Nevirapine pharmacokinetics in HIV-infected persons receiving rifapentine and isoniazid for TB prevention.

BACKGROUND: The use of rifamycin antibiotics for TB prevention carries a risk of detrimental drug-drug interactions with concomitantly used ART. OBJECTIVES: To evaluate the interaction of the antiretroviral drug nevirapine in combination with 4 weeks of daily rifapentine and isoniazid for TB prevention in people living with HIV. METHODS: Participants were individuals enrolled in the BRIEF-TB study receiving nevirapine and randomized to the rifapentine/isoniazid arm of the study. Participants provided sparse pharmacokinetic (PK) sampling at baseline and weeks 2 and 4 for trough nevirapine determination. Nevirapine apparent oral clearance (CL/F) was estimated and the geometric mean ratio (GMR) of CL/F prior to and during rifapentine/isoniazid was calculated. RESULTS: Seventy-eight participants had evaluable PK data: 61 (78%) female, 51 (65%) black non-Hispanic and median (range) age of 40 (13-66) years. Median (IQR) nevirapine trough concentrations were: week 0, 7322 (5266-9302) ng/mL; week 2, 5537 (3552-8462) ng/mL; and week 4, 5388 (3516-8243) ng/mL. Sixty out of 78 participants (77%) had nevirapine concentrations ≥3000 ng/mL at both week 2 and 4. Median (IQR) nevirapine CL/F values were: week 0 pre-rifapentine/isoniazid, 2.03 (1.58-2.58) L/h; and during rifapentine/isoniazid, 2.62 (1.81-3.42) L/h. The GMR (90% CI) for nevirapine CL/F was 1.30 (1.26-1.33). CONCLUSIONS: The CL/F of nevirapine significantly increased with concomitant rifapentine/isoniazid. The decrease in nevirapine trough concentrations during rifapentine/isoniazid therapy suggests induction of nevirapine metabolism, consistent with known rifapentine effects. The magnitude of this drug-drug interaction suggests daily rifapentine/isoniazid for TB prevention should not be co-administered with nevirapine-containing ART.

International neurocognitive normative study: neurocognitive comparison data in diverse resource-limited settings: AIDS Clinical Trials Group A5271.

Infrastructure for conducting neurological research in resource-limited settings (RLS) is limited. The lack of neurological and neuropsychological (NP) assessment and normative data needed for clinical interpretation impedes research and clinical care. Here, we report on ACTG 5271, which provided neurological training of clinical site personnel and collected neurocognitive normative comparison data in diverse settings. At ten sites in seven RLS countries, we provided training for NP assessments. We collected normative comparison data on HIV- participants from Brazil (n = 240), India (n = 480), Malawi (n = 481), Peru (n = 239), South Africa (480), Thailand (n = 240), and Zimbabwe (n = 240). Participants had a negative HIV test within 30 days before standardized NP exams were administered at baseline and 770 at 6 months. Participants were enrolled in eight strata, gender (female and male), education (<10 and ≥10 years), and age (<35 and ≥35 years). Of 2400 enrolled, 770 completed the 6-month follow-up. As expected, significant between-country differences were evident in all the neurocognitive test scores (p < 0.0001). There was variation between the age, gender, and education strata on the neurocognitive tests. Age and education were important variables for all tests; older participants had poorer performance, and those with higher education had better performance. Women had better performance on verbal learning/memory and speed of processing tests, while men performed better on motor tests. This study provides the necessary neurocognitive normative data needed to build infrastructure for future neurological and neurocognitive studies in diverse RLS. These normative data are a much-needed resource for both clinicians and researchers.

Renal and metabolic toxicities following initiation of HIV-1 treatment regimen in a diverse, multinational setting: a focused safety analysis of ACTG PEARLS (A5175).

BACKGROUND: Convenient dosing, potency, and low toxicity support use of tenofovir disoproxil fumarate (TDF) as preferred nucleotide reverse transcriptase inhibitor (NRTI) for HIV-1 treatment. However, renal and metabolic safety of TDF compared to other NRTIs has not been well described in resource-limited settings. METHODS: This was a secondary analysis examining the occurrence of renal abnormalities (RAs) and renal and metabolic serious non-AIDS-defining events (SNADEs) through study follow-up between participants randomized to zidovudine (ZDV)/lamivudine/ efavirenz and TDF/emtricitabine/efavirenz treatment arms within A5175/PEARLS trial. Exact logistic regression explored associations between baseline covariates and RAs. Response profile longitudinal analysis compared creatinine clearance (CrCl) over time between NRTI groups. RESULTS: Twenty-one of 1,045 participants developed RAs through 192 weeks follow-up; there were 15 out of 21 in the TDF arm (P = .08). Age 41 years or older (odds ratio [OR], 3.35; 95% CI, 1.1-13.1), his- tory of diabetes (OR, 10.7; 95% CI, 2.1-55), and lower baseline CrCl (OR, 3.1 per 25 mL/min decline; 95% CI, 1.7-5.8) were associated with development of RAs. Renal SNADEs occurred in 42 participants; 33 were urinary tract infections and 4 were renal failure/insufficiency; one event was attributed to TDF. Significantly lower CrCl values were maintained among patients receiving TDF compared to ZDV (repeated measures analysis, P = .05), however worsening CrCl from baseline was not observed with TDF exposure over time. Metabolic SNADEs were rare, but were higher in the ZDV arm (20 vs 3; P < .001). CONCLUSIONS: TDF is associated with lower serious metabolic toxicities but not higher risk of RAs, serious renal events, or worsening CrCl over time compared to ZDV in this randomized multinational study.

Final 192-week efficacy and safety of once-daily darunavir/ritonavir compared with lopinavir/ritonavir in HIV-1-infected treatment-naïve patients in the ARTEMIS trial.

OBJECTIVE: This paper presents the final analysis of once-daily darunavir/ritonavir (DRV/r) vs. lopinavir/ritonavir (LPV/r) in treatment-naïve HIV-1-infected adults. METHODS: ARTEMIS (AntiRetroviral Therapy with TMC114 ExaMined In naïve Subjects; NCT00258557) was a randomized, open-label, phase-III, 192-week trial. Patients were stratified by baseline HIV-1 RNA and CD4 count, and randomized to once-daily DRV/r 800/100 mg or LPV/r 800/200 mg total daily dose (either once or twice daily) plus tenofovir/emtricitabine. RESULTS: Of 689 randomized patients receiving treatment (DRV/r: 343; LPV/r: 346), 85 and 114 patients in the DRV/r and LPV/r arms, respectively, had discontinued by week 192. Noninferiority was shown in the primary endpoint of virological response (HIV-1 RNA < 50 copies/mL) [DRV/r: 68.8%; LPV/r: 57.2%; P < 0.001; intent to treat (ITT)/time to loss of virological response; estimated difference in response 11.6% (95% confidence interval 4.4-18.8%)]. Statistical superiority in virological response of DRV/r over LPV/r was demonstrated for the primary endpoint (P = 0.002) and for the ITT non-virological-failure-censored analysis (87.4% vs. 80.8%, respectively; P = 0.040). No protease inhibitor (PI) primary mutations developed and only low levels of nucleoside reverse transcriptase inhibitor (NRTI) resistance developed in virological failures in both groups. Significantly fewer discontinuations because of adverse events were observed with DRV/r (4.7%) than with LPV/r (12.7%; P = 0.005). Grade 2-4 treatment-related diarrhoea was significantly less frequent with DRV/r than with LPV/r (5.0% vs. 11.3%, respectively; P = 0.003). DRV/r was associated with smaller median increases in total cholesterol and triglyceride levels than LPV/r. Changes in low- and high-density lipoprotein cholesterol were similar between groups. Similar increases in aspartate aminotransferase and alanine aminotransferase for DRV/r and LPV/r were observed. CONCLUSION: Over 192 weeks, once-daily DRV/r was noninferior and statistically superior in virological response to LPV/r, with a more favourable gastrointestinal profile, demonstrating its suitability for long-term use in treatment-naïve patients.

Treatment outcomes of patients co-infected with tuberculosis and HIV at Chiang Mai University Hospital, Thailand.

Thailand has been greatly affected by the tuberculosis (TB) and HIV syndemic. This study aimed to determine treatment outcomes among HIV/TB co-infected patients. A retrospective cohort study was conducted at Chiang Mai University Hospital from 1 January 2000 to 31 December 2009. Of 171 patients, 100 patients were male (58.5%) and the mean age was 36.8 ± 8.0 years. Seventy-two patients (42.1%) had pulmonary tuberculosis. Median CD4+ count before TB treatment was 69 cells/mm(3) (interquartile range [IQR] 33, 151). The overall mortality was 3.5% (6 patients). Immune reconstitution inflammatory syndrome (IRIS) occurred in eight patients (6.0%). Disseminated TB infections increased risk of death (odds ratio [OR] = 2.55, 95% confidence interval [CI] 1.25, 5.18) and IRIS (OR = 9.16, 95% CI 1.67, 50.07). Initiating combination antiretroviral therapy (cART) within two months after TB treatment increased risk of IRIS (OR = 6.57, 95% CI 1.61-26.86) and physicians caring for HIV/TB co-infected patients should be aware of this condition.

Improved neuropsychological and neurological functioning across three antiretroviral regimens in diverse resource-limited settings: AIDS Clinical Trials Group study a5199, the International Neurological Study.

BACKGROUND: AIDS Clinical Trials Group (ACTG) A5199 compared the neurological and neuropsychological (NP) effects of 3 antiretroviral regimens in participants infected with human immunodeficiency virus type 1 (HIV-1) in resource-limited settings. METHODS: Participants from Brazil, India, Malawi, Peru, South Africa, Thailand, and Zimbabwe were randomized to 3 antiretroviral treatment arms: A (lamivudine-zidovudine plus efavirenz, n = 289), B (atazanavir, emtricitabine, and didanosine-EC, n = 293), and C (emtricitabine-tenofovir-disoproxil fumarate plus efavirenz, n = 278) as part of the ACTG PEARLS study (A5175). Standardized neurological and neuropsychological (NP) screening examinations (grooved pegboard, timed gait, semantic verbal fluency, and finger tapping) were administered every 24 weeks from February 2006 to May 2010. Associations with neurological and neuropsychological function were estimated from linear and logistic regression models using generalized estimating equations. RESULTS: The median weeks on study was 168 (Q1 = 96, Q3 = 192) for the 860 participants. NP test scores improved (P < .05) with the exception of semantic verbal fluency. No differences in neurological and neuropsychological functioning between treatment regimens were detected (P > .10). Significant country effects were noted on all NP tests and neurological outcomes (P < .01). CONCLUSIONS: The study detected no significant differences in neuropsychological and neurological outcomes between randomized ART regimens. Significant improvement occurred in neurocognitive and neurological functioning over time after initiation of ARTs. The etiology of these improvements is likely multifactorial, reflecting reduced central nervous system HIV infection, better general health, and practice effects. This study suggests that treatment with either of the World Health Organization -recommended first-line antiretroviral regimens in resource-limited settings will improve neuropsychological functioning and reduce neurological dysfunction. CLINICAL TRIALS REGISTRATION: NCT00096824.

Predictors of poor clinical outcome of cryptococcal meningitis in HIV-infected patients.

The aim of this study was to identify baseline prognostic factors for poor clinical outcome of HIV-associated cryptococcal meningitis. We conducted a trial in Thailand and the USA comparing low- and high-dose concomitant use of amphotericin B and fluconazole for HIV-associated cryptococcal meningitis to amphotericin B followed by fluconazole. Subjects who were either alive and cerebrospinal fluid (CSF) culture-positive or dead were considered to have a poor outcome. At day 14, baseline characteristics associated with poor outcome included: low weight, high CSF cryptococcal antigen (CrAg) titre and low CSF white blood cell (WBC) count. At day 70, the associated baseline characteristics included: CSF CrAg titre >1:1024 and low Karnofsky performance status. Overall, consistent with published findings, low weight, high CSF CrAg titre and low CSF WBC counts at baseline were predictors for poor clinical outcome. In addition, we found that low Karnofsky performance status was predictive of poor outcome. Prompt management with appropriate antifungal therapy for this particular group of patients may improve the outcomes.

Monitoring and impact of fluconazole serum and cerebrospinal fluid concentration in HIV-associated cryptococcal meningitis-infected patients.

OBJECTIVES: The aim of the present study was to assess fluconazole pharmacokinetic measures in serum and cerebrospinal fluid (CSF); and the correlation of these measures with clinical outcomes of invasive fungal infections. METHODS: A randomized trial was conducted in HIV-infected patients receiving three different regimens of fluconazole plus amphotericin B (AmB) for the treatment of cryptococcal meningitis. Regimens included fluconazole 400 mg/day+AmB (AmB+Fluc400) or fluconazole 800 mg/day+AmB (AmB+Fluc800) (14 days followed by fluconazole alone at the randomized dose for 56 days); or AmB alone for 14 days followed by fluconazole 400 mg/day for 56 days. Serum (at 24 h after dosing) and CSF samples were taken at baseline and days 14 and 70 (serum only) for fluconazole measurement, using gas-liquid chromatography. RESULTS: Sixty-four treated patients had fluconazole measurements: 11 in the AmB group, 12 in the AmB+Fluc400 group and 41 in the AmB+Fluc800 group. Day 14 serum concentration geometric means were 24.7 mg/L for AmB+Fluc400 and 37.0 mg/L for AmB+Fluc800. Correspondingly, CSF concentration geometric means were 25.1 mg/L and 32.7 mg/L. Day 14 Serum and CSF concentrations were highly correlated with AmB+Fluc800 (P<0.001, r=0.873) and AmB+Fluc400 (P=0.005, r=0.943). Increased serum area under the curve (AUC) appears to be associated with decreased mortality at day 70 (P=0.061, odds ratio=2.19) as well as with increased study composite endpoint success at days 42 and 70 (P=0.081, odds ratio=2.25 and 0.058, 2.89, respectively). CONCLUSION: High fluconazole dosage (800 mg/day) for the treatment of HIV-associated cryptococcal meningitis was associated with high serum and CSF fluconazole concentration. Overall, high serum and CSF concentration appear to be associated with increased survival and primary composite endpoint success.

Efficacy and tolerability of a double boosted protease inhibitor (lopinavir + saquinavir/ritonavir) regimen in HIV-infected patients who failed treatment with nonnucleoside reverse transcriptase inhibitors.

OBJECTIVES: Long-term nonnucleoside reverse transcriptase inhibitor (NNRTI)-based antiretroviral treatment failure in most developing countries has led to broad cross-resistance within NNRTI and nucleoside reverse transcriptase inhibitor (NRTI) classes. In this study, we investigated the efficacy and tolerability of a double boosted protease inhibitor (PI) regimen in this setting. METHODS: A total of 64 HIV-infected patients who had failed NNRTI-based regimens were randomized to receive either lopinavir/saquinavir/ritonavir [LPV/SQV/r; 400/1000/100 mg twice a day (bid)] alone or indinavir/ritonavir (IDV/r; 800/100 mg bid) plus two NRTIs optimized with genotypic drug resistance guidance. Patients who had no available optimized NRTI backbone were allocated to the LPV/SQV/r arm. RESULTS: At 48 weeks, the percentages of patients with plasma viral load<50 HIV-1 RNA copies/mL were 60% (31 of 52 patients) in the LPV/SQV/r arm vs 50% (six of 12) in the IDV/r/2NRTIs arm in the intent-to-treat (ITT) analysis, and 61% (31 of 51) vs 71% (five of seven), respectively, in the as-treated analysis. The median (interquartile range) increases in absolute CD4 cell count from baseline were 177 (91-269) and 100 (52-225) cells/microL in the LPV/SQV/r and IDV/r/2NRTIs groups, respectively (P=0.32). Four of 12 patients (33%) in the IDV/r/2NRTIs group experienced severe nausea and vomiting and four patients (8%) in the LPV/SQV/r group had significant hepatitis. CONCLUSIONS: LPV/SQV/r and high-dose boosted IDV were not well tolerated and led to <65% ITT virological efficacy outcomes. A randomized larger scale study with new formulations and/or more tolerable boosted PIs in NNRTI-based failure is warranted.

Autochthonous visceral leishmaniasis: a report of a second case in Thailand.

Visceral leishmaniasis (VL) is a rare disease in Thailand. Only one previous case has been reported in which transmission was likely autochthonous. We conducted an investigation of a case of VL, which included serological and symptom surveys of people who lived near the case in Nan Province and Bangkok, serological surveys of domestic animals in his home village and sand fly surveys in his home village and in Bangkok. No humans interviewed met our case definition for possible VL. One hundred thirty-one villagers were seronegative for Leishmania antibodies. We found three cows and one cat that had positive direct agglutination tests for Leishmania spp, but we were unable to confirm current infection by PCR. Sand fly surveys showed that most of the flies were of the Sergentomyia genus, which has not previously been reported as a competent vector in Thailand. Nonetheless, we conclude, based on the patient's lack of travel outside Thailand and the presence of seropositive domestic animals in his home village, that he was most likely infected by the bite of a sand fly in Thailand. We believe this is the second case of autochthonously transmitted VL in Thailand.

A controlled trial of itraconazole to prevent relapse of Penicillium marneffei infection in patients infected with the human immunodeficiency virus.

BACKGROUND: In Southeast Asia, disseminated infection with Penicillium marneffei is common among patients with human immunodeficiency virus (HIV) infection. Even after successful primary treatment, the relapse rate for this potentially fatal systemic fungal infection is about 50 percent. METHODS: We conducted a double-blind trial in Thailand to evaluate itraconazole as secondary prophylaxis against P. marneffei infection in patients with the acquired immunodeficiency syndrome (AIDS) who were in complete remission after treatment for culture-proved P. marneffei infection. The patients were randomly assigned to receive either oral itraconazole (200 mg daily) or placebo as maintenance therapy. RESULTS: Of the 72 HIV-infected patients who completed initial treatment for P. marneffei infection, 71 were enrolled in the maintenance study. None of the 36 patients assigned to itraconazole had a relapse of P. marneffei infection within one year, whereas 20 of the 35 patients assigned to placebo (57 percent) had relapses (P<0.001). Among the 20 patients who had relapses, P. marneffei was cultured from blood (15 patients), lymph-node tissue (3 patients), skin (3 patients), and sputum (1 patient). The median time to relapse was 24 weeks after the completion of the initial treatment (95 percent confidence interval, 19.0 to 36.1). Survival and toxic effects were similar in the two groups. CONCLUSIONS: In patients infected with HIV who have completed successful primary treatment of P. marneffei infection, secondary prophylaxis with oral itraconazole is well tolerated and prevents relapses of this opportunistic infection.

Epidemiology and management of penicilliosis in human immunodeficiency virus-infected patients.

Penicillium marneffei is a dimorphic fungus that can cause systemic mycosis in humans. It is endemic in Southeast Asia, the Guangxi province of China, Hong Kong, and Taiwan. Prior to the epidemic of human immunodeficiency virus (HIV), penicilliosis was a rare event. The incidence of this fungal infection has increased markedly during the past few years, paralleling the incidence of HIV infection. The patients usually present with fever, anemia, weight loss, skin lesions, generalized lymphadenopathy, and hepatomegaly. The skin lesions are most commonly papules with central necrotic umbilication. The average number of CD4+ T lymphocytes at presentation is 64 cells/mm3. The fungus is usually sensitive to amphotericin B, itraconazole, and ketoconazole. The response to antifungal treatment is good if the treatment is started early. After the initial treatment the patient may need to take an antifungal drug as secondary prophylaxis for life. New tests for the laboratory diagnosis of penicilliosis have been reported. Further studies of these tests, as well as the epidemiology, natural history, and management of this potentially fatal systemic fungal infection are needed.

Amphotericin B and itraconazole for treatment of disseminated Penicillium marneffei infection in human immunodeficiency virus-infected patients.

Disseminated infection with Penicillium marneffei is common in patients infected with human immunodeficiency virus (HIV) in Southeast Asia. Treatment with amphotericin B alone is effective but requires a prolonged hospital stay. We conducted an open-label nonrandomized study to evaluate the efficacy and safety of treatment with amphotericin B at a dosage of 0.6 mg/(kg.d) intraveneously for 2 weeks, followed by a 400-mg/d dosage of oral itraconazole for 10 weeks. Of the 74 HIV-infected patients we studied who had disseminated P. marneffei infection, diagnosed by positive fungal culture and clinical evidence of infection, 72 (97.3%) responded to the treatment. There were no serious adverse drug effects. It was concluded that the regimen was effective and safe for treatment of disseminated P. marneffei infection in HIV-infected patients.

Case-control study of risk factors for Penicillium marneffei infection in human immunodeficiency virus-infected patients in northern Thailand.

A case-control study was done in Chiang Mai, Thailand, comparing risk-related behavior and exposures in 80 incident cases of disseminated Penicillium marneffei infection in patients with AIDS and 160 control patients with AIDS who did not have P. marneffei infection. All subjects were admitted to Chiang Mai University Hospital between December 1993 and October 1995. Cases were younger than controls (16-30 years vs. > 30 years of age; odds ratio [OR] = 2.22; 95% CI, 1.22-4.07). Patients with a recent history of occupational or other exposure to soil, especially during the rainy season (May to October), were more likely to present with P. marneffei infection (OR = 1.91; 95% CI, 1.04-3.52). History of exposure to or consumption of bamboo rats, the only known nonhuman hosts of P. marneffei, was not a risk factor for infection. Our data suggest that recent exposure to a potential environmental reservoir of organisms in the soil may be associated with disseminated P. marneffei infections among patients with AIDS in Northern Thailand.

Cross-reactivity in Histoplasma capsulatum variety capsulatum antigen assays of urine samples from patients with endemic mycoses.

We evaluated cross-reactivity in the antigen assay used for the diagnosis of histoplasmosis by testing urine samples from patients with disseminated fungal infections. The mycoses chosen for this study were selected on the basis of the observation that during clinical testing, cross-reactions may occur between Histoplasma capsulatum var. capsulatum, Paracoccidioides brasiliensis, Blastomyces dermatitidis, Coccidioides immitis, and Penicillium marneffei. We detected antigen in 12 of 19 patients with blastomycosis, 8 of 9 with paracoccidioidomycois, in 17 of 18 with P. marneffei infection, and in one with disseminated H. capsulatum var. duboisii infection. Cross-reactions were not observed in the assays for six patients with disseminated coccidioidomycosis. Cross-reactivity between the agents of other endemic mycoses should be considered in interpreting a positive H. capsulatum var. capsulatum antigen assay. Antigen detection may provide a rapid, provisional diagnosis for patients with serious infections caused by one of these organisms.

Western immunoblot analysis of protein antigens of Penicillium marneffei.

Protein antigens of Penicillium marneffei prepared during the yeast and mould phases of in vitro growth were analyzed by gel electrophoresis and immunoblot assay. More than 20 yeast phase proteins were detected by Coomassie staining; among these, at least 10 reacted with IgG in the pooled sera of 28 AIDS patients with penicilliosis. Four immunogenic proteins of 200, 88, 54 and 50 kDa were produced in large quantity during the deceleration and early stationary phases of growth. When these proteins were reacted with individual sera derived from 33 AIDS patients with penicilliosis, reactivities to the 200, 88, 54 and 50 kDa protein were detected in 72.7, 93.9, 60.6 and 57.6%, respectively. The bands of 88, 54 and 50 kDa gave strong reactions with about a half of serum samples. In one serum derived from an AIDS patient, reactivities to the 54 and 50 kDa proteins could be strongly detected two months before the definite diagnosis by fungal culture. Protein components from the mould form were of lower yield and gave weaker signal in immunoblot analysis. These results indicate that at least two yeast-phase immunoreactive proteins (54 and 50 kDa) are relatively specific to the P. marneffei infection, thereby suggesting its potential for clinical application to the diagnosis of this emerging disease.

Seasonal variation of disseminated Penicillium marneffei infections in northern Thailand: a clue to the reservoir?

Disseminated Penicillium marneffei infections are common AIDS-defining opportunistic infections among persons with human immunodeficiency virus (HIV) infection in northern Thailand. Penicilliosis due to P. marneffei is the third most frequent AIDS-defining infection in this population, after tuberculosis and cryptococcosis. Very little is known about the epidemiology and natural reservoir of P. marneffei. The seasonal distribution of two common AIDS-defining fungal infections was compared among patients diagnosed between 1991 and 1994 at Chiang Mai University Hospital. There were 550 cases (492 male, 58 female patients) of P. marneffei and 793 cases (685 male, 108 female patients) of Cryptococcus neoformans infection diagnosed. In each year, P. marneffei but not C. neoformans infections were more frequent in the rainy than the dry season. Seasonal variation of P. marneffei infections in AIDS patients in northern Thailand may provide valuable information in determining the important reservoirs and exposures to this organism that lead to disseminated disease in these patients.

Disseminated Penicillium marneffei infection in southeast Asia.

Disseminated infection with the fungal pathogen Penicillium marneffei is, after extrapulmonary tuberculosis and cryptococcal meningitis, the third most common opportunistic infection in HIV disease in northern Thailand. We report the clinical, microbiological, and therapeutic features of a large series of HIV-infected adults with disseminated P marneffei infection. From August, 1987, to June, 1992, 92 patients with P marneffei infection confirmed by culture were seen at Chiang Mai University Hospital, of whom 86 were also infected with HIV. Clinical information was available for 80 of these patients. The most common presenting symptoms and signs were fever (92%), anaemia (77%), weight loss (76%), and skin lesions (71%). 87% of patients presenting with skin lesions had generalised papules with central umbilication. Presumptive diagnosis was made in 50 patients by microscopic examination of Wright's-stained bone-marrow aspirate and/or touch smears of skin biopsy or lymph-node biopsy specimens. Most patients who were diagnosed responded initially to amphotericin or itraconazole, whereas most who were not diagnosed and treated died. 12 patients relapsed within 6 months of cessation of treatment. P marneffei has become an important pathogen of HIV-associated opportunistic infection in Thailand.

PIP: Penicillium marneffei (PM) is the only Penicillium species which is dimorphic and can cause systemic mycosis in human beings; it is endemic in southeast Asia and China. The prevalence of PM infection has increased substantially during the past few years, occurring exclusively among patients infected with HIV. After extrapulmonary tuberculosis and cryptococcal meningitis, disseminated infection with PM is the most common opportunistic infection of HIV disease in northern Thailand. The clinical, microbiological, and therapeutic features of a large series of well-documented cases have not, however, been reported. The authors describe the clinical and laboratory features of 80 HIV-infected adults with disseminated PM infection seen over the period August 1987 - June 1992 at Chiang Mai University Hospital, Thailand. Subjects were of mean age 32.4 years in a range of 18-63. 74 subjects were male and 76 acquired HIV via heterosexual relations. Fever was present in 92%, anemia in 77%, weight loss in 76%, and skin lesions in 71%, while 87% of patients presenting with skin lesions had generalized papules with central umbilication. Most patients who were diagnosed responded initially to amphotericin or itraconazole, while most who were not diagnosed and treated died. More precisely, 40 of the 68 patients treated responded to the therapy. Twelve patients relapsed within six months of cessation of treatment.

Disseminated Penicillium marneffei infection diagnosed on examination of a peripheral blood smear of a patient with human immunodeficiency virus infection.

We describe a case of disseminated Penicillium marneffei infection in a patient infected with human immunodeficiency virus. The diagnosis was made by examination of a peripheral blood smear. The patient presented with fever, jaundice, generalized lymphadenopathy, hepatosplenomegaly, and an erythematous, papular rash. Microscopic examination of a Wright's-stained peripheral blood smear revealed many yeast cells in neutrophils. Some yeast cells had clear central septation. Presumptive diagnosis of disseminated P. marneffei infection was made, and treatment was started several days before the culture results were available.