Cost-effectiveness of early treatment with first-line NNRTI-based HAART regimens in the UK, 1996-2006

Aim

Calculate time to first-line treatment failure, annual cost and cost-effectiveness of NNRTI versus PIboosted first-line HAART regimens in the UK, 1996–2006.

Background

Population costs for HIV services are increasing in the UK and interventions need to be effective and efficient to reduce or stabilize costs. 2NRTIs + NNRTI regimens are cost-effective regimens for first-line HAART, but these regimens have not been compared with first-line PI_boosted regimens.

Methods

Times to first-line treatment failure and annual costs were calculated for first-line HAART regimens by CD4 count when starting HAART (2006 UK prices). Cost-effectiveness of 2NRTIs+NNRTI versus 2NRTIs+PI_boosted regimens was calculated for four CD4 strata.

Results

55% of 5,541 people living with HIV (PLHIV) started HAART with CD4 count ≤200 cells/mm3, many of whom were Black Africans. Annual treatment cost decreased as CD4 count increased; most marked differences were observed between starting HAART with CD4 ≤200 cells/mm3 compared with CD4 count >200 cells/mm3. 2NRTI+PI_boosted and 2NRTI+NNRTI regimens were the most effective regimens across the four CD4 strata; 2NRTI+NNRTI was cost-saving or cost-effective compared with 2NRTI + PI_boosted regimens.

Conclusion

To ensure more effective and efficient provision of HIV services, 2NRTI+NNRTI should be started as first-line HAART regimen at CD4 counts ≤350 cell/mm3, unless specific contra-indications exist. This will increase the number of PLHIV receiving HAART and will initially increase population costs of providing HIV services. However, starting PLHIV earlier on cost-effective regimens will maintain them in better health and use fewer health or social services, thereby generating fewer treatment and care costs, enabling them to remain socially and economically active members of society. This does raise a number of ethical issues, which will have to be acknowledged and addressed, especially in countries with limited resources.     

Cost-effectiveness of primary prophylaxis of AIDS associated cryptococcosis in Cambodia

Background

Cryptococcal infection is a frequent cause of mortality in Cambodian HIV-infected patients with CD4+ count ≤100 cells/µl. This study assessed the cost-effectiveness of three strategies for cryptococcosis prevention in HIV-infected patients.

Methods

A Markov decision tree was used to compare the following strategies at the time of HIV diagnosis: no intervention, one time systematic serum cryptococcal antigen (CRAG) screening and treatment of positive patients, and systematic primary prophylaxis with fluconazole. The trajectory of a hypothetical cohort of HIV-infected patients with CD4+ count ≤100 cells/µl initiating care was simulated over a 1-year period (cotrimoxazole initiation at enrollment; antiretroviral therapy within 3 months). Natural history and cost data (US$ 2009) were from Cambodia. Efficacy data were from international literature.

Results

In a population in which 81% of patients had a CD4+ count ≤50 cells/ µl and 19% a CD4+ count between 51–100 cells/µl, the proportion alive 1 year after enrolment was 61% (cost $ 472) with no intervention, 70% (cost $ 483) with screening, and 72% (cost $ 492) with prophylaxis. After one year of follow-up, the cost-effectiveness of screening vs. no intervention was US$ 180/life year gained (LYG). The cost-effectiveness of prophylaxis vs. screening was $ 511/LYG. The cost-effectiveness of prophylaxis vs. screening was estimated at $1538/LYG if the proportion of patients with CD4+ count ≤50 cells/µl decreased by 75%.

Conclusion

In a high endemic area of cryptococcosis and HIV infection, serum CRAG screening and prophylaxis are two cost effective strategies to prevent AIDS associated cryptococcosis in patients with CD4+ count ≤100 cells/µl, at a short-term horizon, screening being more cost-effective but less effective than prophylaxis. Systematic primary prophylaxis may be preferred in patients with CD4+ below 50 cells/µl while systematic serum CRAG screening for early targeted treatment may be preferred in patients with CD4+ between 51–100 cells/µl.     

Association of differentiation state of CD4+ T cells and disease progression in HIV-1 perinatally infected children

Background

In the USA, most HIV-1 infected children are on antiretroviral drug regimens, with many individuals surviving through adolescence and into adulthood. The course of HIV-1 infection in these children is variable, and understudied.

Methodology/Principal Findings

We determined whether qualitative differences in immune cell subsets could explain a slower disease course in long term survivors with no evidence of immune suppression (LTS-NS; CD4%≥25%) compared to those with severe immune suppression (LTS-SS; CD4%≤15%). Subjects in the LTS-NS group had significantly higher frequencies of naïve (CCR7+CD45RA+) and central memory (CCR7+CD45RA−) CD4+ T cells compared to LTS-SS subjects (p = 0.0005 and <0.0001, respectively). Subjects in the rapid progressing group had significantly higher levels of CD4+ T_EMRA (CCR7−CD45RA+) cells compared to slow progressing subjects (p<0.0001).

Conclusions/Significance

Rapid disease progression in vertical infection is associated with significantly higher levels of CD4+ T_EMRA (CCR7−CD45RA+) cells.     

CD4 Cell Count and the Risk of AIDS or Death in HIV-Infected Adults on Combination Antiretroviral Therapy with a Suppressed Viral Load: A Longitudinal Cohort Study from COHERE

Background

Most adults infected with HIV achieve viral suppression within a year of starting combination antiretroviral therapy (cART). It is important to understand the risk of AIDS events or death for patients with a suppressed viral load.

Methods and Findings

Using data from the Collaboration of Observational HIV Epidemiological Research Europe (2010 merger), we assessed the risk of a new AIDS-defining event or death in successfully treated patients. We accumulated episodes of viral suppression for each patient while on cART, each episode beginning with the second of two consecutive plasma viral load measurements <50 copies/µl and ending with either a measurement >500 copies/µl, the first of two consecutive measurements between 50–500 copies/µl, cART interruption or administrative censoring. We used stratified multivariate Cox models to estimate the association between time updated CD4 cell count and a new AIDS event or death or death alone. 75,336 patients contributed 104,265 suppression episodes and were suppressed while on cART for a median 2.7 years. The mortality rate was 4.8 per 1,000 years of viral suppression. A higher CD4 cell count was always associated with a reduced risk of a new AIDS event or death; with a hazard ratio per 100 cells/µl (95% CI) of: 0.35 (0.30–0.40) for counts <200 cells/µl, 0.81 (0.71–0.92) for counts 200 to <350 cells/µl, 0.74 (0.66–0.83) for counts 350 to <500 cells/µl, and 0.96 (0.92–0.99) for counts ≥500 cells/µl. A higher CD4 cell count became even more beneficial over time for patients with CD4 cell counts <200 cells/µl.

Conclusions

Despite the low mortality rate, the risk of a new AIDS event or death follows a CD4 cell count gradient in patients with viral suppression. A higher CD4 cell count was associated with the greatest benefit for patients with a CD4 cell count <200 cells/µl but still some slight benefit for those with a CD4 cell count ≥500 cells/µl. Please see later in the article for the Editors'' Summary     

Randomized trial of time-limited interruptions of protease inhibitor-based antiretroviral therapy (ART) vs. continuous therapy for HIV-1 infection

Background

The clinical outcomes of short interruptions of PI-based ART regimens remains undefined.

Methods

A 2-arm non-inferiority trial was conducted on 53 HIV-1 infected South African participants with viral load <50 copies/ml and CD4 T cell count >450 cells/µl on stavudine (or zidovudine), lamivudine and lopinavir/ritonavir. Subjects were randomized to a) sequential 2, 4 and 8-week ART interruptions or b) continuous ART (cART). Primary analysis was based on the proportion of CD4 count >350 cells(c)/ml over 72 weeks. Adherence, HIV-1 drug resistance, and CD4 count rise over time were analyzed as secondary endpoints.

Results

The proportions of CD4 counts >350 cells/µl were 82.12% for the intermittent arm and 93.73 for the cART arm; the difference of 11.95% was above the defined 10% threshold for non-inferiority (upper limit of 97.5% CI, 24.1%; 2-sided CI: −0.16, 23.1). No clinically significant differences in opportunistic infections, adverse events, adherence or viral resistance were noted; after randomization, long-term CD4 rise was observed only in the cART arm.

Conclusion

We are unable to conclude that short PI-based ART interruptions are non-inferior to cART in retention of immune reconstitution; however, short interruptions did not lead to a greater rate of resistance mutations or adverse events than cART suggesting that this regimen may be more forgiving than NNRTIs if interruptions in therapy occur.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00100646","term_id":"NCT00100646"}}NCT00100646     

T cell subsets in HIV infected patients after successful combination antiretroviral therapy: impact on survival after 12 years

Objectives

Immune activation is decreased by combination antiretroviral therapy (cART) in patients infected with human immunodeficiency virus (HIV), but residual activation remains and has been proposed as a cause of premature aging and death, but data are lacking. We analyzed the relationship between T-cell subsets after 18 months of cART and overall survival during 12 years of follow up.

Methods

A cohort of 101 HIV infected patients who had undetectable plasma HIV after starting cART was included in 1997–1998. T cell subsets were analyzed by flowcytometry after 18 months of cART. Relation to survival was calculated using Kaplan-Meier curves and multiple Cox regression.

Results

Seventeen patients died during the observation period. The leading causes of death were non-AIDS cancer and cardiovascular disease. Higher levels of CD8 memory T cells (CD8+,CD45RO+,CD45RA-) showed a significant beneficiary effect on survival, HR of 0.95 (95% confidence interval 0.91–0.99, P = 0.016) when adjusted for age, nadir CD4 count, CD4 count, and AIDS and hepatitis C status. T cell activation was not associated with increased risk of death.

Conclusions

Larger and longitudinal studies are needed to accurately establish prognostic factors, but overall results seem to suggest that prognostic information exists within the CD8 compartment.     

Comparison of a clinical prediction rule and a LAM antigen-detection assay for the rapid diagnosis of TBM in a high HIV prevalence setting

Background/Objective

The diagnosis of tuberculous meningitis (TBM) in resource poor TB endemic environments is challenging. The accuracy of current tools for the rapid diagnosis of TBM is suboptimal. We sought to develop a clinical-prediction rule for the diagnosis of TBM in a high HIV prevalence setting, and to compare performance outcomes to conventional diagnostic modalities and a novel lipoarabinomannan (LAM) antigen detection test (Clearview-TB®) using cerebrospinal fluid (CSF).

Methods

Patients with suspected TBM were classified as definite-TBM (CSF culture or PCR positive), probable-TBM and non-TBM.

Results

Of the 150 patients, 84% were HIV-infected (median [IQR] CD4 count = 132 [54; 241] cells/µl). There were 39, 55 and 54 patients in the definite, probable and non-TBM groups, respectively. The LAM sensitivity and specificity (95%CI) was 31% (17;48) and 94% (85;99), respectively (cut-point ≥0.18). By contrast, smear-microscopy was 100% specific but detected none of the definite-TBM cases. LAM positivity was associated with HIV co-infection and low CD4 T cell count (CD4<200 vs. >200 cells/µl; p = 0.03). The sensitivity and specificity in those with a CD4<100 cells/µl was 50% (27;73) and 95% (74;99), respectively. A clinical-prediction rule ≥6 derived from multivariate analysis had a sensitivity and specificity (95%CI) of 47% (31;64) and 98% (90;100), respectively. When LAM was combined with the clinical-prediction-rule, the sensitivity increased significantly (p<0.001) to 63% (47;68) and specificity remained high at 93% (82;98).

Conclusions

Despite its modest sensitivity the LAM ELISA is an accurate rapid rule-in test for TBM that has incremental value over smear-microscopy. The rule-in value of LAM can be further increased by combination with a clinical-prediction rule, thus enhancing the rapid diagnosis of TBM in HIV-infected persons with advanced immunosuppression.     

Association of serum albumin with markers of nutritional status among HIV-infected and uninfected Rwandan women

Introduction

The objectives of this study are to address if and how albumin can be used as an indication of malnutrition in HIV infected and uninfected Africans.

Methods

In 2005, 710 HIV-infected and 226 HIV-uninfected women enrolled in a cohort study. Clinical/demographic parameters, CD4 count, albumin, liver transaminases; anthropometric measurements and Bioelectrical Impedance Analysis (BIA) were performed. Malnutrition outcomes were defined as body mass index (BMI), Fat-free mass index (FFMI) and Fat mass index (FMI). Separate linear predictive models including albumin were fit to these outcomes in HIV negative and HIV positive women by CD4 strata (CD4>350,200–350 and <200 cells/µl).

Results

In unadjusted models for each outcome in HIV-negative and HIV positive women with CD4>350 cells/µl, serum albumin was not significantly associated with BMI, FFMI or FMI. Albumin was significantly associated with all three outcomes (p<0.05) in HIV+ women with CD4 200–350 cells/µl, and highly significant in HIV+ women with CD4<200 cells/µl (P<0.001). In multivariable linear regression, albumin remained associated with FFMI in women with CD4 count<200 cells/µl (p<0.01) but not in HIV+ women with CD4>200.

Discussion

While serum albumin is widely used to indicate nutritional status it did not consistently predict malnutrition outcomes in HIV- women or HIV+ women with higher CD4. This result suggests that albumin may measure end stage disease as well as malnutrition and should not be used as a proxy for nutritional status without further study of its association with validated measures.     

Evaluation of portable point-of-care CD4 counter with high sensitivity for detecting patients eligible for antiretroviral therapy

Background

Accurate, inexpensive point-of-care CD4+ T cell testing technologies are needed that can deliver CD4+ T cell results at lower level health centers or community outreach voluntary counseling and testing. We sought to evaluate a point-of-care CD4+ T cell counter, the Pima CD4 Test System, a portable, battery-operated bench-top instrument that is designed to use finger stick blood samples suitable for field use in conjunction with rapid HIV testing.

Methods

Duplicate measurements were performed on both capillary and venous samples using Pima CD4 analyzers, compared to the BD FACSCalibur (reference method). The mean bias was estimated by paired Student''s t-test. Bland Altman plots were used to assess agreement.

Results

206 participants were enrolled with a median CD4 count of 396 (range; 18–1500). The finger stick PIMA had a mean bias of −66.3 cells/µL (95%CI −83.4−49.2, P<0.001) compared to the FACSCalibur; the bias was smaller at lower CD4 counts (0–250 cells/µL) with a mean bias of −10.8 (95%CI −27.3−+5.6, P = 0.198), and much greater at higher CD4 cell counts (>500 cells/µL) with a mean bias of −120.6 (95%CI −162.8, −78.4, P<0.001). The sensitivity (95%CI) of the Pima CD4 analyzer was 96.3% (79.1–99.8%) for a <250 cells/ul cut-off with a negative predictive value of 99.2% (95.1–99.9%).

Conclusions

The Pima CD4 finger stick test is an easy-to-use, portable, relatively fast device to test CD4+ T cell counts in the field. Issues of negatively-biased CD4 cell counts especially at higher absolute numbers will limit its utility for longitudinal immunologic response to ART. The high sensitivity and negative predictive value of the test makes it an attractive option for field use to identify patients eligible for ART, thus potentially reducing delays in linkage to care and ART initiation.     

Scaling up the 2010 World Health Organization HIV Treatment Guidelines in resource-limited settings: a model-based analysis

Background

The new 2010 World Health Organization (WHO) HIV treatment guidelines recommend earlier antiretroviral therapy (ART) initiation (CD4<350 cells/µl instead of CD4<200 cells/µl), multiple sequential ART regimens, and replacement of first-line stavudine with tenofovir. This paper considers what to do first in resource-limited settings where immediate implementation of all of the WHO recommendations is not feasible.

Methods and Findings

We use a mathematical model and local input data to project clinical and economic outcomes in a South African HIV-infected cohort (mean age = 32.8 y, mean CD4 = 375/µl). For the reference strategy, we assume that all patients initiate stavudine-based ART with WHO stage III/IV disease and receive one line of ART (stavudine/WHO/one-line). We rank—in survival, cost-effectiveness, and equity terms—all 12 possible combinations of the following: (1) stavudine replacement with tenofovir, (2) ART initiation (by WHO stage, CD4<200 cells/µl, or CD4<350 cells/µl), and (3) one or two regimens, or lines, of available ART. Projected life expectancy for the reference strategy is 99.0 mo. Considering each of the guideline components separately, 5-y survival is maximized with ART initiation at CD4<350 cells/µl (stavudine/<350/µl/one-line, 87% survival) compared with stavudine/WHO/two-lines (66%) and tenofovir/WHO/one-line (66%). The greatest life expectancies are achieved via the following stepwise programmatic additions: stavudine/<350/µl/one-line (124.3 mo), stavudine/<350/µl/two-lines (177.6 mo), and tenofovir/<350/µl/two-lines (193.6 mo). Three program combinations are economically efficient: stavudine/<350/µl/one-line (cost-effectiveness ratio, US$610/years of life saved [YLS]), tenofovir/<350/µl/one-line (US$1,140/YLS), and tenofovir/<350/µl/two-lines (US$2,370/YLS).

Conclusions

In settings where immediate implementation of all of the new WHO treatment guidelines is not feasible, ART initiation at CD4<350 cells/µl provides the greatest short- and long-term survival advantage and is highly cost-effective. Please see later in the article for the Editors'' Summary     

KIR-HLA genotypes in HIV-infected patients lacking immunological recovery despite effective antiretroviral therapy

Background

In HIV-infected individuals, mechanisms underlying unsatisfactory immune recovery during effective combination antiretroviral therapy (cART) have yet to be fully understood. We investigated whether polymorphism of genes encoding immune-regulating molecules, such as killer immunoglobulin-like receptors (KIR) and their ligands class I human leukocyte antigen (HLA), could influence immunological response to cART.

Methods

KIR and HLA frequencies were analyzed in 154 HIV-infected and cART-treated patients with undetectable viral load divided into two groups: ‘immunological non responders’ (INR, N = 50, CD4⁺ T-cell count <200/mm³) and full responders (FR, N = 104, CD4⁺ T-cell count >350/mm³). Molecular KIR were typed using polymerase chain reaction-based genotyping. Comparisons were adjusted for baseline patient characteristics.

Results

The frequency of KIR2DL3 allele was significantly higher in FR than in INR (83.7% vs. 62%, P = 0.005). The functional compound genotype HLA-C1⁺/KIR2DL3⁺, even at multivariable analysis, when adjusted for nadir CD4⁺ T-cell count, was associated with reduced risk of INR status: odds ratio (95% Confidence Intervals) 0.34 (0.13−0.88), P = 0.03.

Conclusions

Reduced presence of the inhibitory KIR2DL3 genotype detected in INR might provoke an imbalance in NK function, possibly leading to increased immune activation, impaired killing of latently infected cells, and higher proviral burden. These factors would hinder full immune recovery during therapy.     

IL-17A expression is localised to both mononuclear and polymorphonuclear synovial cell infiltrates

Introduction

This study examines the expression of IL-17A-secreting cells within the inflamed synovium and the relationship to in vivo joint hypoxia measurements.

Methods

IL-17A expression was quantified in synovial tissue (ST), serum and synovial fluid (SF) by immunohistochemistry and MSD-plex assays. IL-6 SF and serum levels were measured by MSD-plex assays. Dual immunofluorescence for IL-17A was quantified in ST CD15+ cells (neutrophils), Tryptase+ (mast cells) and CD4+ (T cells). Synovial tissue oxygen (tpO₂) levels were measured under direct visualisation at arthroscopy. Synovial infiltration was assessed using immunohistochemistry for cell specific markers. Peripheral blood mononuclear and polymorphonuclear cells were isolated and exposed to normoxic or 3% hypoxic conditions. IL-17A and IL-6 were quantified as above in culture supernatants.

Results

IL-17A expression was localised to mononuclear and polymorphonuclear (PMN) cells in inflamed ST. Dual immunoflourescent staining co-localised IL-17A expression with CD15+ neutrophils Tryptase+ mast cells and CD4+T cells. % IL-17A positivity was highest on CD15+ neutrophils, followed by mast cells and then CD4+T-cells. The number of IL-17A-secreting PMN cells significantly correlated with sublining CD68 expression (r = 0.618, p<0.01). IL-17A SF levels correlated with IL-6 SF levels (r = 0.675, p<0.01). Patients categorized according to tp0₂< or >20mmHg, showed those with low tp0₂<20mmHg had significantly higher IL-17A+ mononuclear cells with no difference observed for PMNs. Exposure of mononuclear and polymorphonuclear cells to 3% hypoxia, significantly induced IL-6 in mononuclear cells, but had no effect on IL-17A expression in mononuclear and polymorphonuclear cells.

Conclusion

This study demonstrates IL-17A expression is localised to several immune cell subtypes within the inflamed synovial tissue, further supporting the concept that IL-17A is a key mediator in inflammatory arthritis. The association of hypoxia with Il-17A expression appears to be indirect, probably through hypoxia-induced pro-inflammatory pathways and leukocyte influx within the joint microenvironment.     

Development and validation of decision rules to guide frequency of monitoring CD4 cell count in HIV-1 infection before starting antiretroviral therapy

Background

Although CD4 cell count monitoring is used to decide when to start antiretroviral therapy in patients with HIV-1 infection, there are no evidence-based recommendations regarding its optimal frequency. It is common practice to monitor every 3 to 6 months, often coupled with viral load monitoring. We developed rules to guide frequency of CD4 cell count monitoring in HIV infection before starting antiretroviral therapy, which we validated retrospectively in patients from the Swiss HIV Cohort Study.

Methodology/Principal Findings

We built up two prediction rules (“Snap-shot rule” for a single sample and “Track-shot rule” for multiple determinations) based on a systematic review of published longitudinal analyses of CD4 cell count trajectories. We applied the rules in 2608 untreated patients to classify their 18 061 CD4 counts as either justifiable or superfluous, according to their prior ≥5% or <5% chance of meeting predetermined thresholds for starting treatment. The percentage of measurements that both rules falsely deemed superfluous never exceeded 5%. Superfluous CD4 determinations represented 4%, 11%, and 39% of all actual determinations for treatment thresholds of 500, 350, and 200×10⁶/L, respectively. The Track-shot rule was only marginally superior to the Snap-shot rule. Both rules lose usefulness for CD4 counts coming near to treatment threshold.

Conclusions/Significance

Frequent CD4 count monitoring of patients with CD4 counts well above the threshold for initiating therapy is unlikely to identify patients who require therapy. It appears sufficient to measure CD4 cell count 1 year after a count >650 for a threshold of 200, >900 for 350, or >1150 for 500×10⁶/L, respectively. When CD4 counts fall below these limits, increased monitoring frequency becomes advisable. These rules offer guidance for efficient CD4 monitoring, particularly in resource-limited settings.     

Expanding ART for treatment and prevention of HIV in South Africa: estimated cost and cost-effectiveness 2011-2050

Background

Antiretroviral Treatment (ART) significantly reduces HIV transmission. We conducted a cost-effectiveness analysis of the impact of expanded ART in South Africa.

Methods

We model a best case scenario of 90% annual HIV testing coverage in adults 15–49 years old and four ART eligibility scenarios: CD4 count <200 cells/mm³ (current practice), CD4 count <350, CD4 count <500, all CD4 levels. 2011–2050 outcomes include deaths, disability adjusted life years (DALYs), HIV infections, cost, and cost per DALY averted. Service and ART costs reflect South African data and international generic prices. ART reduces transmission by 92%. We conducted sensitivity analyses.

Results

Expanding ART to CD4 count <350 cells/mm³ prevents an estimated 265,000 (17%) and 1.3 million (15%) new HIV infections over 5 and 40 years, respectively. Cumulative deaths decline 15%, from 12.5 to 10.6 million; DALYs by 14% from 109 to 93 million over 40 years. Costs drop $504 million over 5 years and $3.9 billion over 40 years with breakeven by 2013. Compared with the current scenario, expanding to <500 prevents an additional 585,000 and 3 million new HIV infections over 5 and 40 years, respectively. Expanding to all CD4 levels decreases HIV infections by 3.3 million (45%) and costs by $10 billion over 40 years, with breakeven by 2023. By 2050, using higher ART and monitoring costs, all CD4 levels saves $0.6 billion versus current; other ART scenarios cost $9–194 per DALY averted. If ART reduces transmission by 99%, savings from all CD4 levels reach $17.5 billion. Sensitivity analyses suggest that poor retention and predominant acute phase transmission reduce DALYs averted by 26% and savings by 7%.

Conclusion

Increasing the provision of ART to <350 cells/mm3 may significantly reduce costs while reducing the HIV burden. Feasibility including HIV testing and ART uptake, retention, and adherence should be evaluated.     

Gender differences in immune reconstitution: a multicentric cohort analysis in sub-Saharan Africa

Background

In sub-Saharan Africa, men living with HIV often start ART at more advanced stages of disease and have higher early mortality than women. We investigated gender difference in long-term immune reconstitution.

Methods/Principal Findings

Antiretroviral-naïve adults who received ART for at least 9 months in four HIV programs in sub-Saharan Africa were included. Multivariate mixed linear models were used to examine gender differences in immune reconstitution on first line ART.A total of 21,708 patients (68% women) contributed to 61,912 person-years of follow-up. At ART start,. Median CD4 at ART were 149 [IQR 85–206] for women and 125 cells/µL [IQR 63–187] for men. After the first year on ART, immune recovery was higher in women than in men, and gender-based differences increased by 20 CD4 cells/µL per year on average (95% CI 16–23; P<0.001). Up to 6 years after ART start, patients with low initial CD4 levels experienced similar gains compared to patients with high initial levels, including those with CD4>250cells/µL (difference between patients with <50 cells/µL and those with >250 was 284 cells/µL; 95% CI 272–296; LR test for interaction with time p = 0.63). Among patients with initial CD4 count of 150–200 cells/µL, women reached 500 CD4 cells after 2.4 years on ART (95% CI 2.4–2.5) and men after 4.5 years (95% CI 4.1–4.8) of ART use.

Conclusion

Women achieved better long-term immune response to ART, reaching CD4 level associated with lower risks of AIDS related morbidity and mortality quicker than men.     

Risk of all-cause mortality in HIV infected patients is associated with clinical, immunologic predictors and the CCR5 Δ32 deletion

Objective

Investigation of the interplay between the CCR5 Δ32/wt genotype and demographic, epidemiological, clinical and immunological factors associated with mortality in the cART era.

Design

Longitudinal data from 507 HIV-infected patients following the Δ32 allele detection were analyzed.

Methods

Cumulative 15 years mortality was calculated using Kaplan-Meyer methodology. Hazard ratios were estimated using univariate Cox models. Basing on Akakie information criteria and statistical significance multivariate Cox model was constructed and effect plots presenting adjusted hazard ratio time-dependency were drawn. Analysis of the association of all-cause mortality and CCR5 Δ32/wt genotype prior to the antiretroviral treatment (cART) initiation (n = 507) and on the therapy (n = 422) was also performed.

Results

A mortality rate of 2.66 (CI 2.57–3.19) per 100 person-years was observed. Univariate analysis factors modifying the risk of death included the CCR5 genotype, gender, history of cART, AIDS diagnosis and also CD4 lymphocyte nadir, zenith, the latest CD4 count and stable levels >500 cells/µl. For multivariate analysis the following predictors were selected: CCR5 genotype (HR for wt/wt 2.53, CI 1.16–5.53, p = 0.02), gender (HR for males 1.91, 95%CI 1.1–3.36, p = 0.023), introduction of combined antiretroviral treatment (HR 4.85, CI 3.0–7.89, if untreated or treated <1 month, p<0.0001) CD4 count of 500 cells/µl for six months or more (HR 4.16, CI 1.95–8.88 if not achieved, p = 0.028), the latest CD4 count (HR 5.44, CI 3.39–8.74 for <100 cells/µl, p<0.0001) and history of AIDS (HR 1.69, CI 1.03–2.79, p = 0.039). Among untreated individuals the Δ32/wt genotype was associated with notably better survival (p = 0.026), while among cART treated individuals the Δ32 mutation did not correlate significantly with higher survival rates (p = 0.23).

Conclusions

The Δ32 CCR5 allele is associated with a reduction of the risk of all-cause mortality in HIV (+) patients alongside clinical and immunologic predictors such as AIDS, history of cART, lymphocyte CD4 cell count and gender.     

A plasma biomarker signature of immune activation in HIV patients on antiretroviral therapy

Background

Immune activation is a strong predictor of disease progression in HIV infection. Combinatorial plasma biomarker signatures that represent surrogate markers of immune activation in both viremic and aviremic HIV patients on combination antiretroviral therapy (cART) have not been defined. Here, we identify a plasma inflammatory biomarker signature that distinguishes between both viremic and aviremic HIV patients on cART and healthy controls and examine relationships of this signature to markers of disease progression.

Methods

Multiplex profiling and ELISA were used to detect 15 cytokines/chemokines, soluble IL-2R (sIL-2R), and soluble CD14 (sCD14) in plasma from 57 HIV patients with CD4 nadir <300 cells/µl and 29 healthy controls. Supervised and unsupervised analyses were used to identify biomarkers explaining variance between groups defined by HIV status or drug abuse. Relationships between biomarkers and disease markers were examined by Spearman correlation.

Results

The majority (91%) of HIV subjects were on cART, with 38% having undetectable viral loads (VL). Hierarchical clustering identified a biomarker cluster in plasma consisting of two interferon-stimulated gene products (CXCL9 and CXCL10), T cell activation marker (sIL-2R), and monocyte activation marker (sCD14) that distinguished both viremic and aviremic HIV patients on cART from controls (p<0.0001) and were top-ranked in variables important in projection plots. IL-12 and CCL4 were also elevated in viremic and aviremic patients compared to controls (p<0.05). IL-12 correlated with IFNα, IFNγ, CXCL9, and sIL-2R (p<0.05). CXCL10 correlated positively with plasma VL and percentage of CD16+ monocytes, and inversely with CD4 count (p = 0.001, <0.0001, and 0.04, respectively).

Conclusion

A plasma inflammatory biomarker signature consisting of CXCL9, CXCL10, sIL-2R, and sCD14 may be useful as a surrogate marker to monitor immune activation in both viremic and aviremic HIV patients on cART during disease progression and therapeutic responses.