Slow Acceptance of Universal Antiretroviral Therapy (ART) Among Mothers Enrolled in IMPAACT PROMISE Studies Across the Globe.

The PROMISE trial enrolled asymptomatic HIV-infected pregnant and postpartum women not eligible for antiretroviral treatment (ART) per local guidelines and randomly assigned proven antiretroviral strategies to assess relative efficacy for perinatal prevention plus maternal/infant safety and maternal health. The START study subsequently demonstrated clear benefit in initiating ART regardless of CD4 count. Active PROMISE participants were informed of results and women not receiving ART were strongly recommended to immediately initiate treatment to optimize their own health. We recorded their decision and the primary reason given for accepting or rejecting the universal ART offer after receiving the START information. One-third of participants did not initiate ART after the initial session, wanting more time to consider. Six sessions were required to attain 95% uptake. The slow uptake of universal ART highlights the need to prepare individuals and sensitize communities regarding the personal and population benefits of the "Treat All" strategy.

Oseltamivir and inhaled zanamivir as influenza prophylaxis in Thai health workers: a randomized, double-blind, placebo-controlled safety trial over 16 weeks.

OBJECTIVES: Long-term chemoprophylaxis using neuraminidase inhibitors may be needed during influenza epidemics but safety data are limited to several weeks. We sought to assess the tolerability of oseltamivir and zanamivir as primary prophylaxis over 16 weeks. METHODS: We conducted a parallel group, double blind, 2 (active drug) :1 (placebo) randomized trial of oral oseltamivir/placebo or inhaled zanamivir/placebo over 16 weeks in healthy, Thai hospital professionals at two Bangkok hospitals. The primary endpoint was study withdrawal due to drug-related (possibly, probably, definitely) serious or adverse events (AEs) graded ≥ 2. RESULTS: Recruited subjects numbered 129 oseltamivir/65 placebo and 131 zanamivir/65 placebo. A total of 102 grade ≥ 2 AEs were reported or detected in 69 subjects: 23/129 (17.8%) versus 15/65 (23.1%) (P=0.26), and 23/131 (17.6%) versus 8/65 (12.3%) (P=0.28). Intercurrent infections/fevers [26/102 (25.5%)], abnormal biochemistry [25/102 (24.5%)] and gastrointestinal symptoms [18/102 (17.6%)] were the most frequently reported AEs. There were no drug-related study withdrawals. Eight serious AEs were all due to intercurrent illnesses. Laboratory, lung function and ECG parameters were similar between drugs and placebos. CONCLUSIONS: Oseltamivir and zanamivir were well tolerated in healthy hospital professionals. Both drugs can be recommended for primary influenza prophylaxis for up to 16 weeks.

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.

Practical management of avian influenza in humans.

There has been much alarm about avian influenza and its potential for a global pandemic ever since the current epidemic of avian influenza infections in humans began in 2003. While there have been a number of published reports on the clinical features of avian influenza, there are few guidelines on the practical management of patients with avian influenza. A symposium organised by the Society of Infectious Disease (Singapore), Society of Intensive Care Medicine and the Singapore General Hospital was held in Singapore to gather the views of experts from Turkey, Thailand, Vietnam and Indonesia who collectively had first-hand experience of the management of the majority (more than 100 of 192) of cases of avian influenza worldwide. The experts emphasised the importance of adapting international guidelines to the practicalities of situations on the ground. There was stress on wide screening using clinical criteria primarily, molecular diagnostic techniques (with reference laboratory confirmation) for diagnosis, and rational use of antiviral prophylaxis as well as infection control using at least surgical masks, gowns and gloves. A detailed analysis of data from a pooled database from these and other affected countries is critical to building up the evidence base for practical internationally applicable guidelines.

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.

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.

Gastrointestinal histoplasmosis in patients with AIDS: case report and review.

Histoplasmosis is the most common endemic mycosis in individuals with AIDS, occurring in 2%-5% of this population. Infection is more likely to be disseminated than in immunocompetent individuals and generally presents insidiously with nonspecific symptoms. The gastrointestinal tract is involved in 70%-90% of cases of disseminated histoplasmosis, yet gastrointestinal histoplasmosis per se is infrequently encountered in patients with AIDS. The diagnosis of gastrointestinal histoplasmosis is often not suspected, particularly in areas of nonendemicity, and a delay in diagnosis may lead to increased morbidity and risk of death. Since antifungal therapy improves outcome for >80% of AIDS patients with histoplasmosis, it is essential that caregivers be aware of the varied presentations of gastrointestinal histoplasmosis in order to diagnose and to treat this potentially life-threatening infection effectively.