Theshinee Chuenyam

Pharmacokinetics and short-term efficacy of a double-boosted protease inhibitor regimen in treatment-naive HIV-1-infected adults

OBJECTIVES To study the pharmacokinetics and short-term efficacy of low and standard dose lopinavir/ritonavir and saquinavir combinations in Thai, human immunodeficiency virus (HIV)-infected, treatment-naive patients. METHODS In this open-label, 24-week, prospective study, 48 treatment-naive patients were randomized to lopinavir/ritonavir 400/100 mg+saquinavir 1000 mg twice daily (arm A), lopinavir/ritonavir 400/100 mg+saquinavir 600 mg twice daily (arm B), lopinavir/ritonavir 266/66 mg+saquinavir 1000 mg twice daily (arm C), or lopinavir/ritonavir 266/66 mg+saquinavir 600 mg twice daily (arm D). A 12 h. pharmacokinetic profile in all patients was performed. Plasma concentrations of saquinavir and lopinavir were determined using an HPLC technique. HIV-1 RNA was measured over 24 weeks. RESULTS Forty-three subjects were included in the pharmacokinetic analysis. The total exposure differed significantly for the different arms. Median values for lopinavir area under the curve at 0-12 h were 128.2, 119.2, 66.1 and 68.5 mg.h/L for arms A-D, respectively. For saquinavir, the median values were 36.9, 19.2, 25.3 and 12.4 mg.h/L for arms A-D, respectively. The proportion of patients having a viral load below 50 copies/mL at week 24 was 39% for arm A, 63% for arm B, 55.0% for arm C, and 69% for arm D. CONCLUSIONS The pharmacokinetic parameters for the different treatment arms were adequate. However, the proportion of subjects with an undectable viral load at week 24 was lower than anticipated.

Pharmacokinetics of Stavudine and Didanosine Coadministered with Nelfinavir in Human Immunodeficiency Virus-Exposed Neonates

ABSTRACT We evaluated the pharmacokinetics of stavudine (d4T) and didanosine (ddI) in neonates. Eight neonates born to human immunodeficiency virus-infected mothers were enrolled to receive 1 mg of d4T per kg of body weight twice daily and 100 mg of ddI per m2 once daily in combination with nelfinavir for 4 weeks after birth. Pharmacokinetic evaluations were performed at 14 and 28 days of age. For d4T, on days 14 and 28, the median areas under the concentration-time curves from 0 to 12 h (AUC0–12s) were 1,866 and 1,603, ng · h/ml, respectively, and the median peak concentrations (Cmaxs) were 463 and 507 ng/ml, respectively. For ddI, on days 14 and 28, the median AUC0–10s were 1,573 and 1,562 h · ng/ml, respectively, and the median Cmaxs were 627 and 687 ng/ml, respectively. Systemic levels of exposure to d4T were comparable to those seen in children, suggesting that the pediatric dose of 1 mg/kg twice daily is appropriate for neonates at 2 to 4 weeks of age. Levels of exposure to ddI were modestly higher than those seen in children. Whether this observation warrants a reduction of the ddI dose in neonates is unclear.

Population pharmacokinetics of itraconazole in Thai HIV-1-infected persons

The authors describe the development of a population pharmacokinetic model using NONMEM for itraconazole and its active metabolite hydroxyitraconazole in a Thai cohort of HIV-infected patients who were using itraconazole as an addition to their antiretroviral therapy. The data were best described with an open two-compartment model for both itraconazole and hydroxyitraconazole. The model adequately described the data and provided population pharmacokinetic parameters which were not different from those described for other populations. The authors found that concomitant use of co-trimoxazole leads to a reduced formation rate (−51%) of hydroxyitraconazole.

Transtheoretical model and risky sexual behaviour in HIV + youth in Thailand

Abstract The purpose of the study was to determine the applicability of the Transtheoretical Model for predicting unprotected intercourse in HIV+ Thai youth. Questionnaires and interviews about sexual behaviour, readiness to change, self-efficacy, substance use, emotional distress and social support were obtained from 70 HIV+ Thai youth (ages 17 to 25). Path analysis suggested the model was an excellent fit with the data. Readiness to change but not self-efficacy was directly related to unprotected intercourse acts. This differed from HIV+ youth in the US where self-efficacy fully mediated the relationship between readiness to change and condom use. In the Thai sample, social support and self-efficacy were indirectly related to unprotected intercourse through stage of change. Substance use was unrelated to unprotected intercourse, but rates of use were low. Potential cultural differences in the construct of self-efficacy and its relationship to risky behaviours in Thailand require further study. However, results highlight the potential of prevention interventions that increase readiness to change through boosting self-efficacy and social support specific to practicing safer sex while addressing mental health concerns.

Dyslipidemia in an Asian population after treatment for two years with protease inhibitor-containing regimens.

There are limited data about dyslipidemia in Asian patients treated with combination antiretroviral therapy. To assess the relative association of different protease-inhibitor-containing regimens with the degree of dyslipidemia, fasting lipid levels were compared during 110 weeks in 250 nucleoside-experienced but protease-inhibitor-naïve Thai patients beginning treatment with 5 protease-inhibitor-containing regimens. Regimens were (1) stavudine, didanosine, and saquinavir; (2) zidovudine, lamivudine, and saquinavir; (3) zidovudine, lamivudine, and indinavir; (4) zidovudine, lamivudine, and ritonavir-boosted indinavir; and (5) efavirenz and ritonavir-boosted indinavir. Triglyceride levels were available for all patients; total cholesterol and high-densitylipoprotein cholesterol levels were available for patients receiving indinavir. The strongest predictors of dyslipidemia after beginning protease-inhibitor-based therapy were treatment regimen and baseline dyslipidemia. Triglycerides, total cholesterol, and high-density-lipoprotein cholesterol changes from baseline to week 110 were significant in patients taking ritonavir-boosted indinavir. Efavirenz and ritonavir-boosted indinavir were associated with significant high-density-lipoprotein cholesterol increases compared with other regimens. Non-stavudine-containing non-boosted protease-inhibitor-based highly active antiretroviral treatment regimens had the least association with dyslipidemia.

Poor quality of life among untreated Thai and Cambodian children without severe HIV symptoms

There are limited data on quality of life (QOL)1in untreated HIV-infected children who do not have severe HIV symptoms. Moreover, such data do not exist for Asian children. Poor QOL could be a factor in deciding if antiretroviral therapy (ART) should be initiated. Thai and Cambodian children (n=294), aged 1–11 years, naïve to ART, with mild to moderate HIV symptoms and CD4 15–24% were enrolled. Their caregivers completed the Pediatric AIDS Clinical Trials Group QOL questionnaire prior to ART commencement. Six QOL domains were assessed using transformed scores that ranged from 0 to 100. Higher QOL scores indicated better health. Mean age was 6.1 (SD 2.8) years, mean CD4 was 723 (SD 369) cells/mm3, 57% was female, and%CDC N:A:B was 2:63:35%. One-third knew their HIV diagnosis. Mean (SD) scores were 69.9 (17.6) for health perception, 64.5 (16.2) for physical resilience, 84.2 (15.6) for physical functioning, 77.9 (16.3) for psychosocial well-being, 74.7 (28.7) for social and role functioning, 90.0 (12.1) for health care utilization, and 87.4 (11.3) for symptoms domains. Children with CD4 counts above the 2008 World Health Organization (WHO) ART-initiation criteria (n=53) had higher scores in health perception and health care utilization than those with lower CD4 values. Younger children had poorer QOL than older children despite having similar mean CD4%. In conclusion, untreated Asian children without severe HIV symptoms had relatively low QOL scores compared to published reports in Western countries. Therapy initiation criteria by the WHO identified children with lower QOL scores to start ART; however, children who did not fit ART-initiation criteria and those who were younger also displayed poor QOL. QOL assessment should be considered in untreated children to inform decisions about when to initiate ART.

A feasibility study of immediate versus deferred antiretroviral therapy in children with HIV infection

ObjectiveTo evaluate the feasibility of a large immediate versus deferred antiretroviral therapy (ART) study in children.MethodsWe conducted an open-label pilot randomized clinical trial study in 43 Thai children with CD4 15 to 24% of starting generic AZT/3TC/NVP immediately (Arm 1) or deferring until CD4 < 15% or CDC C (Arm 2). Primary endpoints were recruitment rate, adherence to randomized treatment and retention in trial. Secondary endpoints were % with CDC C or CD4 < 15%. Children were in the trial until the last child reached 108 weeks. Intention to treat and on treatment analyses were performed.ResultsRecruitment took 15 months. Twenty-six of 69 (37.7%) were not eligible due mainly to low CD4%. Twenty four and 19 were randomized to arms 1 and 2 respectively. All accepted the randomized arm; however, 3 in arm 1 stopped ART and 1 in arm 2 refused to start ART. Ten/19 (53%) in arm 2 started ART. At baseline, median age was 4.8 yrs, CDC A:B were 36:7, median CD4 was 19% and viral load was 4.8 log. All in arm 1 and 17/19 in arm 2 completed the study (median of 134 weeks). No one had AIDS or death. Four in immediate arm had tuberculosis. Once started on ART, deferred arm children achieved similar CD4 and viral load response as the immediate arm. Adverse events were similar between arms. The deferred arm had a 26% ART saving.ConclusionAlmost 40% of children were not eligible due mainly to low CD4% but adherence to randomized treatment and retention in trial were excellent. A larger study to evaluate when to start ART is feasible.

In vivo cell-mediated immunity in subjects with undetectable viral load on protease inhibitor-based versus non-protease inhibitor-based highly active antiretroviral therapy.

To the Editor: Delayed hypersensitivity skin testing (DTH) is a widely available, cost-effective, and relatively easy-to-use tool for detection of cell-mediated immunity (CMI). A response to DTH signifies intact CMI, whereas a negative response may represent a possible defect in CMI or a lack of previous exposure. In HIV infection, DTH predicts clinical progression (1,2) and has been shown to correlate with CD4 cell count (1,3). Highly active antiretroviral therapy (HAART) has significantly improved clinical progression of HIV infection (4,5). HAART with protease inhibitors (PIs) has also rapidly restored immunologic abnormalities in HIV infection (6,7). Although studies have shown the virologic efficacy of non-PI HAART (8–10), data on the recovery of immunologic functions with these regimens is scarce. Indeed, it has been postulated by some that PI-based regimens may result in better immune reconstitution compared with regimens without PIs. In this prospective, nonrandomized, cross-sectional study, HIV-infected subjects with and without HAART were recruited between August 1 and September 30, 2001. Recruitment was done at the Thai Red Cross AIDS Research Center and the Immune Clinic at Chulalongkorn Hospital in Bangkok, Thailand. Inclusion criteria for subjects on HAART were viral load (VL) <50 copies/mL for at least 6 months and maintenance on one of these regimens: triple nucleoside reverse transcriptase inhibitor (NRTI), dual NRTI plus nonnucleoside reverse transcriptase inhibitor (NNRTI), or dual NRTI plus PIs during the period of viral suppression. HIV-infected untreated subjects served as controls. The most recent CD4 cell count within 6 months of the recruitment date was used. The multitest CMI (11) used in this study includes the following antigens: Candida, Trichophyton, Proteus mirabilis, old tuberculin, Streptococcus group C, diphtheria, and tetanus (MULTITEST CMI; Aventis Pasteur Thailand, Ltd, Thailand). The DTH was placed by trained personnel and read at 48 to 72 hours after placement by 2 immunologists. The average of combined horizontal and vertical diameters in millimeters represented the DTH response to each antigen. Subjects with response of 5 mm to tuberculin were advised to obtain chest radiography (CXR). Subjects with normal CXR were advised to take isoniazid for 9 months, whereas subjects with abnormal CXR were advised to visit their physician for further investigation for tuberculosis. The primary outcome was the summed DTH response, defined as the summation of induration in millimeters to each antigen divided by the number of antigens with induration. Furthermore, the percentage of subjects with intact CMI, defined as a positive DTH response ( 2 mm) to at least two antigens, and the ability of individual antigens to elicit a DTH response were investigated. For the groups of subjects compared (PI-HAART, non-PI–HAART, HAART-treated, and HAART-untreated), stratified analysis was performed based on a CD4 count of <350 or 350 cells/mm, according to the current recommendation for the initiation of HAART (12). Differences between groups were calculated using the Mann-Whitney U test at an value of 0.05. For three-group comparison, the Kruskal-Wallis H test was performed. Multiple linear regression was used to determine factors related to DTH response. A total of 142 subjects underwent DTH. Ninety-three subjects were treated with HAART, and 49 were untreated. Subjects on HAART were divided into a group of PI-HAART (n 22) and a group of non-PI–HAART (n 71; 10 triple NRTI and 61 dual NRTI plus NNRTI). There were significant differences between HAART-untreated and HAART-treated groups in age (younger in untreated group, 33.2 ± 7.9 years versus 38.1 ± 5.4 years in treated group; p < .01) and median CD4 cell count (lower in the <350 cells/mm strata for untreated subjects, 149 (53–225) versus 242 (176–291) for treated subjects; p < .002). Between the HAART-treated groups, baseline differences were Centers for Disease Control and Prevention (CDC) clinical class (more subjects in CDC class A for nonPI–HAART, 55.1% versus 22.7% for PI-HAART; p < .001) and time on HAART (longer for patients with PIs, 2.41 ± 0.7 years versus 1.67 ± 0.92 years without PIs; p < .01). Otherwise, the groups were well balanced. Table 1 demonstrates the summed DTH response and the percentages of subjects with intact CMI and with a positive old tuberculin test according to HAART status, CD4 categories, and treatment regimens. Overall, there was no statistically significant difference between the summed DTH response in subjects on HAART with and without PIs. This also applied when subjects were stratified within the <350 cells/mm and 350 cells/mm groups. The percentage of subjects with intact CMI was higher in the non-PI group, however. When comparing subjects on HAART with subjects without HAART, summed DTH response was significantly better in the CD4 <350 cells/mm category for subjects with HAART. Overall, DTH response and chance for intact CMI were significantly better in subjects who had CD4 350 cells/mm 3 compared with subjects with CD4 <350 cells/mm. In the univariate linear regression analysis, summed DTH response was significantly and positively associated with a viral load <50 copies/mL, the absolute CD4 cell count, and HAART. In the multivariable analysis, only the absolute CD4 cell count remained significantly and positively associated with the summed DTH response, although there was a trend for the association between summed DTH response and viral load <50 copies/mL (p .149). The antigens that elicited DTH response from largest to smallest were as follows: diphtheria, tetanus, old tuberculin, Candida, Proteus mirabilis, Streptococcus group C, and trichophyton. Our results show that the immune recovery measured by summed DTH response is independent of the HAART regimen. These findings are in accordance with recent studies showing that immune reconstitution achieved after therapy with a PIsparing or PI-containing regimen was similar (13) and independent of virologic efficacy (13,14). Summed DTH response in our study was positively associated with increasing CD4 cell count independent of the HAART regimen or any antiretroviral treatment. A positive correlation between CD4 cell count and JAIDS Journal of Acquired Immune Deficiency Syndromes 32:570–575