Hannah Green

Early Structural and Functional Changes of the Vasculature in HIV-Infected Children Impact of Disease and Antiretroviral Therapy

Background—Premature cardiovascular disease is increasingly recognized in HIV-infected patients, but the mechanisms involved are unclear. The purpose of this study was to determine the impact of HIV infection and antiretroviral therapy (ART) on markers of early vascular disease in children. Methods and Results—We studied 83 HIV-infected children (56 had taken ART, of whom 31 received a regimen containing protease inhibitors [PIs]; 27 were never treated) and a control group of 59 healthy children. Carotid intima-media thickness (IMT) and brachial artery flow-mediated dilatation (FMD) were measured. IMT was significantly greater in HIV-infected children compared with the control subjects (P<0.001). Among the HIV-infected children, age and treatment were significantly associated with increased IMT. Children exposed to PIs had greater IMT compared with both non-PI-treated children and untreated children (P=0.02). FMD was also significantly reduced in the HIV-infected children compared with control subjects (P=0.02). Pairwise comparisons of different treatment exposure groups revealed that FMD was impaired by a mean of 3.6% (95% CI, 1.8 to 5.3; P<0.001) for children exposed to PIs compared with untreated children and by a mean of 1.8% (95% CI, 0.01 to 3.5; P=0.05) compared with non-PI-treated children. HIV-infected children had lipid abnormalities, but they did not account for the observed differences in either FMD or IMT. Conclusions—HIV infection in childhood is associated with adverse structural and functional vascular changes that are most pronounced in children exposed to PI therapy. Longitudinal studies are required to differentiate the relative impact of HIV disease and ART and to assess the potential for prevention.

Effect of HIV-1 subtype on virologic and immunologic response to starting highly active antiretroviral therapy.

BACKGROUND It has been proposed that subtype-related human immunodeficiency virus type 1 (HIV-1) variability may influence virologic and immunologic responses to highly active antiretroviral therapy (HAART). Studies to date, however, have described treatment outcomes predominantly in persons with subtype B infection or compared subtype B with diverse non-B subtypes grouped together. METHODS With use of data from the linked UK Collaborative Group on HIV Drug Resistance and the UK Collaborative HIV Cohort Study databases, time to viral load undetectability (viral load, <50 copies/mL), time to virologic rebound (viral load, >1000 copies/mL), and increases in the CD4 cell count were compared for a median of 39 months (interquartile range, 23-67 months) in drug-naive patients infected with subtype B (n=1550), subtype C (n=272), subtype A (n=66), circulating recombinant form AG (n=57), or subtype D (n=41) disease who started HAART. RESULTS Overall, 1906 (90%) of 2116 patients achieved viral load undetectability within 12 months after they started HAART, of whom 335 (18%) subsequently experienced virologic rebound. In adjusted analyses, viral load suppression occurred more rapidly in patients infected with subtype C (hazard ratio, 1.16; 95% confidence interval, 1.01-1.33; P=.04) and subtype A (hazard ratio, 1.35; 95% confidence interval, 1.04-1.74; P=.02) relative to subtype B infection. The virologic rebound occurred marginally more rapidly in patients with subtype C infection (hazard ratio, 1.40; 95% confidence interval, 1.00-1.95; P=.05), but the hazard of virologic rebound was similar with other subtypes. Although persons with subtype B infection showed higher baseline CD4 cell counts and maintained the advantage throughout therapy, CD4 cell count recovery occurred at similar rates with all subtypes. CONCLUSIONS Patients infected with prevalent non-B subtypes were as likely to achieve viral load suppression as persons infected with subtype B and showed comparable rates of CD4 cell count recovery. HAART achieves excellent outcomes regardless of the infecting subtype.

Zidovudine plus lamivudine in Human T-Lymphotropic Virus type-I-associated myelopathy: a randomised trial.

BackgroundNo therapies have been proven to persistently improve the outcome of HTLV-I-associated myelopathy. Clinical benefit has been reported with zidovudine and with lamivudine in observational studies. We therefore conducted a randomised, double blind, placebo controlled study of six months combination therapy with these nucleoside analogues in sixteen patients.ResultsPrimary outcomes were change in HTLV-I proviral load in PBMCs and clinical measures. Secondary endpoints were changes in T-cell subsets and markers of activation and proliferation.Six patients discontinued zidovudine. No significant changes in pain, bladder function, disability score, gait, proviral load or markers of T-cell activation or proliferation were seen between the two arms. Active therapy was associated with an unexplained decrease in CD8 and non-T lymphocyte counts.ConclusionFailure to detect clinical improvement may have been due irreversible nerve damage in these patients with a long clinical history and future studies should target patients presenting earlier. The lack of virological effect but may reflect a lack of activity of these nucleoside analogues against HTLV-I RT in vivo, inadequate intracellular concentrations of the active moiety or the contribution of new cell infection to maintaining proviral load at this stage of infection may be relatively small masking the effects of RT inhibition.

Effect of early antiretroviral therapy on the risk of AIDS/death in HIV-infected infants

Objective:In the absence of treatment, rapid progression to AIDS occurs in approximately 20% of HIV-1-infected infants over the first year of life. The prognosis of these children has considerably improved with highly active antiretroviral therapy. As data from well resourced countries are lacking, the objective of this collaborative study was to evaluate the impact of early treatment in vertically infected infants. Design:Children born to HIV-infected mothers between 1 September 1996 and 31 December 2004, who were diagnosed with HIV and free of AIDS before 3 months, were eligible. Demographics and pregnancy data, details of antiretroviral therapy, and clinical outcome were collected from 11 European countries. Methods:The risk of AIDS or death, by whether or not an infant started treatment before 3 months of age, was estimated by Kaplan–Meier survival analysis and Cox proportional hazards models. Results:Among 210 children, 21 developed AIDS and three died. Baseline characteristics of the 124 infants treated before 3 months were similar to those of the 86 infants treated later. The risk of developing AIDS/death at 1 year was 1.6 and 11.7% in the two groups, respectively (P < 0.001). Deferring treatment was associated with increased risk of progression [crude hazard ratio 5.0; 95% confidence interval (CI) 2.0–12.6; P = 0.001] that persisted after adjusting for cohort in multivariate models (adjusted hazard ratio 3.0; 95% CI 1.2–7.9; P = 0.021). Conclusion:In HIV-1 vertically infected infants, starting antiretroviral therapy before the age of 3 months is associated with a significant reduction in progression to AIDS and death.

Estimating HIV-1 drug resistance in antiretroviral-treated individuals in the United Kingdom.

Good estimates of the prevalence of human immunodeficiency virus drug resistance are important for assessing requirements for new drug classes and modeling the spread of resistance. However, little consensus exists on optimal methodologies to generate such data. To compare methodologies, we used the national data set of resistance tests from >4000 patients in the United Kingdom performed between 1998 and 2002. When single-time-point analysis (method 1) was used, the proportion of tests with any form of resistance was approximately 80%, with little time trend. When a cumulative model of resistance (method 2) was used and placed in the context of all treated patients, the prevalence of any resistance increased by year, reaching 17% of treated patients in 2002. Method 2 also nearly doubles estimates of numbers of individuals infected with multiclass drug-resistant virus. Our results identify an urgent need for new drugs within existing classes and new classes of antiretroviral therapy.

Lamivudine/abacavir maintains virological superiority over zidovudine/lamivudine and zidovudine/abacavir beyond 5 years in children

Objective:To describe the long-term efficacy over 5 years of regimens including combinations of abacavir, lamivudine and/or zidovudine in previously untreated children in the PENTA 5 trial. Design:PENTA 5 was a 48-week randomised controlled trial comparing three dual nucleoside reverse transcriptase inhibitor (NRTI) combinations as part of first triple antiretroviral therapy (ART). Methods:128 ART-naïve children were randomised to zidovudine\lamivudine (n = 36), zidovudine\abacavir (45) or lamivudine\abacavir (47). Asymptomatic children (n = 55) were also randomised to nelfinavir or placebo; all other children received open-label nelfinavir. Analyses are intent-to-treat and adjusted for minor baseline imbalances and receipt of nelfinavir/placebo. Results:Median follow-up was 5.8 years. By 5 years, 17 (47%), 28 (64%) and 18 (39%) children had changed their randomised NRTIs in the zidovudine\lamivudine, zidovudine\abacavir and lamivudine\abacavir groups respectively, but 18%, 50% and 50% of these changes were either early single drug substitutions for toxicity or switches with viral suppression (HIV-1 RNA < 400 copies/ml; e.g. to simplify regimen delivery). At 5 years, 55%/32% zidovudine\lamivudine, 50%/25% zidovudine\abacavir and 79%/63% lamivudine\abacavir had HIV-1 RNA < 400/< 50 copies/ml respectively (p = 0.03/p = 0.003). Mean increase in height-for-age 0.42, 0.68, 1.05 (p = 0.02); weight-for-age 0.03, 0.13, 0.75 (p = 0.02). Reverse transcriptase resistance mutations emerging on therapy differed between the groups: zidovudine\lamivudine (M41L, D67N, K70R, M184V, L210W, T215Y); zidovudine\abacavir (M41L, D67N, K70R, L210W, T215F/Y, K219Q); lamivudine\abacavir (K65R, L74V, Y115F, M184V). Conclusions:Five year data demonstrate that lamivudine\abacavir is more effective in terms of HIV-1 RNA suppression and growth changes, with lower rates of switching with detectable HIV-1 RNA than zidovudine\lamivudine or zidovudine\abacavir, and should be preferred as first-line NRTI backbone.

Identification of accessory mutations associated with high-level resistance in HIV-1 reverse transcriptase

Objective:To identify accessory mutations associated with high levels of resistance to reverse transcriptase inhibitors (RTI). Design:HIV pol sequences from routine resistance tests from over 3000 patients who were treatment experienced and infected with subtype B HIV-1 were analysed. Changes relative to the wild-type amino acid for codons 1–400 of reverse transcriptase were determined in two series: (i) samples showing the accumulation of thymidine analogue mutations (TAMs); and (ii) samples showing the accumulation of non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance mutations. Methods:Accessory mutations were identified as occurring in those codons in which there was a statistically significant association between the distribution of amino acids and the number of TAMs/NNRTI resistance mutations. Positions already established as drug resistance positions by the International AIDS Society – USA Panel were not included in this analysis. Results:Twenty-four positions were identified where accessory mutations were associated with the accumulation of TAMs (20, 35, 39, 43, 60, 83, 98, 101, 122, 135, 179, 196, 203, 208, 218, 223, 228, 284, 322, 356, 359, 360, 371 and 381). Likewise changes at 25 positions (6, 20, 35, 39, 43, 53, 68, 90, 98, 101, 122, 179, 200, 203, 208, 218, 221, 223, 228, 284, 318, 320, 348, 359 and 371) were associated with NNRTI mutations. The accumulation of accessory mutations correlated with increasing numbers of TAMs and NNRTI mutations. Conclusion:The development of high-level resistance to RTI is associated not only with the accumulation of recognized mutations but also with accessory mutations.

HIV-1 drug resistance in HIV-1-infected children in the United Kingdom from 1998 to 2004.

We reviewed HIV-1 genotypes from 200 of 979 (20%) HIV-infected children in the U.K. Collaborative HIV in Pediatric Study (CHIPS) cohort (343 resistance tests). Three of 44 samples had major primary resistance mutations before antiretroviral therapy. Three-class resistance was noted in 42 samples (14.1%). Our study also highlighted underutilization of testing and the need for prompt genotyping after drug discontinuation which may have lead to an underestimation of HIV-1 resistance.

Adherence and acceptability of once daily Lamivudine and abacavir in human immunodeficiency virus type-1 infected children.

Background: Data on adherence to and acceptability of once daily lamivudine and abacavir are few. Methods: Twenty-four U.K. human immunodeficiency virus type-1 infected children 2–13 years of age participated in the Pediatric European Network for the Treatment of AIDS (PENTA) 13 single arm, open label pharmacokinetic study of twice (every 12 hours) versus once (every 24 hours) daily lamivudine and abacavir. Caregivers were asked to complete an adherence questionnaire at screening, week 0 (switch once daily to twice daily) and weeks 4, 12 and 24. Acceptability was also assessed at screening and week 24. Results: Fifteen children were taking lamivudine and abacavir as part of their regimens, 8 lamivudine only and 1 abacavir only. After switching to lamivudine/abacavir every 24 hours, 7 (29%) received once daily regimens for all drugs. Twenty-three (96%) caregivers thought that switching to once daily lamivudine/abacavir would make things a lot/a little easier for their child: 17 (71%) thought it was actually easier after switching. Six mothers with children taking a mixture of twice/once daily drugs changed their mind, whereas all mothers of children on once daily regimens agreed that it was a lot easier. Nonadherence (missing doses in the last 3 days) was reported for 8 of 118 (7%) completed questionnaires; missed doses were reported for every drug in the regimen with reasons such as “not at home,” “forgot” or “routine different from normal.” However, viral loads in all these children remained <100 copies/mL. Conclusion: Adherence to once daily abacavir/lamivudine was good with no evidence of an association between nonadherence and virologic rebound. Acceptability of once daily drugs was best when the whole regimen was dosed once daily.

The impact of different definitions on the estimated rate of transmitted HIV drug resistance in the United Kingdom.

Background:The use of different lists of resistance mutations has resulted in estimates of transmitted HIV drug resistance (THDR) that are often not comparable. Methods:We estimated the rate of THDR based on the 3 definitions: ≥1 major mutation(s) listed on the International AIDS Society (IAS)-USA drug resistance mutation (DRM) 2006 list; ≥1 surveillance drug resistance mutation(s) (SDRM) on the published list by Shafer et al; and low-level/intermediate/high-level resistance to ≥1 drug(s) according to the Stanford HIVdb interpretation algorithm. Analyses were based on genotypic resistance tests conducted during 1997-2005 on antiretroviral therapy-naive patients and reported to the UK HIV Drug Resistance Database. The effect on THDR rates of revisions to the IAS-DRM list was also examined. Results:Overall, 10.0%, 9.2%, and 10.4% of the 8272 samples available for analysis were classified as having THDR by the IAS-DRM, SDRM, and Stanford definitions, respectively; however, there was discordance for 244 (3%) samples. Changes in the version of the IAS-DRM list over time resulted in 4%-7% differences in the estimated rate of THDR, which increased from 4%-5% during 1997-2000 to 5%-7% during 2001-2005. Conclusions:The choice of genotypic definition had a minor influence on the estimated rate of THDR. The SDRM list is recommended for epidemiological estimates of THDR as it has been designed with such studies in mind.