Prospective International Study of Incidence and Predictors of Immune Reconstitution Inflammatory Syndrome and Death in People Living With Human Immunodeficiency Virus and Severe Lymphopenia.

BACKGROUND: Patients living with human immunodeficiency virus (PLWH) with low CD4 counts are at high risk for immune reconstitution inflammatory syndrome (IRIS) and death at antiretroviral therapy (ART) initiation. METHODS: We investigated the clinical impact of IRIS in PLWH and CD4 counts <100 cells/µL starting ART in an international, prospective study in the United States, Thailand, and Kenya. An independent review committee adjudicated IRIS events. We assessed associations between baseline biomarkers, IRIS, immune recovery at week 48, and death by week 48 with Cox models. RESULTS: We enrolled 506 participants (39.3% were women). Median age was 37 years, and CD4 count was 29 cells/µL. Within 6 months of ART, 97 (19.2%) participants developed IRIS and 31 (6.5%) died. Participants with lower hemoglobin at baseline were at higher IRIS risk (hazard ratio [HR], 1.2; P = .004). IRIS was independently associated with increased risk of death after adjustment for known risk factors (HR, 3.2; P = .031). Being female (P = .004) and having a lower body mass index (BMI; P = .003), higher white blood cell count (P = .005), and higher D-dimer levels (P = .044) were also significantly associated with increased risk of death. Decision-tree analysis identified hemoglobin <8.5 g/dL as predictive of IRIS and C-reactive protein (CRP) >106 µg/mL and BMI <15.6 kg/m2 as predictive of death. CONCLUSIONS: For PLWH with severe immunosuppression initiating ART, baseline low BMI and hemoglobin and high CRP and D-dimer levels may be clinically useful predictors of IRIS and death risk.

Effectiveness of fixed-dose combination stavudine, lamivudine and nevirapine (GPO-VIR) for treatment of naïve HIV patients in Thailand: a 3-year follow-up.

Generic fixed dose combination stavudine (d4T), lamivudine (3TC) and nevirapine (NVP), named GPO-VIR is recommended in the HIV treatment guidelines for Thailand. The long term effectiveness and adverse effects of this drug combination for the treatment of HIV were evaluated in an ambispective study at Bamrasnaradura Infectious Diseases Institute, Nonthaburi Province, Thailand from March 2002 to January 2006. A total of 152 adult treatment naive HIV patients who had received at least 12 months of GPO-VIR were enrolled. The median (IQR) CD4 cell count increased from 23 (8-94) cells/microl at baseline to 126 (38-180), 136 (98-189), 199 (141-255) and 334 (243-414) cells/microl at 3, 6, 12 and 24 months (p < 0.001), respectively. The median (IQR) percentage of body weights increased from baseline by 3.0% (0.3-6.3), 6.2% (2.2-9.3), 7.3% (3.9-10.9) and 8.1% (3.4-11.9) at 3, 6, 12 and 24 months, respectively and then remained at a plateau until the end of the 3-year study. The occurrence of new opportunistic infections decreased significantly (p < 0.001) with GPO-VIR treatment. Drug resistance occurred in 5 cases (3.3%) with a median (IQR) time of 18.0 (16.5-32.5) months to occurrence. Adverse effects included hypercholesterolemia (43.2%), lipodystrophy (35.5%), hypertriglyceridemia (25%), hypertension (13.1%), peripheral neuropathy (11.9%), hyperlactatemia (2.6%) and lactic acidosis (1.3%). Thirty-six patients (27%) switched from GPO-VIR to other anti-retroviral drugs regimens due to lipodystrophy. This study showed GPO-VIR had clinical and immunological benefits, but one-third of patients had adverse effects.

Temporary external lumbar drainage for reducing elevated intracranial pressure in HIV-infected patients with cryptococcal meningitis.

The aim of this study was to investigate safety and impact of temporary external lumbar drainage for continuous release of cerebrospinal fluid among patients with HIV-associated cryptococcal meningitis and elevated intracranial pressure (ICP). We conducted a retrospective cohort study among patients with cryptococcal meningitis in whom temporary external lumbar drains were placed to reduce intractable elevated ICP between January 2002 and December 2005. Patients were followed for three months after the procedure. Among 601 HIV-infected patients with cryptococcal meningitis, 54 (8.9%) underwent lumbar drain placement. Of these patients, mean age was 33 years and 80% were males. The median duration of an indwelling lumbar drain was seven days. There were 61 placement procedures among 54 patients, totalling to 473 device-days of observation. Overall incidence of secondary bacterial infections was 6.3 per 1000 device-days, and three (4.9%) of 61 catheters became secondarily infected with nosocomially acquired bacteria. All three drains were removed and appropriate antibiotics were given. There was no difference in median duration of placement between infected and uninfected drains (six days vs. seven days, P=0.572). The overall mortality rate was 5.6% in this cohort of 54 patients. In conclusion, the incidence of nosocomial infection of external lumbar drains is low. In resource-limited settings, the use of temporary external lumbar drainage is a safe and effective management strategy for intractable elevated ICP in HIV-infected patients with cryptococcal meningitis.

Incidence and risk factors of nevirapine-associated severe hepatitis among HIV-infected patients with CD4 cell counts less than 250 cells/microL.

OBJECTIVES: To determine incidence and risk factors of nevirapine (NVP)-associated severe hepatitis that led to NVP discontinuation among HIV-infected patients with CD4 < 250 cells/microL. MATERIAL AND METHOD: A retrospective cohort study was conducted among antiretroviral-naïve HIV-infected patients who had baseline CD4 < 250 cells/microL and were initiated NVP-based antiretroviral therapy (ART) between January 2003 and October 2005. All patients were categorized to group A: occurred clinical hepatitis and group B: did not occur clinical hepatitis. All were followed until 6 months after ART. RESULTS: There were 910 patients with a mean age of 35.4 years, 57% were males and median (IQR) CD4 cell count was 27 (9-80) cells/microL; contributing 5,006 person-months of observations. Ten (1.1%) patients were in group A and 900 (98.9%) patients were in group B. Incidence of clinical hepatitis was 2 per 1,000 person-months. Probabilities of clinical hepatitis at 0.5, 1, 2, 3 and 6 months after ART were 0.2%, 0.5%, 0.7%, 0.8% and 1.1%, respectively. By Cox regression analysis, baseline AST > or = 1.5 times of upper limit was associated with higher incidence of clinical hepatitis (p = 0.019, HR = 5.83, 95% CI = 1.33-25.51). CONCLUSION: Incidence of NVP-associated severe hepatitis that lead to NVP discontinuation among HIV-infected patients with baseline CD4 < 250 cells/microL is low. The higher baseline AST is also associated with a higher risk of severe hepatitis.

Guidelines for antiretroviral therapy in HIV-1 infected adults and adolescents: the recommendations of the Thai AIDS Society (TAS) 2008.

BACKGROUND: More than 100,000 patients have been treated, since the implementation of the National Universal Coverage for antiretroviral therapy (ART) in Thailand Although there are several comprehensive guidelines available internationally, there is a need to have guidelines that can be implemented in Thailand. MATERIAL AND METHOD: The guidelines were developed by a panel of 17 members who are the experts on HIV research and/or HIV patient care and appointed without incentive by the Thai AIDS Society (TAS). The recommendations were based on evidences from the published studies and availability of antiretroviral agents. Published studies that are relevant and applicable to Thailand in particular have been taken into consideration. RESULTS: The recommendations include: when to start ART; what to start; how to monitor the therapy; adverse effects and its management; diagnosis of treatment failure; and antiretroviral treatment options in patients with treatment failure. ART in special circumstances, i.e., patients with co-infection of tuberculosis or hepatitis B virus, is also included Appropriate level of CD4+ T-cell count to start ART among Thai patients has been considered carefully. The authors recommend to start ART at CD4+ T-cell count < 200 cells/mm3. CONCLUSION: ART should be initiated in adults and adolescents HIV-1 infected patients with a history of HIV-related illness or AIDS or with a CD4+ T-cell count <200 cells/mm3. For treatment-naive patients, the preferred initial therapy is a non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimen. CD4' T-cell count and viral load should be monitored for at least twice and once a year, respectively. Proper management of antiretroviral-related toxicity and enhancement of adherence are crucial for the long-term success of ART.

Effectiveness and metabolic complications after 96 weeks of a generic fixed-dose combination of stavudine, lamivudine, and nevirapine among antiretroviral-naive advanced HIV-infected patients in Thailand: A prospective study.

BACKGROUND: Generic fixed-dose combination (FDC) antiretroviral therapy (ART) has been widely used in resource-limited settings. Treatment based on these combinations provide low pill burden and are less expensive. OBJECTIVE: The aim of this study was to determine the long-term effectiveness and metabolic complications of a generic FDC of stavudine (d4T)/lamivudine (3TC)/ nevirapine (NVP), among ART-naive HIV-infected patients. METHODS: A prospective study was conducted among patients who were initiated on d4T/3TC/NVP between November 2004 and March 2005. Plasma HIV-1 RNA, CD4 and alanine transaminase were assessed every 12 weeks. Fasting plasma glucose (FPG) and lipid profile were determined at 96 weeks. Adverse events and genotypic drug resistance were recorded. The primary outcome of interest was the proportion of patients who achieved plasma HIV-1 RNA <50 copies/mL after 96 weeks of ART and analyzed by intent-to-treat (ITT) and on-treatment (OT) populations. RESULTS: There were 140 patients (mean [SD] age, 35.7 [7.6] years; male, 67.9%) enrolled in the study. Median (interquartile range [IQR]) baseline CD4 was 31 (14-79) cells/mm(3) and HIV-1 RNA count was 433,500 (169,000-750,000) copies/mL. At week 96, 87 patients (ITT, 62.1%; OT, 87.0%) achieved HIV-1 RNA -50 copies/mL. Median (IQR) CD4 at 96 weeks was 328 (229-450) cells/mm(3). The reasons for drug discontinuation were as follows: drug resistance (9.3%), lost to follow-up (9.3%), NVP- related rashes (7.9%), death (5.0%), d4T-related adverse events (3.6%), and transferred to another hospital (2.1%). At 96 weeks, 25 patients (28.7%) had low-density lipoprotein cholesterol (LDL-C) >130 mg/dL, 7 (8.0%) had LDL-C >160 mg/dL, 6 (6.9%) had triglycerides >400 mg/dL, and 2 (2.3%) had FPG >126 mg/dL. Eleven patients (12.6%) had a lactic acid level >2.5 mmol/L. Eight patients (9.2%) needed to take antihypertensive agents. Of 13 patients who developed virologic failure, 76.9% and 61.5% had M184V/I and Y181C/I mutations, respectively. CONCLUSIONS: Initiation of this FDC ofd4T/3TC/NVP in these ART-naive patients with advanced HIV infection and low baseline CD4 cell count was effective at 96 weeks of follow-up with regard to virologic and immunologic responses. However, long-term metabolic complications, particularly dyslipidemia, were common and should be closely monitored.

Incidence and risk factors of nevirapine-associated skin rashes among HIV-infected patients with CD4 cell counts <250 cells/microL.

The objective of the study was to determine cumulative incidence and risk factors of nevirapine (NVP)-associated rashes that lead to NVP discontinuation among HIV-infected patients with CD4 <250 cells/microL. A retrospective cohort study was conducted among antiretroviral-naïve HIV-infected patients who had baseline CD4 <250 cells/microL and were initiated NVP-based antiretroviral therapy (ART) between January 2003 and October 2005. There were 910 patients with a mean age of 35.4 years and 43% were women. Median CD4 cell count was 27 cells/microL and median HIV RNA was 5.5 log copies/mL. Cumulative incidences of rashes at 0.5, 1, 2, 3 and 6 months after ART were 3.7%, 6.2%, 8.1%, 8.5% and 8.5%, respectively. By Kaplan-Meier analysis, the higher baseline CD4 cell counts had a higher probability of NVP-associated rashes (log-rank test, P=0.041). By Cox regression analysis, higher baseline CD4 cell count was associated with a higher incidence of rashes (hazard ratio=1.244, 95% confidence interval=1.045-1.482, for every 50 cells/microL increment of baseline CD4 stratum). In conclusion, NVP-associated skin rashes that lead to NVP discontinuation are common among HIV-infected patients with baseline CD4 <250 cells/microL. Despite the low baseline in this population, the higher number of baseline CD4 cells is continuously associated with a higher risk for skin rashes.

Predisposing factors for nevirapine toxicity among AIDS patients with low baseline CD4 count.

The objective of the study was to determine the predisposing factors and incidence of toxicity among AIDS patients treated with a nevirapine (NVP)-based regimen in clinical practice. A retrospective cohort study of representative samples of AIDS patients treated with a NVP-based regimen was performed. A total of 206 adult HIV/AIDS cases with median age (IQR) 33 years (range, 29-38 years), 51% male, treated between January 2004-December 2005, were included. Most (92.2%) of the patients were naïve to antiretroviral drug. The incidence of NVP toxicity was 1.09/100 person-months. The median onset time was 4 weeks post NVP initiation (2.57 weeks for skin toxicity and 12.43 weeks for hepatic toxicity). History of drug allergy and NVP toxicity were significantly associated (p = 0.006), as were sulfamethoxazole allergy and toxicity (p = 0.015). Regarding concomitant medication, concurrent anti-tuberculosis drugs significantly increased the risk of NVP associated liver toxicity (p = 0.001). Therefore, it is important to monitor adverse events from NVP, including liver function tests among HIV/AIDS patients with history of drug allergy, especially against sulfamethoxazole, and those concurrently treated with antituberculosis drugs.

Incidence and risk factors of major opportunistic infections after initiation of antiretroviral therapy among advanced HIV-infected patients in a resource-limited setting.

OBJECTIVE: To study incidence, risk factors, and impact of major opportunistic infections (OIs) after initiation of antiretroviral therapy (ART). METHODS: A retrospective cohort study was conducted among naïve HIV-infected patients who were initiated ART during January 2003-December 2004. All patients were followed until 15 months after ART. RESULTS: There were 793 patients with mean+/-SD age of 35.2+/-7.4 years and 56.3% male. Median (IQR) CD4 was 26 (9-78) cells/mm3. Of 793 patients, 61 (8%) patients developed 81 episodes of OIs after ART. These included tuberculosis (48.1%), CMV retinitis (19.8%), MAC infection (14.8%), PCP (9.9%), cryptococcosis (6.2%) and penicilliosis (1.2%). Overall incidence of new episode of OIs after ART was 8.0% during the first year of ART. Probabilities of OIs at 1, 2, 3, 6, and 12 months after ART were 2.6%, 4.0%, 5.3%, 6.9% and 8.0%, respectively. Baseline CD4 < or = 50 cells/mm3, male gender, and low body weight were associated with higher incidence of OIs after ART (P<0.05). CONCLUSIONS: Most of new episodes of major OIs develop within the first three months after ART. Tuberculosis is the most frequent OIs in this situation. The substantial increase of new episode of OIs after ART was observed among HIV-infected patients with CD4 cell counts < or = 50 cells/mm3 at ART initiation.

Comparison of one week with two week regimens of amphotericin B both followed by fluconazole in the treatment of cryptococcal meningitis among AIDS patients.

BACKGROUND: Amphotericin B treatment in cryptococcosis requires daily hospital visits or admission. Its toxicities and hospital costs have been concerned. Short course amphotericin B regimen warrants to be evaluated. OBJECTIVE: To compare the safety and efficacy of one-week (AmB1) with two-week (AmB2) amphotericin B both followed by fluconazole. MATERIAL AND METHOD: 57 AIDS with cryptococcal meningitis were randomly assigned to either AmB1 or AmB2. Microbiological and clinical clearances were the outcomes of the study. RESULTS: The treatment success at 6 weeks was 63.3% in AmB1 and 70.4% in AmB2 (p = 0.574). Clinical assessment at week 10 and renal toxicities were not significantly different between both regimens. Mortality rate was 14% however, 75% of deaths were in AmB2. CONCLUSION: AmB1 was comparably effective and safe as the standard AmB2 regimen in the treatment of AIDS related cryptococcal meningitis. It can be an alternative regimen to lower hospital based care and improve cost effective for source limiting health care centers.

Effect of rifampicin on the pharmacokinetics of fluconazole in patients with AIDS.

OBJECTIVE: To study the effect of rifampicin on the pharmacokinetics of fluconazole and on clinical outcomes of fluconazole treatment in patients with AIDS-related cryptococcal meningitis. PATIENTS: Forty Thai patients with AIDS and cryptococcal meningitis, of whom 20 had been receiving oral rifampicin for at least 2 weeks to treat tuberculosis. METHODS: Patients were treated for cryptococcal meningitis with amphotericin 0.7 mg/kg/day for 14 days followed by fluconazole 400 mg/day, which was reduced to 200 mg/day once culture of cerebrospinal fluid (CSF) became negative. Patients with tuberculosis received oral rifampicin 600 mg/day at night. Blood samples were collected from the first 12 patients in each group and pharmacokinetic parameters for fluconazole were calculated. CSF samples were collected by lumbar puncture and monitored for eradication of Cryptococcus neoformans. RESULTS: Concomitant administration of rifampicin with fluconazole resulted in significant changes in the pharmacokinetic parameters of fluconazole, including a 39% increase in elimination rate constant, 28% shorter elimination half-life, 22% decrease in area under the concentration-time curve, 17% decrease in maximum concentration and 30% increase in clearance (p < 0.05). Different fluconazole regimens did not affect the extent of change in the elimination rate constant. Although serum concentrations of fluconazole during the time that patients received rifampicin concomitantly with fluconazole 200 mg/day were generally lower than the minimum inhibitory concentration for C. neoformans, there were no significant differences in clinical outcomes between the two groups to date (p = 0.792). CONCLUSIONS: Coadministration of rifampicin with fluconazole caused significant changes in the pharmacokinetic parameters of fluconazole. Long-term monitoring for recurrence rates of cryptococcal meningitis is required to assess the clinical significance of this interaction.