Resource utilization for multidrug-resistant tuberculosis household contact investigations (A5300/I2003).

BACKGROUND: Current guidelines recommend evaluation of the household contacts (HHCs) of individuals with multidrug-resistant tuberculosis (MDR-TB); however, implementation of this policy is challenging. OBJECTIVE: To describe the resource utilization and operational challenges encountered when identifying and characterizing adult MDR-TB index cases and their HHCs. DESIGN: Cross-sectional study of adult MDR-TB index cases and HHCs at 16 clinical research sites in eight countries. Site-level resource utilization was assessed with surveys. RESULTS: Between October 2015 and April 2016, 308 index cases and 1018 HHCs were enrolled. Of 280 index cases with sputum collected, 94 were smear-positive (34%, 95%CI 28-39), and of 201 with chest X-rays, 87 had cavitary disease (43%, 95%CI 37-50) after a mean duration of treatment of 8 weeks. Staff required 512 attempts to evaluate the 308 households, with a median time per attempt of 4 h; 77% (95%CI 73-80) of HHCs were at increased risk for TB: 13% were aged <5 years, 8% were infected with the human immunodeficiency virus, and 79% were positive on the tuberculin skin test/interferon-gamma release assay. One hundred and twenty-one previously undiagnosed TB cases were identified. Issues identified by site staff included the complexity of personnel and participant transportation, infection control, personnel safety and management of stigma. CONCLUSION: HHC investigations can be high yield, but are labor-intensive.

HIV testing uptake among the household contacts of multidrug-resistant tuberculosis index cases in eight countries.

SETTING: The household contacts (HHCs) of multidrug-resistant tuberculosis (MDR-TB) index cases are at high risk of tuberculous infection and disease progression, particularly if infected with the human immunodeficiency virus (HIV). HIV testing is important for risk assessment and clinical management. METHODS: This was a cross-sectional, multi-country study of adult MDR-TB index cases and HHCs. All adult and child HHCs were offered HIV testing if never tested or if HIV-negative >1 year previously when last tested. We measured HIV testing uptake and used logistic regression to evaluate predictors. RESULTS: A total of 1007 HHCs of 284 index cases were enrolled in eight countries. HIV status was known at enrolment for 226 (22%) HHCs; 39 (4%) were HIV-positive. HIV testing was offered to 769 (98%) of the 781 remaining HHCs; 544 (71%) agreed to testing. Of 535 who were actually tested, 26 (5%) were HIV-infected. HIV testing uptake varied by site (median 86%, range 0-100%; P < 0.0001), and was lower in children aged <18 years than in adults (59% vs. 78%; adjusted for site P < 0.0001). CONCLUSIONS: HIV testing of HHCs of MDR-TB index cases is feasible and high-yield, with 5% testing positive. Reasons for low test uptake among children and at specific sites-including sites with high HIV prevalence-require further study to ensure all persons at risk for HIV are aware of their status.

Antiretroviral regimens in pregnancy and breast-feeding in Botswana.

BACKGROUND: The most effective highly active antiretroviral therapy (HAART) to prevent mother-to-child transmission of human immunodeficiency virus type 1 (HIV-1) in pregnancy and its efficacy during breast-feeding are unknown. METHODS: We randomly assigned 560 HIV-1-infected pregnant women (CD4+ count, > or = 200 cells per cubic millimeter) to receive coformulated abacavir, zidovudine, and lamivudine (the nucleoside reverse-transcriptase inhibitor [NRTI] group) or lopinavir-ritonavir plus zidovudine-lamivudine (the protease-inhibitor group) from 26 to 34 weeks' gestation through planned weaning by 6 months post partum. A total of 170 women with CD4+ counts of less than 200 cells per cubic millimeter received nevirapine plus zidovudine-lamivudine (the observational group). Infants received single-dose nevirapine and 4 weeks of zidovudine. RESULTS: The rate of virologic suppression to less than 400 copies per milliliter was high and did not differ significantly among the three groups at delivery (96% in the NRTI group, 93% in the protease-inhibitor group, and 94% in the observational group) or throughout the breast-feeding period (92% in the NRTI group, 93% in the protease-inhibitor group, and 95% in the observational group). By 6 months of age, 8 of 709 live-born infants (1.1%) were infected (95% confidence interval [CI], 0.5 to 2.2): 6 were infected in utero (4 in the NRTI group, 1 in the protease-inhibitor group, and 1 in the observational group), and 2 were infected during the breast-feeding period (in the NRTI group). Treatment-limiting adverse events occurred in 2% of women in the NRTI group, 2% of women in the protease-inhibitor group, and 11% of women in the observational group. CONCLUSIONS: All regimens of HAART from pregnancy through 6 months post partum resulted in high rates of virologic suppression, with an overall rate of mother-to-child transmission of 1.1%. (ClinicalTrials.gov number, NCT00270296.)

Predictors of growth and body composition in HIV-infected children beginning or changing antiretroviral therapy.

OBJECTIVES: The aim of the study was to describe growth and body composition changes in HIV-positive children after they had initiated or changed antiretroviral therapy (ART) and to correlate these with viral, immune and treatment parameters. METHODS: Ninety-seven prepubertal HIV-positive children were observed over 48 weeks upon beginning or changing ART. Anthropometry and bioelectrical impedance analysis results were compared with results from the National Health and Nutrition Examination Survey 1999-2002 (NHANES) to generate z-scores and with results for HIV-exposed, uninfected children from the Women and Infants Transmission Study (WITS). Multivariate analysis was used to evaluate associations between growth and body composition and disease parameters. RESULTS: All baseline lean and fat mass measures were below those of controls from NHANES. Weight, height and fat free mass (FFM) index (FFM/height(2)) z-scores increased over time (P = 0.004, 0.037 and 0.027, respectively) and the waist:height ratio z-score decreased (P = 0.045), but body mass index and per cent body fat z-scores did not change. Measures did not increase more than in uninfected WITS controls. In multivariate analysis, baseline height, mid-thigh circumference and FFM z-scores related to CD4 percentage (P = 0.029, P = 0.008 and 0.020, respectively) and change in FFM and FFM index z-scores to CD4 percentage increase (P = 0.010 and 0.011, respectively). Compared with WITS controls, baseline differences in height and mid-thigh muscle circumference were also associated with CD4 percentage. Case-control differences in change in both subscapular skinfold (SSF) thickness and the SSF:triceps skinfold ratio were inversely associated with viral suppression. No measures related to ART class(es) at baseline or over time. CONCLUSIONS: In these HIV-positive children, beginning or changing ART was associated with improved growth and lean body mass (LBM), as indicated by FFM index. Height and LBM related to CD4 percentage at baseline and over time. Altered fat distribution and greater central adiposity were associated with detectable virus but not ART class(es) received.

Safety and efficacy of nevirapine- and efavirenz-based antiretroviral treatment in adults treated for TB-HIV co-infection in Botswana.

BACKGROUND: The safety and efficacy of nevirapine (NVP) and efavirenz (EFV) based highly active antiretroviral treatment (ART) with concurrent anti-tuberculosis treatment in sub-Saharan Africa has not been well established. METHODS: We performed a retrospective study comparing human immunodeficiency virus (HIV) infected adults exposed and not exposed to tuberculosis (TB) treatment with similar baseline HIV-1 RNA levels who were started on ART as part of Botswana's ART Programme. ART regimens, HIV-1 RNA, CD4+ cell count, and liver function tests were reviewed for 12 months following ART initiation. RESULTS: Among 155 patients on ART only and 155 exposed to TB treatment, there was no difference in virologic or immunologic response throughout the first year of ART. Furthermore, there remained no differences in virologic or immunologic outcomes when NVP and EFV groups were stratified by TB treatment exposure status. While more hepatotoxic events occurred in the group exposed to TB treatment than in those not exposed (9% vs. 3%, P = 0.05), there was no difference between patients treated with NVP and those treated with EFV. CONCLUSIONS: Patients co-infected with HIV and TB in Botswana can be treated effectively with either NVP- or EFV-based ART and TB treatment. As hepatotoxic events were more common in the group exposed to TB treatment, liver function tests should be monitored closely.

Magnetic resonance imaging as a surrogate outcome for multiple sclerosis relapses.

BACKGROUND: Magnetic resonance imaging (MRI) of lesions in the brain may be the best current candidate for a surrogate biological marker of clinical outcomes in relapsing remitting multiple sclerosis (MS), based on its role as an objective indicator of disease pathology. No biological surrogate marker has yet been validated for MS clinical outcomes. OBJECTIVE: The objective of this study was to use a multi-phased study to determine if a valid surrogate relationship could be demonstrated between counts of contrast enhancing lesions (CELs) and occurrence of relapses in MS. METHODS: We examined correlations for the concurrent and predictive relationship between CELs over 6 months and MS relapses over the same 6 months and an additional 6 months (total: 12 months), using available data on untreated patients from a large clinical trial and natural history database. RESULTS: Concurrent and predictive correlations were inadequate to justify continuation of this study to the planned additional phases required to demonstrate a surrogate relationship between CELs and MS relapses. CONCLUSIONS: Confidence intervals for correlations between CELs and MS relapses exclude the possibility that CELs can be a good surrogate for relapses over the time scales we investigated. Further exploration of surrogacy between MRI measures and MS clinical outcomes may require improved datasets, the development of MRI techniques that couple better to clinical disease, and the ability to test a wide range of imaging- and clinically-based hypotheses for surrogacy.

Pharmacokinetics and safety of nelfinavir when used in combination with zidovudine and lamivudine in HIV-infected pregnant women: Pediatric AIDS Clinical Trials Group (PACTG) Protocol 353.

BACKGROUND: Combination antiretroviral regimens including nelfinavir (NFV) are commonly used in pregnancy. We studied the safety, antiviral effect, and pharmacokinetics of NFV and its M8 metabolite with two dosing regimens in combination with zidovudine (ZDV) and lamivudine (3TC) in HIV-infected pregnant women. METHOD: HIV-infected pregnant women between 14 and 34 weeks gestation received NFV (Cohort 1: 750 mg tid, n = 10; Cohort 2: 1250 mg bid, n = 23) with ZDV and 3TC. Serial blood sampling for NFV concentrations was performed antepartum (AP) and 6 weeks postpartum (PP). Maternal and cord blood samples were also obtained at delivery. NFV and M8 levels were determined by high-performance liquid chromatography. The pharmacokinetic (PK) target was an extrapolated NFV AUC0-24 > 30 mug . h/mL. Mothers were followed frequently for potential clinical and laboratory toxicity. RESULTS: Overall, NFV in combination with ZDV and 3TC was well tolerated. The PK target was met in 3/8 AP and 5/7 PP in Cohort 1 and 17/21 AP and 16/17 PP in Cohort 2. When Cohort 2 NFV PK parameters AP and PP were compared, median Cmax (3.90 microg/mL vs. 5.01 microg/mL, p < .05) and AUC0-24 (56.6 vs. 86.8 microg . h/mL, p < .05) were increased PP and oral clearance (Cl/F; 44.2 vs. 28.8 L/h, p < .05) was decreased PP. The average M8/NFV ratio was increased PP compared to AP (0.085 vs. 0.29, p < .001). Placental transfer of NFV was low with a median cord blood:maternal plasma ratio at delivery of 0.05. Maternal mean CD4+ T cell counts increased significantly and plasma HIV-1 RNA levels decreased from entry to delivery and 6 to 12 weeks postpartum. CONCLUSION: NFV used in combination with ZDV and 3TC was well tolerated in pregnant HIV-infected women and produced a significant improvement in HIV disease parameters. NFV drug exposure is inadequate in most pregnant women receiving 750 mg tid but is much improved with 1250 mg bid. NFV crosses the placenta poorly. The AP increase in NFV oral clearance and decrease in M8/NFV ratio suggest that CYP3A activity increases relative to CYP2C19 activity during pregnancy.

Splanchnic and peripheral vascular resistance during lower body negative pressure (LBNP) and tilt.

We tested the hypothesis that vasoconstriction in response to LBNP or head up tilt would be reflected in a reduction in splanchnic (portal vein) blood flow (PVF) and increases in forearm and total peripheral vascular resistance (TPR). Changes in vascular resistance indicators were obtained from measurement of PVF from portal vein cross-sectional area and blood velocity by Doppler ultrasound, from forearm vascular resistance (FVR, by Doppler) and total peripheral resistance (TPR, by impedance cardiography). 21 subjects were tested during LBNP (0, -10, -20 and -30 mmHg) and 9 subjects during tilt (0, 45 and 70 degrees). During progressive LBNP, PVF decreased approximately linearly with LBNP (-30, -48 and -64% at -10, -20 and -30 mmHg) and with tilt angle (-39 and -58% at 45 and 70 degrees). The increase in FVR approximately mirrored these changes during LBNP (20.1, 44.7 and 55.3%) and tilt (45.6 and 63.6%). However, the changes in TPR during LBNP (12.0, 16.9 and 26.4%) and tilt (25.2 and 29.2%) were markedly less. This observation of different percent changes in forearm versus total peripheral resistance might reflect true physiological differences in the forearm (and splanchnic) circulations compared with the whole body, or the data might suggest that impedance cardiography did not provide a reliable indicator of cardiac output and therefore TPR under these conditions. The primary observation in this study was that Doppler ultrasound measurement of portal vein blood flow provided a non-invasive estimate of splanchnic vascular resistance during postural or LBNP challenge and that using the reduction in portal vein flow as an index of increased vasoconstriction paralleled the change in forearm vascular resistance.

Predictors of virologic and clinical outcomes in HIV-1-infected patients receiving concurrent treatment with indinavir, zidovudine, and lamivudine. AIDS Clinical Trials Group Protocol 320.

BACKGROUND: A substantial proportion of patients with HIV infection will not respond to antiretroviral therapy. Early predictors of response to treatment are needed to identify patients who are at risk for treatment failure. OBJECTIVE: To determine predictors of virologic and clinical response to indinavir, zidovudine, and lamivudine therapy. DESIGN: Observational analysis of one treatment group in a phase III trial. SETTING: 40 AIDS Clinical Trials units. PATIENTS: 489 patients receiving indinavir, zidovudine, and lamivudine who had 1) a CD4 count of 0.200 x 10(9) cells/L or less after 8 or more weeks of study therapy and 2) plasma HIV-1 RNA measurements obtained at baseline and week 8. MEASUREMENTS: HIV-1 RNA level and CD4 cell count at weeks 0, 4, 8, 24, and 40. Clinical progression was defined as a new AIDS-defining illness or death. RESULTS: Patients' levels of HIV-1 RNA at the 8th study week of therapy predicted whether patients would achieve virologic suppression to below 500 (or 50) copies/mL at study week 24. An HIV-1 RNA level less than 500 copies/mL at week 24 was achieved in 71% of patients whose level at week 8 had been less than 500 copies/mL, 53% of those with a level of 500 copies/mL or more and at least 2-log(10) copies/mL reduction since baseline, 29% of those with a level of 500 copies/mL or more with a 1- to 1.99-log(10) copies/mL reduction, and 9% of those with a level of 500 copies/mL or greater and less than 1-log(10) copies/mL reduction since baseline (P < 0.001). HIV-1 RNA level at week 8 also predicted clinical progression. HIV-1 disease progressed in 2.2% of the patients with a week-8 HIV-1 RNA level less than 500 copies/mL, 2.3% of patients with 500 copies/mL or greater and at least 2-log(10) copies/mL reduction since baseline, 4.9% of patients with 500 copies/mL or greater and 1- to 1.99-log(10) copies/mL reduction since baseline, and 10.6% of patients with 500 copies/mL or greater and less than 1-log(10) copies/mL decrease since baseline (P = 0.009). After adjustment for HIV-1 RNA level, patients with a higher week-8 CD4 cell count were more likely to have a week-24 HIV-1 RNA level less than 500 copies/mL (relative risk for patients with a week-8 CD4 count >/= 0.10 x 10(9) cells/L, 1.47 [95% CI, 1.00 to 2.16] compared with <0.050 x 10(9) cells/L; relative risk for patients with a week-8 CD4 count of 0.05 to 0.099 x 10(9) cells/L, 0.98 [CI, 0.61 to 1.57] compared with <0.050 x 10(9) cells/L). After adjustment for HIV-1 RNA level, patients with a week-8 CD4 count of 0.05 x 10(9) cells/L or greater (compared with <0.05 x 10(9) cells/L) had a decreased hazard for clinical progression (hazard ratio, 0.25 [CI, 0.09 to 0.67]). CONCLUSIONS: The HIV-1 RNA level and CD4 cell count achieved at 8 weeks of treatment are important predictors of subsequent virologic and clinical outcomes.

Impact of protease inhibitor-containing combination antiretroviral therapies on height and weight growth in HIV-infected children.

OBJECTIVE: To examine beneficial or detrimental effects of protease inhibitor (PI)-containing antiretroviral regimens on height and weight growth in children with human immunodeficiency virus (HIV) infection. METHODS: A prospective cohort study was conducted of 906 HIV-infected children, from pediatric research clinics in the United States, who were between 3 months and 18 years of age and who had height and weight assessed in 1995 (before introduction of PIs in this population) and at least once more through 1999. Changes in age- and gender-adjusted height and weight growth associated with PI use were assessed. RESULTS: Compared with a healthy reference population, children were more affected in height (mean z score: -0.90 [18th percentile]) than in weight (mean z score: -0.42 [34th percentile]) at baseline (1995). Two thirds of children received at least 1 PI during 1996 to 1999. In the multivariate mixed effects regression models adjusted for baseline log(10) CD4 cell count, baseline age, gender, and race/ethnicity, the use of PIs was associated with per-year gains of 0.13 z scores in height and 0.05 z scores in weight relative to the expected growth with non-PI-containing regimens (eg, after 1 year of PI use, a representative 6-year-old boy in our study would be approximately 0.7 cm taller and 0.1 kg heavier than if he had not received PIs). No significant differential effects of PIs on height or weight growth according to specific agents or children's sociodemographic or clinical characteristics were found. CONCLUSIONS: Although the use of PI-containing regimens was not associated with growth retardation, it was associated with only small annual increments in height and weight growth in HIV-infected children.

The cellular delivery of antisense oligonucleotides and ribozymes.

The design and development of antisense oligonucleotides and ribozymes for the treatment of diseases arising from genetic abnormalities has become a real possibility over the past few years. Improvements in oligonucleotide chemistry have led to the synthesis of nucleic acids that are relatively stable in the biological milieu. However, advances in cellular targeting and intracellular delivery will probably lead to more widespread clinical applications. This review looks at recent advances in the in vitro and in vivo delivery of antisense oligodeoxynucleotides and ribozymes.

Virologic and CD4 cell response to zidovudine or zidovudine and lamivudine following didanosine treatment of human immunodeficiency virus infection.

To optimize nucleoside reverse transcriptase inhibitor (nRTI) antiretroviral therapy, 137 subjects who had been treated with didanosine monotherapy for more than 3 years in the AIDS Clinical Trials Group (ACTG) 175 study were randomized to zidovudine and didanosine (dual therapy) or zidovudine, didanosine, and lamivudine (triple therapy). Evaluation of early (8 week) change in HIV plasma RNA demonstrated that addition of lamivudine and zidovudine provided significantly greater virologic suppression compared to the addition of zidovudine alone (mean decrease of 1.27 vs. 0.74 log(10) copies/ml, n = 108, p = 0.007). Both dual and triple therapy provided significant long-term decreases (from study entry to mean at Weeks 40 and 48) in HIV plasma RNA: 0.62 and 0.86 log(10) copies/ml, respectively (n = 110). However, the difference between treatments was not significant (p = 0.16). At 48 weeks, 26% of subjects starting study treatment had <500 copies/ml of plasma HIV RNA. The CD4 count response was greater at 4 weeks for triple versus dual therapy: a mean increase of 51 vs. 12 CD4 cells/ml(3) (n = 126, p = 0.039). The difference at Weeks 40 and 48 was not significant (a 22 cell increase vs. a 1 cell decrease, n = 129, p = 0.41). Zidovudine and didanosine treatment, with or without lamivudine, was well tolerated and only 2 of 137 (1.5%) of study participants developed an AIDS-defining event over 48 weeks.

Dose-finding designs for HIV studies.

We present a class of simple designs that can be used in early dose-finding studies in HIV. Such designs, in contrast with Phase I designs in cancer, have a lot of the Phase II flavor about them. Information on efficacy is obtained during the trial and is as important as that relating to toxicity. The designs proposed here sequentially incorporate the information obtained on viral reduction. Initial doses are given from some fixed range of dose regimens. The doses are ordered in terms of their toxic potential. At any dose, a patient can have one of three outcomes: inability to take the treatment (toxicity), ability to take the treatment but insufficient reduction in viral load (viral failure), and ability to take the treatment as well as a sufficient reduction of viral load (success). A clear goal for some class of designs would be the identification of the dose leading to the greatest percentage of successes. Under certain assumptions, which we identify and discuss, we can obtain efficient designs for this task. Under weaker, sometimes more realistic assumptions, we can still obtain designs that have good operating characteristics in identifying a level, if such a level exists, having some given or greater success rate. In the absence of such a level, the designs will come to an early closure, indicating the ineffectiveness of the new treatment.

Analysis and design issues for studies using censored biomarker measurements with an example of viral load measurements in HIV clinical trials.

For many biomarkers, the range (L,R) over which they can be quantified is restricted by technical limitations, leading to some measurements that are left or right censored. However, despite the widespread availability of statistical methods for the analysis of censored data, many studies use an imputed value for censored measurements (for example, replacing a value

Effect of lamivudine in HIV-infected persons with prior exposure to zidovudine/didanosine or zidovudine/zalcitabine.

Nucleoside analog-based regimens remain an integral component of combination therapy for use in both antiretroviral treatment-naive and experienced HIV-infected patients. To further define treatment responses to new antiretroviral therapy in patients with long-term experience to dual nucleoside analog therapy (zidovudine [ZDV] plus didanosine [ddI] or ZDV plus zalcitabine [ddC]), 325 subjects derived from the AIDS Clinical Trials Group (ACTG) 175 trial were randomized to three different combination regimens: (1) continuation of ZDV + ddI or ZDV + ddC (continuation arm), (2) addition of 3TC to ZDV + ddI or ZDV + ddC (addition arm), or (3) a switch to ZDV + 3TC therapy (switch arm). Both the addition and switch arms sustained significantly greater short-term (baseline to week 4) mean CD4+ cell count increases compared with the continuation arm (+36, +28 versus -4 cells/mm3; p = 0.012) and long-term CD4+ cell count responses (baseline to weeks 40/48: +32, +19 versus -9 cells/mm3; p = 0.003). Superior short-term (baseline to week 8) mean decreases in plasma HIV RNA (p < 0.001) were achieved by both the addition and switch arms (0.53 log10 and 0.54 log10 copies/ml, respectively) compared with the continuation arm (0.13 copies/ml) whereas no differences in long-term virologic suppression were observed (p = 0.30). At week 48, no differences were observed in the proportions of subjects who had HIV RNA levels below 500 copies/mL: 18% of subjects in each treatment arm (3-way p = 1.0). Overall, the treatments were well tolerated and only nine subjects (3%) died or developed one or more AIDS-defining events. While this study confirms the intrinsic antiretroviral activity of 3TC, only modest marker changes and limited short-term viral suppression are seen with incremental addition of the drug. The current approach of using 3TC in maximally suppressive regimens is preferred.

Differences between women and men in adverse events and CD4+ responses to nucleoside analogue therapy for HIV infection. The Aids Clinical Trials Group 175 Team.

OBJECTIVE: To prospectively examine differences in baseline characteristics and study outcomes between HIV-infected women and men during a clinical trial of nucleoside analogue therapy. METHODS: ACTG 175 randomized HIV-infected patients with CD4+ counts between 200 and 500 cells/mm3 to one of four nucleoside analogue regimens: zidovudine (ZDV), didanosine (ddI), ZDV + ddI, or ZDV + zalcitabine (ddC). Differences in time to first dose modification, voluntary withdrawal, development of toxicity and symptomatology, and AIDS progression were compared by gender. RESULTS: The study included 438 women and 2029 men. Baseline values of HIV RNA plasma concentrations were significantly lower for women (0.3 log10) than men in a subset of patients in whom assays were taken and this difference persisted after adjustment for CD4+ count. Women reported reducing dosage and discontinue ddI-containing regimens more frequently than men did; adjustment for weight did not completely explain this difference. Women were at lower risk than men for progression to a study endpoint (19% of women versus 24% of men; p <.0001). Among those antiretroviral-naive study subjects receiving ZDV, men were four times more likely to progress to a study endpoint than women. CONCLUSIONS: Differences in pretreatment characteristics and on study experiences were demonstrated between women and men enrolled in this clinical trial. The suggestion of a gender difference in response to ZDV monotherapy by antiretroviral-naive study subjects and the lower baseline values for HIV RNA in women compared with those in men provides evidence for gender differences in the relationship between virus replication, CD4+ decline, and responses to nucleoside analogue therapy.

The delivery of antisense therapeutics.

Antisense oligonucleotides, ribozymes and DNAzymes have emerged as novel, highly selective inhibitors or modulators of gene expression. Indeed, their use in the treatment of diseases arising from genetic abnormalities has become a real possibility over the past few years. The first antisense drug molecule is now available for clinical use in Europe and USA. However, their successful application in the clinic will require improvements in cellular targeting and intracellular delivery. This review aims to look at recent advances in the in vitro and in vivo delivery of antisense oligodeoxynucleotides and ribozymes.

Treatment-mediated changes in human immunodeficiency virus (HIV) type 1 RNA and CD4 cell counts as predictors of weight growth failure, cognitive decline, and survival in HIV-infected children.

This meta-analysis of 5 large studies of the Pediatric AIDS Clinical Trials Group was undertaken to evaluate the predictive value of antiretroviral treatment-mediated changes in 3 markers of human immunodeficiency virus (HIV) type 1 disease progression-HIV-1 RNA level, CD4 cell count, and CD4 percentage-for weight growth failure, cognitive decline, and survival in HIV-infected children. Proportional hazards models were used to assess the prognostic value of the markers at baseline and after 24 weeks of treatment, with data from 1089 children. Among children receiving nucleoside with or without nonnucleoside reverse-transcriptase inhibitors, higher immunologic and lower virologic markers at baseline and after 24 weeks were significant independent predictors of survival, whereas virologic markers were significant predictors of weight growth and cognitive failure in children >1 year old. The finding of differential age effects on pediatric-specific clinical outcomes emphasizes the need for continued investigation of treatment effects in children.

The values of quantitative serum HIV-1 RNA levels and CD4 cell counts for predicting survival time among HIV-positive individuals with CD4 counts of < or = 50 x 10(6) cells/l.

OBJECTIVE: To evaluate the HIV-1 RNA level as a predictor of survival time among individuals with advanced AIDS. METHODS: The serum HIV-1 RNA level, the CD4 cell count, and other clinical variables were evaluated at baseline, as predictors of survival time, among 56 retrospectively identified HIV-1 positive individuals with < or = 50 x 10(6) CD4 cells/l who attended the Beth Israel Deaconess Medical Center, Division of Infectious Diseases, between 1 July 1989 and 30 September 1993. RESULTS: During follow-up, 55 of these 56 patients died. The median survival time was 20.5 months. In univariate Cox proportional hazard modeling neither the baseline HIV-1 RNA level nor the CD4 cell count were predictive of survival time. However, in multivariate models longer survival time was associated with the use of trimethoprim-sulphamethoxazole at entry [hazard ratio (HR), 0.42; P = 0.007], whereas shorter survival time was associated with a history of an AIDS-defining illness other than Pneumocystis carinii pneumonia (HR, 2.87; P = 0.007). Correlative analysis revealed a modest correlation of the baseline CD4 cell count with survival time (Spearman p = 0.41; P = 0.002). However, no correlation was found between HIV RNA levels and survival time (P = 0.5). CONCLUSIONS: In this population with very advanced disease, the HIV-1 RNA level was a poor discriminator of survival time, being inferior to the CD4 cell count and to specific clinical variables such as the nature of the prior AIDS-defining illness and the type of Pneumocystis carinii pneumonia prophylaxis employed. Among individuals with advanced AIDS, these data emphasize the relative importance of the CD4 cell count and of specific clinical factors, over the HIV-1 RNA level in predicting survival time.

Both serum HIV type 1 RNA levels and CD4+ lymphocyte counts predict clinical outcome in HIV type 1-infected subjects with 200 to 500 CD4+ cells per cubic millimeter. AIDS Clinical Trials Group Study 175 Virology Study Team.

To evaluate HIV-1 RNA and CD4+ cell responses to therapy as predictors of clinical progression and to evaluate levels and trends of these markers prior to clinical failure, HIV-1 RNA measurements were retrospectively obtained on subjects who progressed to AIDS or death and a random sample of subjects who did not. Samples were taken from AIDS Clinical Trials Group Study 175, a randomized trial comparing nucleoside analog therapies in subjects with CD4+ cell counts of between 200 and 500 cells/mm3. HIV-1 RNA and CD4+ cell count independently predicted clinical progression. Risk of subsequent progression is best captured by the change to the last measured value for CD4+ cell count and the area under the curve minus baseline, a measure of viral replication over time, for HIV-1 RNA. Subjects who failed had lower CD4+ cell counts, greater rates of CD4+ cell decline, and higher HIV-1 RNA levels, but not greater rates of HIV-1 RNA increase than subjects who did not. Subjects who maintained more than 200 CD4+ cells/mm3 and fewer than 10,000 copies of HIV-1 RNA per milliliter had low risk of progression. During the first few months of therapy, treatments are best monitored by regular HIV-1 RNA and less frequent CD4+ cell measurements. Thereafter, both markers should be monitored on a similar schedule to identify rapidly declining CD4+ cell counts, or adverse levels of either. These results further delineate the prognostic significance of HIV-1 RNA and CD4+ cell count and should help to better define their utility in the practice setting.