Sasiwimol Ubolyam

HIV increases markers of cardiovascular risk: results from a randomized, treatment interruption trial.

Objectives:Plasma soluble inflammatory molecules are associated with the risk of ischaemic cardiovascular events. We investigated whether HIV replication modified the levels of these proteins in a combination antiretroviral therapy (cART) interruption trial. Method and results:In 145 HIV-infected Thai patients (62% women, median CD4 cell count 271 cells/μl, median plasma HIV-RNA 4.66 log10 copies/ml) included in the Swiss–Thai–Australia Treatment Interruption Trial (STACCATO) trial, leptin, adiponectin, C-reactive protein, soluble vascular cell adhesion molecule-1 (s-VCAM-1), P-selectin, chemokine ligand 2, chemokine ligand 3, interleukin (IL)-6, IL-10, granulocyte macrophage colony-stimulating factor and D-dimer were measured before cART was initiated, after cART had suppressed HIV replication to less than 50 copies/ml plasma (median 8 months) and again 12 weeks after randomization to continued cART (n = 48) or interrupted cART (n = 97). Multiple linear regression and logistic regression were used to investigate the association between each cardiovascular marker and plasma HIV-RNA. Initiation of cART resulted in significant declines in s-VCAM-1, P-selectin, leptin and D-dimer, whereas mediators with anti-inflammatory properties, such as adiponectin and IL-10, increased. At 12 weeks after randomization, we found positive associations between levels of s-VCAM-1 and chemokine ligand 2 with an increase in plasma HIV-RNA (r = 0.271, P = 0.001 and r = 0.24, P = 0.005, respectively), whereas levels of adiponectin decreased for each 1 log increase in plasma HIV-RNA (r = −0.24, P = 0.002). Detectable IL-10 was less likely (odds ratio = 0.64, 95% confidence interval = 0.43–0.96) for each 1 log increase in plasma HIV-RNA. Conclusion:Plasma levels of several inflammatory, anti-inflammatory and endothelial activation markers of cardiovascular disease are associated with HIV-RNA replication.

Immunopathogenesis of hepatic flare in HIV/hepatitis b virus (Hbv)-coinfected individuals after the initiation of Hbv-active antiretroviral therapy

BACKGROUND The pathogenesis of and risk factors for hepatic flare (HF) after the initiation of hepatitis B virus (HBV)-active antiretroviral therapy (ART) in HIV/HBV-coinfected individuals is not well understood. METHODS We studied HF in ART-naive HIV/HBV-coinfected individuals in Thailand (n = 36) who were beginning HBV-active ART as part of a prospective clinical trial. HF was defined as an alanine aminotransferase (ALT) level>5 times the upper limit of normal or >200 IU/L higher than that at baseline. Immune mediators (interleukin [IL]-18, IL-2, IL-6, IL-8, IL-10, soluble CD26 [sCD26], sCD30, sCD8, CXCL-10, CCL-2, tumor necrosis factor-alpha, interferon [IFN]-gamma, and IFN-alpha) and activated NK cells were quantified. RESULTS HBV DNA and ALT levels at baseline were higher in patients with HF (n=8) than in patients without HF (n=28) (P=.01). After the initiation of ART, CXCL-10 levels remained elevated in patients with HF but decreased in patients without HF (P<.01). sCD30 levels increased and were significantly higher at week 8 in patients with HF (P<.05). There was a positive correlation between levels of ALT and levels of CXCL-10, sCD30, CCL-2, and IL-18 at week 8 (the time of peak ALT level) but not at other time points. CONCLUSION Elevated HBV DNA and ALT levels before the initiation of HBV-active ART are risk factors for HF. The pathogenesis of HF after the initiation of HBV-active ART is probably consistent with immune restoration disease.

Early versus deferred antiretroviral therapy for children older than 1 year infected with HIV (PREDICT): a multicentre, randomised, open-label trial

BACKGROUND The optimum time to start antiretroviral therapy for children diagnosed with HIV infection after 1 year of age is unknown. We assessed whether antiretroviral therapy could be deferred until CD4 percentages declined to less than 15% without affecting AIDS-free survival. METHODS In our multicentre, randomised, open-label trial at nine research sites in Thailand and Cambodia, we enrolled children aged 1-12 years who were infected with HIV and had CD4 percentages of 15-24%. Participants were randomly assigned (1:1) by a minimisation scheme to start antiretroviral therapy at study entry (early treatment group) or antiretroviral therapy to start when CD4 percentages declined to less than 15% (deferred treatment group). The primary endpoint was AIDS-free survival (based on US Centers for Disease Control and Prevention category C events) at week 144, assessed with the Kaplan-Meier analysis and the log-rank approach. This study is registered with ClinicalTrials.gov, number NCT00234091. FINDINGS Between March 28, 2006, and Sept 10, 2008, we enrolled 300 Thai and Cambodian children infected with HIV, with a median age of 6·4 years (IQR 3·9-8·4). 150 children were randomly allocated early antiretroviral therapy (one participant was excluded from analyses after withdrawing before week 0) and 150 children were randomly allocated deferred antiretroviral therapy. Median baseline CD4 percentage was 19% (16-22%). 69 children (46%) in the deferred treatment group started antiretroviral therapy during the study. AIDS-free survival at week 144 in the deferred treatment group was 98·7% (95% CI 94·7-99·7; 148 of 150 patients) compared with 97·9% (93·7-99·3; 146 of 149 patients) in the early treatment group (p=0·6). INTERPRETATION AIDS-free survival in both treatment groups was high. This low event rate meant that our study was underpowered to detect differences between treatment start times and thus additional follow-up of study participants or future studies are needed to answer this clinical question.

A randomized controlled 24-week study of intermittent subcutaneous interleukin-2 in HIV-1 infected patients in Thailand.

ObjectivesTo assess the immunological and virological effects, safety profile and feasibility of subcutaneous interleukin-2 (scIL-2) therapy in an HIV-infected Thai population. DesignSeventy-two patients with baseline CD4 cell count of ⩾ 350 × 106/l and no history of opportunistic infection were randomized to receive antiretroviral therapy plus scIL-2 (scIL-2 group) or antiretroviral therapy alone (control group). scIL-2 was administered at one of three doses for at least 24 weeks. The main measure of treatment efficacy was change in CD4 cell count. ResultsThe time-weighted mean change in CD4 cell count from baseline to week 24 was + 252 × 106/l for the scIL-2 group compared with + 42 × 106/l for the control group (P < 0.0001). Changes in plasma HIV RNA were not significantly different between the groups over the same time period: there was a 0.83 log10 copies/ml decrease for the scIL-2 group and a 0.70 log copies/ml decrease for the control group (P = 0.362). ConclusionsThis study provides the most extensive experience of scIL-2 therapy in HIV-1 infected women and Asians, and demonstrates the immunological efficacy, tolerability and feasability of scIL-2 therapy in this population. Data from this study were instrumental in guiding the selection of the scIL-2 dosing regimen for ongoing phase III trials.

Development of HIV with drug resistance after CD4 cell count-guided structured treatment interruptions in patients treated with highly active antiretroviral therapy after dual-nucleoside analogue treatment.

BACKGROUND For patients with human immunodeficiency virus (HIV) infection, structured treatment interruption (STI) is an attractive alternative strategy to continuous treatment, particularly in resource-restrained settings, because it reduces both side effects and costs. One major concern, however, is the development of resistance to antiretroviral drugs that can occur during multiple cycles of starting and stopping therapy. METHODS HIV genotypic drug resistance was investigated in 20 HIV-infected Thai patients treated with highly active antiretroviral therapy (HAART) and CD4 cell count-guided STI after dual nucleoside reverse-transcriptase inhibitor (NRTI) treatment. Resistance was tested at the time of the switch from dual-NRTI treatment to HAART and when HAART was stopped during the last interruption. RESULTS After STI, one major drug-resistance mutation occurred (T215Y), and, in the 4 samples with preexisting major mutations (D67N [n=2], K70R [n=2], T215Y [n=2], and T215I [n=1]), the mutations disappeared. All mutations in the HIV protease gene were minor mutations already present, in most cases, before STI was started, and their frequency was not increased through STI, whereas the frequency of reverse-transcriptase gene mutations significantly decreased after the interruptions. After the 48-week study period, no patients had virological failure. Long-term follow-up (108 weeks) showed 1 case of virological failure in the STI arm and 1 in the continuous arm. No virological failure was seen in patients with major mutations. CONCLUSIONS Major HIV drug-resistance mutations were not induced through CD4 cell count-guided treatment interruptions in HIV-infected patients successfully treated with HAART after dual-NRTI therapy.

A randomized, dose-finding study with didanosine plus stavudine versus didanosine alone in antiviral-naive, HIV-infected Thai patients.

ObjectivesTo evaluate the safety and efficacy of four different regimens of didanosine (ddI) + stavudine (d4T) in HIV-infected Thais. DesignProspective, open-label, randomized study. MethodsPatients were randomized to four regimens of high and low doses of ddI and d4T or to ddI alone. D4T was added to the ddI-alone arm after week 24. The duration of study was 48 weeks. ResultsSeventy-eight patients were randomized (mean CD4 cell count, 255 × 106/l; mean plasma HIV-1 RNA; 4.3 log10 copies/ml). In the intent-to-treat analysis, 78% of patients in the pooled combination arms and 20% of the patients in the ddI alone arm (to which d4T was added after 24 weeks) showed plasma HIV-1 RNA < 500 copies/ml at week 24 (P  < 0.001), and 59% versus 53% at week 48, respectively. In addition, the proportion of patients with < 50 HIV-1 RNA copies/ml was 13% versus 7% at week 24 (P  = 0.5) and 17% versus 20% at week 48 respectively. At week 24, median CD4 cell count increases from baseline were 101 × 106/l in the pooled combination versus 76 × 106/l in the ddI alone arm (P  = 0.78). Logistic regression modeling suggested a correlation between receiving high dose ddI and achieving HIV-1 RNA < 500 copies/ml at week 48 (P  = 0.07). ConclusionsThe d4T/ddI combination was superior to ddI alone in producing HIV-1 viral suppression. At week 48, > 60% of patients treated with this combination reached HIV-1 RNA levels < 500 copies/ml. Receiving high dose ddI but not d4T may correlate with a better viral suppression.

Comparisons between validated estimated glomerular filtration rate equations and isotopic glomerular filtration rate in HIV patients

Objective:Understanding how best to measure renal function in HIV-infected patients is critical because estimated glomerular filtration rate (eGFR) in HIV-infected patients can be affected by ethnicity and body composition. We validated the available eGFR equations and compared them to the plasma 99mTc-diethylenetriaminepentaacetic acid (99mTc-DTPA) clearance in HIV-infected patients. Design:Test of diagnostic accuracy. Methods:One hundred and ninety-six HIV-infected patients underwent measuring of 99mTc-DTPA plasma clearance, five creatinine-based eGFR equations, cystatin-C GFR, and 24-h urine creatinine clearance (CrCl). Results:Mean (SD) 99mTc-DTPA GFR was 117.7 ± 29.2 ml/min per 1.73 m2. The re-expressed Modification of Diet in Renal Disease (MDRD), Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI), re-expressed MDRD formula with Thai racial correction factor, Thai eGFR equation, Cockcroft–Gault equation, cystatin-C GFR, and 24-h urine CrCl underestimated the reference GFR. The bias estimated by the mean of differences (SD) for the re-expressed MDRD equation, CKD-EPI, re-expressed MDRD formula with Thai racial correction factor, Thai eGFR, Cockcroft–Gault equation, cystatin-C, and 24-h urine CrCl can be expressed as 18.9 ± 27.3, 11.1 ± 25.5, 6.2 ± 28.8, 15.4 ± 27.0, 30.4 ± 28.0, 3.2 + 36.1, and 5.0 ± 12.1 ml/min per 1.73 m2, respectively. Conclusion:The available eGFR equations underestimated GFR in HIV-infected adults. However, the eGFR by cystatin-C GFR was the most precise and accurate. Among creatinine-based eGFR equations, re-expressed MDRD formula with Thai racial correction factor was the most precise and accurate. The racial factor for each ethnicity is important and the existing eGFR equation should be validated before using it in the HIV population.

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.

EVIDENCE OF THREE HIV-1 SUBTYPES IN SUBGROUPS OF INDIVIDUALS IN THAILAND

It has been well established through genotyping that there are two distinct HIV-1 subtypes circulating in Thailand E and B(Thai). By peptide enzyme immunoassay sera from HIV-1 infected heterosexual homosexual/bisexual and IV drug using (IVDU) Thais were assayed against V(3) loop peptides. 8 of the 20 sera from homosexuals 3 of the 13 sera from bisexuals 17 of the 20 sera from heterosexuals and 14 of the 16 sera from IVDUs were typable as either E or B(Thai) strains. To determine the possibility of other HIV-1 strains in the untypable specimens in particular from the homosexual/bisexual groups the V(3) peptide of the HIV-1(MN) strain was used in analysis. The initially untypable sera from homosexual bisexual heterosexual and IVDU individuals were identified as MN serotype in 9 of 12 8 of 10 1 of 3 and 2 of 2 respectively. Subtypes E B(Thai) and B(MN) were found predominantly in heterosexual (75%) IVDUs (75%) and homosexual/bisexual (52%) individuals respectively. The authors believe that this is the first evidence of the association of the B(MN) subtype in Thai homosexual/bisexual individuals. It is currently being investigated whether there are other strains in the untypable sera whether the GPGR motif will be found in HIV-1 isolates circulating in most of the homosexual/bisexual individuals and whether superinfection in the dual reactive specimens is possible.

Efavirenz, in contrast to nevirapine, is associated with unfavorable progesterone and antiretroviral levels when coadministered with combined oral contraceptives.

Background:Effective contraception has been widely promoted for HIV-positive women. However, there are limited data on the interactions between combined hormonal contraceptives and nonnucleoside reverse transcriptase inhibitors . Methods:This study assessed the steady-state contraceptive effectiveness and safety of combined oral contraceptive (COC) containing 0.150 mg desogestrel /0.030 mg ethinyl estradiol with either nevirapine (NVP) or efavirenz (EFV) in 34 HIV-positive women. The targeted level for contraceptive effectiveness was endogenous progesterone level < 3.0 ng/mL. We measured NVP/EFV plasma concentrations 12 hours after administration (C12) with and without COC. The desired therapeutic levels were >3.1 mg/L for NVP and 1.0–4.0 mg/L for EFV, respectively. Results:All 18 subjects in the NVP group had serum progesterone <1.0 ng/mL. Four of 16 subjects (25%) in the EFV group had serum progesterone >1.0 ng/mL, including 3 subjects with >3.0 ng/mL (might indicate ovulation). The difference in progesterone levels between the 2 groups was statistically significant (P = 0.04). The median C12 of NVP increased insignificantly by 17% with COC; the median C12 of EFV decreased significantly (P = 0.02) by 22%. In 3 of 16 subjects (19%) in the EFV group, C12 of EFV dropped below 1.0 mg/L. Conclusions:In contrast to NVP, coadministrating desogestrel/ethinyl estradiol containing COC with EFV was associated with unfavorable progesterone and antiretroviral levels. Our results suggest that NVP may be superior to EFV when used with COC in HIV-positive women.