Torsak Bunupuradah

Pattern and Predictors of Immunologic Recovery in Human Immunodeficiency Virus-Infected Children Receiving Non-Nucleoside Reverse Transcriptase Inhibitor-Based Highly Active Antiretroviral Therapy

Background: Non-nucleoside reverse transcription inhibitor (NNRTI)-based highly active antiretroviral therapy (HAART) is the recommended first-line regimen for children in Thailand. This study was aimed to assess pattern and predictors of immune recovery in antiretroviral-naive Thai children starting NNRTI-based HAART. Methods: Records were extracted from clinical databases of 2 treatment cohorts in Thailand. The inclusion criteria were HIV-infected naive children who initiated NNRTI-based HAART when CD4 <25%. Immune recovery was defined as achieving a target CD4% of 25. The impact of age, gender, baseline clinical category, CD4 and HIV RNA titer, and regimen on immune recovery to weeks 96 was assessed using multiple logistic regression. Results: There were 274 patients (52% females) with a median baseline age of 7 (Interquartile range [IQR]: 4–9) years and a median CD4% of 5 (IQR: 1–12) who started treatment with nevirapine (66%) or efavirenz (34%) based HAART. Median duration of follow-up was 168 (IQR: 120–192) weeks. The median CD4% increase from baseline was 7% (IQR: 5–11) and 18% (IQR: 12–23) at weeks 24 and 96, respectively. The probability of reaching target CD4% was 51% (95% confidence interval: 45%–57%) by week 96. The predictors of immune recovery at week 96 were younger age, female gender, higher baseline CD4%, and sustained virologic suppression after week 24. Conclusion: In this cohort of children with low baseline CD4, half achieved immune recovery after 96 weeks of HAART. The predictors for immune recovery are younger children, female gender, high baseline CD4%, and long-term virologic suppression.

The immunogenicity and safety of live attenuated varicella-zoster virus vaccine in human immunodeficiency virus-infected children.

Background: The live attenuated varicella vaccine is recommended for HIV-infected children who are not severely immunosuppressed. This study aimed to assess the immunogenicity and safety of varicella vaccination among HIV-infected children who had severe immunosuppression before receiving antiretroviral therapy. Methods: Sixty HIV-infected children with no history of chickenpox or herpes zoster infection with CD4 T lymphocyte counts ≥15% or ≥200 cell/mm3 were enrolled. Two doses of varicella vaccine were administered at the time of enrollment and at 3 months. Varicella zoster virus (VZV) antibody was tested at baseline and 3 months after each dose by the enzyme-linked immunosorbent assay technique. An antibody titer >20 HU/mL was regarded as protective. Results: The median (interquartile range) of age, CD4 nadir, and current CD4 percentage were 11.2 (8.5–12.8) years, 9.5% (3–14), and 28% (22–32), respectively. Fifty-seven children (95%) received antiretroviral therapy for a median of 27 months. Among 34 children (57%) who were VZV seronegative at baseline, 11.8% (95% CI, 3.3%–27.5%) and 79.4% (95% CI, 62.1%–91.3%) were VZV seroconverted after first and second dose of vaccine, respectively. Children who had VZV seroconversion were more likely to have HIV RNA <1.7 copies/mL (92.6% vs. 71.4%, P = 0.18). Among 26 children who were seropositive at baseline, the geometric mean titers were increased from 56.7 to 107.9 and 134.6 unit/mL, respectively. Local and systemic reactions of grade 1 and 2 were reported in 13% and 4% of children, respectively. There was a trend toward better response among children with younger age, high CD4, and viral suppression. Conclusions: Administration of the 2 doses of varicella vaccine resulted in high seroconversion rates without serious adverse reactions. Varicella vaccination for HIV-infected children should be encouraged.

Double boosted protease inhibitors, saquinavir, and lopinavir/ritonavir, in nucleoside pretreated children at 48 weeks.

Objectives: To assess the 48-week efficacy, safety, pharmacokinetics, and resistance of double boosted protease inhibitors (PI), saquinavir (SQV), and lopinavir/ritonavir (LPV/r), in children who have failed nucleoside reverse transcription inhibitors /non-nucleoside reverse transcription inhibitors-based regimens. Methods: Fifty children at 2 sites in Thailand were treated with standard dosing of SQV and LPV/r. CD4, HIV-RNA viral load (VL), plasma drug concentrations and safety laboratory evaluations were monitored. Virologic failure was defined as having 2 consecutive VL >400 copies/mL after week 12 of therapy. Intention to treat analysis was performed. Results: Baseline data were a median age of 9.3 years (interquartile range [IQR]: 7.1–11.2), Center for Disease Control and Prevention (CDC) classification N:A:B:C 4%:14%:68%:14%, VL 4.8 log10 (IQR: 4.5–5.1), CD4 7% (IQR: 3–9.5). At 48 weeks, 3 had died of bacterial infection but no cases had progressed CDC classification. Median CD4% rise was 9 (IQR: 5–16) and median HIV RNA reduction was −2.8 log10 (IQR: −3.2 to −1.4), both P < 0.001. Thirty-nine (78%) and 32 (64%) children had VL <400 and <50 with significant differences between the 2 sites. Five children (10%) had VL failure as a result of poor adherence to the drug regimen but no one had major PI mutations. Median serum cholesterol and triglyceride increased significantly (+35 mg/dL, +37 mg/dL, respectively, both P < 0.001). Mean minimum plasma concentrations (Cmin) of LPV and SQV were 4.6 and 1.24 mg/L, respectively. Conclusions: Double boosted SQV/LPV/r resulted in significant CD4 rise and VL decline at 48 weeks. Hyperlipidemia was common. Cmin of both PIs exceeded therapeutic concentrations. Poor adherence caused failure in 10%. No major PI mutations were found.

Immunologic and virologic failure after first-line NNRTI-based antiretroviral therapy in Thai HIV- infected children

BackgroundThere are limited data of immunologic and virologic failure in Asian HIV-infected children using non-nucleoside reverse transcriptase inhibitor (NNRTI)-based highly active antiretroviral therapy (HAART). We examined the incidence rate of immunologic failure (IF) and virologic failure (VF) and the accuracy of using IF to predict VF in Thai HIV-infected children using first-line NNRTI-based HAART.MethodsAntiretroviral (ART)-naïve HIV-infected children from 2 prospective cohorts treated with NNRTI-based HAART during 2001-2008 were included. CD4 counts were performed every 12 weeks and plasma HIV-RNA measured every 24 weeks. Immune recovery was defined as CD4%≥25%. IF was defined as persistent decline of ≥5% in CD4% in children with CD4%<15% at baseline or decrease in CD4 count ≥30% from baseline. VF was defined as HIV-RNA>1,000 copies/ml after at least 24 weeks of HAART. Clinical and laboratory parameter changes were assessed using a paired t-test, and a time to event approach was used to assess predictors of VF. Sensitivity and specificity of IF were calculated against VF.Results107 ART-naive HIV-infected children were included, 52% female, % CDC clinical classification N:A:B:C 4:44:30:22%. Baseline data were median (IQR) age 6.2 (4.2-8.9) years, CD4% 7 (3-15), HIV-RNA 5.0 (4.9-5.5) log10copies/ml. Nevirapine (NVP) and efavirenz (EFV)-based HAART were started in 70% and 30%, respectively.At 96 weeks, none had progressed to a CDC clinical classification of AIDS and one had died from pneumonia. Overall, significant improvement of weight for age z-score (p = 0.014), height for age z-score, hemoglobin, and CD4 were seen (all p < 0.001). The median (IQR) CD4% at 96 weeks was 25 (18-30)%. Eighty-nine percent of children had immune recovery (CD4%≥25%) and 75% of children had HIV-RNA <1.7log10copies/ml.Thirty five (32.7%) children experienced VF within 96 weeks. Of these, 24 (68.6%) and 31 (88.6%) children had VF in the first 24 and 48 weeks respectively.Only 1 (0.9%) child experienced IF within 96 weeks and the sensitivity (95%CI) of IF to VF was 4 (0.1-20.4)% and specificity was 100 (93.9-100)%.ConclusionImmunologic failure, as defined here, had low sensitivity compared to VF and should not be recommended to detect treatment failure. Plasma HIV-RNA should be performed twice, at weeks 24 and 48, to detect early treatment failure.Trial RegistrationClinicaltrials.gov identification numberNCT00476606

Nucleoside Reverse Transcriptase Inhibitor Resistance Mutations Associated with First-Line Stavudine-Containing Antiretroviral Therapy: Programmatic Implications for Countries Phasing Out Stavudine

BACKGROUND The World Health Organization Antiretroviral Treatment Guidelines recommend phasing-out stavudine because of its risk of long-term toxicity. There are two mutational pathways of stavudine resistance with different implications for zidovudine and tenofovir cross-resistance, the primary candidates for replacing stavudine. However, because resistance testing is rarely available in resource-limited settings, it is critical to identify the cross-resistance patterns associated with first-line stavudine failure. METHODS We analyzed HIV-1 resistance mutations following first-line stavudine failure from 35 publications comprising 1,825 individuals. We also assessed the influence of concomitant nevirapine vs. efavirenz, therapy duration, and HIV-1 subtype on the proportions of mutations associated with zidovudine vs. tenofovir cross-resistance. RESULTS Mutations with preferential zidovudine activity, K65R or K70E, occurred in 5.3% of individuals. Mutations with preferential tenofovir activity, ≥ two thymidine analog mutations (TAMs) or Q151M, occurred in 22% of individuals. Nevirapine increased the risk of TAMs, K65R, and Q151M. Longer therapy increased the risk of TAMs and Q151M but not K65R. Subtype C and CRF01_AE increased the risk of K65R, but only CRF01_AE increased the risk of K65R without Q151M. CONCLUSIONS Regardless of concomitant nevirapine vs. efavirenz, therapy duration, or subtype, tenofovir was more likely than zidovudine to retain antiviral activity following first-line d4T therapy.

Use of taste-masking product, FLAVORx, to assist Thai children to ingest generic antiretrovirals

We evaluated whether FLAVORx helped thirty Thai children take opened capsule, crushed tablets and liquid generic ARVs with more ease. All children had excellent adherence, evaluated by PACTG Standard International Questionnaire and interviewing, before and after one month of FLAVORx. Eighty percent took ARV with more ease and wish to continue FLAVORx. Strawberry was the most popular flavor.

Etravirine and rilpivirine resistance in HIV-1 subtype CRF01_AE-infected adults failing non-nucleoside reverse transcriptase inhibitor-based regimens.

BACKGROUND We studied prevalence of etravirine (ETR) and rilpivirine (RPV) resistance in HIV-1 subtype CRF01_AE infection with first-line non-nucleoside reverse transcriptase inhibitor (NNRTI) failure. METHODS A total of 225 adults failing two nucleoside reverse transcriptase inhibitors (NRTIs) plus 1 NNRTI in Thailand with HIV RNA>1,000 copies/ml were included. Genotypic resistance results and HIV-1 subtype were interpreted by Stanford DR database. ETR resistance was calculated by the new Monogram weighted score (Monogram WS; ≥ 4 indicating high-level ETR resistance) and by DUET weighted score (DUET WS; 2.5-3.5 and ≥ 4 resulted in intermediate and reduce ETR response, respectively). RPV resistance interpretation was based on previous reports. RESULTS Median (IQR) age was 38 (34-42) years, 41% were female and CDC A:B:C were 22%:21%:57%. HIV subtypes were 96% CRF01_AE and 4% B. Antiretrovirals at failure were lamivudine (100%), stavudine (93%), nevirapine (90%) and efavirenz (10%) with a median (IQR) duration of 3.4 (1.8-4.5) years. Median (IQR) CD4(+) T-cell count and HIV RNA were 194 (121-280) cells/mm³ and 4.1 (3.6-4.6) log₁₀ copies/ml, respectively. The common NNRTI mutations were Y181C (41%), G190A (22%) and K103N (19%). The proportion of patients with Monogram WS score ≥ 4 was 61.3%. By DUET WS, 49.8% and 7.5% of patients were scored 2.5-3.5 and ≥4, respectively. Only HIV RNA ≥ 4 log₁₀ copies/ml at failure was associated with both Monogram WS ≥ 4 (OR 2.3, 95% CI 1.3-3.9; P=0.003) and DUET WS ≥ 2.5 (OR 1.9, 95% CI 1.1-3.3; P=0.02). The RVP resistance-associated mutations (RAMs) detected were K101P (1.8%), Y181I (2.7%) and Y181V (3.6%). All patients with RPV mutation had ETR resistance. No E138R/E138K mutations were detected. CONCLUSIONS Approximately 60% of patients had high-level ETR resistance. The role of ETR in second-line therapy is limited in late NNRTI failure settings. RVP RAMs were uncommon, but cross-resistance between ETR and RVP was high.

Prevalence and risk factors of low bone mineral density among perinatally HIV-infected Thai adolescents receiving antiretroviral therapy.

Background:Low bone mineral density (BMD) has been reported among 10%–54% of HIV-infected adolescents in developed countries. We studied the prevalence and predictors of low BMD among HIV-infected Thai adolescents receiving antiretroviral therapy. Methods:A cross-sectional study of lumbar spine (L2–L4) BMD as measured by dual-energy X-ray absorptiometry in Thai HIV-infected adolescents aged 12–20 years was performed. The BMD Z score was analyzed using age-matched healthy Thai children as a reference. Serum 25-hydroxyvitamin D was performed. Osteopenia was defined as BMD Z score ⩽ −2. Results:From October 2010 to February 2011, 101 adolescents, 50% male, with a median age of 14.3 (range: 13.0–15.7) years were enrolled. The median [interquartile range (IQR)] current CD4 T-cell count was 646 (506–796) cells per cubic millimeter and 90% had plasma HIV-1 RNA <50 copies per milliliter. The mean BMD among HIV-infected adolescents and controls were 0.855 and 0.980 g/cm2 (P < 0.001). The median (IQR) L2–L4 spine BMD Z score was −1.0 (−1.9 to −0.1), of which 24% had BMD Z score ⩽ −2.0. The median (IQR) of 25-hydroxyvitamin D level was 24.8 (20.0–31.4) ng/mL, of which 25% had vitamin D level < 20 ng/mL. In multivariate analysis, the height for age Z score < −1.5 (adjusted odds ratio: 6.2; 95% confidence interval: 2.2 to 17.7) and history of World Health Organization clinical stage 4 before antiretroviral therapy (adjusted odds ratio: 3.7; 95% confidence interval: 1.3 to 10.7) were significantly associated with osteopenia. Conclusion:One fourth of HIV-infected Thai adolescents have osteopenia. Children with history of advanced-staging or having low height for age are at risk of osteopenia. Preventive measures to prevent osteopenia should be incorporated in routine care for these adolescents.

Age at menopause and menopause-related symptoms in human immunodeficiency virus-infected Thai women.

Objective There are limited data for age at menopause (AM) and menopause-related symptoms in human immunodeficiency virus (HIV)–infected Asian women. We investigated AM and menopause-related symptoms in HIV-infected Thai women. Methods HIV-infected Thai women 40 years or older who did not receive any hormone therapy in the 8-week period preceding the study were enrolled. Participants completed the Menopause-Specific Quality of Life survey for their symptoms in the past 30 days. Menopause was defined as having the last menstrual period more than 1 year ago. Multivariate Cox proportional hazard regression analysis was used to identify factors associated with menopause. Results Two hundred sixty-eight HIV-infected women were enrolled; their median age was 44.6 (41.8-48.7) years, and the ratio of their Centers for Disease Control and Prevention clinical classifications (A:B:C) was 53%:34%:13%; 95% were using highly active antiretroviral therapy. The median (interquartile range [IQR]) CD4 count was 575 (437-758) cells/&mgr;L, and 93% had HIV-RNA of less than 1.7log10 copies/mL. Among the 55 women who had reached menopause, the mean (SD) AM was 47.3 (5.1) years. The mean (SD) AM in our study was earlier than the previous report of 49.5 (3.6) years in non–HIV-infected Thai women (difference, −2.2 y; 95% CI, −3.2 to −1.2, P < 0.01). Postmenopausal women had more symptoms, including night sweats (P = 0.03), change in sexual desire (P = 0.01), and avoiding intimacy (P = 0.01), compared with nonpostmenopausal women. No differences in psychosocial or physical domains between groups were found. Factors associated with menopause were Centers for Disease Control and Prevention clinical classification B or C (hazard ratio, 1.7; 95% CI, 1.0-3.03, P = 0.04), and no sexual act in the past month (hazard ratio, 4.9; 95% CI, 1.5-16.0, P = 0.01). No associations of later age of menarche, parity, marital status, educational level, income, body mass index, CD4 count, and HIV-RNA with menopause were found. Conclusions AM in HIV-infected Thai women was 47.3 years, which is significantly earlier than the findings of a previous AM report on non–HIV-infected women. Postmenopausal HIV-infected women had more vasomotor and sexual symptoms. More studies are needed to investigate the cause and appropriate interventions for accelerated menopause in HIV-infected women.

Pharmacokinetics and 48 week efficacy of low-dose lopinavir/ritonavir in HIV-infected children

BACKGROUND Lopinavir/ritonavir is a common protease inhibitor (PI) used for second-line regimens in children. Several studies have shown higher plasma concentrations of antiretroviral agents in Thai adults than in Caucasians, suggesting that lower doses may be used. METHODS An open label study in 24 HIV-infected children between the age of 2 and 18 years, naive to PIs, randomized to receive either the WHO-recommended dose of lopinavir/ritonavir or a low dose (70% of the standard dose) twice daily in combination with zidovudine and lamivudine. A 12 h pharmacokinetic study was done at 4-6 weeks after starting treatment. Treatment outcomes were evaluated at week 48. The clinical trial number of the study is NCT00887120. RESULTS The medians [interquartile ranges (IQRs)] of age, body surface area, percentage CD4 and plasma HIV RNA were 9.5 years (7.0-12.3), 0.9 m(2) (0.8-1.1), 17% (11%-24%) and 4.6 log(10) copies/mL (4.1-4.9), respectively. The median (IQR) lopinavir dose was 279 mg/m(2)/dose (263-294) and 194 mg/m(2)/dose (176-206) in the standard and low-dose arms, respectively. Median (IQR) AUC(0-12) and C(trough) of lopinavir were 117.6 mg.h/L (74.0-128.5) and 4.9 mg/L (2.7-8.0) for the standard arm and 83.8 mg.h/L (56.0-112.9) and 3.4 mg/L (2.7-5.4) for the low-dose arm. One child in the low-dose arm had a lopinavir pre-dose level of <1.0 mg/L. At week 48, the median percentage CD4 was 22% (15%-28%) and 27% (21%-31%) in the standard and low-dose arms, respectively, while 50% and 83% of children had HIV RNA <50 copies/mL, respectively (P = 0.19). CONCLUSIONS Low-dose lopinavir displayed adequate pharmacokinetic parameters and good efficacy as compared with standard-dose lopinavir in Thai children. A larger study to investigate the efficacy of low-dose lopinavir is warranted.