Characteristics of HIV-1 serodiscordant couples enrolled in a clinical trial of antiretroviral pre-exposure prophylaxis for HIV-1 prevention

Introduction

Stable heterosexual HIV-1 serodiscordant couples in Africa have high HIV-1 transmission rates and are a critical population for evaluation of new HIV-1 prevention strategies. The Partners PrEP Study is a randomized, double-blind, placebo-controlled trial of tenofovir and emtricitabine-tenofovir pre-exposure prophylaxis to decrease HIV-1 acquisition within heterosexual HIV-1 serodiscordant couples. We describe the trial design and characteristics of the study cohort.

Methods

HIV-1 serodiscordant couples, in which the HIV-1 infected partner did not meet national guidelines for initiation of antiretroviral therapy, were enrolled at 9 research sites in Kenya and Uganda. The HIV-1 susceptible partner was randomized to daily oral tenofovir, emtricitabine-tenofovir, or matching placebo with monthly follow-up for 24–36 months.

Results

From July 2008 to November 2010, 7920 HIV-1 serodiscordant couples were screened and 4758 enrolled. For 62% (2966/4758) of enrolled couples, the HIV-1 susceptible partner was male. Median age was 33 years for HIV-1 susceptible and HIV-1 infected partners [IQR (28–40) and (26–39) respectively]. Most couples (98%) were married, with a median duration of partnership of 7.0 years (IQR 3.0–14.0) and recent knowledge of their serodiscordant status [median 0.4 years (IQR 0.1–2.0)]. During the month prior to enrollment, couples reported a median of 4 sex acts (IQR 2–8); 27% reported unprotected sex and 14% of male and 1% of female HIV-1 susceptible partners reported sex with outside partners. Among HIV-1 infected partners, the median plasma HIV-1 level was 3.94 log₁₀ copies/mL (IQR 3.31–4.53) and median CD4 count was 496 cells/µL (IQR 375–662); the majority (64%) had WHO stage 1 HIV-1 disease.

Conclusions

Couples at high risk of HIV-1 transmission were rapidly recruited into the Partners PrEP Study, the largest efficacy trial of oral PrEP. (ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00557245","term_id":"NCT00557245"}}NCT00557245)     

Switching virally suppressed, treatment-experienced patients to a raltegravir-containing regimen does not alter levels of HIV-1 DNA

Background

Current HIV-1 antiretroviral therapy (ART) greatly reduces virus replication but does not significantly affect the viral reservoir. Raltegravir, a recently introduced integrase inhibitor, could, at least theoretically, reduce residual viremia in patients on ART and affect the viral reservoir size. The aim of this study was to assess whether switching therapy in treatment-experienced patients that were virally suppressed to a raltegravir-containing regimen reduces the size of the viral reservoir, and if such treatment leads to a change in levels of HIV 2-LTR circles in this patient group.

Methods

14 ART experienced individuals with a suppressed viral load (<50 HIV-1 RNA copies/mL plasma) at baseline (for at least 2 months) were switched to a raltegravir-containing regimen. Blood samples were taken at baseline and at ≥2 timepoints up to 48±6 weeks. Levels of total HIV-1 DNA and 2-LTR circles in peripheral blood mononuclear cells (PBMCs) were measured using real-time PCR assays.

Results

There was no significant change in HIV-1 total DNA levels over the study duration (p = 0.808), median slope 0.24 (conservative nonparametric 95% CI: −11.78, 26.23). Low levels of 2-LTR circles were detected in 2 patients. One had 16 copies/10⁶ PBMCs at baseline and the other had 34 copies/10⁶ PBMCs at week 51.

Conclusions

The switch to a raltegravir containing regimen was not associated with a significant change in HIV-1 total DNA levels in this cohort. There were no observed changes in the levels of HIV-1 2-LTR circles associated with raltegravir treatment initiation.     

MRKAd5 HIV-1 Gag/Pol/Nef Vaccine-Induced T-Cell Responses Inadequately Predict Distance of Breakthrough HIV-1 Sequences to the Vaccine or Viral Load

Background

The sieve analysis for the Step trial found evidence that breakthrough HIV-1 sequences for MRKAd5/HIV-1 Gag/Pol/Nef vaccine recipients were more divergent from the vaccine insert than placebo sequences in regions with predicted epitopes. We linked the viral sequence data with immune response and acute viral load data to explore mechanisms for and consequences of the observed sieve effect.

Methods

Ninety-one male participants (37 placebo and 54 vaccine recipients) were included; viral sequences were obtained at the time of HIV-1 diagnosis. T-cell responses were measured 4 weeks post-second vaccination and at the first or second week post-diagnosis. Acute viral load was obtained at RNA-positive and antibody-negative visits.

Findings

Vaccine recipients had a greater magnitude of post-infection CD8+ T cell response than placebo recipients (median 1.68% vs 1.18%; p = 0·04) and greater breadth of post-infection response (median 4.5 vs 2; p = 0·06). Viral sequences for vaccine recipients were marginally more divergent from the insert than placebo sequences in regions of Nef targeted by pre-infection immune responses (p = 0·04; Pol p = 0·13; Gag p = 0·89). Magnitude and breadth of pre-infection responses did not correlate with distance of the viral sequence to the insert (p>0·50). Acute log viral load trended lower in vaccine versus placebo recipients (estimated mean 4·7 vs 5·1) but the difference was not significant (p = 0·27). Neither was acute viral load associated with distance of the viral sequence to the insert (p>0·30).

Interpretation

Despite evidence of anamnestic responses, the sieve effect was not well explained by available measures of T-cell immunogenicity. Sequence divergence from the vaccine was not significantly associated with acute viral load. While point estimates suggested weak vaccine suppression of viral load, the result was not significant and more viral load data would be needed to detect suppression.     

Uridine metabolism in HIV-1-infected patients: effect of infection, of antiretroviral therapy and of HIV-1/ART-associated lipodystrophy syndrome

Background

Uridine has been advocated for the treatment of HIV-1/HAART-associated lipodystrophy (HALS), although its metabolism in HIV-1-infected patients is poorly understood.

Methods

Plasma uridine concentrations were measured in 35 controls and 221 HIV-1-infected patients and fat uridine in 15 controls and 19 patients. The diagnosis of HALS was performed following the criteria of the Lipodystrophy Severity Grading Scale. Uridine was measured by a binary gradient-elution HPLC method. Analysis of genes encoding uridine metabolizing enzymes in fat was performed with TaqMan RT-PCR.

Results

Median plasma uridine concentrations for HIV-1-infected patients were 3.80 µmol/l (interquartile range: 1.60), and for controls 4.60 µmol/l (IQR: 1.8) (P = 0.0009). In fat, they were of 6.0 (3.67), and 2.8 (4.65) nmol/mg of protein, respectively (P = 0.0118). Patients with a mixed HALS form had a median plasma uridine level of 4.0 (IC95%: 3.40–4.80) whereas in those with isolated lipoatrophy it was 3.25 (2.55–4.15) µmol/l/l (P = 0.0066). The expression of uridine cytidine kinase and uridine phosphorylase genes was significantly decreased in all groups of patients with respect to controls. A higher expression of the mRNAs for concentrative nucleoside transporters was found in HIV-1-infected patients with respect to healthy controls.

Conclusions

HIV-1 infection is associated with a decrease in plasma uridine and a shift of uridine to the adipose tissue compartment. Antiretroviral therapy was not associated with plasma uridine concentrations, but pure lipoatrophic HALS was associated with significantly lower plasma uridine concentrations.     

Haemolysis as a first sign of thromboembolic event and acute pump thrombosis in patients with the continuous-flow left ventricular assist device HeartMate II

Background

Despite advances in pump technology, thromboembolic events/acute pump thrombosis remain potentially life-threatening complications in patients with continuous-flow left ventricular assist devices (CF-LVAD). We sought to determine early signs of thromboembolic event/pump thrombosis in patients with CF-LVAD, which could lead to earlier intervention.

Methods

We analysed all HeartMate II recipients (n = 40) in our centre between December 2006 and July 2013. Thromboembolic event/pump thrombosis was defined as a transient ischaemic attack (TIA), ischaemic cerebrovascular accident (CVA), or pump thrombosis.

Results

During median LVAD support of 336 days [IQR: 182–808], 8 (20 %) patients developed a thromboembolic event/pump thrombosis (six TIA/CVA, two pump thromboses). At the time of the thromboembolic event/pump thrombosis, significantly higher pump power was seen compared with the no-thrombosis group (8.2 ± 3.0 vs. 6.4 ± 1.4 W, p = 0.02), as well as a trend towards a lower pulse index (4.1 ± 1.5 vs. 5.0 ± 1.0, p = 0.05) and a trend towards higher pump flow (5.7 ± 1.0 vs. 4.9 ± 1.9 L m, p = 0.06).The thrombosis group had a more than fourfold higher lactate dehydrogenase (LDH) median 1548 [IQR: 754–2379] vs. 363 [IQR: 325–443] U/L, p = 0.0001). Bacterial (n = 4) or viral (n = 1) infection was present in 5 out of 8 patients. LDH > 735 U/L predicted thromboembolic events/pump thrombosis with a positive predictive value of 88 %.

Conclusions

In patients with a CF-LVAD (HeartMate II), thromboembolic events and/or pump thrombosis are associated with symptoms and signs of acute haemolysis as manifested by a high LDH, elevated pump power and decreased pulse index, especially in the context of an infection.     

HIV-1 inhibits phagocytosis and inflammatory cytokine responses of human monocyte-derived macrophages to P. falciparum infected erythrocytes

HIV-1 infection increases the risk and severity of malaria by poorly defined mechanisms. We investigated the effect of HIV-1_Ba-L infection of monocyte-derived macrophages (MDM) on phagocytosis of opsonised P. falciparum infected erythrocytes (IE) and subsequent proinflammatory cytokine secretion. Compared to mock-infected MDM, HIV-1 infection significantly inhibited phagocytosis of IE (median (IQR) (10 (0–28) versus (34 (27–108); IE internalised/100 MDM; p = 0.001) and decreased secretion of IL-6 (1,116 (352–3,387) versus 1,552 (889–6,331); pg/mL; p = 0.0078) and IL-1β (16 (7–21) versus 33 (27–65); pg/mL; p = 0.0078). Thus inadequate phagocytosis and cytokine production may contribute to impaired control of malaria in HIV-1 infected individuals.     

Brown adipose tissue in humans is activated by elevated plasma catecholamines levels and is inversely related to central obesity

Background

Recent studies have shown that adult human possess active brown adipose tissue (BAT), which might be important in controlling obesity. It is known that ß-adrenoceptor-UCP1 system regulates BAT in rodent, but its influence in adult humans remains to be shown. The present study is to determine whether BAT activity can be independently stimulated by elevated catecholamines levels in adult human, and whether it is associated with their adiposity.

Methodology/Principal Findings

We studied 14 patients with pheochromocytoma and 14 normal subjects who had performed both ¹⁸F-fluorodeoxyglucose positron emission tomography/computed tomography (¹⁸F-FDG PET/CT) and plasma total metanephrine (TMN) measurements during 2007–2010. The BAT detection rate and the mean BAT activity were significantly higher in patients with elevated TMN levels (Group A: 6/8 and 6.7±2.1 SUVmean· g/ml) than patients with normal TMN concentrations (Group B: 0/6 and 0.4±0.04 SUVmean· g/ml) and normal subjects (Group C: 0/14 and 0.4±0.03 SUVmean·g/ml). BAT activities were positively correlated with TMN levels (R = 0.83, p<0.0001) and were inversely related to body mass index (R = −0.47, p = 0.010), visceral fat areas (R = −0.39, p = 0.044), visceral/total fat areas (R = −0.52, p = 0.0043) and waist circumferences (R = −0.43, p = 0.019). Robust regression revealed that TMN (R = 0.81, p<0.0001) and waist circumferences (R = −0.009, p = 0.009) were the two independent predictors of BAT activities.

Conclusions/Significance

Brown adipose tissue activity in adult human can be activated by elevated plasma TMN levels, such as in the case of patients with pheochromocytoma, and is negatively associated with central adiposity.     

Prevalence and impact of minority variant drug resistance mutations in primary HIV-1 infection

Objective

To evaluate minority variant drug resistance mutations detected by the oligonucleotide ligation assay (OLA) but not consensus sequencing among subjects with primary HIV-1 infection.

Design/Methods

Observational, longitudinal cohort study. Consensus sequencing and OLA were performed on the first available specimens from 99 subjects enrolled after 1996. Survival analyses, adjusted for HIV-1 RNA levels at the start of antiretroviral (ARV) therapy, evaluated the time to virologic suppression (HIV-1 RNA<50 copies/mL) among subjects with minority variants conferring intermediate or high-level resistance.

Results

Consensus sequencing and OLA detected resistance mutations in 5% and 27% of subjects, respectively, in specimens obtained a median of 30 days after infection. Median time to virologic suppression was 110 (IQR 62–147) days for 63 treated subjects without detectable mutations, 84 (IQR 56–109) days for ten subjects with minority variant mutations treated with ≥3 active ARVs, and 104 (IQR 60–162) days for nine subjects with minority variant mutations treated with <3 active ARVs (p = .9). Compared to subjects without mutations, time to virologic suppression was similar for subjects with minority variant mutations treated with ≥3 active ARVs (aHR 1.2, 95% CI 0.6–2.4, p = .6) and subjects with minority variant mutations treated with <3 active ARVs (aHR 1.0, 95% CI 0.4–2.4, p = .9). Two subjects with drug resistance and two subjects without detectable resistance experienced virologic failure.

Conclusions

Consensus sequencing significantly underestimated the prevalence of drug resistance mutations in ARV-naïve subjects with primary HIV-1 infection. Minority variants were not associated with impaired ARV response, possibly due to the small sample size. It is also possible that, with highly-potent ARVs, minority variant mutations may be relevant only at certain critical codons.     

Incidence and correlates of HIV-1 RNA detection in the breast milk of women receiving HAART for the prevention of HIV-1 transmission

Background

The incidence and correlates of breast milk HIV-1 RNA detection were determined in intensively sampled women receiving highly active antiretroviral therapy (HAART) for the prevention of mother-to-child HIV-1 transmission.

Methods

Women initiated HAART at 34 weeks of pregnancy. Breast milk was collected every 2–5 days during 1 month postpartum for measurements of cell-associated HIV DNA and cell-free HIV RNA. Plasma and breast milk were also collected at 2 weeks, 1, 3 and 6 months for concurrent HIV-1 RNA and DNA measurements. Regression was used to identify cofactors for breast milk HIV-1 RNA detection.

Results

Of 259 breast milk specimens from 25 women receiving HAART, 34 had detectable HIV-1 RNA (13%, incidence 1.4 episodes/100 person-days 95% CI = 0.97–1.9). Fourteen of 25 (56%) women had detectable breast milk HIV-1 RNA [mean 2.5 log₁₀ copies/ml (range 2.0–3.9)] at least once. HIV-1 DNA was consistently detected in breast milk cells despite HAART, and increased slowly over time, at a rate of approximately 1 copy/10⁶ cells per day (p = 0.02). Baseline CD4, plasma viral load, HAART duration, and frequency of breast problems were similar in women with and without detectable breast milk HIV-1 RNA. Women with detectable breast milk HIV-1 RNA were more likely to be primiparous than women without (36% vs 0%, p = 0.05). Plasma HIV-1 RNA detection (OR = 9.0, 95%CI = 1.8–44) and plasma HIV-1 RNA levels (OR = 12, 95% CI = 2.5–56) were strongly associated with concurrent detection of breast milk HIV-1 RNA. However, no association was found between breast milk HIV-1 DNA level and concurrent breast milk HIV-1 RNA detection (OR = 0.96, 95%CI = 0.54–1.7).

Conclusions

The majority of women on HAART had episodic detection of breast milk HIV-1 RNA. Breast milk HIV-1 RNA detection was associated with systemic viral burden rather than breast milk HIV-1 DNA.     

Characteristics of HIV-2 and HIV-1/HIV-2 Dually Seropositive Adults in West Africa Presenting for Care and Antiretroviral Therapy: The IeDEA-West Africa HIV-2 Cohort Study

Background

HIV-2 is endemic in West Africa. There is a lack of evidence-based guidelines on the diagnosis, management and antiretroviral therapy (ART) for HIV-2 or HIV-1/HIV-2 dual infections. Because of these issues, we designed a West African collaborative cohort for HIV-2 infection within the framework of the International epidemiological Databases to Evaluate AIDS (IeDEA).

Methods

We collected data on all HIV-2 and HIV-1/HIV-2 dually seropositive patients (both ARV-naive and starting ART) and followed-up in clinical centres in the IeDEA-WA network including a total of 13 clinics in five countries: Benin, Burkina-Faso Côte d’Ivoire, Mali, and Senegal, in the West Africa region.

Results

Data was merged for 1,754 patients (56% female), including 1,021 HIV-2 infected patients (551 on ART) and 733 dually seropositive for both HIV-1 and HIV 2 (463 on ART). At ART initiation, the median age of HIV-2 patients was 45.3 years, IQR: (38.3–51.7) and 42.4 years, IQR (37.0–47.3) for dually seropositive patients (p = 0.048). Overall, 16.7% of HIV-2 patients on ART had an advanced clinical stage (WHO IV or CDC-C). The median CD4 count at the ART initiation is 166 cells/mm³, IQR (83–247) among HIV-2 infected patients and 146 cells/mm³, IQR (55–249) among dually seropositive patients. Overall, in ART-treated patients, the CD4 count increased 126 cells/mm³ after 24 months on ART for HIV-2 patients and 169 cells/mm³ for dually seropositive patients. Of 551 HIV-2 patients on ART, 5.8% died and 10.2% were lost to follow-up during the median time on ART of 2.4 years, IQR (0.7–4.3).

Conclusions

This large multi-country study of HIV-2 and HIV-1/HIV-2 dual infection in West Africa suggests that routine clinical care is less than optimal and that management and treatment of HIV-2 could be further informed by ongoing studies and randomized clinical trials in this population.     

Are Long-Term Non-Progressors Very Slow Progressors? Insights from the Chelsea and Westminster HIV Cohort, 1988–2010

Define and identify long-term non-progressors (LTNP) and HIV controllers (HIC), and estimate time until disease progression. LTNP are HIV-1⁺ patients who maintain stable CD4⁺ T-cell counts, with no history of opportunistic infection or antiretroviral therapy (ART). HIC are a subset of LTNP who additionally have undetectable viraemia. These individuals may provide insights for prophylactic and therapeutic development. Records of HIV-1⁺ individuals attending Chelsea and Westminster Hospital (1988–2010), were analysed. LTNP were defined as: HIV-1⁺ for >7 years; ART-naïve; no history of opportunistic infection and normal, stable CD4⁺ T-cell counts. MIXED procedure in SAS using random intercept model identified long-term stable CD4⁺ T-cell counts. Survival analysis estimated time since diagnosis until disease progression. Subjects exhibiting long-term stable CD4⁺ T-cell counts with history below the normal range (<450 cells/µl blood) were compared to LTNP whose CD4⁺ T-cell count always remained normal. Within these two groups subjects with HIV-1 RNA load below limit of detection (BLD) were identified. Of 14,227 patients, 1,204 were diagnosed HIV-1⁺ over 7 years ago and were ART-naïve. Estimated time until disease progression for the 20% (239) whose CD4⁺ T-cell counts remained within the normal range, was 6.2 years (IQR: 2.0 to 9.6); significantly longer than 4.0 years (IQR: 1.0 to 7.3) for patients with historical CD4⁺ T-cell count below normal (Logrank chi-squared = 21.26; p<0.001). Within a subpopulation of 312 asymptomatic patients, 50 exhibited long-term stable CD4⁺ T-cell counts. Of these, 13 were LTNP, one of whom met HIC criteria. Of the remaining 37 patients with long-term stable low CD4⁺ T-cell counts, 3 controlled HIV-1 RNA load BLD. Individuals with stable, normal CD4⁺ T-cell counts progressed less rapidly than those with low CD4⁺ T-cell counts. Few LTNP and HIC identified in this and other studies, endorse the need for universal definitions to facilitate comparison.     

Recent HIV-1 infection: identification of individuals with high viral load setpoint in a voluntary counselling and testing centre in rural Mozambique

Background

Identification of recent HIV-infections is important for describing the HIV epidemic and compiling HIV-RNA-setpoint data for future HIV intervention trials. We conducted a study to characterize recent infections, and HIV-RNA-setpoint within the adult population presenting at a voluntary counselling and testing centre (VCT) in southern Mozambique.

Methods

All adults attending the Manhiça District-Hospital VCT between April and October 2009 were recruited if they had at least one positive rapid HIV-serology test. Patients were screened for recent HIV-1 infection by BED-CEIA HIV-incidence test. Clinical examination, assessment of HIV-RNA and CD4 cell counts were performed at enrollment, 4 and 10 months.

Results

Of the 492 participants included in this study, the prevalence of recent infections as defined by BED-CEIA test, CD4 counts >200 cells/µl and HIV-RNA >400 copies/mL, was 11.58% (57/492; 95% CI 8.89–14.74). Due to heterogeneity in HIV-RNA levels in recently infected patients, individuals were categorized as having “high” HIV-RNA load if their HIV-RNA level was above the median (4.98 log₁₀ copies/mL) at diagnosis. The “high” HIV-RNA group sustained a significantly higher HIV-viral load at all visits with a median HIV-RNA setpoint of 5.22 log₁₀ copies/mL (IQR 5.18–5.47) as compared to the median of 4.15 log₁₀ copies/ml (IQR 3.37–4.43) for the other patients (p = 0.0001).

Conclusion

The low proportion of recent HIV-infections among HIV-seropositive VCT clients suggests that most of this population attends the VCT at later stages of HIV/AIDS. Characterization of HIV-RNA-setpoint may serve to identify recently infected individuals maintaining HIV viral load>5 log10 copies/mL as candidates for antiretroviral treatment as prevention interventions.     

Plasma levels of alpha-1-antichymotrypsin are elevated in patients with chronic heart failure,but are of limited prognostic value

Background

There is increasing interest in utilising novel markers of cardiovascular disease risk in patients with chronic heart failure (HF). Recently, it was shown that alpha-1-antichymotrypsin (ACT), an acute-phase protein and major inhibitor of cathpesin G, plays a role in the pathophysiology of HF and may serve as a marker for myocardial distress.

Objective

To assess whether ACT is independently associated with long-term mortality in chronic HF patients.

Methods

ACT plasma levels were categorised into quartiles. Survival times were analysed using Kaplan-Meier curves and Cox proportional hazards regression, without and with correction for clinically relevant risk factors, including sex, age, duration of HF, kidney function (MDRD), ischaemic HF aetiology and NT-proBNP.

Results

Twenty healthy individuals and 224 patients (mean age 71 years, 72 % male, median HF duration 1.6 years) with chronic HF were included. In total, 159 (71 %) patients died. The median survival time was 5.3 (95 % CI 4.5–6.1) years. ACT was significantly elevated in patients (median 433 μg/ml, IQR 279–680) in comparison with controls (median 214 μg/ml, IQR 166–271; p < 0.001). Cox regression analysis demonstrated that ACT was not independently related to long-term mortality in chronic HF patients (crude HR = 1.03, 95 % CI 0.75–1.41, p = 0.871; adjusted HR = 1.12, 95 % CI 0.78–1.60, p = 0.552), which was confirmed by Kaplan-Meier curves.

Conclusion

ACT levels are elevated in chronic HF patients, but no independent association with long-term mortality can be established.     

Are Plasma Biomarkers of Immune Activation Predictive of HIV Progression: A Longitudinal Comparison and Analyses in HIV-1 and HIV-2 Infections?

Background

Chronic immune activation is a hallmark of HIV infection and has been associated with disease progression. Assessment of soluble biomarkers indicating immune activation provide clues into pathogenesis and hold promise for the development of point-of-care monitoring of HIV in resource-poor-settings. Their evaluation in cohort resources is therefore needed to further their development and use in HIV research.

Methodology/Principal Findings

Longitudinal evaluation of βeta-2 microglobulin (β-2 m), neopterin and suPAR soluble urokinase-type plasminogen activator receptor (suPAR) was performed with archived plasma samples to predict disease progression and provided the first direct comparison of levels in HIV-1 and HIV-2 infections. At least 2095 samples from 137 HIV-1 and 198 HIV-2 subjects with starting CD4% of ≥28 and median follow up of 4 years were analysed. All biomarkers were correlated negatively to CD4% and positively to viral load and to each other. Analyses in subjects living for ≥5 years revealed increases in median β-2 m and neopterin and decreases in CD4% over this period and the odds of death within 5 years were positively associated with baseline levels of β-2 m and neopterin. ROC analyses strengthened the evidence of elevation of biomarkers in patients approaching death in both HIV-1 and HIV-2 infections. Regression models showed that rates of biomarker fold change accelerated from 6–8 years before death with no significant differences between biomarker levels in HIV-1 and HIV-2 at equal time points prior to death.An ‘immune activation index’ analysis indicative of biomarker levels at equivalent viral loads also showed no differences between the two infections.

Conclusions/Significance

Our results suggest that β-2 m and neopterin are useful tools for disease monitoring in both HIV-1 and HIV-2 infections, whereas sUPAR performed less well. Levels of immune activation per amount of virus were comparable in HIV-1 and HIV-2 infected subjects.     

Herpes simplex virus type 2, genital ulcers and HIV-1 disease progression in postpartum women

Background

Co-infection with herpes simplex virus type 2 (HSV-2) has been associated with increased HIV-1 RNA levels and immune activation, two predictors of HIV-1 progression. The impact of HSV-2 on clinical outcomes among HIV-1 infected pregnant women is unclear.

Methods

HIV-1 infected pregnant women in Nairobi were enrolled antenatally and HSV-2 serology was obtained. HIV-1 RNA and CD4 count were serially measured for 12–24 months postpartum. Survival analysis using endpoints of death, opportunistic infection (OI), and CD4<200 cells µL, and linear mixed models estimating rate of change of HIV-1 RNA and CD4, were used to determine associations between HSV-2 serostatus and HIV-1 progression.

Results

Among 296 women, 254 (86%) were HSV-2-seropositive. Only 30 (10%) women had prior or current genital ulcer disease (GUD); median baseline CD4 count was 422 cells µL. Adjusting for baseline CD4, women with GUD were significantly more likely to have incident OIs (adjusted hazard ratio (aHR) 2.79, 95% CI: 1.33–5.85), and there was a trend for association between HSV-2-seropositivity and incident OIs (aHR 3.83, 95% CI: 0.93–15.83). Rate of change in CD4 count and HIV-1 RNA did not differ by HSV-2 status or GUD, despite a trend toward higher baseline HIV-1 RNA in HSV-2-seropositive women (4.73 log10 copies/ml vs. 4.47 log10 copies/ml, P = 0.07).

Conclusions

HSV-2 was highly prevalent and pregnant HIV-1 infected women with GUD were significantly more likely to have incident OIs than women without GUD, suggesting that clinically evident HSV-2 is a more important predictor of HIV-1 disease progression than asymptomatic HSV-2.     

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.     

Critical appraisal of four IL-6 immunoassays

Background

Interleukin-6 (IL-6) contributes to numerous inflammatory, metabolic, and physiologic pathways of disease. We evaluated four IL-6 immunoassays in order to identify a reliable assay for studies of metabolic and physical function. Serial plasma samples from intravenous glucose tolerance tests (IVGTTs), with expected rises in IL-6 concentrations, were used to test the face validity of the various assays.

Methods and Findings

IVGTTs, administered to 14 subjects, were performed with a single infusion of glucose (0.3 g/kg body mass) at time zero, a single infusion of insulin (0.025 U/kg body mass) at 20 minutes, and frequent blood collection from time zero to 180 minutes for subsequent Il-6 measurement. The performance metrics of four IL-6 detection methods were compared: Meso Scale Discovery immunoassay (MSD), an Invitrogen Luminex bead-based multiplex panel (LX), an Invitrogen Ultrasensitive Luminex bead-based singleplex assay (ULX), and R&D High Sensitivity ELISA (R&D). IL-6 concentrations measured with MSD, R&D and ULX correlated with each other (Pearson Correlation Coefficients r = 0.47–0.94, p<0.0001) but only ULX correlated (r = 0.31, p = 0.0027) with Invitrogen Luminex. MSD, R&D, and ULX, but not LX, detected increases in IL-6 in response to glucose. All plasma samples were measurable by MSD, while 35%, 1%, and 4.3% of samples were out of range when measured by LX, ULX, and R&D, respectively. Based on representative data from the MSD assay, baseline plasma IL-6 (0.90±0.48 pg/mL) increased significantly as expected by 90 minutes (1.29±0.59 pg/mL, p = 0.049), and continued rising through 3 hours (4.25±3.67 pg/mL, p = 0.0048).

Conclusion

This study established the face validity of IL-6 measurement by MSD, R&D, and ULX but not LX, and the superiority of MSD with respect to dynamic range. Plasma IL-6 concentrations increase in response to glucose and insulin, consistent with both an early glucose-dependent response (detectable at 1–2 hours) and a late insulin-dependent response (detectable after 2 hours).