To investigate the pharmacokinetics of darunavir/ritonavir and raltegravir, in HIV-infected subjects, in both plasma and at the intracellular (IC) site of action.
HIV-infected patients on antiretroviral therapy received raltegravir 400 mg twice daily for 21 days (period 1); darunavir/ritonavir 800/100 mg once daily was added for 14 days (period 2), and patients were randomized to continue raltegravir twice daily (group 1) or to switch to 800 mg once daily (group 2), then they all stopped raltegravir intake and continued darunavir/ritonavir once daily for 14 days (period 3). Drug concentrations in plasma and cells (peripheral blood mononuclear cell) were measured, and differences in geometric mean ratios (GMR) and 90% confidence intervals (CI) between period 2 versus period 3 and period 2 versus period 1 were assessed.
Twenty-four patients completed the study. Group 1 GMR (90% CI) of darunavir area under the curve (AUC) with and without raltegravir was 1.24 (1.13 to 1.45) for plasma and 1.24 (1.07 to 1.73) for cells and for group 2 was 1.14 (1.07 to 1.24) and 1.03 (0.94 to 1.16). GMR (90% CI) of raltegravir AUC without and with darunavir/ritonavir (plasma and cells) for group 1 was 0.90 (0.73 to 1.44) and 1.02 (0.81 to 1.67) and for group 2 was 1.21 (1.03 to 1.77) and 1.27 (1.07 to 1.94). Geometric mean IC to plasma AUC ratios were 5.3 and 4.9 for darunavir in groups 1 and 2 when darunavir/ritonavir was given alone and 4.9 and 5.6 for raltegravir when given alone. These ratios were not altered by the coadministered drug.
No remarkable interactions between darunavir/ritonavir and raltegravir in plasma or cells were seen. Raltegravir IC concentrations are higher than previously reported; the difference being due to modified cell isolation procedures that reduced drug loss caused by washing.
darunavir/ritonavir; raltegravir; intracellular pharmacokinetics; drug interactions
Conflicting data exist regarding the effect of pregnancy on steady-state nevirapine pharmacokinetics (PK), although steady-state nevirapine concentrations during pregnancy have never been characterized in sub-Saharan Africa.
This was a longitudinal intensive PK study in Ugandan pregnant women receiving nevirapine-based antiretroviral therapy. Participants underwent intensive 12-hour PK sampling during the second trimester (T2; n = 4), third trimester (T3; n = 15) and 6 weeks postpartum (PP; n = 15). HIV-1 RNA was performed within 2 weeks of each visit. Nevirapine C12 above 3000 ng/mL was classified as optimal based on the suggested value for therapeutic drug monitoring.
The pharmacokinetics of nevirapine were influenced by pregnancy, demonstrated by a 20% reduction in the maximum concentration, minimum concentration (C12), and area under the curve between T3 and PP visits (P = 0.001, P = 0.011 and P = 0.005, respectively). Ten subjects (66.7%) had C12 values <3000 ng/mL during T3. Of these participants, 7 partcipant’s C12 concentrations increased to >3000 ng/mL during the PP visit. HIV-1 RNA were <1000 copies per milliliter at T3 and <400 copies per milliliter at PP in all patients.
Nevirapine exposure was reduced in Ugandan women during their third trimester compared with the same women PP, however, HIV RNA remained <1000 copies per milliliter. The long-term impact of intermittent suboptimal nevirapine concentrations during pregnancy is unknown.
antiretroviral agents; HIV; pregnancy; pharmacokinetics; Sub-Saharan Africa
The impact of pregnancy on efavirenz pharmacokinetics is unknown.
International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) P1026s is an on-going, prospective, non-blinded study of antiretroviral pharmacokinetics in HIV-infected pregnant women that included a cohort receiving 600 mg efavirenz once daily as part of combination antiretroviral therapy. Intensive steady-state 24-hour blood sampling was performed during the third trimester and at 6–12 weeks postpartum. Maternal and umbilical cord blood samples were drawn at delivery. Pharmacokinetics targets were the estimated 10th percentile efavirenz AUC in non-pregnant historical controls (40.0 mcg.hr/mL) and a trough concentration of 1 mcg/mL.
Twenty five women were enrolled during the third trimester: median (range) age was 29.3 (18.9–42.9) years, weight 69.0 (40–130) kg, gestational age 32.9 (30.1–38.7) weeks. Median (range) efavirenz AUC0-24, Cmax and C24hour were 55.4 mcg.hr/mL (13.5–220.3), 5.4 mcg/mL (1.9–12.2) and 1.6 mcg/ml (0.23–8.13), respectively. Efavirenz AUC and Cmax did not differ during pregnancy and postpartum but C24hour was lower during the third trimester (1.6 vs. 2.1 mcg/mL, p=0.01). During the third trimester, 5 of 25 (20%) women had an efavirenz AUC below the target and 3 of 25 (12%) had a trough concentration below 1 mcg/mL. Efavirenz cord blood/maternal concentration ratio was 0.49 (0.37–0.74). All women had a HIV-1 RNA viral load less than 400 copies/mL at delivery and 19 (76%) had a viral load below 50 copies/mL. One child was perinatally HIV-infected. Three women were exposed to efavirenz throughout the first 6 weeks of pregnancy. EFV was well tolerated and among the 25 infants no congenital anomalies or newborn complications were reported.
Changes in efavirenz pharmacokinetics during pregnancy compared to postpartum are not sufficiently large enough to warrant a dose adjustment during pregnancy.
efavirenz; pregnancy; pharmacokinetics; HIV; prevention of mother-to-child transmission of HIV
New HIV-1 infections are increasing in older American women largely through heterosexual transmission. Activated CD4+ T-cells and CCR5 expression are linked to HIV-1 susceptibility, but whether these parameters are altered in the cervix of older women is unknown.
Whole blood and in some instances endocervical brush samples were collected from healthy premenopausal (n=22) and postmenopausal women (n=24). Percentages of HLA-DR(DR)+CD38(38)+CD4+ T-cells, and HIV-1 chemokine coreceptor expression were determined by flow cytometry.
Percentages of DR+38+CD4+ T-cells were 6-times greater in cervix (median, 6.4%) than blood (median, 1.1%; p<0.001), but did not differ within each compartment between premenopausal and postmenopausal women (p=0.2). Postmenopausal women had greater percentages of CCR5+CD4+ and CCR5+DR+38+CD4+ T-cells compared to premenopausal women in cervix (median, 70% vs. 42%, p=0.005; and 80% vs. 57%; p<0.05, respectively) and blood (medians, 22% vs. 13%, and 76% vs. 62%, respectively; p<0.001). Postmenopausal women had more CCR5 molecules on cervical DR+38+CD4+ T-cells (median, 3,176) than premenopausal women (median, 1,776; p=0.02). Age and percent CCR5+CD4+ and CCR5+DR+38+CD4+-cells were linearly related in cervix (r2=0.47, p<0.001 and r2=0.25, p=0.01, respectively) and blood (r2=0.20, p=0.001 and r2=0.31, respectively; p<0.001), but confounding of age with menopause could not be excluded. Cervical CXCR4 expression did not differ substantially between premenopausal and postmenopausal women.
Elevated cervical CCR5 expression in postmenopausal women may increase their risk for HIV-1 acquisition. Studies are needed to confirm whether elevated CCR5 expression confers increased HIV-1 susceptibility in postmenopausal women, and if it is related to hormonal or nonhormonal effects of aging.
Cluster heat maps were used to investigate relationships between body composition, lipid levels and glucose metabolism in HIV-infected and HIV-uninfected children and young adults using data from a cross-sectional study. Three distinct clusters of participants were identified. One group had lower body fat and higher lipid measures and was mostly HIV-infected. The other two groups were a mix of HIV-infected and uninfected participants. Of these, one cluster had more participants with higher body fat and insulin resistance, which are risk factors for future cardiovascular disease, and the other had relatively normal measurements on all outcomes.
children and young adults; metabolic abnormalities; heat maps; clusters
Controversy continues regarding the extent of ongoing viral replication in HIV-1-infected patients on effective antiretroviral therapy (ART). Adding an additional potent agent, such as raltegravir, to effective ART in patients with low-level residual viremia may reveal whether there is ongoing HIV-1 replication.
We previously reported the outcome of a randomized, placebo-controlled study of raltegravir intensification in patients on ART with HIV-1 RNA <50 copies/mL that showed no effect on residual viremia measured by single copy assay (SCA). We now report the effects of raltegravir intensification in that trial on other potential measures of ongoing HIV-1 replication: 2-LTR HIV-1 circles, total cellular HIV-1 DNA and T cell activation.
Of 50 patients tested, 12 (24%) had 2-LTR-circles detected at baseline. Patients who were 2-LTR-positive had higher plasma HIV-1 RNA and HIV-1 DNA levels than 2-LTR-negative individuals. At week 12 of raltegravir intensification, there was no change from baseline in 2-LTR circles, in total HIV-1 DNA or in the ratio of 2-LTR circles to total HIV-1 DNA. There was also no change in markers of T cell activation.
In HIV-1-infected individuals on effective antiretroviral therapy, we find no evidence of ongoing viral replication in the blood that is suppressible by raltegravir intensification. The results imply that raltegravir intensification alone will not eradicate HIV-1 infection.
Raltegravir; HIV-1; viral replication; reservoirs; 2-LTR circles; HIV-1 DNA; T cell activation
HIV; Concurrent sexual partners; marriage; Uganda
We developed a mathematical model to simulate the impact of various partially effective preventive HIV vaccination scenarios in a population at high risk for heterosexually transmitted HIV. We considered an adult population defined by gender (male/female), disease stage (HIV-negative, HIV-positive, AIDS, and death), and vaccination status (unvaccinated/vaccinated) in Soweto, South Africa. Input data included initial HIV prevalence of 20% (women) and 12% (men), vaccination coverage of 75%, and exclusive male negotiation of condom use. We explored how changes in vaccine efficacy and post-vaccination condom use would affect HIV prevalence and total HIV infections prevented over a 10-year period. In the base-case scenario, a 40% effective HIV vaccine would avert 61,000 infections and reduce future HIV prevalence from 20% to 13%. A 25% increase (or decrease) in condom use among vaccinated individuals would instead avert 75,000 (or only 46,000) infections and reduce the HIV prevalence to 12% (or only 15%). Furthermore, certain combinations of increased risk behavior and vaccines with <43% efficacy could worsen the epidemic. Even modestly effective HIV vaccines can confer enormous benefits in terms of HIV infections averted and decreased HIV prevalence. However, programs to reduce risk behavior may be important components of successful vaccination campaigns.
AIDS vaccines; mathematical models; sexual behavior; heterosexual transmission; Africa; condoms; models/projections
Data on outcomes of antiretroviral treatment (ART) programs in rural sub-Saharan African are scarce. We describe early losses and long-term outcomes in six rural programs in Southern Africa with limited access to viral load monitoring and second-line ART.
Patients aged ≥16 years starting ART in two programs each in Zimbabwe, Mozambique and Lesotho were included. We evaluated risk factors for no follow-up after starting ART and mortality and loss to follow-up (LTFU) over 3 years of ART, using logistic regression and competing risk models. Odds ratios and sub-distribution hazard ratios, adjusted for gender, age category, CD4 category and WHO stage at start of ART are reported.
Among 7,725 patients, 449 (5.8%) did not return after initiation of ART. Over 9,575 person-years, 698 (9.6%) of those with at least one follow-up visit died and 1,319 (18.1%) were LTFU. At 3 years the cumulative incidence of death and LTFU were 12.5% (11.5–13.5%) and 25.4% (24.0–26.9%), respectively, with important differences between countries: in Zimbabwe 75.1% (72.8–77.3%) were alive and on ART at 3 years compared to 55.4% (52.8–58.0%) in Lesotho and 51.6% (48.0–55.2%) in Mozambique. In all settings young age and male gender predicted LTFU, whereas advanced clinical stage and low baseline CD4 counts predicted death.
In African ART programs with limited access to second-line treatment, mortality and LTFU are high in the first 3 years of ART. Low retention in care is a major threat to the sustainability of ART delivery in Southern Africa, particularly in rural sites.
Antiretroviral treatment; Cohort study; rural Southern Africa; retention in care
In HIV-1 subtype C infected populations in south India, we searched for novel mutations associated with failing antiretroviral therapy that included nucleoside reverse transcriptase (RT) inhibitors. HIV-1 RT sequences were generated from treated and untreated groups and each nucleotide position was analysed with appropriate corrections for multiple testing. We found that nonsynonymous mutations at positions 208 and 228 were strongly associated with the presence of thymidine analogue mutations in the treated group, and were not present at all in the naïve group. The role of these substitutions on treatment outcomes and the evolution of drug resistance in HIV-1 subtype-C infected populations warrant further investigation.
HIV-1 Drug Resistance Mutation; HIV-1 Subtype C; HIV in India; Thymidine Analogue Mutation (TAMs); HIV-1 RT mutation at codon 208; 228; HIV Drug Resistance in India
The aim of this study was to examine the effect of the 3% SPL 7013 gel (VivaGel®) on mucosal immune markers hypothesized to be associated with HIV-1 acquisition.
Phase 1, placebo-controlled, randomized, double-blind clinical trial was performed in 54 young women in the U.S. and Kenya. Participants used carbopol gel with and without (placebo) SPL 7013 twice daily over 14 days. Cervical specimens were collected for cytokines, chemokines, T-cells, and dendritic cells at day (D) 0, 7, 14, and 21. A negative binomial regression model was used to assess differences between study arms.
Several mucosal immune parameters were increased in the VivaGel® arm compared to placebo. For cytokines: D 7, IL-6 (p=0.05); D 14, IFN-γ (p=0.03), IL-2 (p=0.04), IL-5 (p=0.003) and IL-10 (p=0.001) were increased. On D 7, CD8+/CD69+ T-cells tended to be increased (p<0.08); limiting analysis to visits without blood or bacterial vaginosis, these findings were stronger: at D7, CD8+/CD69+ T-cells were increased in the VivaGel® arm (p<0.005), as were CD4+/CD69+ cells (p=0.001) and CD4+/CCR5+ T-cells (p=0.01). The changes described for D7 and 14 were no longer seen at D21.
Markers associated with inflammation and epithelial damage were reversibly elevated in the VivaGel® arm compared to the placebo arm after 7–14 days of twice daily product use.
Vaginal microbicide; mucosal immune markers
American men who have sex with men (MSM) continue to have increased rates of HIV and STD. Between 2004 and 2010, 1155 MSM were screened for HIV and/or STD at a Providence, RI, bathhouse. The prevalence of HIV was 2.3%; syphilis, 2.0%; urethral gonorrhea, 0.1%; urethral Chlamydia, 1.3%; 2.2% of the men had hepatitis C antibodies. Although 43.2% of the men engaged in unprotected anal intercourse in the prior two months, the majority of the men thought that their behaviors did not put them at increased risk for HIV or STDs. Multivariate analyses found that men who engaged in unprotected anal intercourse were more likely to have had sex with unknown status or HIV-infected partners; have sex while under the influence of drugs; tended to find partners on the internet; and were more likely to have a primary male partner. Men who were newly diagnosed with HIV or syphilis tended to be over 30 years old; had sex with an HIV-infected partner; had a prior STD diagnosis; and met partners on the internet. For 10.5% of the men, their HIV testing in the bathhouse was the first time that they had ever been screened for HIV. Of 24 men who were newly diagnosed with HIV infection, only one was not successfully linked to care. These data suggest that offering HIV and STD screening in a bathhouse setting is successful in attracting MSM who were at increased risk for HIV and/or STD acquisition or transmission, and may help decrease spread.
Sexually transmitted infections; HIV; sexual risk; men having sex with men (MSM); bathhouse
To compare neuropsychological scores in women infected with HIV, women infected with both HIV and hepatitis C, and uninfected subjects.
Some, but not all, studies have demonstrated that dual infection with HCV and HIV has worse effects on cognition than infection with HIV alone.
The Women’s Interagency HIV Study (WIHS) is an ongoing prospective study of the natural history of HIV in women where participants are reevaluated every 6 months. In a cross-sectional analysis, we evaluated the effects of active HIV and HCV-infections on scores on symbol-digit test (SDMT), the Stroop interference test, and trails A and B after controlling for age, ethnicity, education, depression, liver disease, and current or past substance abuse.
Data were available for 1338 women – 17.8 % had detectable hepatitis C virus and 67% were HIV-seropositive. In fully adjusted general linear models, HCV viremia was not associated with scores on any of the cognitive tests.
In this large sample of women, active HCV infection was not associated with scores on a small battery of neuropsychological tests.
Hepatitis C; HIV; neurocognition; women
Although many new prevention modalities that include the use of antiretroviral drugs (ARVs) show promise, there is no question that a global solution to the HIV epidemic will not be economically or logistically feasible without the development of vaccine that provides durable protection. In the best case scenario, the vaccine has to protect against acquisition of infection, likely mediated by Env-specific B cell responses combined with CD4+ T cell responses to evoke full maturation and maintenance of protective antibodies. But HIV-specific CD8+ T cell responses are also likely to be a key element, particularly for those inevitable situations in which full vaccine-induced protection from acquisition is not achieved, in which case durable control of established infection will be required. Although there is reason to be optimistic that an effective HIV vaccine is possible, one of the major constraints moving forward will likely be constraints on funding to support a diversity of concepts at a time that the correlates of protection from acquisition and disease progression are still unknown. Given the scope of the epidemic and the economic climate, we must strive to do much more with less and seek to access additional resources, both scientific and monetary, from every possible source.
Vaccine; Antiretrovirals; Economy
Delayed access to HIV care and treatment in sub-Saharan Africa meant that the early years of HIV scale-up were characterized by a largely North-to-South transfer of knowledge and resources. Clinicians from wealthy countries were amongst the first to gain experience with antiretroviral treatment and care of people living with HIV, and shared key lessons with their colleagues in sub-Saharan Africa when widespread access to HIV services became available. Ten years later, South-to-North lessons learned from the remarkable achievements of HIV programs in Africa now have the potential to inform the response to the US domestic epidemic.
HIV scale-up; program implementation; lessons; Africa
HIV/AIDS trends in the United States depict a concentrated epidemic with hot spots that vary by location, poverty, race/ethnicity, and transmission mode. HIV/AIDS is a leading cause of death among US women of color; two thirds of new infections among women occur in black women, despite the fact that black women account for just 14% of the US female population. The gravity of the HIV epidemic among US women is often not appreciated by those at risk as well as by the broader scientific community. We summarize the current epidemiology of HIV/AIDS among US women and discuss clinical, research, and public health intervention components that must be brought together in a cohesive plan to reduce new HIV infections in US women. Only by accelerating research and programmatic efforts will the hidden epidemic of HIV among US women emerge into the light and come under control.
HIV in women; HIV prevention science; racial disparity
Chromatin-associated repression is one mechanism that maintains HIV-1 latency. Inhibition of histone deacetylases (HDAC) reverses this repression resulting in viral expression from quiescently infected cells. Clinical studies with the HDAC inhibitor valproic acid (VPA) failed to substantially decrease the latent pool within resting CD4+ cells. Here we compared the efficacy of ITF2357, an orally active and safe HDAC inhibitor, with VPA for HIV-1 expression from latently infected cells in vitro. We also evaluated the effect of ITF2357 on the surface expression of CXCR4 and CCR5.
Latently infected cell lines were incubated with either ITF2357 or VPA and p24 levels were measured. Peripheral blood mononuclear cells of un-infected donors were treated with ITF2357 and HIV-1 co-receptors expression was assessed by flow cytometry.
At clinically relevant concentrations, ITF2357 increased p24 by 15-fold in ACH2 cells and by 9-fold in U1 cells whereas VPA increased expression less than 2-fold. Analogues of ITF2357 primarily targeting HDAC-1 increased p24 up to 30-fold. In CD4+ T-cells treated with ITF2357, CXCR4 expression decreased by 54% (P<0.001).
ITF2357 is superior to VPA in inducing HIV-1 from latently infected cells. Safely used in humans, ITF2357 is an attractive candidate for HIV-1 clinical purging.
HIV-1; latency; histone deacetylase inhibitors; CCR5; CXCR4
Following HIV diagnosis and linkage to care, achieving and sustaining viral load (VL) suppression has implications for patient outcomes and secondary HIV prevention. We evaluated factors associated with expeditious VL suppression and cumulative VL burden among patients establishing outpatient HIV care.
Patients initiating HIV medical care from January 2007-October 2010 at the University of Alabama at Birmingham and University of Washington were included. Multivariable Cox proportional hazards and linear regression models were used to evaluate factors associated with time to VL suppression (<50 copies/mL) and cumulative VL burden, respectively. Viremia copy-years (VCY), a novel area under the longitudinal VL curve measure, was used to estimate 2-year cumulative VL burden from clinic enrollment.
Among 676 patients, 63% achieved VL<50 copies/mL in a median 308 days. In multivariable analysis, patients with more time-updated “no show” visits experienced delayed VL suppression (HR=0.83 per “no show” visit, 95%CI=0.76,0.91). In multivariable linear regression, visit non-adherence was independently associated with greater cumulative VL burden (log10VCY) during the first two years in care (Beta coefficient=0.11 per 10% visit non-adherence, 95%CI=0.04-0.17). Across increasing visit adherence categories, lower cumulative VL burden was observed (mean ± standard deviation log10 copy × years/mL); 0-79% adherence: 4.6 ± 0.8; 80-99% adherence: 4.3 ± 0.7; and 100% adherence: 4.1 ± 0.8 log10 copy × years/mL, respectively (P<0.01).
Higher rates of early retention in HIV care are associated with achieving VL suppression and lower cumulative VL burden. These findings are germane for a test and treat approach to HIV prevention.
HIV; Viral load; Retention in care; Adherence; Engagement in care
To quantify the impact of TB co-infection on death and loss to follow-up (LTFU) 12 months after entry into an ART program.
Prospective intervention study
From May 2007-2008, patients undergoing pre-ART training in Durban, South Africa were screened for pulmonary TB using mycobacterial culture. Subjects missing appointments for >3 months were phoned. Patients who could not be reached were considered LTFU. Deaths were ascertained by report from family members. We used the Kaplan-Meier method to estimate time to LTFU or death for 3 groups at enrollment: 1) newly-diagnosed with TB by sputum culture; 2) on TB treatment (i.e. previously-diagnosed); and 3) TB free. We evaluated the role of TB on mortality and LTFU using Cox proportional hazards models.
Nine-hundred fifty-one HIV-infected subjects were enrolled; 59% were female and median baseline CD4 count was 90/μl (IQR 41-148/μl). One hundred forty-four (15%) were newly-diagnosed with TB by sputum culture; an additional 199 (21%) were already on TB treatment. By 12 months, 26% newly-diagnosed with TB at enrollment died or were LTFU, compared to 19% already on TB treatment, and 14% who were TB free (p=0.001). Controlling for age, sex, smoking, CD4, and opportunistic infection history, subjects newly-diagnosed with pulmonary TB were 76% more likely to die or be LTFU (HR 1.76, 95% CI 1.20-2.60) than those without TB.
HIV/TB co-infected individuals are more likely to die or be LTFU within 12 months of ART clinic entry in South Africa. These patients require intensive follow-up during ART initiation.
HIV; Tuberculosis; South Africa; long-term outcomes; mortality
As African countries scale up couples HIV testing, little is known about sexual behaviors and HIV risk for HIV uninfected partners in known HIV serodiscordant relationships.
We conducted a prospective study of 3,380 HIV serodiscordant partnerships from 7 African countries. Self-reported sexual behavior data were collected quarterly from HIV uninfected partners.
The proportion of HIV uninfected partners reporting sex with their known primary HIV infected partner decreased during follow-up (from 93.5% in the prior month at baseline to 73.2% at 24 months, p<0.001). Simultaneously, an increasing proportion reported sex with an outside partner (from 3.1% to 13.9%, p<0.001). A small proportion (<5%, stable throughout follow-up) reported sex with the infected partner and an outside partner in the same month (concurrent). Unprotected sex was more common with outside partners than with their primary known HIV infected partners (risk ratio 4.6; 95% CI 4.2–5.2). HIV incidence was similar for those reporting sex only with their primary HIV infected partner compared to those who reported an outside partner (2.87 vs. 3.02 per 100 person-years, p=0.7), although those who had outside partners were more likely to acquire HIV that was virologically distinct from that of their primary partner (p<0.001).
For uninfected members of HIV serodiscordant couples, sex with the infected partner declined as sex with outside partners increased, likely reflecting relationship dissolution and risk shifting from a known infected partner. Risk reduction messages for HIV uninfected partners in serodiscordant partnerships should include strategies to reduce HIV acquisition from outside partners.
HIV serodiscordant couples; sexual behavior; condom use
Describing the distribution and clearance of HIV surrogates within the gastrointestinal (GI) tract to inform rectal microbicide development.
Radiolabeled, simulated HIV-infected semen was administered, imaged, and biopsied to simulate and measure colonic HIV distribution following anal intercourse.
Healthy male subjects with a history of receptive anal intercourse and experience with the use of anal sex toys were recruited to this study. Apheresis isolated leukocytes were collected prior to simulated intercourse. These autologous leukocytes, radiolabeled with 9.25 MBq 111Indium-oxine (cell-associated HIV surrogate), and sulfur colloid particles, labeled with 37 MBq 99mTechnectium (cell-free HIV surrogate), were mixed in 3 mL autologous seminal plasma. This simulated HIV-infected semen was administered to subjects via an artificial phallus with urethra after 5 minutes of simulated intercourse. Post-dosing, dual isotope SPECT/CT images were acquired at 1, 4, 8, and 24 hours. At 5 hours post-dosing, colon biopsies were collected, CD4 cells were extracted, and samples analyzed for radioactivity.
SPECT/CT images showed similar luminal distribution for both surrogates, with migration limited to the recto-sigmoid colon in all subjects. SPECT showed at least 75% overlap in distribution of both surrogates up to 4 hrs following dosing. Biopsies indicate that 2.4% of CD4 cells extracted from recto-sigmoid colon tissue were exogenously administered.
Our HIV surrogates stayed within the recto-sigmoid colon for 24 hours. Exogenously dosed autologous lymphocytes and HIV-sized particles migrate to similar locations, and associate with the colonic tissue in the lumen.
HIV; Rectal microbicide; Anal intercourse; Sexual transmission; Pharmacokinetics
Induction of HIV-1-specific CD4+ T cell responses by therapeutic vaccination represents an attractive intervention to potentially increase immune control of HIV-1.
We performed a double-blinded, randomized, placebo-controlled clinical trial to determine the safety and immunogenicity of GSK Biologicals' HIV-1 gp120/NefTat subunit protein vaccine formulated with the AS02A adjuvant in subjects with well controlled chronic HIV-1 infection on HAART. Ten individuals received the vaccine; while adjuvant alone or placebo was given to five subjects each. Immunogenicity was monitored by intracellular cytokine flow cytometry and CFSE-based proliferation assays.
The vaccine was well tolerated with no related SAEs. Vaccine recipients had significantly stronger gp120-specific CD4+ T cell responses which persisted until week 48 and greater gp120-specific CD4+ T cell proliferation activity as compared to controls. In the vaccine group, the number of participants that demonstrated positive responses for both gp120-specific CD4+ T cell IL-2 production and gp120-specific CD8+ T cell proliferation was significantly higher at week 6.
The gp120/NefTat/AS02A vaccine induced strong gp120-specific CD4+ T cell responses, and a higher number of vaccinees developed both HIV-1-specific CD4+ T cell responses and CD8+ T cell proliferation. The induction of these responses may be important in enhancing immune-mediated viral control.
HIV-1; Vaccination; Therapeutic Vaccination; HIV-1-specific CD4+ cells
To investigate the effect of helminth infections and their treatment during pregnancy on HIV load, we conducted a 2×2 factorial randomised controlled trial of albendazole versus placebo and praziquantel versus placebo in pregnant women in Entebbe, Uganda
Two hundred and sixty-four HIV-infected women from the Entebbe Mother and Baby Study (ISRCTN32849447) were included in this analysis. Women were tested for helminth infections at enrolment and mean HIV load was compared between infected and uninfected groups. The effect of anthelminthic treatment on HIV load was evaluated at six weeks post-treatment and at delivery using linear regression and adjusting for enrolment viral load.
Hookworm and Trichuris infections were associated with higher mean viral load at enrolment (adjusted mean difference 0.24log10 copies/ml, 95% confidence interval (CI): 0.01 to 0.47, p=0.03 and 0.37log10 copies/ml, 95%CI: 0.00 to 0.74, p=0.05, respectively). There were no associations between viral load and other helminth species. There was some evidence that albendazole reduced viral load at six weeks post-treatment (adjusted mean difference −0.17, 95% CI: −0.36 to 0.01, p=0.07), however this effect did not differ according to mother’s hookworm infection status and had diminished at delivery (adjusted mean difference −0.11, 95% CI: −0.28 to 0.07, p=0.23). There was no effect of praziquantel treatment on HIV load at any time point.
Infection with some soil-transmitted helminth species is associated with increased HIV load in pregnancy. Treatment with albendazole causes a small decrease in HIV load, however this may not represent a direct effect of worm removal.
HIV; viral load; helminths; anthelminthic treatment; clinical trial
We determined the diagnostic yield of the Xpert MTB/RIF assay for tuberculosis (TB) when testing small volumes of urine from ambulatory HIV-infected patients prior to starting antiretroviral therapy (ART) in South Africa. Compared to a gold standard of sputum culture, the sensitivity of urine Xpert among those with CD4 cell counts of <50, 50-100 and >100 cells/μL were 44.4%, 25.0% and 2.7% (P=0.001), respectively. Urine Xpert testing provides a means of rapid TB diagnosis in patients with advanced immunodeficiency and poor prognosis. These data are indicative of high rates of TB dissemination and renal involvement in this clinical population.
HIV; tuberculosis; screening; diagnosis; Africa; urine; Xpert MTB/RIF; antiretroviral
Although tenofovir (TDF) is a common component of antiretroviral therapy (ART), recent evidence suggests inferior outcomes when it is combined with nevirapine (NVP).
We compared outcomes among patients initiating TDF+emtricitabine or lamivudine (XTC)+NVP, TDF+XTC+efavirenz (EFV), zidovudine (ZDV)+lamuvidine (3TC)+NVP, and ZDV+3TC+EFV. We categorized drug exposure by initial ART dispensation, by a time-varying analysis that accounted for drug substitutions, and by predominant exposure (>75% of drug dispensations) during an initial window period. Risks for death and program failure were estimated using Cox proportional hazard models. All were regimens were compared to ZDV+3TC+NVP.
Between July 2007 and November 2010, 18,866 treatment-naïve adults initiated ART: 18.2% on ZDV+3TC+NVP, 1.8% on ZDV+3TC+EFV, 36.2% on TDF+XTC+NVP, and 43.8% on TDF+XTC+EFV. When exposure was categorized by initial prescription, patients on TDF+XTC+NVP (adjusted hazard ratio [AHR]:1.45; 95%CI:1.03–2.06) had a higher post-90 day mortality. TDF+XTC+NVP was also associated with an elevated risk for mortality when exposure was categorized as time-varying (AHR:1.51; 95%CI:1.18–1.95) or by predominant exposure over the first 90 days (AHR:1.91, 95%CI:1.09–3.34). However, these findings were not consistently observed across sensitivity analyses or when program failure was used as a secondary outcome.
TDF+XTC+NVP was associated with higher mortality when compared to ZDV+3TC+NVP, but not consistently across sensitivity analyses. These findings may be explained in part by inherent limitations to our retrospective approach, including residual confounding. Further research is urgently needed to compare the effectiveness of ART regimens in use in resource-constrained settings.
tenofovir; zidovudine; nevirapine; antiretroviral therapy; Africa