pre-ART Viral Load Research Articles

CYP2B6 Genetic Polymorphisms, Depression, and Viral Suppression in Adults Living with HIV Initiating Efavirenz-Containing Antiretroviral Therapy Regimens in Uganda: Pooled Analysis of Two Prospective Studies.

Single-nucleotide polymorphisms (SNPs) in CYP2B6 have been shown to predict variation in plasma efavirenz concentrations, but associations between these SNPs and efavirenz-mediated depression and viral suppression are less well described. We evaluated three SNPs in CYP2B6 (rs3745274, rs28399499, and rs4803419) in Ugandan persons living with HIV. To define exposure, we used previously published pharmacokinetic modeling data to categorize participants as normal, intermediate, and poor efavirenz metabolizers. Our outcomes were probable depression in the first 2 years after antiretroviral therapy (ART) initiation (mean score of >1.75 on the Hopkins Symptom Depression Checklist) and viral suppression 6 months after ART initiation. We fit generalized estimating equation and modified Poisson regression models adjusted for demographic, clinical, and psychosocial characteristics with or without individuals with depression at the time of ART initiation. Among 242 participants, there were no differences in the pre-ART depression or viral load by efavirenz metabolism strata (p > .05). Participants were classified as normal (32%), intermediate (50%), and poor (18%) metabolizers. Seven percent (56/242) of follow-up visits met criteria for depression. Eighty-five percent (167/202) of participants who completed a 6-month visit achieved viral suppression. CYP2B6 metabolizer strata did not have a statistically significant association with either depression [adjusted risk ratio (aRR) comparing intermediate or poor vs. normal, 1.46; 95% confidence interval (CI), 0.72-2.95] or 6-month viral suppression (aRR, 1.01; 95% CI, 0.88-1.15). However, in analyses restricted to participants without pre-ART depression, poorer CYP2B6 metabolism was associated with increased odds of depression (adjusted odds ratio, 4.11; 95% CI, 1.04-16.20). Efavirenz-metabolizing allele patterns are strongly associated with risk of incident depression. Future work should elucidate further region-specific gene-environment interactions and whether alternate polymorphisms may be associated with efavirenz metabolism.

Long-term efficacy and safety of rilpivirine plus abacavir and lamivudine in HIV-1 infected patients with undetectable viral load.

IntroductionA regimen with rilpivirine (RPV), abacavir (ABC) and lamivudine (3TC) is simple and may allow the sparing of tenofovir and protease inhibitors. However, data on use of this combination as a strategy of switch are limited. Aims of the study were to assess the long-term efficacy and safety of this regimen.MethodsRetrospective study on HIV-1 infected patients followed at the Infectious Disease Department of the San Raffaele Scientific Institute, HBsAg-negative, HLA B5701-negative, with no documented resistance to RPV, ABC and 3TC, with HIV-RNA<50 copies/mL who started RPV plus ABC/3TC from March 2013 to September 2015.The primary outcome was durability [no treatment failure (TF)]. Secondary objectives were to evaluate changes in immunological, metabolic and other safety parameters.TF was defined as the occurrence of virological failure (VF, 2 consecutive values >50 copies/mL) or discontinuation of any drug in the regimen for any reason.Patients’ follow-up accrued from the date of RPV plus ABC/3TC initiation to the date of TF (VF or discontinuation of any drug in the regimen) or to the date of last available visit.Time to TF was evaluated by use of the Kaplan-Meier curves. Mixed linear models were applied to evaluate changes in immunological, metabolic and other safety parameters.Results and discussionIn this analysis, 100 patients starting RPV plus ABC/3TC were included. By 12, 24 and 36 months after switching to RPV plus ABC/3TC, the proportions of individuals without TF were 88% [95% confidence interval (CI): 79%-93%], 82% (95% CI:73%-89%) and 78% (95% CI:68%-86%), respectively. Time to TF was not significantly influenced by CD4+ nadir (≤200 vs >200 cells/μl; log-rank test: p = 0.311) or pre-ART viral load (<100000 vs ≥100000 copies/mL; log-rank test: p = 0.574) or the type of previous antiretroviral regimen (PI+2NRTIs vs NNRTI+2NRTIs vs Other; log-rank test: p = 0.942).Over a median follow-up of 2.9 years (IQR: 1.9–3.5), 26 subjects discontinued the treatment [10 due to toxicity, 7 for interactions with other drugs, 3 due to cardiovascular risk concern, 2 due to single viral blip, 1 due to VF, 1 for asthma, 1 patient’s decision, 1 due to enrolment in a study protocol].ConclusionsIn this retrospective study, long-term use of RPV plus ABC/3TC regimen is effective and safe. Efficacy of this regimen was not found to be affected by low CD4+ nadir or high pre-ART viral load.

Efavirenz-metabolizing polymorphisms, viral suppression, and depression in HIV-infected individuals initiating antiretroviral therapy in southwestern Uganda

BackgroundSingle-nucleotide polymorphisms (SNPs) in CYP2B6 have previously been associated with a 10-fold range in trough plasma efavirenz concentrations, but associations between these SNPs and efavirenz (EFV)-mediated viral suppression and tolerability remain unclear.MethodsWe evaluated three SNPs in CYP2B6 (rs3745274, rs28399499, and rs4803419, Illumina OmniExpress) among HIV-infected Ugandans observed in a cohort study every 3–4 months from 2005–2015. Genotypes from these SNPs were used to group participants into previously described pharmacokinetic strata: extensive (EXT), intermediate (INT), and slow metabolizers (Figure 1). The primary outcomes were viral suppression, defined by an undetectable viral load in the first measurement a minimum of three months after ART initiation, and incident depression in the first two years, defined by a mean score >1.75 on the Hopkins Symptom Checklist. We fitted standard and generalized estimating equations (GEE) logistic regression models for viral suppression and depression, respectively. Models were adjusted for clinical and demographic covariates that reached a significance of P < 0.25 in unadjusted models.ResultsAmong 103 participants with genotyping, there were no differences in pre-ART viral load or depression by metabolism strata (P > 0.5). Minor allele frequencies for rs3745274, rs28399499, and rs4803419 were 33%, 7%, and 4%, respectively. Approximately 79%, 78%, and 94% of participants were suppressed at their first viral load measurement in the extensive, intermediate, and slow metabolizer strata, respectively (Figure 2; P = 0.35). In adjusted models, metabolism strata were not associated with viral suppression (AORINT 0.81, 95% CI 0.26–2.56; AORSLOW 3.92, 95% CI 0.39–39.40) or with depression (AORINT 1.95, 95% CI 0.75–5.09; AORSLOW 0.72, 95% CI 0.17–3.02; Table).ConclusionWe did not identify an association between efavirenz-metabolizing polymorphisms and viral suppression or depression in a cohort of HIV-infected individuals initiating ART in southwestern Uganda. Future work should reassess these relationships with larger samples and longer-term outcomes and explore additional polymorphisms that may be associated with efavirenz metabolism in this population.Disclosures P. Hunt, Merck: Consultant, Consulting fee; Gilead: Consultant, Consulting fee; Viiv: Consultant, Consulting fee

Misdiagnosed HIV infection in pregnant women initiating universal ART in South Africa.

Introduction: Rapid diagnostic tests (RDTs) are the primary diagnostic tools for HIV used in resource-constrained settings. Without a proper confirmation algorithm, there is concern that false-positive (FP) RDTs could result in misdiagnosis of HIV infection and inappropriate antiretroviral treatment (ART) initiation, but programmatic data on FP are few. Methods: We examined the accuracy of RDT diagnosis among HIV-infected pregnant women attending public sector antenatal services in Cape Town, South Africa. We describe the proportion of women found to have started on ART erroneously due to FP RDT results based on pre-ART viral load (VL) testing and enzyme-linked immunosorbent assay (ELISA). Results: We analysed 952 consecutively enrolled pregnant women diagnosed as HIV infected based on two RDTs per local guideline and found 4.5% (43/952) of pre-ART VL results to be <50 copies/ml. After excluding 6 women who had detectable virus on subsequent VL measurements, ELISA was performed on the 37 remaining women. Of these, 3/952 (0.3%) HIV RDT diagnoses were found to be FP. We estimate that using ELISA to confirm all positive RDTs would cost $1110 (uncertainty interval $381–$5382) to identify one patient erroneously initiated on ART, while it costs $3912 for a lifetime of antiretrovirals with VL monitoring for one person. Conclusions: Compared to the cost of confirming the RDT-based diagnoses, the cost of HIV misdiagnosis is high. While testing programmes based on RDT should strive for constant quality improvement, where resources permit, laboratory confirmation algorithms can play an important role in strengthening the quality of HIV diagnosis in the era of universal ART.

Virologic Response to First-line Efavirenz- or Nevirapine-based Antiretroviral Therapy in HIV-infected African Children.

Poorer virologic response to nevirapine- versus efavirenz-based antiretroviral therapy (ART) has been reported in adult systematic reviews and pediatric studies. We compared drug discontinuation and viral load (VL) response in ART-naïve Ugandan/Zimbabwean children ≥3 years of age initiating ART with clinician-chosen nevirapine versus efavirenz in the ARROW trial. Predictors of suppression <80, <400 and <1000 copies/mL at 36, 48 and 144 weeks were identified using multivariable logistic regression with backwards elimination (P = 0.1). A total of 445 (53%) children received efavirenz and 391 (47%) nevirapine. Children receiving efavirenz were older (median age, 8.6 vs. 7.5 years nevirapine, P < 0.001) and had higher CD4% (12% vs. 10%, P = 0.05), but similar pre-ART VL (P = 0.17). The initial non-nucleoside-reverse-transcriptase-inhibitor (NNRTI) was permanently discontinued for adverse events in 7 of 445 (2%) children initiating efavirenz versus 9 of 391 (2%) initiating nevirapine (P = 0.46); at switch to second line in 17 versus 23, for tuberculosis in 0 versus 26, for pregnancy in 6 versus 0 and for other reasons in 15 versus 5. Early (36-48 weeks) virologic suppression <80 copies/mL was superior with efavirenz, particularly in children with higher pre-ART VL (P = 0.0004); longer-term suppression was superior with nevirapine in older children (P = 0.05). Early suppression was poorer in the youngest and oldest children, regardless of NNRTI (P = 0.02); longer-term suppression was poorer in those with higher pre-ART VL regardless of NNRTI (P = 0.05). Results were broadly similar for <400 and <1000 copies/mL. Short-term VL suppression favored efavirenz, but long-term relative performance was age dependent, with better suppression in older children with nevirapine, supporting World Health Organization recommendation that nevirapine remains an alternative NNRTI.

Durability of viral suppression with first-line antiretroviral therapy in patients with HIV in the UK: an observational cohort study

SummaryBackgroundThe length of time that people with HIV on antiretroviral therapy (ART) with viral load suppression will be able to continue before developing viral rebound is unknown. We aimed to investigate the rate of first viral rebound in people that have achieved initial suppression with ART, to determine factors associated with viral rebound, and to use these estimates to predict long-term durability of viral suppression.MethodsThe UK Collaborative HIV Cohort (UK CHIC) Study is an ongoing multicentre cohort study that brings together in a standardised format data on people with HIV attending clinics around the UK. We included participants who started ART with three or more drugs and who had achieved viral suppression (≤50 copies per mL) by 9 months after the start of ART (baseline). Viral rebound was defined as the first single viral load of more than 200 copies per mL or treatment interruption (for ≥1 month). We investigated factors associated with viral rebound with Poisson regression. These results were used to calculate the rate of viral rebound according to several key factors, including age, calendar year at start of ART, and time since baseline.ResultsOf the 16 101 people included, 4519 had a first viral rebound over 58 038 person-years (7·8 per 100 person-years, 95% CI 7·6–8·0). Of the 4519 viral rebounds, 3105 (69%) were defined by measurement of a single viral load of more than 200 copies per mL, and 1414 (31%) by a documented treatment interruption. The rate of first viral rebound declined substantially over time until 7 years from baseline. The other factors associated with viral rebound were current age at follow-up and calendar year at ART initiation (p<0·0001) and HIV risk group (p<0·0001); higher pre-ART CD4 count (p=0·0008) and pre-ART viral load (p=0·0003) were associated with viral rebound in the multivariate analysis only. For 1322 (29%) of the 3105 people with observed viral rebound, the next viral load value after rebound was 50 copies per mL or less with no regimen change. For HIV-positive men who have sex with men, our estimates suggest that the probability of first viral rebound reaches a plateau of 1·4% per year after 45 years of age, and 1·0% when accounting for the fact that 29% of viral rebounds are temporary elevations.InterpretationA substantial proportion of people on ART will not have viral rebound over their lifetime, which has implications for people with HIV and the planning of future drug development.FundingUK Medical Research Council.

Determinants of virological outcome and adverse events in African children treated with paediatric nevirapine fixed-dose-combination tablets.

Nevirapine is the only nonnucleoside reverse transcriptase inhibitor currently available as a paediatric fixed-dose-combination tablet and is widely used in African children. Nonetheless, the number of investigations into pharmacokinetic determinants of virological suppression in African children is limited, and the predictive power of the current therapeutic range was never evaluated in this population, thereby limiting treatment optimization. We analysed data from 322 African children (aged 0.3-13 years) treated with nevirapine, lamivudine, and either abacavir, stavudine, or zidovudine, and followed up to 144 weeks. Nevirapine trough concentration (Cmin) and other factors were tested for associations with viral load more than 100 copies/ml and transaminase increases more than grade 1 using proportional hazard and logistic models in 219 initially antiretroviral treatment (ART)-naive children. Pre-ART viral load, adherence, and nevirapine Cmin were associated with viral load nonsuppression [hazard ratio = 2.08 (95% confidence interval (CI): 1.50-2.90, P < 0.001) for 10-fold higher pre-ART viral load, hazard ratio = 0.78 (95% CI: 0.68-0.90, P < 0.001) for 10% improvement in adherence, and hazard ratio = 0.94 (95% CI: 0.90-0.99, P = 0.014) for a 1 mg/l increase in nevirapine Cmin]. There were additional effects of pre-ART CD4 cell percentage and clinical site. The risk of virological nonsuppression decreased with increasing nevirapine Cmin, and there was no clear Cmin threshold predictive of virological nonsuppression. Transient transaminase elevations more than grade 1 were associated with high Cmin (>12.4 mg/l), hazard ratio = 5.18 (95% CI 1.95-13.80, P < 0.001). Treatment initiation at lower pre-ART viral load and higher pre-ART CD4 cell percentage, increased adherence, and maintaining average Cmin higher than current target could improve virological suppression of African children treated with nevirapine without increasing toxicity.

Effect of Pregnancy on Response to Antiretroviral Therapy in HIV-Infected African Women.

Background:While most recent evidence does not support a role for pregnancy in accelerating HIV disease progression, very little information is available on the effects of incident pregnancy in response to antiretroviral therapy (ART). Hormonal, immune, and behavioral changes during pregnancy may influence response to ART. We sought to explore the effects of incident pregnancy (after ART initiation) on virologic, immunologic, and clinical response to ART.Methods:Data were collected from HIV-infected women participating in 3 prospective studies (Partners in Prevention Herpes simplex virus/HIV Transmission Study, Couples Observational Study, and Partners Preexposure Prophylaxis Study) from 7 countries in Africa from 2004 to 2012. Women were included in this analysis if they were ≤45 years of age, were started on ART during the study and were not pregnant at ART initiation. Pregnancy was treated as a time-dependent exposure variable covering the duration of pregnancy, including all pregnancies occurring after ART initiation. Virologic failure was defined as a viral load (VL) greater than 400 copies per milliliter ≥6 months after ART initiation and viral suppression was defined as VL ≤400 copies per milliliter. Multivariable Cox proportional hazards models were used to assess the association between pregnancy and time to viral suppression, virologic failure, World Health Organization clinical stage III/IV, and death. Linear mixed-effects models were used to assess the association between pregnancy and CD4+ count and VL. All analyses were adjusted for confounders, including pre-ART CD4+ count and plasma VL.Results:A total of 1041 women were followed, contributing 1196.1 person-years of follow-up. Median CD4+ count before ART initiation was 276 cells per cubic millimeter (interquartile range, 209–375); median pre-ART VL was 17,511 copies per milliliter (interquartile range, 2480–69,286). One hundred ten women became pregnant after ART initiation. Pregnancy was not associated with time to viral suppression (adjusted hazard ratio [aHR], 1.20, 95% confidence interval [CI]: 0.82 to 1.77), time to virologic failure (aHR, 0.67, 95% CI: 0.37 to 1.22), time to World Health Organization clinical stage III or IV (aHR, 0.79, 95% CI: 0.19 to 3.30), or time to death (aHR, 2.04, 95% CI: 0.25 to 16.8). Incident pregnancy was associated with an adjusted mean decrease in CD4+ T-cell count of 47.3 cells per cubic millimeter (P < 0.001), but not with difference in VL (P = 0.06).Conclusions:For HIV-infected women on ART, incident pregnancy does not affect virologic control or clinical HIV disease progression. A modest decrease in CD4+ T-cell count could be due to physiologic effects of pregnancy.

Frequency of Viremic Episodes in HIV-Infected Women Initiating Antiretroviral Therapy During Pregnancy: A Cohort Study.

The numbers of human immunodeficiency virus (HIV)-infected women initiating antiretroviral therapy (ART) in pregnancy are increasing rapidly with global policy changes. There are widespread concerns about ART adherence during pregnancy and postpartum but few data on viral suppression (VS) over time in these populations. We followed a cohort of 523 women in Cape Town, South Africa, initiating ART in pregnancy (once-daily tenofovir 300 mg, emtricitabine 200 mg, and efavirenz 600 mg) and achieving VS (<50 copies/mL). Participants provided specimens through 12 months postpartum for batched viral load (VL) testing separate from routine care. Analyses described the incidence of major (>1000 copies/mL) and minor (50-1000 copies/mL) viremic episodes (VEs) and factors associated with major VEs. In the cohort (median age, 28 years; median pre-ART VL, 3.99 copies/mL; 3% previously defaulted ART; 24% with previous exposure to short-course antiretrovirals), the median time of follow-up from VS was 322 days. Overall, 70% maintained VS throughout follow-up, 8% experienced minor VEs only, and at least 1 major VE was documented in 22% of women. In women with VEs, peak viremia (median, 3.79 log10 copies/mL) was linearly related to pre-ART VL. The incidence of major VEs after initial VS was independently associated with younger age, ART initiation during the third trimester, previous defaulting on ART, and postpartum follow-up. Viremia appears to occur frequently, particularly postpartum, among HIV-infected women after initial VS in this setting. More intensive VL monitoring is warranted in this population; the immediate causes and long-term implications of VE require investigation.

High Viremia and Wasting Before Antiretroviral Therapy Are Associated With Pneumonia in Early-Treated HIV-Infected Kenyan Infants.

Human immunodeficiency virus (HIV)-infected children are particularly susceptible to acute respiratory infections (ARIs). We determined incidence and cofactors for ARIs in HIV-infected infants receiving antiretroviral therapy (ART). Human immunodeficiency virus-infected infants initiated ART at ≤12 months of age and were observed monthly for 2 years in Nairobi. Acute respiratory infection rates and cofactors were determined using Andersen-Gill models, allowing for multiple events per infant. Among 111 HIV-infected infants, median age at ART initiation was 4.5 months. Pre-ART median CD4% was 19%, and 29% had wasting. During 24-months follow-up while on ART, upper respiratory infection (URI) and pneumonia rates were 122.6 and 34.7 per 100 person-years (py), respectively. Infants with higher pre-ART viral load (VL) (plasma HIV ribonucleic acid [RNA] ≥7 log10 copies/mL) had 4.12-fold increased risk of pneumonia (95% confidence interval [CI], 2.17-7.80), and infants with wasting (weight-for-height z-score < -2) had 2.87-fold increased risk (95% CI, 1.56-5.28). Infants with both high pre-ART VL and wasting had a higher pneumonia rate (166.8 per 100 py) than those with only 1 of these risk factors (44.4 per 100 py) or neither (17.0 per 100 py). Infants with exposure to wood fuel had significantly higher risk of URI (hazard ratio [HR] = 1.82; 95% CI, 1.44-2.28) and pneumonia (HR = 3.31; 95% CI, 1.76-6.21). In early ART-treated HIV-infected infants, higher HIV RNA and wasting before ART were independent risk factors for pneumonia. Wood fuel use was associated with URI and pneumonia. Additional data on air pollution and respiratory outcomes in HIV-infected children may help optimize interventions to improve their lung health.

HIV viraemia and mother‐to‐child transmission risk after antiretroviral therapy initiation in pregnancy in Cape Town, South Africa

Maternal HIV viral load (VL) drives mother-to-child HIV transmission (MTCT) risk but there are few data from sub-Saharan Africa, where most MTCT occurs. We investigated VL changes during pregnancy and MTCT following antiretroviral therapy (ART) initiation in Cape Town, South Africa. We conducted a prospective study of HIV-infected women initiating ART within routine antenatal services in a primary care setting. VL measurements were taken before ART initiation and up to three more times within 7 days postpartum. Analyses examined VL changes over time, viral suppression (VS) at delivery, and early MTCT based on polymerase chain reaction (PCR) testing up to 8 weeks of age. A total of 620 ART-eligible HIV-infected pregnant women initiated ART, with 2425 VL measurements by delivery (median gestation at initiation, 20 weeks; median pre-ART VL, 4.0 log10 HIV-1 RNA copies/mL; median time on ART before delivery, 118 days). At delivery, 91% and 73% of women had VL ≤ 1000 and ≤ 50 copies/mL, respectively. VS was strongly predicted by time on therapy and pre-ART VL. The risk of early MTCT was strongly associated with delivery VL, with risks of 0.25, 2.0 and 8.5% among women with VL < 50, 50-1000 and > 1000 copies/mL at delivery, respectively (P < 0.001). High rates of VS at delivery and low rates of MTCT can be achieved in a routine care setting in sub-Saharan Africa, indicating the effectiveness of currently recommended ART regimens. Women initiating ART late in pregnancy and with high VL appear substantially less likely to achieve VS and require targeted research and programmatic attention.

Short-term treatment outcomes in human immunodeficiency virus type-1 and hepatitis B virus co-infections.

BackgroundCo-infection of HIV with HBV is common in West Africa but little information is available on the effects of HBV on short-term therapy for HIV patients. A 28 day longitudinal study was conducted to examine short-term antiretroviral therapy (ART) outcomes in HIV infected individuals with HBV co-infection.MethodsPlasma from 18 HIV infected individuals co-infected with HBV and matched controls with only HIV infection were obtained at initiation, and 7 and 28 days after ART. HIV-1 viral load changes were monitored. Clinical and demographic data were also obtained from patient folders, and HIV-1 drug resistance mutation and subtype analysis performed.ResultsThe presence of HBV co-infection did not significantly affect HIV-1 viral load changes within 7 or 28 days. The CD4+ counts on the other hand of patients significantly affected the magnitude of HIV-1 viral load decline after 7 days (ρ = −0.441, p = 0.040), while the pre-ART HIV-1 VL (ρ = 0.844, p = <0.001) and sex (U = 19.0, p = 0.020) also determined HIV-1 viral load outcomes after 28 days of ART. Even though the geometric sensitivity score of HIV-1 strains were influenced by the HIV-1 subtypes (U = 56.00; p = 0.036), it was not a confounder for ART outcomes.ConclusionsThere may be the need to consider the confounder effects of sex, pre-ART CD4+, and pre-ART HIV-1 viral load in the discourse on HIV and HBV co-infection.

Factors associated with HIV viral load "blips" and the relationship between self-reported adherence and efavirenz blood levels on blip occurrence: a case-control study.

BackgroundThe uncertain etiology of HIV viral load (VL) blips may lead to increased use of clinical resources. We evaluated the association of self-reported adherence (SRA) and antiretroviral (ART) drug levels on blip occurrence in US Military HIV Natural History Study (NHS) participants who initiated the single-tablet regimen efavirenz/emtricitabine/tenofovir disoproxil fumarate (EFV/FTC/TDF).MethodsART-naïve NHS participants started on EFV/FTC/TDF between 2006 and 2013 who achieved VL suppression (<50 copies/mL) within 12 months and had available SRA and stored plasma samples were included. Participants with viral blips were compared with those who maintained VL suppression without blips. Untimed EFV plasma levels were evaluated on consecutive blip and non-blip dates by high performance liquid chromatography, with a level ≥1 mcg/mL considered therapeutic. SRA was categorized as ≥85 or <85 %. Descriptive statistics were performed for baseline characteristics and univariate and multivariate Cox proportional hazard models were used to assess the relationship between covariates and blip occurrence.ResultsA total of 772 individuals met inclusion criteria, including 99 (13 %) blip and 673 (87 %) control participants. African-American was the predominant ethnicity and the mean age was 29 years for both groups. SRA ≥ 85 % was associated with therapeutic EFV levels at both blip and non-blip time points (P = 0.0026); however no association was observed between blips and SRA or EFV levels among cases. On univariate analysis of cases versus controls, blips were associated with higher mean pre-treatment VL (HR 1.45, 95 % CI 1.11–1.89) and pre-treatment CD4 count <350 cells/µL (68.1 vs 49.7 %). Multivariate analysis also showed that blips were associated with a higher mean VL (HR 1.42, 95 % CI 1.08–1.88; P = 0.0123) and lower CD4 count at ART initiation, with CD4 ≥500 cells/µL having a protective effect (HR 0.45, 95 % CI 0.22–0.95; P = 0.0365). No association was observed for demographic characteristics or SRA.ConclusionBlips are commonly encountered in the clinical management of HIV-infected patients. Although blip occurrence was not associated with SRA or EFV blood levels in our study, blips were associated with HIV-related factors of pre-ART high VL and low CD4 count. Additional studies are needed to determine the etiology of blips in HIV-infected patients.

A case for preART-adjusted endpoints in HIV therapeutic vaccine trials

BackgroundIn a randomized, double-blind, placebo-controlled phase 2 clinical trial of Vacc-4x, a peptide-based therapeutic HIV-1 p24Gag vaccine candidate, 135 HIV-infected participants (vaccine:placebo=92:43) received a series of six immunizations while on combination antiretroviral therapy (cART). At week 28, all participants underwent an analytical treatment interruption (ATI) for up to 24 weeks. preART VL appeared to be higher among Vacc-4x recipients. Based on a previous analysis, during ATI viral load (VL) appeared to be lower in Vacc-4x recipients, but no difference in CD4 level was observed between Vacc-4x and placebo groups. We propose fold-change-based endpoints and report comparative analyses accounting for imbalanced preART VL and missing data. MethodsAll analyses included per-protocol (PP) participants who received the full immunization and underwent ATI. Linear regression models were used to identify predictors of study endpoints and to estimate the vaccine effect based on fold changes in CD4 counts or VL over preART values at week 40 or at set-point (geometric mean over weeks 48 and 52 values). We adjusted for potential baseline factors and used a multiple imputation approach to account for missing endpoints due to cART resumption or dropout. P-values were adjusted for multiple comparisons using q-values. ResultspreART VL and CD4 count were significant predictors of study endpoints. The vaccine recipients had a higher fold change in week 40 CD4 counts (vaccine vs. placebo mean fold-change difference=0.08; p=0.02; q=0.03), a higher fold change in CD4 count set-point (0.06; p=0.06; q=0.07), a lower fold change in week 40 VL (−0.47; p=0.03; q=0.05), and a lower fold change in VL set-point (−0.50; p=0.02; q=0.03). ConclusionsThese exploratory analyses consistently suggested that Vacc-4x provided positive effects on both CD4 counts and VL. Future HIV therapeutic vaccine studies may adopt similar preART-adjusted endpoints and missing data imputation methods in vaccine effect evaluations.

High Prevalence of Dyslipidemia and Insulin Resistance in HIV-infected Prepubertal African Children on Antiretroviral Therapy.

Data describing the true extent of antiretroviral therapy (ART)-induced dyslipidemia and insulin resistance in perinatally infected children on ART in Africa are sparse. Fasting total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglycerides, insulin and glucose were performed on the first 100 of 190 pediatric ART clinic attendees. Diet assessment was performed by a trained dietician. Lipoatrophy was formally graded by consensus between 2 expert HIV pediatricians. Durations of previous ART exposures, clinical stage, pre-ART viral load, nadir and current CD4 were recorded. Dual-energy X-ray absorptiometry was performed on a subset of 42 patients selected semi-randomly. Prevalences of insulin resistance, abnormal total cholesterol, LDL, HDL and triglyceride were 10%, 13%, 12%, 13% and 9%, respectively. Overall, 40% had at least 1 lipid abnormality or insulin resistance. Adjusted mean LDL cholesterol increased by 0.24 mmol/L for each additional year of cumulative lopinavir/r exposure (P = 0.03) after correcting for age, gender, body mass index, previous stavudine exposure, age at ART initiation, dietary fat and refined carbohydrate, whereas adjusted mean LDL cholesterol was 0.9 mmol/L higher in children exposed to efavirenz within the previous 6 months (P = 0.02). Adjusting for age, gender and ethnicity, dual-energy X-ray absorptiometry revealed that greater trunk fat and lower peripheral subcutaneous fat were associated with elevated triglycerides but not with total cholesterol, LDL, HDL or homeostatic model assessment. Similarly, the presence of visually obvious lipoatrophy was associated with elevated triglycerides but not with total cholesterol, LDL, HDL, homeostatic model assessment or lactate. Prevalences of insulin resistance and dyslipidemia were high. Cumulative lopinavir is an independent risk factor for dyslipidemia, with efavirenz exposure having only transitory effect.

Single-dose nevirapine exposure does not affect response to antiretroviral therapy in HIV-infected African children aged below 3 years.

To assess the impact of exposure to single-dose nevirapine (sdNVP) on virological response in young Ugandan/Zimbabwean children (<3 years) initiating antiretroviral therapy (ART), and to investigate other predictors of response. Observational analysis within the ARROW randomized trial. sdNVP exposure was ascertained by the caregiver's self-report when the child initiated non-nucleoside reverse transcriptase inhibitor (NNRTI)-based ART. Viral load was assayed retrospectively over a median 4.1 years of follow-up. Multivariable logistic regression models were used to identify independent predictors of viral load below 80 copies/ml, 48 and 144 weeks after ART initiation (backwards elimination, exit P = 0.1). Median (IQR) age at ART initiation was 17 (10-23) months in 78 sdNVP-exposed children vs. 21 (14-27) months in 289 non-exposed children (36 vs. 20% <12 months). At week 48, 49 of 73 (67%) sdNVP-exposed and 154 of 272 (57%) non-exposed children had viral load below 80 copies/ml [adjusted odds ratio (aOR) 2.34 (1.26-4.34), P = 0.007]; 79 and 77% had viral load below 400 copies/ml. Suppression was significantly lower in males (P = 0.009), those with higher pre-ART viral load (P = 0.001), taking syrups (P = 0.05) and with lower self-reported adherence (P = 0.04). At week 144, 55 of 73 (75%) exposed and 188 of 272 (69%) non-exposed children had less than 80 copies/ml [aOR 1.75 (0.93-3.29), P = 0.08]. There was no difference between children with and without previous sdNVP exposure in intermediate/high-level resistance to NRTIs (P > 0.3) or NNRTIs (P > 0.1) (n = 88) at week 144. Given the limited global availability of lopinavir/ritonavir, its significant formulation challenges in young children, and the significant paediatric treatment gap, tablet fixed-dose-combination NVP-based ART remains a good alternative to syrup lopinavir-based ART for children, particularly those over 1 year and even if exposed to sdNVP.

During Stably Suppressive Antiretroviral Therapy Integrated HIV-1 DNA Load in Peripheral Blood is Associated with the Frequency of CD8 Cells Expressing HLA-DR/DP/DQ

BackgroundCharacterising the correlates of HIV persistence improves understanding of disease pathogenesis and guides the design of curative strategies. This study investigated factors associated with integrated HIV-1 DNA load during consistently suppressive first-line antiretroviral therapy (ART). MethodTotal, integrated, and 2-long terminal repeats (LTR) circular HIV-1 DNA, residual plasma HIV-1 RNA, T-cell activation markers, and soluble CD14 (sCD14) were measured in peripheral blood of 50 patients that had received 1–14years of efavirenz-based or nevirapine-based therapy. ResultsIntegrated HIV-1 DNA load (per 106 peripheral blood mononuclear cells) was median 1.9 log10 copies (interquartile range 1.7–2.2) and showed a mean difference of 0.2 log10 copies per 10years of suppressive ART (95% confidence interval −0.2, 0.6; p=0.28). It was positively correlated with total HIV-1 DNA load and frequency of CD8+HLA-DR/DP/DQ+ cells, and was also higher in subjects with higher sCD14 levels, but showed no correlation with levels of 2-LTR circular HIV-1 DNA and residual plasma HIV-1 RNA, or the frequency of CD4+CD38+ and CD8+CD38+ cells. Adjusting for pre-ART viral load, duration of suppressive ART, CD4 cell counts, residual plasma HIV-1 RNA levels, and sCD14 levels, integrated HIV-1 DNA load was mean 0.5 log10 copies higher for each 50% higher frequency of CD8+HLA-DR/DP/DQ+ cells (95% confidence interval 0.2, 0.9; p=0.01). ConclusionsThe observed positive association between integrated HIV-1 DNA load and frequency of CD8+DR/DP/DQ+ cells indicates that a close correlation between HIV persistence and immune activation continues during consistently suppressive therapy. The inducers of the distinct activation profile warrant further investigation.

Rate of viral load failure over time in people on ART in the UK Collaborative HIV Cohort (CHIC) study.

IntroductionMost people achieve and maintain viral load (VL) suppression on first-line antiretroviral therapy (ART) but for a minority this does not happen. It is unclear whether those who have maintained VL suppression for several years will be able to continue to do so, or if rates of VL failure – due to poor adherence, ART interruption and/or resistance – remain at appreciable levels.MethodsEligible participants were ART-naïve and started treatment after 1st January 2000, with ≥3 antiretrovirals and ≥9 months follow-up. VL failure was defined as failure to achieve VL suppression (≤50 copies/mL) by 9 months on ART or a single VL >200 copies/mL after 9 months after start of ART. Kaplan-Meier estimates were used to examine the cumulative probability of experiencing a VL >200 copies/mL over time, irrespective of treatment interruption (Figure 1). Follow-up was censored at last VL assessment but not at treatment interruption. In a sensitivity analysis, VL failure was instead defined as two consecutive VL >1000 copies/mL.ResultsA total of 13,556 participants were included. Median (IQR) age at start of ART was 37 (32–43), median follow-up 4.1 (2.3–6.7) years, pre-ART VL 71,400 (17,400–221,900) copies/mL and pre-ART CD4 count 204 (110–290) cells/mm3. Fifty-one percent were white, 71% male and 50% MSM. Of which, 5,351 (39%) participants experienced a VL >200 copies/mL. In sub-groups of participants the proportion experiencing a VL >200 copies/mL by one year after start of ART were: <50 years 22%, ≥50 years 17%, men 20%, women 26%, MSM 19%, black heterosexuals 23%, white heterosexuals 26% and other 23%. The median time to VL >200 copies/ml was 8 years. In sensitivity analyses based on 12,811 participants, 4274 (33%) experienced two consecutive VL >1000 copies/mL. Table 1 presents the rate of experiencing a VL >200 copies/mL (two consecutive VL >1000 copies/mL) by time since start of ART. The rate of VL >200 copies/mL declines over time, from 30 per 100 person-years after up to two years after ART, to two per 100 person-years after up to 11.5 years after ART. A sum of 2,047 (15%) participants stopped ART at some point (10, 14 and 17% had stopped ART by 1, 3, and 5 years, respectively). ConclusionsAlthough resistance will often not be present and, even if present, several drug options will likely remain, first occurrence of VL > 200 copies/mL after having attained viral suppression continues to occur after 10 years on ART.

Diabetes mellitus in HIV-infected patients receiving antiretroviral therapy

There is little in the literature on HIV and diabetes mellitus (DM) in sub-Saharan Africa. To assess the characteristics of HIV and DM in patients receiving antiretroviral therapy (ART) in Botswana. A retrospective case-control study was conducted at 4 sites. Each HIV-infected patient with DM (n=48) was matched with 2 HIV-infected controls (n=108) by age (±2 years) and sex. Primary analysis was conditional logistic regression to estimate univariate odds and 95% confidence intervals (CIs) for each characteristic. There was no significant association between co-morbid diseases, tuberculosis, hypertension or cancer and risk of diabetes. DM patients were more likely to have higher pre-ART weight (odds ratio (OR) 1.09; 95% CI 1.04 - 1.14). HIV-infected adults >70 kg were significantly more likely to have DM (OR 12.30; 95% CI 1.40 - 107.98). Participants receiving efavirenz (OR 4.58; 95% CI 1.44 - 14.57) or protease inhibitor therapy (OR 20.7; 95% CI 1.79 - 240.02) were more likely to have DM. Neither mean pre-ART CD4 cell count (OR 1.0; 95% CI 0.99 - 1.01) nor pre-ART viral load >100 000 copies/ml (OR 0.71; 95% CI 0.21 - 2.43) were associated with a significant risk of diabetes. These findings suggest a complex interrelation among traditional host factors and treatment-related metabolic changes in the pathogenesis of DM inpatients receiving ART. Notably, pre-ART weight, particularly if >70 kg, is associated with the diagnosis of diabetes in HIV-infected patients in Botswana.

Nevirapine/zidovudine/lamivudine has superior immunological and virological responses not reflected in clinical outcomes in a 48‐week randomized comparison with abacavir/zidovudine/lamivudine in HIV‐infected Ugandan adults with low CD4 cell counts

Triple nucleoside reverse transcriptase inhibitor regimens have advantages as first-line antiretroviral therapy (ART), avoiding hepatotoxicity and interactions with anti-tuberculosis therapy, and sparing two drug classes for second-line ART. Concerns exist about virological potency; efficacy has not been assessed in Africa. A safety trial comparing nevirapine with abacavir was conducted in two Ugandan Development of Antiretroviral Therapy in Africa (DART) centres: 600 symptomatic antiretroviral-naïve HIV-infected adults with CD4 counts <200 cells/microL were randomized to zidovudine/lamivudine plus abacavir or nevirapine (placebo-controlled to 24-week primary toxicity endpoint, and then open-label). Documented World Health Organization (WHO) stage 4 events were independently reviewed and plasma HIV-1 RNA assayed retrospectively. Exploratory efficacy analyses are intention-to-treat. The median pre-ART CD4 count was 99 cells/microL, and the median pre-ART viral load was 284 600 HIV-1 RNA copies/mL. A total of 563 participants (94%) completed 48 weeks of follow-up, 25 (4%) died and 12 (2%) were lost to follow-up. The randomized drug was substituted in 21 participants (7%) receiving abacavir vs. 34 (11%) receiving nevirapine (P=0.09). At 48 weeks, 62% of participants receiving abacavir vs. 77% of those receiving nevirapine had viral loads <50 copies/mL (P<0.001), and mean CD4 count increases from baseline were +147 vs. +173 cells/microL, respectively (P=0.006). Nine participants (3%) receiving abacavir vs. 16 (5%) receiving nevirapine died [hazard ratio (HR) 0.55; 95% confidence interval (CI) 0.24-1.25; P=0.15]; 20 receiving abacavir vs. 32 receiving nevirapine developed new or recurrent WHO 4 events or died (HR=0.60; 95% CI 0.34-1.05; P=0.07) and 48 receiving abacavir vs. 68 receiving nevirapine developed new or recurrent WHO 3 or 4 events or died (HR=0.67; 95% CI 0.46-0.96; P=0.03). Seventy-one participants (24%) receiving abacavir experienced 91 grade 4 adverse events compared with 130 events in 109 participants (36%) on nevirapine (P<0.001). The clear virological/immunological superiority of nevirapine over abacavir was not reflected in clinical outcomes over 48 weeks. The inability of CD4 cell count/viral load to predict initial clinical treatment efficacy is unexplained and requires further evaluation.