Mycobacterium avium complex infection in patients with human immunodeficiency virus: A systematic review and meta-analysis.

BACKGROUND: Mycobacterium avium-intracellulare complex (MAC) is one of the leading causes of death among people living with human immunodeficiency virus (HIV). The current study was aimed to determine the frequency of MAC infection in patients infected with HIV. METHODS: Embase, PubMed, and Web of Science were searched for relevant studies. All statistical analyses were performed by STATA version 14. RESULTS: From 6,627 retrieved articles, 23 were included in the final analysis. A total of 18,463 patients with HIV were included in the analysis. The frequency of MAC infection in patients with HIV was found to be 10.6% (95% confidence interval, 6.9-14.2). CONCLUSION: The relatively large fractions of HIV-infected patients were coinfected with MAC, which may poses significant public health problems. Continued progress in the development of rapid diagnostic methods and preventive therapy for MAC should lead to further improvements in survival and quality of life in patients with HIV.

High recurrence rate supports need for secondary prophylaxis in non-HIV patients with disseminated mycobacterium avium complex infection: a multi-center observational study.

BACKGROUND: Long-term outcomes in non-HIV immunocompromised patients with disseminated Mycobacterium avium complex (dMAC) infections are unknown and the need for post-treatment secondary prophylaxis against MAC is uncertain in this setting. The objective of this study was to determine the need of continuing secondary anti-MAC prophylaxis in non-HIV patients after completing treatment of the primary dMAC episode. METHODS: We conducted a ten-year multi-center analysis of non-HIV immunosuppressed patients with dMAC infections in Hong Kong. RESULTS: We observed sixteen patients with dMAC during the study period of which five (31 %) were non-HIV immunosuppressed patients. In the non-HIV immunosuppressed group, three patients completed a treatment course without secondary prophylaxis, one patient received azithromycin-based secondary prophylaxis and one patient was still receiving therapy for the first dMAC episode. All the three patients who completed treatment without being given secondary prophylaxis developed recurrent dMAC infection requiring retreatment. CONCLUSIONS: In view of the high rate of dMAC infection recurrence in non-HIV immunocompromised patients following treatment completion, our data support long-term anti-MAC suppression therapy after treatment of the first dMAC infection episode in immunocompromised non-HIV patients, as is recommended for patients with advanced HIV. Tests of cell mediated immune function need to be evaluated to guide prophylaxis discontinuation in non-HIV patients.

Interventions for the prevention of mycobacterium avium complex in adults and children with HIV.

BACKGROUND: Mycobacterium avium complex (MAC) infection is a common complication of advanced acquired immunodeficiency syndrome (AIDS) disease and is an independent predictor of mortality and shortened survival. OBJECTIVES: To determine the effectiveness and safety of interventions aimed at preventing MAC infection in adults and children with HIV infection. SEARCH METHODS: We searched MEDLINE, EMBASE, and The Cochrane Library (search date December 2012). SELECTION CRITERIA: Randomised controlled trials comparing different strategies for preventing MAC infection in HIV-infected individuals. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed trial eligibility and quality, and extracted data. Where data were incomplete or unclear, a third reviewer resolved conflicts and/or trial authors were contacted for further details. Development of MAC infection and survival were compared using risk ratios (RR) and 95% confidence intervals (CI). The quality of evidence has been assessed using the GRADE methodology. MAIN RESULTS: Eight studies met the inclusion criteria. Placebo-controlled trials: There was no statistically significant difference between clofazimine and no treatment groups in the number of patients that developed MAC infection (RR 1.01; 95% CI 0.37 to 2.80). Rifabutin (one study; RR 0.48; 95% CI 0.35 to 0.67), azithromycin (three studies; RR 0.37; 95% CI 0.19 to 0.74) and clarithromycin (one study; RR 0.35; 95% CI 0.21 to 0.58) were more effective than placebo in preventing the development of MAC infection. There was no statistically significant difference between those treated with clofazimine (one study; RR 0.98; 95% CI 0.41 to 2.32), rifabutin (one study RR 0.91; 95% CI 0.78 to 1.05), azithromycin (three studies, pooled RR 0.96; 95% CI 0.69 to 1.32) and placebo in number of reported deaths. One study found that the risk of death was reduced by 22% in patients treated with clarithromycin compared to those treated with placebo (RR 0.78; 95% CI 0.64 to 0.96). Monotherapy vs. monotherapy: Patients treated with clarithromycin (RR 0.60; 95% CI 0.41 to 0.89) and azithromycin (RR 0.60; 95% CI 0.40 to 0.89) were 40% less likely to develop MAC infection than those treated with rifabutin. There was no statistically significant difference between those treated with clarithromycin (RR 0.98; 95% CI 0.83 to 1.15), azithromycin (RR 0.98; 95% CI 0.77 to 1.24) and rifabutin in the number of reported deaths. Combination therapy versus monotherapy: There was no statistically significant difference between patients treated with a combination of rifabutin and clarithromycin and those treated with clarithromycin alone (RR 0.74; 95% CI 0.46 to 1.20); and those treated with combination of rifabutin and azithromycin and those treated with azithromycin alone (RR 0.59; 95% CI 1.03). Patients treated with a combination of rifabutin plus clarithromycin were 56% less likely to develop MAC infection than those treated with rifabutin alone (RR 0.44; 95% CI 0.29 to 0.69). Patients treated with a combination of rifabutin plus azithromycin were 65% less likely to develop MAC infection than those treated with rifabutin alone (RR 0.35; 95% CI 0.21 to 0.59). There was no statistically significant difference in the number of reported deaths in all the four different comparisons of prophylactic agents. AUTHORS' CONCLUSIONS: Based on limited data, azithromycin or clarithromycin appeared to be a prophylactic agent of choice for MAC infection. Further studies are needed, especially direct comparison of clarithromycin and azithromycin. In additions, studies that will compare different doses and regimens are needed.

[Strategies for Mycobacterium avium complex infection control in Japan: how do they improve the present situation?].

Mycobacterium avium complex (MAC) were the most frequently isolated (about 80%) and most common cause of lung nontuberculosis. Its rate of infection is globally increasing, especially in Japan. In this situation, it is urgently needed to provide scientific evidences and develop therapeutic interventions in MAC infections. Recently, more and more patients are elderly women with no history of smoking, and they have reticulonodular infiltrates and patchy bilateral bronchiectasis. However the prognostic and intractable factors of MAC infections are poorly known. In this symposium, we address five novel strategies for MAC infection, concerning the more accurate incidence and prevalence rates compared with other countries, host defense associated with Th1/Th17 balance, route of MAC infection related soil exposure, MAC IgA antibody as a diagnosis maker, and improved chemotherapy including aminoglycoside or new quinolone. Appropriate clinical intervention may help to reduce the prolongation of MAC infection or enhance the activity of chemotherapy for the improved control of MAC. Below are the abstracts for each of the five speakers. 1. Review of current epidemiological study of pulmonary nontuberculous mycobacterial disease in Japan and the rest of the world: Kozo MORIMOTO (Respiratory Center, Fukujuji Hospital, Japan Anti-Tuberculosis Association) The studies on pulmonary nontuberculous mycobacterial (NTM) disease prevalence were started in early 1970s in Japan by the Mycobacteriosis Research Group of National Chest Hospitals. They were followed by a questionnaire survey in 1990s, by the National Tuberculosis and NTM Survey in late 1990s, and recently by the questionnaire surveys conducted by the NTM Disease Research Committee. The latest data in Japan (from 2007) indicated a morbidity rate of 5.7 per 100,000 population. Deaths from NTM disease were reported for the first time in 1970 and showed a marked, steady increase until 2007, with 912 deaths in that year. We estimated NTM prevalence in our country in 2005 to be 33-65/100,000 using death number and the 1-2% fatality rate obtained from in our hospital. Epidemiologic study conducted by some regions, states and countries estimated the incidence or prevalence of NTM by unique methods in each. Although the microbiologic criteria of diagnosis is attractive to get information of prevalence, we think the most reliable method is to use the health insurance claims that should be done in future in Japan. 2. The elucidation of the pathogenesis of pulmonary MAC disease by using gene modified mice: Masashi MATSUYAMA, Yukio ISHII, Nobuyuki HIZAWA (Division of Respiratory Medicine, Institute of Clinical Medicine, Graduate School of Comprehensive Human Sciences, University of Tsukuba), Kenji OGAWA (Department of Clinical Research, National Hospital Organization Higashi Nagoya National Hospital) Thl immune responses are associated with protective immunity to intracellular pathogens. T-bet is the master regulator for Thl cell differentiation. We therefore investigated the role of T-bet in the host defense against pulmonary MAC infection using T-bet knockout (T-bet-/-) mice and T-bet overexpressing (T-bet tg/tg) mice. Pulmonary MAC infection was induced by intratracheal instillation with 1 X 10(7) CFU of Mycobacterium avium subsp. hominissuis. The degrees of pulmonary inflammation and the number of organisms were much enhanced in T-bet-/- mice than in wild-type mice and T-bet tg/tg mice after MAC infection. A significant decrease in Th1 cytokines and increase in Th17 cytokines were observed in the lungs of T-bett-/-mice, compared with wild-type mice and T-bet tg/tg mice. Interestingly, however, the level of Th2 cytokines was not different among mice genotypes in response to MAC. These findings indicate that T-bet plays a central role in controlling MAC disease progression, through the regulation of both Th1 and Th17, but not Th2 responses. 3. Route of infection in Mycobacterium avium-intracellulare complex disease: Yutaka ITO (Department of Respiratory Medicine, Department of Infection Control and Prevention, Kyoto University) Environmental exposure is considered to be the primary route for Mycobacterium avium-intracellulare complex (MAC) infection. MAC is isolated from drinking water distribution systems, bathroom and showerheads and the genetic relatedness of clinical isolates from MAC patients with water isolates have been reported. We reported that patients with pulmonary MAC disease had significantly more soil exposure (>2 per week) than noninfected control patients after adjustments for the potential confounding diseases and conditions in pulmonary MAC disease. Moreover, we found six pairs of clinical isolates and corresponding soil isolates with identical variable numbers of tandem repeats profiles among patients with high soil exposure, suggesting that residential soils are a likely source of pulmonary MAC infection. 4. Clinical data analysis of Mycobacterium avium complex serodiagnosis kit: Yuta HAYASHI (Department of Respiratory Medicine, National Hospital Organization Higashi Nagoya National Hospital), Taku NAKAGAWA, Kenji OGAWA (Department of Clinical Research, National Hospital Organization Higashi Nagoya National Hospital) Mycobacterium avium complex (MAC) serodiagnosis kit was covered by health insurance in August 2011 in Japan, but experience with this kit in daily clinical practice is still scarce. We analyzed the clinical data of MAC serum diagnostic kit in our hospital. Considering the high diagnostic performance of this kit (specificity 92.9%), that can also be incorporated into the diagnostic criteria. However it should be noted that there can be false-negative even in patients with active pulmonary MAC. Although this test is also expected usefulness as a marker of disease activity, at the present time should be kept for reference. 5. Clinical effect of combined chemotherapy containing aminoglycoside or new quinolone antibiotics for Mycobacterium avium complex disease: Yosihiro KOBASHI, Mikio OKA (Department of Respiratory Medicine, Kawasaki Medical School) Because it was possible to administrate CAM 800 mg/day for the treatment of Mycobacterium avium complex (MAC) disease after 2008, we compared the clinical effect of combined chemotherapy (RFP, EB, CAM 800 mg/day) containing aminoglycoside (SM) and combined chemotherapy (RFP, EB, CAM 400 mg/day or 600 mg/day) containing SM before 2007. Subsequently, the latter treatment was significantly better in the sputum conversion rate and clinical improvement such as clinical symptoms or radiological findings than the former treatment. Concerning the side effects or abnormal laboratory findings, although gastrointestinal symptoms were frequently appeared in the latter period, there was no significant difference between both periods.

Rifabutin corneal deposits in a patient with acquired immunodeficiency syndrome: in vivo confocal microscopy investigation.

PURPOSE: To establish the real localization of rifabutin-related corneal deposits in a patient with human immunodeficiency virus (HIV) infection by in vivo HRT II confocal microscopy with related clinicopathologic implications. METHODS: Observational case report. After Siena University Institutional Review Board approval in May 2008 and specific informed consent, a 54-year-old patient with HIV infection under rifabutin treatment for acquired immunodeficiency syndrome-related Mycobacterium avium complex prevention who developed diffuse corneal deposits was examined at the Department of Ophthalmology of Siena University. He underwent a complete clinical eye examination, biomicroscopy, and digital slit lamp photographs, endothelial specular microscopy, ultrasound pachymetry, and confocal microscopy by HRT II system. RESULTS: Confocal scans revealed the presence of deep stromal and pre descemetic hyperreflective polymorphous deposits. In vivo confocal examination excluded the presence of rifabutin-related deposits at endothelial level. CONCLUSIONS: Confocal microscopy enables establishment of the real localization of rifabutin deposits at deep stromal level, providing a better qualitative analysis of all corneal layers compared to biomicroscopic examination, with clinical and physiopathologic implications.

Effect of Macrolide Prophylactic Therapy on AIDS-Defining Conditions and HIV-Associated Mortality.

BACKGROUND: Mycobacterium avium complex prophylaxis is recommended for patients with advanced HIV infection. With the decrease in incidence of disseminated Mycobacterium avium complex infection and the availability of antiretroviral therapy (ART), the benefits of macrolide prophylaxis were investigated. This study examined the impact of macrolide prophylaxis on AIDS-defining conditions and HIV-associated mortality in a cohort of HIV-infected patients on ART. METHODS: Patients from TREAT Asia HIV Observational Database (September 2015 data transfer) aged 18 years and older with a CD4 count <50 cells/mm at ART initiation were included. The effect of macrolide prophylaxis on HIV-associated mortality or AIDS-defining conditions (as a combined outcome) and HIV-associated mortality alone were evaluated using competing risk regression. Sensitivity analysis was conducted in patients with a CD4 <100 cells/mm at ART initiation. RESULTS: Of 1345 eligible patients, 10.6% received macrolide prophylaxis. The rate of the combined outcome was 7.35 [95% confidence interval (CI): 6.04 to 8.95] per 100 patient-years, whereas the rate of HIV-associated mortality was 3.14 (95% CI: 2.35 to 4.19) per 100 patient-years. Macrolide use was associated with a significantly decreased risk of HIV-associated mortality (hazard ratio 0.10, 95% CI: 0.01 to 0.80, P = 0.031) but not with the combined outcome (hazard ratio 0.86, 95% CI: 0.32 to 2.229, P = 0.764). Sensitivity analyses showed consistent results among patients with a CD4 <100 cells/mm at ART initiation. CONCLUSIONS: Macrolide prophylaxis is associated with improved survival among Asian HIV-infected patients with low CD4 cell counts and on ART. This study suggests the increased usage and coverage of macrolide prophylaxis among people living with HIV in Asia.

Rifabutin-induced hypopyon uveitis in patients with acquired immunodeficiency syndrome infected with Mycobacterium avium complex.

Rifabutin is a semi-synthetic antimycobacterial agent mainly used in the prophylaxis and treatment of Mycobacterium avium complex (MAC) in acquired immunodeficiency syndrome patients. Uveitis as a side effect of rifabutin has been recognized and established since 1994, but there was no case previously described in Taiwan so far. We report 2 cases of rifabutin-induced hypopyon uveitis in patients with human immunodeficiency virus and MAC infection. Both patients received the regimen of clarithromycin and rifabutin to treat MAC infection. Uveitis resolved after discontinuing of rifabutin and treatment with topical corticosteroid and mydriatics. Early recognition of this entity can prevent invasive ocular procedures and treatments. Doctors who prescribe rifabutin should be aware of this ocular complication of uveitis and drug-drug interactions. Ophthalmologists should put this on the list of differential diagnoses for uveitis.

Incidence of disseminated Mycobacterium avium-complex infection in HIV patients receiving antiretroviral therapy with use of Mycobacterium avium-complex prophylaxis.

The incidence of disseminated Mycobacterium avium complex (MAC) infection in HIV patients has fallen markedly since the introduction of effective antiretroviral therapy (ART). However, current guidelines still recommend primary prophylaxis. We conducted a retrospective cohort study in a university-affiliated hospital from January 1998 to January 2014. During that period, HIV patients who had at least one CD4 cell count below 50 cells/mm3 and had been treated with ART were enrolled. We compared incidence of disseminated MAC infection in the 12 months after the first CD4 cell count below 50 cells/mm3 between prophylaxis and nonprophylaxis groups. A total of 157 patients were enrolled and the total observation period was 144 patient-years (PY). Thirty-three patients (21%) received primary MAC prophylaxis. The initial CD4 cell count of the prophylaxis group was lower than that of the nonprophylaxis group ( P = 0.024), but the proportion of patients who reached a CD4 cell count >100 cells/mm3 ( P = 0.234) and were virologically suppressed ( P = 0.513) 12 months after ART commencement was not different in the prophylaxis and nonprophylaxis groups. The incidence of MAC did not differ significantly between the groups (3.4/100 PY versus 0.8/100 PY, P = 0.368). Routine MAC prophylaxis may be not required in the era of effective ART.

Recombinant cytokines for controlling mycobacterial infections.

Knowing how mycobacteria exploit host cytokines to survive and which cytokines have important roles in host defense against mycobacteria should allow the use of these molecules in the treatment of mycobacterial infections. Both interleukin 2 and interferon gamma have been used to treat patients with leprosy, and granulocyte-macrophage colony-stimulating factor is presently being administered to AIDS patients infected with Mycobacterium avium.

Discontinuation of primary prophylaxis against Mycobacterium avium complex infection in HIV-infected persons receiving antiretroviral therapy: observations from a large national cohort in the United States, 1992-2002.

In a large, diverse cohort of human immunodeficiency virus (HIV)-infected persons receiving routine care, the proportion of eligible persons who discontinued primary prophylaxis against Mycobacterium avium complex (MAC) infection, according to guidelines of the US Public Health Service and the Infectious Diseases Society of America, increased from 16.7% (in 1996) to 84.9% (in 2002). The discontinuation of primary prophylaxis was not associated with an increased risk of disseminated MAC infection.

Pharmacokinetics of clarithromycin extended-release (ER) tablets in patients with AIDS.

BACKGROUND: Clarithromycin is a key agent in effective antimycobacterial therapy and prophylaxis for AIDS-related disseminated Mycobacterium avium complex (dMAC) infection. Immediate-release (IR) clarithromycin tablets are dosed at 500 mg bid for these indications. A new extended-release (ER) tablet of clarithromycin has been developed and approved at a dosing interval of once every 24 hours for treatment of respiratory tract bacterial infections. However, the pharmacokinetics of clarithromycin ER in AIDS patients with or at risk for dMAC has not been previously investigated. METHOD: We conducted a randomized, crossover trial in which 14 AIDS patients received clarithromycin ER, 1000 mg once daily, and clarithromycin IR, 500 mg bid, each for 1 week, with pharmacokinetic sampling at the end of each week. RESULTS: The mean of the individual AUC ratios for clarithromycin ER vs. IR was 1.09 (90% CI, 0.94-1.24). Adverse events were no more severe or frequent with clarithromycin ER than IR. CONCLUSION: Clarithromycin ER is a once-daily regimen that is as well tolerated as standard bid IR clarithromycin dosing and has average bioequivalence to the IR formulation in patients with AIDS.

Effect of isoniazid chemoprophylaxis on HIV-related mycobacterial disease.

OBJECTIVES: The aims of this study were to (1) identify trends and risk factors for mycobacterial disease and (2) determine the effect of expanded access to isoniazid chemoprophylaxis on tuberculosis incidence. METHODS: A prospective observational cohort study was conducted among community-based injecting drug users (IDUs); 2960 IDUs (942 human immunodeficiency virus [HIV] seropositive) were followed up from January 1988 to June 1994. Directly observed chemoprophylaxis with twice-weekly isoniazid (10 to 15 mg/kg) was offered to purified protein derivative (PPD) tuberculin-positive (> or = 5-mm induration diameter in HIV-seropositive subjects and > or = 10-mm diameter in HIV-seronegative subjects) individuals but not to those with cutaneous anergy. Overall and annual incidence rates of disease due Mycobacterium tuberculosis, Mycobacterium avium complex, and other atypical mycobacteria were estimated using Poisson regression. RESULTS: HIV seropositivity was the strongest risk factor for tuberculosis, M avium complex, and other mycobacterial disease (relative risk [RR], 3.8, 17.2, and 6.9, respectively). Median CD4 lymphocyte cell counts for the three groups of mycobacterial disease were 0.17, 0.03, and 0.02 x 10(9)/L (167/microL, 30/microL, 18/microL) within 6 months of diagnosis (before or after). Overall incidence rates of tuberculosis, M avium complex disease, and other mycobacterial disease were 1.9, 8.8, and 2.7 per 1000 person-years, respectively. Tuberculosis incidence peaked in 1991 at six per 1000 person-years. However, after access to directly observed preventive therapy was expanded for tuberculin-positive subjects, incidence fell to only one case in 1992 and zero cases for 24 months from mid-1992 to mid-1994. During this period the number of PPD-positive patients who completed at least 26 weeks of therapy (or were still receiving isoniazid) more than tripled (from 21 to 70). None of the 12 patients with tuberculosis diagnosed during follow-up had received any preventive therapy. In addition, no tuberculosis developed among participants with cutaneous anergy. Calendar trends in risk for M avium complex and tuberculosis diverged after expanded access to isoniazid prophylaxis. Compared with 1988-1989, risk of M avium complex increased sevenfold. Tuberculosis risk fell 83% from the peak risk in 1990-1991. CONCLUSIONS: Expanded access to directly observed isonazid therapy for tuberculin-positive IDUs with and without HIV infection was associated with an 83% drop in tuberculosis incidence, while in the same period M avium complex incidence significantly increased. These population-based data are consistent with those obtained from clinical trials of isoniazid prophylaxis and were obtained without offering chemoprophylaxis to HIV-infected patients with cutaneous energy.

Guidelines for preventing opportunistic infections among HIV-infected persons--2002. Recommendations of the U.S. Public Health Service and the Infectious Diseases Society of America.

In 1995, the U.S. Public Health Service (USPHS) and the Infectious Diseases Society of America (IDSA) developed guidelines for preventing opportunistic infections (OIs) among persons infected with human immunodeficiency virus (HIV); these guidelines were updated in 1997 and 1999. This fourth edition of the guidelines, made available on the Internet in 2001, is intended for clinicians and other health-care providers who care for HIV-infected persons. The goal of these guidelines is to provide evidence-based guidelines for preventing OIs among HIV-infected adults and adolescents, including pregnant women, and HIV-exposed or infected children. Nineteen OIs, or groups of OIs, are addressed, and recommendations are included for preventing exposure to opportunistic pathogens, preventing first episodes of disease by chemoprophylaxis or vaccination (primary prophylaxis), and preventing disease recurrence (secondary prophylaxis). Major changes since the last edition of the guidelines include 1) updated recommendations for discontinuing primary and secondary OI prophylaxis among persons whose CD4+ T lymphocyte counts have increased in response to antiretroviral therapy; 2) emphasis on screening all HIV-infected persons for infection with hepatitis C virus; 3) new information regarding transmission of human herpesvirus 8 infection; 4) new information regarding drug interactions, chiefly related to rifamycins and antiretroviral drugs; and 5) revised recommendations for immunizing HIV-infected adults and adolescents and HIV-exposed or infected children.

Corneal endothelial deposits associated with rifabutin use.

PURPOSE: The aim of this study was to report on the possible development of corneal endothelial deposits resulting from the use of rifabutin. METHODS: Case series consisting of 3 patients treated with rifabutin were retrospectively studied. Two of the patients were infected with human immunodeficiency virus. A corneal and external disease specialist performed a complete ophthalmologic exam and obtained medical histories of the patients. RESULTS: All cases developed corneal endothelial deposits after previous use of rifabutin. The deposits were bilateral, yellow-white colored, stellate, and mainly peripheral. CONCLUSIONS: In these 3 cases, the unique positive ocular finding was corneal endothelial deposits, which may be related to the use of rifabutin.

Rifabutin but not clarithromycin prevents cryptosporidiosis in persons with advanced HIV infection.

BACKGROUND: Macrolides have been reported to be effective for the prevention of cryptosporidiosis in persons with HIV infection. OBJECTIVE: To evaluate the efficacy of clarithromycin and rifabutin for the prevention of cryptosporidiosis in persons with advanced HIV infection. DESIGN: Cross-protocol analysis involving 2288 individuals with a history of a CD4 cell counts of < or = 100 x 10(6) cell/l who were enrolled in two prospective clinical trials to prevent Mycobacterium avium complex (MAC) infection and cytomegalovirus (CMV) end-organ disease. INTERVENTIONS: Clarithromycin 500 mg twice daily, rifabutin 300-450 mg daily, the combination of the two or no MAC prophylaxis. MAIN OUTCOME MEASUREMENT: Laboratory-confirmed cryptosporidiosis. Subjects were analyzed in an intent-to-treat and as-treated manner using time-to-event analyses (Cox proportional hazards models). RESULTS: The median length of follow up was 463 days. The median CD4 count at entry was 29 x 10(6) cell/l (range 0-182). There were 60 cases of cryptosporidiosis during the prospective observational period, with an event rate of 2.2 per 100 person-years. In the intent-to-treat [relative risk (RR) 0.50; 95% confidence interval (CI) 0.26-0.96; P = 0.041 and as-treated (RR 0.42; 95% CI 0.20-0.91; P = 0.03) analyses, rifabutin alone was significantly associated with a lower rate of cryptosporidiosis. Clarithromycin alone was not protective in similar analyses (P = 0.98 and 0.90, respectively). CONCLUSIONS: In doses used to prevent MAC infection, rifabutin but not clarithromycin decreases the risk of developing cryptosporidiosis in persons with advanced HIV infection who are not receiving potent combination antiretroviral therapy.

Discontinuing or withholding primary prophylaxis against Mycobacterium avium in patients on successful antiretroviral combination therapy. The Swiss HIV Cohort Study.

OBJECTIVE: To assess the safety of discontinuing or withholding primary prophylaxis against disseminated Mycobacterium avium infection (MAC) in HIV infected patients on successful antiretroviral combination therapy. SETTING: National prospective multicentre cohort study. DESIGN: HIV-infected patients were eligible for the analysis if: (i) they had a history of at least two CD4 cell counts < 50 x 10(6)/l; (ii) they had never had MAC; (iii) they had discontinued or never begun primary prophylaxis against MAC; (iv) they received antiretroviral therapy and demonstrated an increase in CD4 cell counts to > or = 100 x 10(6)/l that was sustained for at least 12 weeks. From this time point until last follow-up, incidence of disseminated MAC disease was measured, and 99% confidence intervals were calculated assuming a Poisson distribution of events. RESULTS: Two-hundred and fifty-three patients (22.5% female; median age, 37 years, 30% injecting drug users) were eligible for analysis. Sixty-six per cent were in Centers for Disease Control and Prevention (CDC) stage C, and 28% were in CDC stage B. Their median nadir CD4 cell count was 10 x 10(6)/l, the median duration of CD4 cell count < 50 x 10(6)/l was 12 months. During a total follow-up of 364.3 patient-years there was no case of disseminated MAC. The one-sided 99% confidence limit for incidence density of MAC was 1.3 per 100 person-years. CONCLUSION: Discontinuing or withholding primary prophylaxis against MAC is safe in patients who have a sustained increase in their CD4 cell count to > or = 100 x 10(6)/l.

Mycobacterium tuberculosis infection and disease are not associated with protection against subsequent disseminated M. avium complex disease.

OBJECTIVE: To determine the relationship between Mycobacterium tuberculosis infection and disease and subsequent disseminated M. avium complex (MAC) disease in HIV-infected persons. DESIGN: A prospective observational cohort study. SETTING: The AIDS Linked to the Intravenous Experience (ALIVE) cohort of injecting drug users and the Johns Hopkins Hospital Adult HIV Clinic (JHHAHC). PARTICIPANTS: HIV-infected persons aged > 18 years with CD4 lymphocytes < 100 x 10(6)/l were followed between July 1989 and 31 October 1996. There were 182 persons in the ALIVE cohort and 1129 persons in JHHAHC who met these criteria. MAIN OUTCOME MEASURE: The relative risk of disseminated MAC was determined according to a history of prior opportunistic infection, MAC prophylaxis, antiretroviral therapy, M. tuberculosis infection or disease, race, sex, and injecting drug use. RESULTS: Amongst the 30 patients with active tuberculosis, eight developed disseminated MAC, compared with 208 cases of disseminated MAC amongst 1148 patients without prior M. tuberculosis infection or disease [relative risk (RR), 1.5; 95% confidence interval (CI), 0.8-2.7; P=0.2]. Amongst the 10 patients with extrapulmonary tuberculosis, five developed disseminated MAC (RR, 2.8; 95% CI, 1.5-5.2; P=0.02). Injecting drug use was associated with a decreased risk of disseminated MAC (RR, 0.7; 95% CI, 0.6-0.9; P=0.007). In a logistic regression analysis, disseminated MAC was significantly associated with extrapulmonary tuberculosis and other opportunistic disease, whereas antibiotic prophylaxis and injecting drug use were protective. CONCLUSIONS: A history of M. tuberculosis infection or disease was not associated with protection against subsequent disseminated MAC disease in HIV-infected persons. However, persons with extrapulmonary tuberculosis were at increased risk for disseminated MAC, particularly at low CD4 cell levels.

Impact of highly active antiretroviral therapy on onset of Mycobacterium avium complex infection and cytomegalovirus disease in patients with AIDS.

OBJECTIVES: To assess the impact of highly active antiretroviral therapy (HAART) on the onset of first disseminated Mycobacterium avium complex (MAC) infection and first cytomegalovirus (CMV) disease episode in HIV-infected at-risk patients. METHODS: The incidence of the two infections occurring in at-risk patients was calculated for two periods (January 1995-June 1996 and July 1996-December 1997) using the database of the HIV-infected patients followed in the Infectious Diseases Department at the Pitié-Salpêtrière Hospital in Paris. HAART was progressively introduced in late June 1996 in France. RESULTS: A total of 91 first disseminated MAC infections and 124 first CMV disease episodes were recorded. The incidence of first disseminated MAC infections fell from 13.4 per 100 person-years in the first 18-month period to 2.6 per 100 person-years in the second 18-month period. Similarly, the incidence of first CMV disease episodes fell from 20.9 to 3.5 per 100 person-years. Fourteen patients on HAART developed a first MAC infection, 12 (85.7%) within 2 months of starting HAART. Nineteen patients on HAART had a first CMV disease episode, 10 (52.6%) within 2 months of starting HAART. CONCLUSIONS: HAART led to a five-fold decrease in the incidence of first disseminated MAC infections and a six-fold decrease in first CMV disease episodes, although patients remain vulnerable to both diseases for approximately 2 months after starting HAART.

Prevention of disseminated Mycobacterium avium complex infection with reduced dose clarithromycin in patients with advanced HIV disease.

OBJECTIVE: To evaluate the ability of once daily reduced dose clarithromycin to prevent disseminated Mycobacterium avium complex (dMAC) infection in patients with advanced HIV disease. DESIGN: Non-randomized, retrospective study. SETTING: Outpatient clinic of an urban university-affiliated municipal hospital. PATIENTS: A group of 192 HIV-infected patients with a CD4 count < 100 x 10(6) cells/l who were followed for at least 90 days during a 6-year period (1991-1996) before the use of protease inhibitors. INTERVENTIONS: Clarithromycin 500 mg orally once daily (n = 84), rifabutin 300 mg orally once daily (n = 47) or no prophylaxis (n = 61). MAIN OUTCOME MEASURES: Positive blood culture for M. avium complex (MAC), time to development of dMAC, and time to death. RESULTS: When compared with no prophylaxis or rifabutin, the incidence of dMAC and time to development of dMAC were improved among those patients receiving clarithromycin (P < 0.001). Prolonged survival was associated with both clarithromycin and rifabutin use when compared with no prophylaxis (P < 0.002). In patients who failed prophylaxis, resistance to clarithromycin and rifabutin was observed. CONCLUSIONS: In the era prior to protease inhibitor use, once daily clarithromycin at a dose of 500 mg was associated with a reduction in the incidence of dMAC, appeared to be superior to rifabutin, and was associated with prolonged survival in patients with advanced HIV disease.

Effects of antiretroviral therapy and opportunistic illness primary chemoprophylaxis on survival after AIDS diagnosis. Adult/Adolescent Spectrum of Disease Group.

OBJECTIVE: To examine the effects of antiretroviral therapy (ART) and opportunistic illness chemoprophylaxis on the survival of persons with AIDS and survival time based on year of AIDS diagnosis. DESIGN: Longitudinal medical record review. SETTING: Ninety-three hospitals and clinics in nine cities in the USA. PATIENTS: We observed 19,565 persons with AIDS from 1990 through January 1998. INTERVENTIONS: Prescribed use of antiretroviral monotherapy, dual- and triple-combination therapies, primary prophylaxis against Pneumocystis carinii pneumonia and Mycobacterium avium complex, and pneumococcal vaccine. MAIN OUTCOME MEASURES: Time from AIDS diagnosis to death in the presence and absence of ART. Survival curves were compared of AIDS cases diagnosed during 1990-1992 and 1993-1995. RESULTS: Triple ART had the greatest effect on the risk of death [relative risk (RR), 0.15; 95% confidence limit (CL), 0.12, 0.17], followed by dual ART (RR, 0.24; 95% CL, 0.22, 0.26), and monotherapy (RR, 0.38; 95% CL, 0.36, 0.40). Risk of death was decreased among persons receiving Pneumocystis carinii pneumonia prophylaxis (RR, 0.79; 95% CL, 0.70, 0.89) and Mycobacterium avium complex prophylaxis (RR, 0.76; 95% CL, 0.68, 0.86). Median survival increased from 31 months [95% confidence interval (CI), 30-32 months] for AIDS cases diagnosed during 1990-1992 to 35 months (95% CI, 35-38 months) for cases diagnosed during 1993-1995. CONCLUSIONS: The risk of death was decreased for persons receiving triple ART compared with persons receiving dual therapy and persons receiving monotherapy. Increased use of ART and improved ART regimens probably contributed to prolonged survival of persons whose diagnosis was made during 1993-1995 compared with persons whose diagnosis was made during 1990-1992.