated NF-kappaB, the downstream consequences of which included augmented expression of tumor necrosis factor alpha and CCR5 receptors, both permissive for sustaining HIV-1 infection. Pronounced viral replication in lymph nodes co-infected with M. avium and HIV-1 paralleled these in vitro findings. Furthermore, reduction in viral burden is associated with treatment of infected or inflamed tissues, underscoring the link between immune activation and viral replication.

Enhanced in vivo human immunodeficiency virus-1 replication in the lungs of human immunodeficiency virus-infected persons with Pneumocystis carinii pneumonia.

The relationship of serum human immunodeficiency virus-1 (HIV-1) RNA levels to HIV-1 RNA levels in other compartments, such as the lungs, is not well characterized. The purpose of this study was to determine the viral burden of HIV-1 in the lungs by comparing HIV-1 RNA in cell-free bronchoalveolar lavage fluid (BALF) with that in serum. Specimens were examined from 77 HIV-seropositive adults (CD4(+) cell counts: 0 to 700 cells/mm(3); 48% receiving prescribed antiretroviral agents), comprising 43 asymptomatic individuals who were compared with 34 persons with active lung disease caused by Pneumocystis carinii (n = 26), bacteria (n = 3), Mycobacterium avium complex (n = 2), Nocardia sp. (n = 1), Aspergillus sp. (n = 1), or pulmonary Kaposi's sarcoma (n = 1). For serum HIV-1 RNA, the proportion of subjects with detectable levels and the mean values were similar for asymptomatic individuals and persons with active lung disease (85% versus 86%, respectively) (6.64 x 10(4) versus 1. 81 x 10(5) HIV-1 RNA copies/ml; p = 0.13). In contrast, HIV-1 RNA in BALF was more often detected (16% versus 62%; p = 0.001), and mean values were higher (1.04 x 10(5) versus 3.31 x 10(6) HIV-1 RNA copies/ml; p = 0.032), in subjects with active lung disease than in asymptomatic subjects, independent of early or advanced clinical stages of HIV-related disease. For both study groups, HIV-1 RNA levels in BALF exceeded those in serum in 56% of cases by up to 66-fold, and did not correlate with local levels of tumor necrosis factor-alpha, granulocyte-macrophage colony-stimulating factor, or interleukin-16. HIV-1 proviral DNA in cells from BALF was detected in up to 86% of subjects, more frequently in persons with advanced HIV disease (p = 0.0496), and often involved > 10% of BALF cells, but did not correlate with HIV-1 RNA detected in BALF. These data provide evidence for active HIV-1 replication in the lungs. HIV-1 replication is compartmentalized relative to serum, may be restricted, is independent of HIV-1 proviral DNA and clinical stage of HIV, and may be influenced by pulmonary disease such as P. carinii pneumonia or by other local or lung-specific factors. The lungs represent a large reservoir for HIV-1, and may present a source of persistent HIV-1 replication even during periods of apparent clinical latency of HIV-1 infection.

Mycobacterium avium complex augments macrophage HIV-1 production and increases CCR5 expression.

Infection with HIV-1 results in pronounced immune suppression and susceptibility to opportunistic infections (OI). Reciprocally, OI augment HIV-1 replication. As we have shown for Mycobacterium avium complex (MAC) and Pneumocystis carinii, macrophages infected with opportunistic pathogens and within lymphoid tissues containing OI, exhibit striking levels of viral replication. To explore potential underlying mechanisms for increased HIV-1 replication associated with coinfection, blood monocytes were exposed to MAC antigens (MAg) or viable MAC and their levels of tumor necrosis factor alpha (TNFalpha) and HIV-1 coreceptors monitored. MAC enhanced TNFalpha production in vitro, consistent with its expression in coinfected lymph nodes. Using a polyclonal antibody to the CCR5 coreceptor that mediates viral entry of macrophage tropic HIV-1, a subset of unstimulated monocytes was shown to be CCR5-positive by fluorescence-activated cell sorter analysis. After stimulation with MAg or infection with MAC, CCR5 expression was increased at both the mRNA level and on the cell surface. Up-regulation of CCR5 by MAC was not paralleled by an increase in the T cell tropic coreceptor, CXCR4. Increases in NF-kappaB, TNFalpha, and CCR5 were consistent with the enhanced production of HIV-1 in MAg-treated adherent macrophage cultures as measured by HIV-1 p24 levels. Increased CCR5 was also detected in coinfected lymph nodes as compared with tissues with only HIV-1. The increased production of TNFalpha, together with elevated expression of CCR5, provide potential mechanisms for enhanced infection and replication of HIV-1 by macrophages in OI-infected cells and tissues. Consequently, treating OI may inhibit not only the OI-induced pathology, but also limit the viral burden.

Human immunodeficiency virus replication in AIDS patients with Mycobacterium avium complex bacteremia: a case control study. California Collaborative Treatment Group.

The development of opportunistic infections and the administration of vaccines have been associated with transient increases of human immunodeficiency virus (HIV) RNA plasma levels in HIV-infected patients. To determine the relationship between Mycobacterium avium complex (MAC) bacteremia and HIV RNA levels, HIV RNA levels in patients who developed MAC bacteremia (cases) were compared with levels in patients who remained free of MAC disease (controls). Cases and controls were matched for CD4 cell count, prophylaxis against MAC disease, antiretroviral therapy, and duration of follow-up. Mean baseline HIV RNA levels were 4.8 log10 copies/mL in cases and 4.6 log10 copies/mL in controls (P = 0.22). HIV RNA levels increased by a median of 0.4 log in cases but not controls at the time of MAC bacteremia (P = 0.01). In AIDS patients, the onset of MAC bacteremia is associated with a modest but significant increase in serum HIV RNA levels. Increased HIV replication may contribute to the higher mortality associated with MAC bacteremia.

Macrophages as a source of HIV during opportunistic infections.

The source of increasing viremia that characterizes the latter stages of human immunodeficiency virus (HIV) disease has remained a paradox because it occurs at a time when lymphoid tissue is quantitatively and qualitatively impaired, and the patients' CD4 T lymphocytes are steadily declining. Here, macrophages, both infected and uninfected with common opportunistic pathogens of HIV disease such as Mycobacterium avium complex and Pneumocystis carinii, were identified as highly productive sources of HIV in coinfected lymph nodes. These observations indicate that tissue macrophages are not only infected with HIV, but that common pathogens of HIV disease can dramatically increase their production of virus. Thus, prevention or successful treatment of opportunistic coinfections, or both, potentially benefits the patient twofold by limiting the pathology caused by opportunistic infection and by controlling induction of HIV replication.

Specificity of diagnostic PCR amplification for M. avium using the probe pMAV22.

We characterized the serovar specificity of the probe pMAV22 using ATCC isolates. Primers from this sequence amplified DNA from serovars 1-6, 8-10, and ATCC strain 19075 but did not amplify MAIS serovars 7, 11, 12, 14, 17-20. This confirmed that the M. avium probe pMAV22 is specific for M. avium, not M. intracellulare.

Human immunodeficiency virus infection presenting as pancytopenia in an infant.

CASE REPORT: A 14-month-old infant presented with pancytopenia and Mycobacterium avium intracellularae (MAI) as the initial manifestation of acquired immunodeficiency syndrome (AIDS). CONCLUSION: Human immunodeficiency virus (HIV-1) infections should be considered in the differential diagnosis of infants and children with cytopenias.