Showing papers by "David A. Cooper published in 2005"

In Vivo, Nucleoside Reverse-Transcriptase Inhibitors Alter Expression of Both Mitochondrial and Lipid Metabolism Genes in the Absence of Depletion of Mitochondrial DNA

Abstract: Background: Nucleoside reverse-transcriptase inhibitors (NRTIs), which are used to treat human immunodeficiency virus (HIV) infection, can cause mitochondrial dysfunction and have been associated with lipoatrophy. The effects of this mitochondrial dysfunction on lipid metabolism, at a molecular level in vivo, have not been described. Methods: We examined early changes (by 2 weeks after initiation of therapy) in expression of mitochondrial and nuclear genes in adipose tissue from 20 HIV-negative subjects randomized to receive dual-NRTI therapy (zidovudine/lamivudine or stavudine/lamivudine) for 6 weeks. Results: We observed decreased transcription of mitochondrial (mt) RNA without significant depletion of mtDNA. Decreases in mtRNA coincided with simultaneous up-regulation of nuclear genes involved in transcriptional regulation of mtRNA (NRF1 and TFAM) and oxidation of fatty acids (PPARA and LPL), whereas PPARG, which is important for differentiation of adipose tissue, was down-regulated. Many nuclear changes correlated with changes in peroxisome proliferator–activated receptor–g coactivator–1 (PGC1), suggesting a central role for PGC1 in nuclear responses to mitochondrial dysfunction. Expression of peripheral blood monocyte mtRNA also decreased, suggesting that monocytes may be surrogates for NRTI-induced mitochondrial dysfunction in other tissues. Conclusions: Independent of HIV, NRTIs decrease transcription of mtRNA in vivo. The absence of depletion of mtDNA suggests that NRTIs cause mitochondrial dysfunction by means other than through inhibition of DNA polymerase-g, whereas disruption of expression of lipid metabolism genes offers an explanation forNRTI-induced lipoatrophy.

Durable efficacy of enfuvirtide over 48 weeks in heavily treatment-experienced HIV-1-infected patients in the T-20 versus optimized background regimen only 1 and 2 clinical trials

Abstract: BACKGROUND The T-20 Versus Optimized Background Regimen Only (TORO) 1 and TORO 2 clinical trials are open-label, controlled, parallel-group, phase 3 studies comparing enfuvirtide plus an optimized background (OB) of antiretrovirals (n = 661) with OB alone (n = 334) in treatment-experienced HIV-1-infected patients. METHODS The primary objective at week 48 was to investigate durability of efficacy, as measured by the percentage of patients maintaining their week 24 response or improving. Efficacy analyses used the intent-to-treat population. RESULTS A total of 73.7% of patients randomized to the enfuvirtide group remained on treatment through week 48 versus 21.3% originally randomized to the control group. At week 48, a higher proportion of week 24 responders maintained their response or were new responders in the enfuvirtide group than in the control group in each responder category: HIV-1 RNA level > or =1.0 log(10) change from baseline, <400 copies/mL and <50 copies/mL (37.4%, 30.4%, and 18.3% in the enfuvirtide group vs. 17.1%, 12.0%, and 7.8% in the control group, respectively; P < 0.0001 for all comparisons). CD4 cell count increases from baseline were twice as great in the enfuvirtide group as in the control group. CONCLUSION These data demonstrate durable efficacy of enfuvirtide plus OB over 48 weeks.

The TREAT Asia HIV Observational Database: baseline and retrospective data.

Abstract: TREAT Asia (Therapeutics Research, Education, and AIDS Training in Asia) Asia is a cooperative network of clinicians throughout Asia and the Pacific that aims to expand the capacity for broader introduction of HIV/AIDS treatments in the region. The TREAT Asia HIV Observational Database (TAHOD) is the first collaborative study by the TREAT Asia network. At present, there are relatively few data available regarding HIV disease in the Asia and Pacific region. It is known that the natural history of HIV is different in certain respects in the region compared with Western countries; for example, higher rates of tuberculosis in HIV-infected patients have been reported from the Asia and Pacific region.1,2 The objectives of this article are, first, to describe the TAHOD working procedure and methods; second, to summarize baseline data on patients so far recruited to the TAHOD; and third, using baseline and retrospective data, to assess the rate of decline in CD4 count in untreated patients and the CD4 and viral load response in patients receiving antiretroviral treatment.

Prolonged transcriptional silencing and CpG methylation induced by siRNAs targeted to the HIV-1 promoter region.

Abstract: In addition to the degradation of homologous RNAs through the RNA interference (RNAi) pathway, small interfering RNAs (siRNAs) can in some systems induce cytosine methylation and transcriptional silencing of homologous promoters. Targeting of HIV-1 by RNAi results in transient suppression of the virus through degradation of viral transcripts. In an effort to prolong the suppressive effect of siRNAs on productive HIV-1 infection, we targeted conserved tandem NF-
B binding motifs in the viral LTR. A 21-nucleotide-RNA duplex induced marked and durable (at least 30 days) suppression of productive HIV-1 infection in chronically infected MAGIC-5 cells. This suppression is associated with CpG methylation within the 5’LTR and marked reduction of HIV-1 transcription in nuclear run-on assays. We then assessed three additional siRNAs targeting other sites within the HIV-1 promoter region. These siRNAs suppressed HIV-1 infection to different extents and the degree of suppression correlated with the extent of de novo methylation of CpG motifs within the HIV-1 promoter region. These findings indicate that HIV-1 can be silenced by an RNA-directed mechanism that suppresses transcription and induces CpG methylation. In addition to providing evidence that this RNA-directed DNA methylation is active in mammalian cells, this is the first report of prolonged suppression of HIV-1 infection induced by siRNA.

Impact of Therapeutic Immunization on HIV-1 Viremia after Discontinuation of Antiretroviral Therapy Initiated during Acute Infection

Abstract: BACKGROUND Treatment strategies that would induce durable virological control of human immunodeficiency virus (HIV)-1 in the absence of continued antiretroviral therapy (ART) are highly desirable.METHODS. We assessed, in a randomized, double-blind, placebo-controlled trial, whether the addition of therapeutic vaccines (ALVAC-HIV [vCP1452] or ALVAC-HIV and Remune) to ART initiated during acute infection could increase the probability of having a plasma viral load

Iatrogenic Cushing's syndrome with osteoporosis and secondary adrenal failure in human immunodeficiency virus-infected patients receiving inhaled corticosteroids and ritonavir-boosted protease inhibitors: six cases.

Abstract: Ritonavir, a protease inhibitor (PI), is a potent inhibitor of cytochrome P450 3A4. This pharmacological effect, even at low doses (

Long‐term survival and concomitant gene expression of ribozyme‐transduced CD4+ T‐lymphocytes in HIV‐infected patients

Abstract: Background An anti-HIV-1 tat ribozyme, termed Rz2, has been shown to inhibit HIV-1 infection/replication and to decrease HIV-1-induced pathogenicity in T-lymphocyte cell lines and normal peripheral blood T-lymphocytes. We report here the results of a phase I gene transfer clinical trial using Rz2. Methods Apheresis was used to obtain a peripheral blood cell population from each of four HIV-negative donors. After enrichment for CD4+ T-lymphocytes, ex vivo expansion and genetic manipulation (approximately equal aliquots of the cells were transduced with the ribozyme-containing (RRz2) and the control (LNL6) retroviral vector), these cells were infused into the corresponding HIV-1-positive twin recipient. Marking was assessed over an initial 24-week period and in total over an approximate 4-year period. Results The gene transfer procedure was shown to be safe, and technically feasible. Both RRz2- and LNL6-gene-containing peripheral blood mononuclear cells (PBMC) were detected at all time points examined to 4 years. There was concomitant gene construct expression in the absence of the need for ex vivo peripheral blood cell stimulation and there was no evidence of immune elimination of the neoR T-lymphocytes nor of silencing of the Moloney murine leukemia virus long terminal repeat. Conclusions The proof of principle results reported here demonstrate safety and feasibility of this type of gene transfer approach. While not specifically tested, T-lymphocytes containing an anti-HIV gene construct may impact on HIV-1 viral load and CD4+ T-lymphocyte count, potentially representing a new therapeutic modality for HIV-1 infection. Copyright © 2005 John Wiley & Sons, Ltd.

Paradoxical CD4+ T-cell decline in HIV-infected patients with complete virus suppression taking tenofovir and didanosine.

Abstract: BACKGROUND: Tenofovir (TDF) and didanosine (ddI) are both adenosine analogues with convenient posology, strong potency and a relatively high genetic barrier for resistance. The popularity of this combination, however, has been questioned due to concerns about pharmacokinetic interactions and increased risk of pancreatitis and hyperglycemia. Less information is available about other possible side effects. PATIENTS AND METHODS: HIV-infected individuals who initiated a protease inhibitor-sparing regimen between September 2002 and June 2003 at five hospitals, and had at least one subsequent visit within the next 12 months, always with complete virus suppression, were retrospectively assessed. Only drug-naive individuals and patients who simplified a prior successful antiretroviral regimen were analysed. RESULTS: Outcomes were analysed in 570 individuals according to treatment modality (98 drug-naive versus 472 simplified); the nucleoside analogue (NA) backbone (298 with TDF + ddI, 88 with ddI, 44 with TDF, and 140 with neither ddI nor TDF); and the third agent used (378 with non-nucleoside analogues versus 192 with NA). Significant CD4+ T-cell declines were seen in patients taking ddI + TDF with respect to all other NA combinations, including ddI or TDF separately. Patients exposed to high ddI doses or taking a third NA showed more pronounced CD4 declines. Plasma levels of ddI correlated with the extent of CD4+ T-cell loss. CONCLUSION: Patients receiving ddI + TDF-based combinations show CD4+ T-cell declines despite achieving complete virus suppression. This effect generally progresses with time. An imbalance in adenosine metabolites within CD4+ T lymphocytes may explain this phenomenon, which resembles the genetic purine nucleoside phosphorylase deficiency syndrome.

Incidence and risk factors for rash in Thai patients randomized to regimens with nevirapine, efavirenz or both drugs.

Abstract: Objective: To determine the incidence and risk factors for rash in Thai patients taking four different non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens. Methods: HIV-positive antiretroviral-naive patients enrolled in the 2NN study in Thailand and followed for at least 1 week were included. Patients were randomized to efavirenz (EFV) 600 mg once daily (OD) versus nevirapine (NVP) 200 mg twice daily (BD) versus NVP 400 mg (OD versus NVP 400 mg OD + EFV 800 mg OD with stavudine/lamivudine. Results: Of 202 patients 95 (47%) and 69 (34.2%) developed a rash from all reasons and from NNRTI respectively. For NNRTI-related rash the incidence were EFV (20%) NVP BD (21%) NVPOD (38%) and NVP + EFV (67%). The proportions of patients with grade I II and III within the four treatment arms are as follows: EFV 4.3 13 and 2.9%; NVP BD 2.3 5.9 and 2.3%; NVP OD 12.8 19.1 and 6.4%; and NVP + EFV 11.9 47.6 and 7.1%. Multivariate analyses showed females with CD4 cell count =250 x 10(6) cells/l high body mass index (>21.3 kg/m(2) and a rise in CD4 (=53 x 10(6) cells/l) and alanine aminotransferase (ALT) (=34 U/l) at week 4 to be risk factors for rash. Conclusions: Thai patients had a high incidence of NNRTI- related rash when treated with NVP + EFV or NVP OD. NVP if used BD had the same rash incidence as EFV for rash of all grades. Females and persons with earlier HIV disease or with a large rise in CD4+ cell count after starting therapy are at greater risk for NNRTI-related rash. (authors)

Safety of enfuvirtide in combination with an optimized background of antiretrovirals in treatment-experienced HIV-1-infected adults over 48 weeks.

Abstract: Background: Antiretroviral tolerability is a critical factor contributing to treatment outcome. The T-20 Versus Optimized Background Regimen Only (TORO) studies assessed the safety and efficacy of enfuvirtide in treatment-experienced HIV-1-infected patients. Methods: A total of 997 patients were randomized at a 2:1 ratio to an optimized background antiretroviral regimen plus enfuvirtide (n = 663) or an optimized background regimen alone (control group; n = 334). Control patients could switch to enfuvirtide on virologic failure. Results: In total, 26.5% of patients randomized to enfuvirtide and 36.6% to the control group discontinued study treatment before week 48; the percentage of patients withdrawn for safety reasons (including adverse events [AEs], deaths, and laboratory abnormalities) was 14.0% in the enfuvirtide group and 11.6% in the control group. Injection site reactions (ISRs) occurred in 98% of enfuvirtide patients and led to treatment discontinuation in 4.4%. Treatment-related (defined as possibly, probably, or remotely) AE rates per 100 patient-years were lower with enfuvirtide (96.2) than in the control group (149.9); diarrhea, nausea, and fatigue, the most frequently reported AEs, were significantly less frequent with enfuvirtide than in the control group. Pneumonia was significantly more frequent in patients treated with enfuvirtide (6.7 vs. 0.6 events per 100 patient-years), although the incidence was within expected ranges for this population. Lymphadenopathy was also higher in enfuvirtide-treated patients (7.1 vs. 1.2 events per 100 patient-years) for control patients. Conclusion: The addition of enfuvirtide to an optimized background regimen does not exacerbate AEs commonly associated with antiretrovirals. ISRs limited treatment in <5% of patients.

A prospective, randomized trial of structured treatment interruption for patients with chronic HIV type 1 infection

Abstract: BACKGROUND: Structured treatment interruption was evaluated in 74 patients who had been pretreated with antiretrovirals, consisting of 2 nucleoside reverse-transcriptase inhibitors (NRTIs) for 1 year followed by 3 years of highly active antiretroviral therapy containing a protease inhibitor. METHODS: Patients with a CD4 cell count of > or =350 cells/microL and a plasma viral load of or =350 cells/microL. Intergroup differences were analyzed using analysis of variance and Kruskal-Wallis tests. RESULTS: Baseline characteristics at the start of the structured treatment interruption were similar. At week 48, no patient had died, and 1 patient in the WOWO group had an AIDS-defining condition. The proportions of patients with a CD4 cell count of > or =350 cells/microL were 100%, 87%, and 96% in treatment arms 1, 2, and 3, respectively. The percentages of weeks of antiretroviral use were 100%, 41.1%, and 69.8% in arms 1, 2, and 3, respectively. The adverse events were not significantly different among arms (P=.27). Thirty-one percent of patients in the WOWO group experienced virological failure. CONCLUSION: WOWO therapy maintained a CD4 cell count of > or =350 cells/microL in almost all patients but was associated with high virological failures rates (possibly resulting from previous dual-NRTI therapy), indicating that this strategy is less useful. Receipt of CD4 cell count-guided therapy resulted in comparable clinical outcomes to continuous therapy and may save antiretroviral-associated costs, but this needs to be confirmed by a larger trial.

Buffalo hump seen in HIV-associated lipodystrophy is associated with hyperinsulinemia but not dyslipidemia.

Abstract: Accumulation of dorsocervical fat, or a "buffalo hump" (BH), is commonly reported in adults with HIV-associated lipodystrophy (HIVLD). The pathogenesis underlying this aspect of a syndrome characterized by loss of subcutaneous fat from other body sites is poorly understood. We aimed to identify risk factors for a BH in HIV-infected adults in cross-sectional analyses of 2 HIV-infected ambulatory populations. The first group (Australian Lipodystrophy Prevalence Survey [APS]) consisted of 1348 Australian HIV-infected adults (95% male) irrespective of changes in body composition. The second group (Lipodystrophy Case Definition [LDCD] study) comprised 417 subjects (83% male) with at least 1 reported moderate or severe feature of HIVLD. A BH was reported in 24 (2%) APS subjects and 79 (19%) LDCD study subjects. A BH was not an isolated finding. Patients with a BH had a high prevalence of other features of HIVLD, similar to lipodystrophic patients without a BH, such as facial lipoatrophy reported in 100% and 61% BH-positive subjects from the APS and LDCD study, respectively. In both groups, those with a BH had higher fasting insulin (P

Atazanavir trough plasma concentration monitoring in a cohort of HIV-1-positive individuals receiving highly active antiretroviral therapy

Abstract: Objectives: Atazanavir is a recently approved HIV protease inhibitor (PI). As with other PIs, careful attention to potential pharmacokinetic drug interactions in clinical practice is necessary. The aim of this study was to assess the clinical associations with plasma atazanavir concentrations in HIV-positive individuals. Methods: Individuals established on an atazanavir-containing regimen, completed an intervieweradministered questionnaire recording atazanavir dosing characteristics, concomitant medication use and adherence. After completion, plasma atazanavir concentrations were measured. Results: Of 100 individuals, mean trough plasma atazanavir concentrations (mg/L) were 282 (95% CI 95–468, n = 19) and 774 (95% CI 646–902, n = 81) in those on non- and ritonavir-boosted atazanavir regimens, respectively. Eighty-five individuals had HIV RNA <50 copies/mL. Seven individuals had atazanavir plasma concentrations below the assay limit of detection (<50 mg/L), all of whom had undetectable plasma HIV RNA. In a multivariate analysis, nevirapine use was associated with significantly lower trough atazanavir concentrations (P = 0.011) and lopinavir/ritonavir use with higher trough atazanavir concentrations (P = 0.032). Dosing characteristics (including food taken), concomitant medications (including drugs used for dyspepsia) and HIV RNA were not significantly associated with trough atazanavir concentrations. Conclusions: In this cohort, despite the wide inter-individual variability of atazanavir trough concentrations, no significant association with dosing characteristics, concomitant medication (with the exception of nevirapine and lopinavir/ritonavir) or virological response was observed. Further work is needed to assess the optimal dosing regimen when using atazanavir with nevirapine.

Nevirapine plasma concentrations and concomitant use of rifampin in patients coinfected with HIV-1 and tuberculosis.

Abstract: Objectives: In countries with high numbers of HIV/tuberculosis coinfection nevirapine and rifampin are used extensively. However, limited data are available about whether or not nevirapine and rifampin can be safely coadministered without the plasma concentration of nevirapine falling below therapeutic levels. Methods: Blood samples for determination of nevirapine plasma concentrations were collected from patients using nevirapine 200 mg twice daily with or without concomitant rifampin. Bivariate and multivariate linear regression models were used to investigate factors possibly related to nevirapine concentrations. Results: We received 74 blood samples from patients using nevirapine plus rifampin, and collected blood samples from an equal number of controls using nevirapine only. Groups were similar for age, gender, weight, height and body mass index (BMI). In the rifampin group the mean nevirapine concentration was 5.47 ±2.66 mg/l, whereas in the control group the mean nevirapine concentration was 8.72 ±3.98 mg/l. In the rifampin group seven nevirapine trough concentrations were low ( 3.1 mg/l. Our results suggest that from a pharmacological point of view the majority of Thai coinfected patients, who have low BMIs, reach nevirapine plasma concentrations that are adequate for treatment of HIV. However this can only be undertaken if nevirapine plasma concentration monitoring is available and can be closely followed.

The use of a triple nucleoside-nucleotide regimen for nonoccupational HIV post-exposure prophylaxis

Abstract: Objectives Nonoccupational post-exposure prophylaxis (NPEP) for HIV is recommended after high-risk sexual exposure. Because of the high incidence of intolerable side effects observed with protease inhibitor- and zidovudine-based NPEP regimens, our unit changed standard NPEP treatment to 28 days of tenofovir-lamivudine-stavudine (TDF-3TC-d4T). The aim of this study was to compare side effects and numbers of individuals completing NPEP before and after this change. Methods Parameters were compared amongst individuals commencing the following NPEP regimens: zidovudine-lamivudine (ZDV-3TC), zidovudine-lamivudine-nelfinavir (ZDV-3TC-NFV) and TDF-3TC-d4T. Results A total of 385 individuals received ZDV-3TC (n=36), ZDV-3TC-NFV (n=225) or TDF-3TC-d4T (n=137) as NPEP for the first time between June 1999 and November 2003. Noncompletion rates were 25%, 32% and 15%, respectively (P=0.001), with odds ratios for noncompletion being 2.0 [95% confidence interval (CI) 0.8–4.8] and 2.7 (95% CI 1.6–4.8) in the first two groups compared with the TDF-3TC-d4T group (P=0.008). Adverse events were less common in the TDF-3TC-d4T group, with significantly lower rates of nausea and headache, but significantly higher rates of peripheral neuropathy and asymptomatic raised transaminases. There was no HIV seroconversion in any group. Conclusions TDF-3TC-d4T is significantly better tolerated than ZDV-3TC or ZDV-3TC-NFV as NPEP and results in greater numbers of individuals completing 28 days of treatment.

Pharmacokinetics of reduced-dose indinavir/ritonavir 400/100 mg twice daily in HIV-1-infected Thai patients.

Abstract: OBJECTIVE: To study the pharmacokinetics of indinavir/ ritonavir 400/100 mg twice daily in antiretroviral-naive patients at Srinagarind Hospital in Khon Kaen, Thailand. METHODS: This was a steady-state, open-label pharmacokinetic study of 19 patients. A 12 h pharmacokinetic curve was recorded after an overnight fast. Plasma levels of indinavir and ritonavir were determined by a validated HPLC method. Virological failure was defined according to the most recent US Department of Health and Human Services guidelines as a viral load above 400 copies/ml at week 24. RESULTS: Median baseline values for CD4 and viral load were 13cells/mm3 and 167000 copies/ml, respectively. The median (interquartile ranges) for indinavir AUC, Cmax and Cmin were 18.1 (15.3-23.8) mg/l x h, 4.1 (3.6-4.8) mg/l and 0.17 (0.12-0.30) mg/l, respectively. These values represent 37%, 39% and 24% of the AUC, Cmax and Cmin values found, respectively, for the indinavir/ritonavir 800/100 mg dose in HIV-1-infected Thai patients. Short-term virological response was satisfactory. There were three subjects with an indinavir Cmin. below the target value of 0.10 mg/l, of whom one had virological failure (33%). Among the other 16 subjects with an indinavir Cmin above 0.10 mg/l, there was also one virological failure (6%) (P=0.30). CONCLUSIONS: Indinavir exposure in this reduced-dose regimen of 400 mg with 100 mg ritonavir twice daily was more than dose-proportionally lower than previously observed with the indinavir/ritonavir 800/100 mg twice daily regimen. Therapeutic Cmin levels of indinavir were achieved in >80% of the subjects and short-term virological response was satisfactory in this cohort of patients starting highly active antiretroviral therapy at an advanced disease stage with high baseline viral loads.

Highly active antiretroviral therapy (HAART) retreatment in patients on CD4-guided therapy achieved similar virologic suppression compared with patients on continuous HAART: the HIV Netherlands Australia Thailand Research Collaboration 001.4 study.

Abstract: OBJECTIVE: To assess the safety of 2 intermittent treatment strategies compared with continuous therapy for patients with virologic suppression on highly active antiretroviral therapy (HAART) at baseline DESIGN: Seventy-four nucleoside reverse transcriptase inhibitor (NRTI) and protease inhibitor (PI) pretreated patients with an HIV RNA level 350 cells/microL and HIV RNA level <400 copies/mL at week 108 METHODS: Patients were followed up every 12 weeks for CD4 count, HIV RNA level, and clinical and laboratory toxicities In the CD4-guided arm, treatment was stopped and restarted using a CD4 count threshold (above or below 350 cells/microL or reduction of 30%) RESULTS: Seventy-four patients were enrolled with a median CD4 count of 644 cells/microL before the structured treatment interruption (STI) The week-on-week-off arm (n=26) was discontinued at week 72 because of high rates (46%) of HIV RNA rebound above 50 copies/mL In the continuous arm, 25 (100%) of 25 patients and 24 (96%) of 25 patients had an HIV RNA level <400 copies/mL and <50 copies/mL, respectively, at week 108, and 96% had a CD4 count above 350 cells/microL, with a median CD4 count of 661 cells/microL Patients in the CD4-guided arm had a significantly lower median CD4 count (489 cells/microL) than the patients in the continuous arm (P=003), but all had a CD4 count above 350 cells/microL and 1 had a new HIV-related illness At week 108, 21 (91%) of 23 patients and 13 (57%) of 23 patients had an HIV RNA level <400 copies/mL and <50 copies/mL, respectively Those who did not achieve an HIV RNA level <50 copies/mL had a higher HIV RNA load before retreatment, and 4 of 5 patients subsequently achieved viral suppression after an additional 12 weeks of HAART (week 120) Therefore, 17 (94%) of 18 evaluable CD4-guided arm patients achieved viral suppression after retreatment Antiretroviral (ARV) side effects were similar in all arms CD4-guided treatment had a 54% ARV cost savings CONCLUSIONS: This pilot study suggests that CD4-guided HAART is a well-tolerated and cost-saving treatment strategy for patients with high pre-ARV and pre-STI CD4 counts Week-on-week-off treatment had a high virologic failure rate and was discontinued The HIV RNA suppression rate was similar in patients treated with continuous HAART and in those retreated with 12 to 24 weeks of HAART after CD4-guided therapy

A new variant cytotoxic T lymphocyte escape mutation in HLA-B27-positive individuals infected with HIV type 1.

Abstract: The immune response in HIV-infected individuals who carry HLA-B27 is characterized by an immunodominant cytotoxic T lymphocyte (CTL) response to a conserved epitope corresponding to amino acids 263–272 of HIV-1 p24 gag. The arginine at position 264 is a crucial anchor residue. Amino acid substitution at 264 from arginine (R) to glycine (G), lysine (K), or threonine (T) results in a low affinity peptide that binds to HLA-B27 inefficiently and is poorly recognized by T cells that respond to the wild-type peptide. These mutants have been characterized as CTL escape mutations. We studied the plasma virus of 20 HLA-B27 longterm nonprogressors: 14 were wild type and 6 were found to be mutant. Five of these carried known escape mutations coding for K or G at position 264. One patient demonstrated a previously undescribed R264Q mutation in 30/31 clones. This altered epitope failed to elicit an IFN-γ response from PBMC isolated from any of four HLA-B27-positive individuals with strong responses to wild-type peptid...

HIV disease progression in a patient cohort treated via a clinical research network in a resource limited setting.

Abstract: Objective: To examine HIV disease progression in a cohort of adult patients treated with antiretroviral therapy (ART) via a clinical research network in Thailand. Design setting participants and intervention: A cohort of 417 patients enrolled in a series of randomized ART trials between 1996 and December 2002. Main outcome measures: Progression to combined endpoint of AIDS defining illness or death according to baseline characteristics ART used immunological and virological responses to initial 6 months of ART. Results: During 1677 person years of follow-up 29 of 417 patients progressed; tuberculosis was the most common event defining progression (14 of 29 events). The rates of progression to combined endpoint or death alone were 1.7 [95% confidence interval (CI) 1.1-2.4] and 0.7 (95% CI 0.3-1.3) per 10 person years respectively. Compared to patients with baseline CD4 cell counts = 350 x 10(6)/l the adjusted hazard ratio (HR) for progression was 3.67 (95% CI 1.31- 10.27) for patients with 4 log(-10). Compared to patients with a 6-month CD4 cell count =350 x 10(6)/l HR for progression was 5.22 (95% CI 1.90-14.37) for patients with <200 x 10(6) cells/l. Conclusions: HIV-infected patients in Thailand who had access to ART appropriate care CD4 cell and viral load monitoring facilities via a clinical research network had progression rates comparable to those in developed countries. In this setting ART initiation could generally be delayed until the CD4 cell count approaches 200 x 10(6)/l. (authors)

Interindividual variability of once-daily ritonavir boosted saquinavir pharmacokinetics in Thai and UK patients

Abstract: Objectives: Differential exposure to saquinavir/ritonavir may lead to therapy failure. The objective was to identify factors that influence variability of saquinavir/ritonavir plasma concentrations. Methods: Saquinavir/ritonavir data, dosed as 1600/100 mg once daily, from three separate pharmacokinetic studies, in 45 patients from Thailand and the UK, were pooled. Pharmacokinetic parameters were based on non-compartmental analysis. Univariate analysis was performed with saquinavir as the dependent variable, and ritonavir area under the curve (AUC), gender, body weight, body mass index (BMI) and study site as independent variables. Variables with a P value <0.10 were included in a multivariate linear regression analysis. Results: Higher saquinavir AUCs, maximum concentrations (C max ) and minimum concentrations (C min ) were seen in Thai patients than in UK patients. Univariate analysis showed associations between body weight, gender, study site and ritonavir AUC and saquinavir AUC (P< 0.05), whereas BMI (P= 0.13) did not. In the multivariate analysis, ritonavir AUC (P= 0.0001) and study site (P = 0.0021) were significantly related to saquinavir AUC (R 2 = 0.50). Conclusions: The ritonavir AUC and study site appeared to be related to exposure of saquinavir. Study site should be viewed as the total of country- and study-specific differences-such as differences in lifestyle, environment, genetic background and dietary composition-between the analysed studies.

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.

Abstract: 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 pre-existing 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.

The normalized inhibitory quotient of boosted protease inhibitors is predictive of viral load response in treatment-experienced HIV-1-infected individuals

Abstract: Objective: The normalized inhibitory quotient (NIQ) has been proposed as a measure for refining the precision of HIV resistance testing when selecting antiretroviral therapy (ART). We undertook an assessment of NIQ and 48-week virological outcome in patients commencing ritonavir-boosted protease inhibitor (PI) regimens. Design: A cohort of 87 HIV-infected individuals who all had extensive prior exposure to ART were assigned a new boosted PI regimen following resistance testing. PI therapy consisted of lopinavir, indinavir, saquinavir and amprenavir at 50, 32, 11 and 6%, respectively. Fold change (FC) for each PI was determined from the resistance test at baseline. Trough drug concentration (C min ) was determined at week 4. Methods: NIQ was derived individually by taking the logarithm of the ratio of C min /FC divided by the fixed ratio of population mean trough drug concentration/clinical cutoff. Associations between viral load (VL) response over 48 weeks with baseline VL, FC, C min , NIQ and selected PI were assessed. Results: Mean change from baseline VL reduced by 0.83 log at week 48. In multivariate analyses, baseline VL and NIQ were the parameters most associated with change from baseline VL at week 48 (P = 0.012 and 0.003, respectively). FC, C min and selected PI were not significantly associated with VL changes. Conclusion: In this cohort of highly treatment-experienced individuals treated with boosted PI regimens, baseline VL and NIQ were significantly predictive of virological response over 48 weeks whereas FC and C min were not. These results support the use of a NIQ at week 4, as a tool for predicting response to therapy in this setting.

Randomized, placebo-controlled, phase I/IIa evaluation of the safety and immunogenicity of fowlpox virus expressing HIV gag-pol and interferon-gamma in HIV-1 infected subjects.

Abstract: We conducted a randomized, placebo-controlled double-blind trial to examine the safety and immunogenicity of a candidate HIV therapeutic vaccine based upon a recombinant fowl pox virus capable of coexpressing the human cytokine interferon-gamma and/or genes from HIV-1 Thirty-five eligible subjects were randomized (12 placebo, 11 fowlpox + HIV genes, 12 fowl pox + HIV genes + interferon gamma) All but one subject (placebo group) received three immunizations (by intramuscular injection on day 0, week 4 and week 12) and all completed 52 weeks of follow-up All subjects continued to take combination antiretroviral therapy for the duration of study There were no significant toxicity or safety concerns and the distribution of adverse events and their severity was consistent across each randomly assigned vaccine group Comparison of placebo recipients with the combined recipients of the two vaccine constructs, in terms of anti-HIV gag ELISpot or lymphoproliferative responses, tended to favour the placebo group, but were not significantly different (difference in time-weighted mean change from baseline = 56 Spot forming units (sfu)/10(6) PBMC; p = 0062 and 44 SI; p = 0337) There were no significant changes in CTL responses by standard Cr(51) release assay Anti-FPV antibodies were detected by week 14 in 0 placebo and 20 (87%) vaccine recipients Although safe, neither vaccine construct appeared to possess detectable T-cell mediated anti-HIV immunogenic properties in HIV infected individuals, as measured by standard T cell assays

Variability in time delay between two models of pulse oximeters for deriving the photoplethysmographic signals.

Abstract: Pulse oximetry is commonly used as an arterial blood oxygen saturation (SaO2) measure. However, its other serial output, the photoplethysmography (PPG) signal, is not as well studied. Raw PPG signals can be used to estimate cardiovascular measures like pulse transit time (PTT) and possibly heart rate (HR). These timing-related measurements are heavily dependent on the minimal variability in phase delay of the PPG signals. Masimo SET Rad-9 and Novametrix Oxypleth oximeters were investigated for their PPG phase characteristics on nine healthy adults. To facilitate comparison, PPG signals were acquired from fingers on the same hand in a random fashion. Results showed that mean PTT variations acquired from the Masimo oximeter (37.89 ms) were much greater than the Novametrix (5.66 ms). Documented evidence suggests that 1 ms variation in PTT is equivalent to 1 mmHg change in blood pressure. Moreover, the PTT trend derived from the Masimo oximeter can be mistaken as obstructive sleep apnoeas based on the known criteria. HR comparison was evaluated against estimates attained from an electrocardiogram (ECG). Novametrix differed from ECG by 0.71+/-0.58% (p 0.05). Modern oximeters can be attractive for their improved SaO2 measurement. However, using raw PPG signals obtained directly from these oximeters for timing-related measurements warrants further investigations.

A prospective study of efficacy and safety of once-daily saquinavir/ritonavir plus two nucleoside reverse transcriptase inhibitors in treatment-naive Thai patients.

Abstract: OBJECTIVE: To assess the efficacy and safety of first-line treatment with once-daily saquinavir/ritonavir with two nucleoside reverse transcriptase inhibitors (NRTIs), as induction therapy before enrollment in a randomized trial of structured treatment interruption strategies. DESIGN: Two-hundred antiretroviral-naive patients with CD4+ cell counts between 200-350 at screening were enrolled in this open-label 24week study. METHODS: Patients were followed up every 8 weeks for CD4+ cells, HIV RNA, and clinical and laboratory toxicities. RESULTS: Two-hundred patients were enrolled with median baseline CD4+ cell count of 267 cells/microl and HIV RNA 50 118 (4.7 log10) copies/mi. After 24 weeks of treatment, 191 of 200 (96%) patients had below 400 copies/ml HIV RNA, with 177/200 (89%) below 50 copies/ml (intent to treat, missing equals failure method), with a median rise in CD4+ cell count of 122 cells/microl. There was no significant correlation between the minimum concentration of saquinavir and HIV RNA reductions at week 8 (P = 0.957) or absolute HIV RNA at week 24 (P = 0.77). CONCLUSION: First-line highly active antiretroviral therapy (HAART) with once-daily saquinavir/ritonavir plus two NRTIs showed strong antiviral efficacy over 24 weeks, and should be evaluated in larger prospective randomized clinical trials.

Pulse transit time as a derived noninvasive mean to monitor arterial distensibility changes in children

Abstract: Changes in arterial distensibility have been widely used to identify the presence of cardiovascular abnormalities like hypertension. Pulse wave velocity (PWV) has shown to be related to arterial distensibility. However, the lack of suitable techniques to measure PWV nonintrusively has impeded its clinical usefulness. Pulse transit time (PTT) is a noninvasive technique derived from the principle of PWV. PTT has shown its capabilities in cardiovascular and cardiorespiratory studies in adults. However, no known study has been conducted to understand the suitability and utility of PTT to estimate PWV in children. Two computational methods to derive PWV from PTT values obtained from 23 normotensive Caucasian children (19 males, aged 5-12 years old) from their finger and toe were conducted. Furthermore, the effects of adopting different postures on the PWV derivations were investigated. Statistical analyses were performed in comparison with two previous PWV studies conducted on children. Results revealed that PWV derived from the upper limb correlated significantly (P<0.05) regardless of computing methods or postures adopted. The findings here suggest that PTT measurement can be used as a convenient and noninvasive surrogate measure of derived PWV in prolonged clinical studies, especially on younger or less cooperative children. Furthermore, the simple set-up and noninvasive nature of PTT can promote its usefulness in ambulatory monitoring.

Clearing the cervical spine in unconscious head injured patients - the evidence.

Abstract: Cervical spine injury occurs in 5-10% of patients with traumatic brain injury (TBI) and the consequences of missing significant cervical injuries in unconscious blunt trauma patients are potentially devastating. An adequate cervical spine clearance protocol for unconscious patients must avoid missed injuries, but must also avoid unnecessary cervical immobilisation and the associated morbidity. Existing protocols include various combinations of plain X-rays, helical CT, dynamic flexion-extension X-rays and MRI. Some clinicians also maintain immobilisation until clinical clearance is eventually enabled by the return of an adequate conscious state. Plain X-rays alone are inadequate and miss 12-16% of cervical injuries. Swimmer's views and/or oblique views identify more injuries, but are frequently inadequate. Helical CT is sensitive to fractures and subluxation/dislocation injuries but may be insufficient to exclude unstable ligamentous injuries. Dynamic flexion-extension fluoroscopy may better identify unstable ligamentous injuries, but at The Alfred Hospital Trauma Centre in Melbourne, this modality was insensitive in the routine protocol and repeatedly missed significant cervical instability. Furthermore at The Alfred Hospital, when routine dynamic flexion/ extension fluoroscopy and helical CT reconstructions were directly compared, flexion/extension identified no new injuries that had not already been diagnosed by early helical CT reconstructions. Cervical MRI is intuitively appealing as it detects ligament, disc interspace, and cord injury more efficiently than other imaging modalities, but MRI also increases cervical clearance times, increases the risks associated with complex transports and is not an ideal acute screening tool. Nevertheless, recently at The Alfred Hospital, extremely high-risk TBI patients have had unstable cervical injuries detected solely by MRI. Current generation multi-slice CT with reconstructions may obviate the need for MRI even in these patients. The current Alfred Hospital cervical clearance protocol for unconscious patients, and the evolutionary steps in its development, will be discussed.