To explore the levels and determinants of loss to follow-up (LTF) under universal lifelong antiretroviral therapy (ART) for pregnant and breastfeeding women (“Option B+”) in Malawi.
DESIGN, SETTING, and PARTICIPANTS
We examined retention in care, beginning at date of ART initiation and up to six months, for women in the Option B+ program. We analysed nation-wide facility-level data on women who started ART at 540 facilities (n=21 939). The study included individual-level data on patients who started ART at 19 large facilities (n=11 534).
Of the women who started ART under Option B+ (n=21 939), 17% appeared to be LTF six months after start. Most losses occurred in the first 3 months of therapy. Option B+ patients who started therapy during pregnancy were five times more likely than women who started ART in WHO stage 3/4 or with a CD4 cell count ≤350 cells/μl, to never return after their initial clinic visit (odds ratio 5.0, 95% CI 4.2-6.1). Option B+ patients who started therapy while breastfeeding were twice as likely to miss their first follow-up visit (odds ratio 2.2, 95% CI 1.8-2.8). LTF was highest in pregnant Option B+ patients who began ART at large clinics on the day they were diagnosed with HIV. LTF varied considerably between facilities, ranging from 0% to 58%.
Decreasing LTF will improve the effectiveness of the Option B+ approach. Tailored interventions, like community- or family-based PMTCT models could improve its effectiveness.
Option B+; Prevention of mother to child transmission / vertical transmission; Antiretroviral therapy; Retention in care; Loss to follow-up
To investigate the impact of HAART-induced HIV suppression on levels of 24 serological biomarkers of inflammation and immune activation.
Prospective cohort study.
Biomarkers were measured with multiplex assays in centralized laboratories using stored serum samples contributed by 1,697 men during 8,903 person-visits in the Multicenter AIDS Cohort Study (MACS) from 1984–2009. Using generalized gamma models, we compared biomarker values across three groups, adjusting for possible confounders: HIV-uninfected (NEG); HIV+, HAART-naïve (NAI); and HAART-exposed with HIV RNA suppressed to <50 copies/mL plasma (SUP). We also estimated changes in biomarker levels associated with duration of HIV suppression, using splined generalized gamma regression with a knot at one year.
Most biomarkers were relatively normalized in the SUP group relative to the NAI group; however, 12 biomarkers in the SUP group were distinct (p<0.002) from NEG values: CXCL10, CRP, sCD14, sTNFR2, TNF-α, sCD27, sGP130, IL-8, CCL13, BAFF, GM-CSF, and IL-12p70. Thirteen biomarkers exhibited significant changes in the first year after viral suppression, but none changed significantly after that time.
Biomarkers of inflammation and immune activation moved toward HIV-negative levels within the first year after HAART-induced HIV suppression. Although several markers of T cell activation returned to levels present in HIV-negative men, residual immune activation, particularly monocyte/macrophage activation, was present. This residual immune activation may represent a therapeutic target to improve the prognosis of HIV-infected individuals receiving HAART.
Acquired Immunodeficiency Syndrome; Antiretroviral Therapy, Highly Active; Biological Markers; Inflammation; Prospective Studies; Male
In sub-Saharan Africa, HIV-exposed uninfected (HEU) infants have higher morbidity and mortality than HIV-unexposed infants. To evaluate whether immune dysfunction contributes to this vulnerability of HEU infants, we conducted a longitudinal, observational cohort study to assess T-cell immune responses to infant vaccines (Mycobacterium bovis BCG and acellular pertussis) and staphylococcal enterotoxin B (SEB). In total, 46 HEU and 46 HIV-unexposed infants were recruited from Khayelitsha, Cape Town.
Vaccine-specific T-cell proliferation (Ki67 expression) and intracellular expression of four cytokines [interferon-γ, interleukin (IL)-2, IL-13 and IL-17] were measured after whole blood stimulation with antigens at 6 and 14 weeks of age.
HEU infants demonstrated elevated BCG-specific CD4+ and CD8+ T-cell proliferative responses at 14 weeks (P = 0.041 and 0.002, respectively). These responses were significantly increased even after adjusting for birth weight, feeding mode and gestational age. Similar to BCG, increased CD4+ and CD8+ T-cell proliferation was evident in response to SEB stimulation (P = 0.004 and 0.002, respectively), although pertussis-specific T cells proliferated comparably between the two groups. Within HEU infants, maternal CD4+ cell count and length of antenatal antiretroviral exposure had no effect on T-cell proliferation to BCG or SEB. HIV exposure significantly diminished measurable cytokine polyfunctionality in response to BCG, Bordetella pertussis and SEB stimulation.
These data show for the first time, when adjusting for confounders, that exposure to HIV in utero is associated with significant alterations to CD4+ and CD8+T-cell immune responses in infants to vaccines and nonspecific antigens.
cytokines; infants; maternal HIV; proliferation; T-cell immunity; vaccination
To estimate the association of age of viral suppression and central nervous system penetration effectiveness (CPE) score with neurocognitive functioning among school-age children with perinatally-acquired HIV infection (PHIV+).
We analyzed data from two U.S.-based multisite prospective cohort studies.
Multivariable general linear regression models were used to evaluate associations of age at viral suppression and CPE scores [of initial ART regimen and weighted average] with WISC-III or WISC-IV neurocognitive assessments [full scale IQ (FSIQ); performance IQ/ perceptual reasoning index (PIQ/PRI); and verbal IQ/ verbal comprehension index (VIQ/VCI)], adjusted for demographic and clinical covariates. Sensitivity analyses were stratified by birth cohort (before vs after 1996).
396 PHIV+ children were included. Estimated differences in mean FSIQ (comparing virally suppressed vs. unsuppressed children) by each age cutoff were 3.7, 2.2, 3.2, 4.4, and 3.9 points at ages 1, 2, 3, 4, and 5, respectively. For PIQ/PRI, estimated mean differences were 3.7, 2.4, 2.2, 4.6, and 4.5 at ages 1 through 5 respectively. In both cases, these differences were significant only at the age 4 and 5 thresholds. After stratifying by birth cohort the association between age at suppression and cognitive function persisted only among those born after 1996. Age at viral suppression was not associated with VIQ/VCI; CPE score was not associated with FSIQ, verbal comprehension or perceptual reasoning indices.
Virologic suppression during infancy or early childhood is associated with improved neurocognitive outcomes in school-aged PHIV+ children. In contrast, CPE scores showed no association with neurocognitive outcomes.
Paediatrics; HIV; cognition; antiretroviral therapy; viral load; central nervous system
HAART largely decreases morbidity and mortality in chronic HIV-1-infected patients, but immune nonresponders (INRs) with full viral suppression still fail to reverse the immune deficiency. This study evaluated the safety and immunological responses of human umbilical cord mesenchymal stem cell (MSC) therapy in HIV-1-infected INRs.
Design and Methods
A total of 13 HIV-1-infected INRs were enrolled in this pilot prospectively open-labeled controlled clinical trial. Seven patients were administered three umbilical cord-MSC transfusions at 1-month interval during 12-months of follow-up, whereas six control patients were treated with saline in parallel. Immunological parameters were monitored in these patients throughout the trial.
All patients tolerated the umbilical cord-MSC transfusions well throughout the trial. The umbilical cord-MSC transfusions preferentially increased circulating naive and central memory CD4 T-cell counts and restored HIV-1-specific IFN-γ and IL-2 production in the INRs. These enhancements in immune reconstitution were also associated with the reduction of systemic immune activation and inflammation in vivo.
umbilical cord-MSC transfusions are well tolerated and can efficiently improve host immune reconstitution in INRs, suggesting that such treatments may be used as a novel immunotherapeutic approach to reversing immune deficiency in HIV-1-infected INRs (ClinicalTrials.gov identifier: NCT01213186).
clinical trial; HIV-1; immune reconstitution; mesenchymal stem cells; T cells
To compare growth patterns in the first year of life between children born to perinatally HIV-infected (PHIV) vs. non-perinatally HIV-infected (NPHIV) women in the U.S.
Retrospective cohort study of HIV-infected pregnant women who received care and delivered a liveborn at two urban tertiary centers from January 2004 - March 2012.
We collected data via chart review on demographics, behavioral risk factors, HIV clinical markers, combination antiretroviral therapy (cART), mode of HIV acquisition, pregnancy outcomes, and infant anthropometrics on study subjects. Mixed effects models were used to assess the association between maternal mode of HIV acquisition and weight-for-age (WAZ), length-for-age (LAZ), and weight-for-length (WLZ) z-scores.
Of 152 pregnancies evaluated, 32 and 120 infants were born to 25 PHIV and 99 NPHIV women respectively. Infants of PHIV women exhibited lower mean WAZ and LAZ throughout the first year of life in unadjusted analyses. After adjusting for potential confounders, the relationship between PHIV & LAZ persisted (β=−0.54, p=0.026). Small for gestational age for each birth anthropometric parameter [birth length, birth weight, and both birth length and weight] was associated with decreased LAZ (β=−0.48, p=0.007), WAZ (β=−0.99, p<0.001) and WLZ (β=−0.36, p=0.027) respectively. A delivery HIV RNA level <400 copies/mL was associated with increased WAZ & WLZ (β=0.43, p=0.015; β=0.38, p=0.021).
Infants of PHIV women may remain at persistently decreased lengths throughout the first year of life. Further studies aimed at understanding intrauterine and environmental factors in PHIV women are warranted.
To determine whether cognitive impairment and brain injury as measured by proton magnetic resonance spectroscopy (MRS) persist in the setting of highly active antiretroviral therapy (HAART).
This study is an observational cohort study.
MRS was performed in 268 patients: HIV-negative controls (N=28), HIV-positive neuroasymptomatic (NA) subjects (N=124), and subjects with AIDS Dementia Complex (ADC; N=50) on stable ART with a mean duration of infection of 12 years and CD4 of 309 cells/mm3. Four metabolites were measured over creatine (Cr): N-acetyl aspartate (NAA), marker of neuronal integrity; Choline (Cho), myoinositol (MI), markers of inflammation, and glutamate and glutamine (Glx) in the basal ganglia (BG), frontal white matter (FWM) and mid-frontal Cortex (MFC). Analyses included ANOVA, ANCOVA, linear and nonparametric regression models.
Cognitive impairment was found in 48% of HIV infected subjects. Both HIV positive groups showed significant increases in MI/Cr or Cho/Cr in all brain regions when compared to controls; a significant decrease in Glx/Cr in the FWM was observed in the NA group; only ADC subjects showed a significant reduction in NAA/ Cr although a significant trend for decreasing NAA/Cr in the BG was found across the groups. Effects related to aging and duration of infection but not central nervous system penetration effectiveness (CPE) were observed.
Brain inflammatory changes remain ubiquitous among HIV-infected subjects whereas neuronal injury occurs predominantly in those with cognitive impairment. Together these findings indicate that despite the widespread use of HAART, HIV-associated cognitive impairment and brain injury persist in the setting of chronic and stable disease.
Neuroimaging; HIV dementia; Magnetic Resonance Spectroscopy; antiretroviral therapies
cellular immunity; myeloid-derived suppressor cell; progressive HIV infection
HIV infection is associated with cancer risk. This relationship has resulted in a growing cancer burden, especially in resource-limited countries where HIV is highly prevalent. Little is known, however, about how HIV affects cancer survival in these settings. We therefore investigated the role of HIV in cancer survival in Uganda.
Retrospective cohort (N = 802).
Eligible cancer patients were residents of Kyadondo County, at least 18 years of age at cancer diagnosis, and diagnosed between 2003 and 2010 with one of the following: breast cancer, cervical cancer, non-Hodgkin’s lymphoma, Hodgkin’s lymphoma, or esophageal cancer. Patients were classified as HIV-infected at cancer diagnosis based on a documented positive HIV antibody test, medical history indicating HIV infection, or an HIV clinic referral letter. The primary outcome, vital status at 1 year following cancer diagnosis, was abstracted from the medical record or determined through linkage to the national hospice database. The risk of death during the year after cancer diagnosis was compared between cancer patients with and without evidence of HIV infection using Cox proportional hazards regression.
HIV-infected cancer patients in Uganda experienced a more than two-fold increased risk of death during the year following cancer diagnosis compared to HIV-uninfected cancer patients [hazard ratio 2.28; 95% confidence interval (CI) 1.61–3.23]. This association between HIV and 1-year cancer survival was observed for both cancers with (hazard ratio 1.56; 95% CI 1.04–2.34) and without (hazard ratio 2.68; 95% CI 1.20–5.99) an infectious cause.
This study demonstrates the role of HIV in cancer survival for both cancers with and without an infectious cause in a resource-limited, HIV-endemic setting.
cancer in Africa; cancer survival; HIV; immunosuppression; Uganda
Routine monitoring of plasma HIV RNA among HIV-infected patients on antiretroviral therapy (ART) is unavailable in many resource-limited settings. Alternative monitoring approaches correlate poorly with virologic failure and can substantially delay switch to second-line therapy. We evaluated the impact of delayed switch on mortality among patients with virologic failure in Africa.
We examined patients with confirmed virologic failure on first-line non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens from four cohorts with serial HIV RNA monitoring in Uganda and South Africa. Marginal structural models aimed to estimate the effect of delayed switch on mortality in a hypothetical trial in which switch time was randomly assigned. Inverse probability weights adjusted for measured confounders including time-updated CD4+ T-cell count and HIV RNA.
Among 823 patients with confirmed virologic failure, the cumulative incidence of switch 180 days after failure was 30% [95% confidence interval (CI) 27–33]. The majority of patients (74%) had not failed immunologically as defined by WHO criteria by the time of virologic failure. Adjusted mortality was higher for individuals who remained on first-line therapy than for those who had switched [odds ratio (OR) 2.1, 95% CI 1.1 –4.2]. Among those without immunologic failure, the relative harm of failure to switch was similar (OR 2.4; 95% CI 0.99–5.8) to that of the entire cohort, although of borderline statistical significance.
Among HIV-infected patients with confirmed virologic failure on first-line ART, remaining on first-line therapy led to an increase in mortality relative to switching. Our results suggest that detection and response to confirmed virologic failure could decrease mortality.
antiretroviral; cohort studies; HIV; HIV RNA level; inverse probability weight; marginal structural model; time-dependent confounding; treatment failure; viral load
The objective of this study is to assess the feasibility and acceptability of an intervention to reduce mental health problems and bolster resilience among children living in households affected by caregiver HIV in Rwanda.
Pre-post design, including 6-month follow-up.
The Family Strengthening Intervention (FSI) aims to reduce mental health problems among HIV-affected children through improved child–caregiver relationships, family communication and parenting skills, HIV psychoeducation and connections to resources. Twenty families (N=39 children) with at least one HIV-positive caregiver and one child 7–17 years old were enrolled in the FSI. Children and caregivers were administered locally adapted and validated measures of child mental health problems, as well as measures of protective processes and parenting. Assessments were administered at pre and postintervention, and 6-month follow-up. Multilevel models accounting for clustering by family tested changes in outcomes of interest. Qualitative interviews were completed to understand acceptability, feasibility and satisfaction with the FSI.
Families reported high satisfaction with the FSI. Caregiver-reported improvements in family connectedness, good parenting, social support and children's pro-social behaviour (P<0.05) were sustained and strengthened from postintervention to 6-month follow-up. Additional improvements in caregiver-reported child perseverance/self-esteem, depression, anxiety and irritability were seen at follow-up (P<.05). Significant decreases in child-reported harsh punishment were observed at postintervention and follow-up, and decreases in caregiver reported harsh punishment were also recorded on follow-up (P<0.05).
The FSI is a feasible and acceptable intervention that shows promise for improving mental health symptoms and strengthening protective factors among children and families affected by HIV in low-resource settings.
adolescent; Africa; child; mental disorders; mental health; paediatrics; psychotherapy
To evaluate the effectiveness and cost-effectiveness of strategies to treat hepatitis C virus (HCV) in HIV/HCV co-infected patients in the U.S.
Simulated cohort of HIV/HCV genotype 1 co-infected, non-cirrhotic, HCV treatment-naïve individuals enrolled in U.S. HIV guideline-concordant care.
Monte Carlo simulation comparing 5 strategies: no treatment; “dual therapy" with pegylated-interferon (PEG) and ribavirin (RBV); starting all patients (“PEG/RBV trial”) or some patients (“IL28B triage”) on PEG/RBV and advancing those with treatment failure to PEG/RBV and telaprevir (TVR), and “triple therapy” PEG/RBV/TVR for all patients. Sensitivity analyses varied efficacies and costs and included a scenario with interferon (IFN)-free therapy.
SVR, life expectancy (LE), discounted quality-adjusted life expectancy (QALE) and lifetime medical cost, and incremental cost-effectiveness ratios (ICERs) in $/QALY gained.
“PEG/RBV trial,” “IL28B triage,” and “triple therapy” each provided 72% sustained virologic response (SVR) and extended QALE compared to “dual therapy” by 1.12, 1.14, and 1.15 QALY respectively. The ICER of “PEG/RBV trial” compared to “dual therapy” was $37,500/QALY. “IL28B triage” and “triple therapy” provided little benefit compared to “PEG/RBV trial” and had ICERs exceeding $300,000/QALY. In sensitivity analyses, IFN-free treatment attaining 90% SVR had an ICER <$100,000/QALY compared to “PEG/RBV trial” when its cost was ≤ $109,000 (125% of the cost of PEG/RBV/TVR).
HCV protease inhibitors are most efficiently used in HIV/HCV co-infection after a trial of PEG/RBV, sparing protease inhibitor for those who attain RVR and SVR. The cost-effectiveness of IFN-free regimens for HIV/HCV will depend on the cost of these therapies.
HIV/HCV co-infection; cost-effectiveness; telaprevir; interferon-free
AIDS-related primary central nervous system lymphoma (AR-PCNSL) has a poor prognosis. Improved understanding of specific patient, infectious, diagnostic, and treatment-related factors that affect overall survival (OS) are required to improve outcomes.
Population-based registry linkage study.
Adult cases from the San Francisco AIDS registry (1990–2000) were matched with the California Cancer Registry (1985–2002) to ascertain AR-PCNSL data. Survival time was assessed through 31 December 2007. Risk factors and temporal trends for death were measured using two-sided Kaplan–Meier and Cox analyses.
Two hundred and seven AR-PCNSL patients were identified: 68% were white, 20% Hispanic, 10% African–American, and 2% Asian. Nineteen percent of patients had central nervous system (CNS) opportunistic infections diagnosed prior to AR-PCNSL. Fifty seven percent of patients received radiation and/or chemotherapy and 12% used HAART prior to or within 30 days of AR-PCSNL diagnosis. One hundred and ninety-nine patients died (34 deaths/100 person-years). In adjusted analysis, prior CNS opportunistic infections diagnosis increased risk of death (hazard ratio 1.9, P = 0.0006) whereas radiation and/or chemotherapy decreased risk (hazard ratio 0.6, P <0.0001). AR-PCNSL diagnosis 1999–2002 had a lower mortality risk (hazard ratio = 0.4, P = 0.02) compared to 1990–1995. African–Americans had an increased risk of death compared to whites or Asians (hazard ratio = 2.0, P = 0.007).
OS among AR-PCSNL patients improved over time but remains poor, especially among African–Americans. Prospective evaluation of curative therapy in AR-PCNSL is urgently needed. Accurate diagnosis of CNS mass lesions in patients with AIDS is required and for those with AR-PCNSL, antiretroviral therapy with concomitant AR-PCNSL therapy, and antimicrobial supportive care may improve OS.
AIDS; AIDS-related lymphoma; brain neoplasms; HAART; prognosis; risk factors; time factors
Diabetes and hypertension, common conditions in antiretroviral (ART) treated HIV-infected individuals, are associated with glomerular hyperfiltration, which precedes the onset of proteinuria and accelerated kidney function decline. In the Multicenter AIDS Cohort Study, we examined the extent to which hyperfiltration is present and associated with metabolic, cardiovascular, HIV and treatment risk factors among HIV-infected men.
Cross-sectional cohort using direct measurement of glomerular filtration rate (GFR) by iohexol plasma clearance for 367 HIV-infected men and 241 HIV-uninfected men who were free of CKD.
Hyperfiltration was defined as GFR >140 ml/min/1.73m2 - 1 ml/min/1.73m2 per each year over age 40. Multivariate logistic regression was used to estimate the odds ratios (OR) of prevalent hyperfiltration for metabolic, cardiovascular, HIV and cumulative ART exposure factors.
Among subjects without CKD, the prevalence of hyperfiltration was higher for HIV-infected participants (25%) compared to uninfected participants (17%; p=0.01). HIV infection was associated with hyperfiltration (OR: 1.70, 95%CI: 1.11, 2.61) and modified the association between diabetes and hyperfiltration, such that the association among HIV-uninfected men (OR: 2.56 95%CI: 1.33, 5.54) was not observed among HIV-infected men (OR: 1.19, 95%CI: 0.69, 2.05). These associations were independent of known risk factors for hyperfiltration. Indicators of hyperglycemia and hypertension were also associated with hyperfiltration as was cumulative zidovudine exposure.
Hyperfiltration, a potential modifiable predictor of kidney disease progression, is common among ART-treated HIV-infected men. HIV infection is associated with significant odds of hyperfiltration in addition to known risk factors for kidney damage.
Glomerular hyperfiltration; glomerular filtration rate; HIV; antiretroviral therapy; iohexol
The efficacy of male circumcision (MC) for HIV prevention over two years has been demonstrated in three randomized trials, but the longer-term effectiveness of MC is unknown.
We conducted a randomized trial of MC in 4996 HIV-negative men aged 15-49 in Rakai Uganda. Following trial closure we offered MC to uncircumcised control arm participants maintained surveillance for up to 4.79 years. HIV incidence per 100 person-years (py) was assessed in an as-treated analysis, and the effectiveness of MC was estimated using Cox regression models, adjusted for sociodemographic and time-dependent sexual behaviors. For men uncircumcised at trial closure, sexual risk behaviors at the last trial and first post-trial visits were assessed by subsequent circumcision acceptance to detect behavioral risk compensation.
By Dec 15, 2010, 78.4% of uncircumcised trial participants accepted MC following trial closure. Retention during post-trial surveillance was was 74%.In control arm participants, post-trial HIV incidence was 0.54/100 py in circumcised and 1.71/100 py in uncircumcised control arm men (adjusted effectiveness 67% (95%CI 38-83%). There were no significant differences in sociodemographic characteristics and sexual behaviors between controls accepting MC and those remaining uncircumcised.
High effectiveness of MC for HIV prevention was maintained for almost 5 years following trial closure. There was no evidence of self-selection or of behavioral risk compensation associated with post-trial MC acceptance.
Suppressive anti-retroviral therapy (ART) substantially decreases HIV transmission in clinical research settings. We sought to measure the frequency and correlates of periods of transmission risk among individuals taking ART during multiple years of observation in rural, southwestern Uganda.
Observational cohort study
We collected sexual behavior and viral load data in a Ugandan cohort of people living with HIV/AIDS from the time of ART initiation. We defined each 90-day visit as a potential transmission period if HIV-1 RNA was > 400 copies/mL and the participant reported sexual transmission risk behavior, defined as unprotected sexual contact with ≥1 HIV-uninfected partners or partners of unknown serostatus in the prior 90 days.
We evaluated data from 463 individuals on ART over a median 3.5 years of observation and 5,293 total study visits. During that time, over half (259, 56%) had detectable viremia or reported sexual transmission risk behavior at least once. However only 23 (5%) had both simultaneously, at 28 (<1%) of all visits. Transmission sexual behavior was reported at 6% of visits with detectable viremia. In multivariable regression modeling, correlates of transmission risk periods included younger age, lower CD4 count, low household asset ownership and increased internalized stigma.
Although detectable viremia and/or sexual transmission risk behavior occurred in over half of individuals, ART reduced periods of HIV transmission risk by over 90% during up to six years of observation time. These findings provide further support for provision of ART, along with interventions to promote long-term adherence, to reduce HIV transmission in HIV-endemic settings.
HIV/AIDS; Anti-retroviral therapy; sub-Saharan Africa; treatment as prevention; Uganda
Studies of neutralizing antibodies in HIV-1 infected individuals provide insights into the quality of the response that should be possible to elicit with vaccines and ways to design effective immunogens. Some individuals make high titres of exceptional broadly reactive neutralizing antibodies that are of particular interest; however, more modest responses may be a reasonable goal for vaccines. We performed a large cross-sectional study to determine the spectrum of neutralization potency and breadth that is seen during chronic HIV-1 infection.
Neutralization potency and breadth were assessed with genetically and geographically diverse panels of 205 chronic HIV-1 sera and 219 Env-pseudotyped viruses representing all major genetic subtypes of HIV-1.
Neutralization was measured by using Tat-regulated luciferase reporter gene expression in TZM-bl cells. Serum-neutralizing activity was compared with a diverse set of human mAbs that are widely considered to be broadly neutralizing.
We observed a uniform continuum of responses, with most sera displaying some level of cross-neutralization, and approximately 50% of sera neutralizing more than 50% of viruses. Titres of neutralization (potency) were highly correlated with breadth. Many sera had breadth comparable to several of the less potent broadly neutralizing human mAbs.
These results help clarify the spectrum of serum-neutralizing activity induced by HIV-1 infection and that should be possible to elicit with vaccines. Importantly, most people appear capable of making low to moderate titres of broadly neutralizing antibodies. Additional studies of these relatively common responses might provide insights for practical and feasible vaccine designs.
HIV-1; immunity; neutralizing antibodies; serum; vaccines
HIV-1 subtype C has emerged as the most prevalent strain of HIV-1 worldwide, leading to speculation that subtype C may be more transmissible than other subtypes. We compared the risk of HIV-1 transmission for subtype C versus non-C subtypes (A, D, G and recombinant forms) among heterosexual African HIV-1 serodiscordant couples.
We conducted a nested case-control analysis using data from two prospective cohort studies of heterosexual HIV-1 serodiscordant couples from 6 countries in eastern and southern Africa. Cases (N=121) included incident HIV-1 transmissions that were established as linked within the serodiscordant partnership by viral sequencing; controls (N=501) were non-transmitting HIV-1 infected partners. Subtype was determined for partial env and gag genes. Multiple logistic regression controlled for age and gender of the HIV-1 infected partner and self-reported unprotected sex. Plasma and genital HIV-1 RNA concentrations were compared between subtype C and non-C subtypes using generalized estimating equations.
HIV-1 subtype C was not associated with increased risk of HIV-1 transmission compared to non-C subtypes: env adjusted odds ratio (adjOR) 1.14 (95% confidence interval [CI] 0.74–1.75, p=0.6) and gag adjOR 0.98 (95% CI 0.63–1.52, p=0.9). Plasma and genital HIV-1 RNA levels did not differ significantly for subtype C versus non-C.
In a geographically diverse population of heterosexual African HIV-1 serodiscordant couples, subtype C was not associated with greater risk of HIV-1 transmission compared to non-C subtypes, arguing against the hypothesis that subtype C is more transmissible compared to other common subtypes.
HIV-1 subtype; transmission; serodiscordant couples; Africa
To evaluate the relationship between incomplete antiretroviral therapy (ART) adherence and levels of residual HIV-1 viremia.
Medication adherence and residual viremia <50 copies/mL were quantified in participants of a cohort of homeless and marginally housed individuals with HIV/AIDS.
Participants had at least 6 months of virologic suppression <50 copies/mL and were in the adherence monitoring cohort with monthly unannounced pill counts. Residual viremia was measured by the single-copy assay.
The median average ART adherence over the prior 1 and 2 months were 94% [IQR 79%–100%] and 93% [IQR 82%–98%], respectively. Average ART adherence over the past 2 months was significantly associated with levels of residual HIV viremia (Spearman r = −0.25, P=0.04). One-third of participants with 100% ART adherence over the past 2 months had detectable residual viremia. On multivariate regression analysis, ART adherence over the past 2 months, but not duration of virologic suppression, CD4+ T cell count, or ART regimen, was significantly associated with levels of residual HIV viremia. Detectable residual viremia was associated with virologic failure (>50 copies/mL) on univariate Cox proportional hazard analysis (HR 2.08, P=0.02). However, on multivariate analysis, only ART adherence was associated with risk of virologic failure.
Incomplete ART adherence is associated with higher levels of residual HIV-1 viremia, but detectable residual viremia can be present despite 100% measured ART adherence.
Residual viremia; HIV reservoir; medication adherence
To study the cytokine/chemokine profiles in response to HIV-1 viremia, and elucidate the pathways leading to HIV-1-induced inflammation.
Plasma levels of 19 cytokines in individuals with early HIV-1 infection and individuals undergoing treatment interruptions were evaluated via multiplex assay. To investigate the cellular sources of relevant cytokines, sorted cells from HIV-1 infected individuals were assessed for mRNA expression. Relevant signaling pathways were assessed by comparing cytokine production patterns of PBMCs stimulated with intact HIV-1 or specific TLR stimulants with and without a TLR7/9 antagonist.
IP-10 plasma concentration was most significantly associated with HIV-1 viral load and was the most significant contributor in a multivariate model. IP-10 mRNA was highly expressed in monocytes and mDCs and these cells were the dominant producers after in vitro stimulation with TLR7/8 ligands (CL097 and ssRNAGag1166), AT-2 HIV-1, and HIV-1NL43 virus. Partial least square discriminant analysis of culture supernatants revealed distinct cytokine/chemokine secretion profiles associated with intact viruses compared to TLR7/8 ligands alone, with IP-10 production linked to the former. A TLR7/9 antagonist blocked IP-10 production following whole virus stimulation, suggesting the involvement of TLR7/9 in the recognition of HIV-1 by these cells.
Monocytes and mDCs produce significant amounts of IP-10 in response to HIV-1 viremia and after in vitro stimulation with HIV-1. Stimulation with HIV-1-derived TLR7/8-ligands versus HIV-1 resulted in distinct cytokine/chemokine profiles, indicating additional pathways other than TLR7/8 that lead to the activation of innate immune cells by HIV-1.
IP-10; immune activation; TLR; monocytes; mDCs
chronic immune activation; combination antiretroviral therapy; HIV; non-AIDS-defining illness; T-cell activation
To facilitate collection of cumulative data on longitudinal HIV disease outcomes during HIV prevention studies by developing recommendations for follow-up of the relatively few study participants with breakthrough infections.
We formed a working group to compare and contrast the various approaches taken in recent HIV prevention trials, to summarize the advantages and disadvantages associated with each, and to explore the feasibility of developing protocols for the long-term follow-up of seroconverters.
We reviewed study designs, objectives, and assessments in 15 interventional studies that followed HIV seroconverters. Protocol team members joined discussions of the various approaches and developed recommendations.
Most HIV prevention clinical trials share a core set of objectives, including the description/comparison of virological, immunological and clinical course of HIV, and sometimes a comparison of pre-and post-seroconversion behavior. Long-term follow-up of seroconverters can be conducted in separate studies if the transition from parent protocol is effectively managed.
We recommend the development of harmonized seroconverter protocols. Although specific research questions in the post-seroconversion period may differ depending on prevention modality, harmonizing key evaluations would create an opportunity to ask overarching questions that inform the prevention field with respect to design and implementation of future combination prevention studies. Follow-up immediately post-seroconversion should be conducted in the parent protocol before rollover into a follow-up protocol. Development of specimen repositories with ample volumes for future assays, standardized definitions of infection, diagnosis and seroconversion dates, and harmonization of study objectives and sample collections at key time points are important.
HIV; prevention; HIV seroconversion; pathogenesis; clinical trials as topic