The F4/AS01B HIV-1 Vaccine Candidate Is Safe and Immunogenic, But Does Not Show Viral Efficacy in Antiretroviral Therapy-Naive, HIV-1-Infected Adults: A Randomized Controlled Trial.
ABSTRACT: The impact of the investigational human immunodeficiency virus type 1 (HIV-1) F4/AS01B vaccine on HIV-1 viral load (VL) was evaluated in antiretroviral therapy (ART)-naive HIV-1 infected adults.This phase IIb, observer-blind study (NCT01218113), included ART-naive HIV-1 infected adults aged 18 to 55 years. Participants were randomized to receive 2 (F4/AS01B_2 group, N?=?64) or 3 (F4/AS01B_3 group, N?=?62) doses of F4/AS01B or placebo (control group, N?=?64) at weeks 0, 4, and 28. Efficacy (HIV-1 VL, CD4 T-cell count, ART initiation, and HIV-related clinical events), safety, and immunogenicity (antibody and T-cell responses) were evaluated during 48 weeks.At week 48, based on a mixed model, no statistically significant difference in HIV-1 VL change from baseline was demonstrated between F4/AS01B_2 and control group (0.073 log10?copies/mL [97.5% confidence interval (CI): -0.088; 0.235]), or F4/AS01B_3 and control group (-0.096 log10?copies/mL [97.5% CI: -0.257; 0.065]). No differences between groups were observed in HIV-1 VL change, CD4 T-cell count, ART initiation, or HIV-related clinical events at intermediate timepoints. Among F4/AS01B recipients, the most frequent solicited symptoms were pain at injection site (252/300 doses), fatigue (137/300 doses), myalgia (105/300 doses), and headache (90/300 doses). Twelve serious adverse events were reported in 6 participants; 1 was considered vaccine-related (F4/AS01B_2 group: angioedema). F4/AS01B induced polyfunctional F4-specific CD4 T-cells, but had no significant impact on F4-specific CD8 T-cell and anti-F4 antibody levels.F4/AS01B had a clinically acceptable safety profile, induced F4-specific CD4 T-cell responses, but did not reduce HIV-1 VL, impact CD4 T-cells count, delay ART initiation, or prevent HIV-1 related clinical events.
Project description:Human immunodeficiency virus (HIV)-infected individuals are at increased risk of herpes zoster (HZ), even in the antiretroviral therapy (ART) era. Because concerns exist about the use of live-attenuated vaccines in immunocompromised individuals, a subunit vaccine may be an appropriate alternative.This phase 1/2, randomized, placebo-controlled study evaluated the immunogenicity and safety of an investigational HZ subunit vaccine (HZ/su). Three cohorts of HIV-infected adults aged ?18 years were enrolled: 94 ART recipients with a CD4(+) T-cell count of ?200 cells/mm(3), 14 ART recipients with a CD4(+) T-cell count of 50-199 cells/mm(3), and 15 ART-naive adults with a CD4(+) T-cell count of ?500 cells/mm(3). Subjects received 3 doses of HZ/su (50 µg varicella-zoster virus glycoprotein E [gE] combined with AS01B adjuvant) or 3 doses of saline at months 0, 2, and 6.One month after dose 3, serum anti-gE antibody concentrations and frequencies of gE-specific CD4(+) T cells were higher following HZ/su vaccination than after receipt of saline (P < .0001). Median cell-mediated immune responses peaked after dose 2. Humoral and cell-mediated immune responses persisted until the end of the study (month 18). No vaccination-related serious adverse events were reported. No sustained impact on HIV load or CD4(+) T-cell count was noted following vaccinations.HZ/su was immunogenic and had a clinically acceptable safety profile in HIV-infected adults.NCT01165203.
Project description:INTRODUCTION:The goals of scale-up of antiretroviral therapy (ART) have expanded from prevention of morbidity and death to include prevention of transmission. Morbidity and mortality risk are associated with CD4 count; transmission risk depends on plasma viral load (VL). This study aimed to describe CD4 count and VL distributions among HIV-infected individuals in a South African township to gain insights into the potential impact of ART scale-up on community HIV transmission risk. METHODS:A random sample of 10% of the adult population was invited to attend an HIV testing service. Study procedures included a questionnaire, HIV testing, CD4 count, and VL testing. RESULTS:One thousand one hundred forty-four (88.0%) of 1300 randomly selected individuals participated in the study. Two hundred sixty tested positive, giving an HIV prevalence of 22.7% [95% confidence interval (CI): 20.3 to 25.3]. A third of all HIV-infected individuals (33.5%, 95% CI: 27.8 to 39.6) reported taking ART. The median CD4 count was 417 cells per microliter (interquartile range, 285-627); 33 (12.7%, 95% CI: 8.9 to 17.4) had a CD4 count of ?200 cells per microliter. VL measurements were available for 219 individuals (84.2%) and were undetectable in 72 (33.9%), >1500 copies per milliliter in 127 (58.0%) and >10,000 copies per milliliter in 96 (43.8%). Of those reporting they were receiving ART, 30.4% had a VL >1500 copies per milliliter compared with 58.0% of those reporting they were not receiving ART. CONCLUSIONS:A small proportion of those living with HIV in this community had a CD4 count of <200 cells per microliter; more than half had a VL high enough to be associated with considerable transmission risk. A substantial proportion of HIV-infected individuals remained at risk of transmitting HIV even after starting ART.
Project description:To assess whether T-cell activation independently predicts the extent of CD4(+) T-cell recovery and mortality in HIV-infected Ugandans initiating antiretroviral therapy (ART).Prospective cohort study.HIV-infected adults starting ART and achieving a plasma HIV RNA level (VL) less than 400 copies/ml by month 6 were sampled from the Uganda AIDS Rural Treatment Outcomes (UARTO) cohort in Mbarara, Uganda. CD4 count, VL, and the percentage-activated (CD38(+)HLA-DR(+)) T cells were measured every 3 months.Of 451 HIV-infected Ugandans starting ART, most were women (70%) with median pre-ART values: age, 34 years; CD4 count, 135 cells/?l; and VL, 5.1 log(10) copies/ml. Of these, 93% achieved a VL less than 400 copies/ml by month 6 and were followed for a median of 24 months, with 8% lost to follow-up at 3 years. Higher pre-ART CD8(+) T-cell activation was associated with diminished CD4 recovery after year 1, after adjustment for pre-ART CD4 count, VL, and sex (P = 0.017). Thirty-four participants died, 15 after month 6. Each 10% point increase in activated CD8(+) T cells at month 6 of suppressive ART was associated with a 1.6-fold increased hazard of subsequent death after adjusting for pretherapy CD4 count (P = 0.048).Higher pre-ART CD8(+) T-cell activation independently predicts slower CD4(+) T-cell recovery and higher persistent CD8(+) T-cell activation during ART-mediated viral suppression independently predicts increased mortality among HIV-infected Ugandans. Novel therapeutic strategies aimed at preventing or reversing immune activation during ART are needed in this setting.
Project description:HIV RNA viral load (VL) has been shown to increase during opportunistic illnesses (OIs), suggesting active HIV replication in response to infection among patients not taking antiretroviral therapy (ART). We assessed the effects of OIs on HIV RNA VL and CD4+ T cell counts among patients on ART with initially suppressed VL.Between 2003 and 2007, we enrolled and followed 1094 HIV-1-infected adults who initiated ART and had quarterly blood draws for VL and CD4+ T cell count. In VL/CD4+ T cell measurement intervals following undetectable VL, we compared the elevation in VL to detectable levels and CD4+ T cell count changes between intervals when participants had episodes of OIs and intervals when they did not have OIs.VL was more likely to be detectable if participants had OIs in the prior three months compared to when they did not (OR=4.0 (95% CI=1.9-8.6)). The CD4+ T cell counts declined 24.1 cells/µL per three months in intervals where the participants had OIs compared to an increase of 21.3 cells/µL per three months in intervals where they did not have OIs (adjusted difference in the rate of CD4+ T cell count change of 61.7 cells/µL per three months (95% CI=13.7-109.7), P value=0.012). The rate of CD4+ T cell count increase was 25.6 cells/µL per three months (95% CI=11.6-39.6) higher for females compared to males (p value=<0.001), 1.4 cells/µL per three months lower per one year increase in age (p value=0.046) and 4 cells/µL per three months lower per 10 cells/µL increase in the starting CD4+ T cell count value (p value=<0.001).Episodes of opportunistic infections among patients taking ART with undetectable VL were associated with elevation of HIV RNA VL to detectable levels and decline in CD4+ T cell counts.NCT00119093.
Project description:<h4>Background</h4>Sequential prime-boost or co-administration of HIV vaccine candidates based on an adjuvanted clade B p24, RT, Nef, p17 fusion protein (F4/AS01) plus a non-replicating adenovirus 35 expressing clade A Gag, RT, Int and Nef (Ad35-GRIN) may lead to a unique immune profile, inducing both strong T-cell and antibody responses.<h4>Methods</h4>In a phase 1, double-blind, placebo-controlled trial, 146 healthy adult volunteers were randomized to one of four regimens: heterologous prime-boost with two doses of F4/AS01E or F4/AS01B followed by Ad35-GRIN; Ad35-GRIN followed by two doses of F4/AS01B; or three co-administrations of Ad35-GRIN and F4/AS01B. T cell and antibody responses were measured.<h4>Results</h4>The vaccines were generally well-tolerated, and did not cause serious adverse events. The response rate, by IFN-? ELISPOT, was greater when Ad35-GRIN was the priming vaccine and in the co-administration groups. F4/AS01 induced CD4+ T-cells expressing primarily CD40L and IL2 +/- TNF-?, while Ad35-GRIN induced predominantly CD8+ T-cells expressing IFN-? +/- IL2 or TNF-?. Viral inhibition was induced after Ad35-GRIN vaccination, regardless of the regimen. Strong F4-specific antibody responses were induced. Immune responses persisted at least a year after the last vaccination. The complementary response profiles, characteristic of each vaccine, were both expressed after co-administration.<h4>Conclusion</h4>Co-administration of an adjuvanted protein and an adenovirus vector showed an acceptable safety and reactogenicity profile and resulted in strong, multifunctional and complementary HIV-specific immune responses.<h4>Trial registration</h4>ClinicalTrials.gov NCT01264445.
Project description:Limited data exist on the effects of contraceptives on HIV disease progression. We studied the association between intramuscular injectable depot medroxyprogesterone acetate (DMPA-IM), the copper intrauterine device (IUD), and the levonorgestrel (LNG) implant on markers of HIV disease progression at the time of HIV detection and 3 months postdetection and time from detection to CD4 count <350 cells/mm3. Among women initiating antiretroviral therapy (ART), we studied the effect of contraceptive group on time from ART initiation to viral load (VL) <40 copies/mL. We included women 16-35 years randomized to DMPA-IM, copper IUD, or LNG implant with incident HIV infection during the Evidence for Contraceptive Options and HIV Outcomes (ECHO) trial (n?=?382). We analyzed HIV VL and CD4 cell count according to participants' randomized method and also conducted a "continuous use" analysis that excluded follow-up time after method discontinuation. We used adjusted linear models to compare mean VL and CD4 cell levels by contraceptive group up to the time of ART initiation. We compared time from HIV detection to CD4 count <350 cells/mm3 and, following ART initiation, time to viral suppression (VL <40 copies/mL) using Cox proportional hazards models. At HIV detection, women allocated to DMPA-IM had lower VL relative to copper IUD (-0.28 log10 copies/mL; 95% confidence interval [CI]: -0.55 to -0.01) and LNG implant (-0.27, CI: -0.55 to 0.02) and higher mean CD4 than copper IUD users by 66 cells/mm3 (CI: 11-121). In continuous use analyses women allocated to DMPA-IM progressed to CD4?<?350 cells/mm3 slower than copper IUD users (hazard ratio [HR]?=?0.6, CI: 0.3-1.1), whereas copper IUD users progressed faster than LNG implant users (HR?=?1.8, CI: 1.0-3.3). Time to viral suppression was faster for DMPA-IM than copper IUD (HR?=?1.5, CI: 1.0-2.3) and LNG implant 1.4 (CI: 0.9-2.2) users. We found no evidence of more rapid early HIV disease progression among women using DMPA-IM than among women using copper IUD or LNG implant. Our finding of more rapid progression among copper IUD compared with DMPA-IM users should be interpreted cautiously.
Project description:BACKGROUND:Kaposi sarcoma (KS) remains common among HIV-infected persons. To better understand KS etiology and to help target prevention efforts, we comprehensively examined a variety of CD4 T-cell count and HIV-1 RNA viral load (VL) measures, as well as antiretroviral therapy (ART) use, to determine independent predictors of KS risk. SETTING:North American AIDS Cohort Collaboration on Research and Design. METHODS:We followed HIV-infected persons during 1996-2009 from 18 cohorts. We used time-updated Cox regression to model relationships between KS risk and recent, lagged, trajectory, and cumulative CD4 count or VL measures, as well as ART use. We used Akaike's information criterion and global P values to derive a final model. RESULTS:In separate models, the relationship between each measure and KS risk was highly significant (P < 0.0001). Our final mutually adjusted model included recent CD4 count [hazard ratio (HR) for <50 vs. ?500 cells/?L = 12.4; 95% confidence interval (CI): 6.5 to 23.8], recent VL (HR for ?100,000 vs. ?500 copies/mL = 3.8; 95% CI: 2.0 to 7.3), and cumulative (time-weighted mean) VL (HR for ?100,000 vs. ?500 copies/mL = 2.5; 95% CI: 1.0 to 5.9). Each P-trend was <0.0001. After adjusting for these measures, we did not detect an independent association between ART use and KS risk. CONCLUSIONS:Our results suggested a multifactorial etiology for KS, with early and late phases of development. The cumulative VL effect suggested that controlling HIV replication promptly after HIV diagnosis is important for KS prevention. We observed no evidence for direct anti-KS activity of ART, independent of CD4 count and VL.
Project description:INTRODUCTION:HIV is a highly diverse virus with significant genetic variability which may confer biologic differences that could impact on treatment outcomes. MATERIALS AND METHODS:We studied the association between HIV subtypes and immunologic and virologic outcomes in a longitudinal cohort of 169 patients on combination antiretroviral therapy. Participants were followed up for 5 years. Demographic data, CD4 cell count and viral loads (VL) were extracted from medical records. Whole protease gene and codon 1-300 of the reverse transcriptase gene were sequenced and analysed. RESULTS:Sixty-four percent of participants were females with a median age of 35 years. Twelve different subtypes were observed, the commonest being CRF 02_AG (55.0%) and subtypes G (23.1%). All subtypes showed steady rise in CD4 count and there was no difference in proportion who achieved CD4+ cell count rise of ?100 cells/?L from baseline within 12 months' post-initiation of ART, or ?350 cells/?L at 60 months' post-initiation. Median time to attaining a rise of ?350 cells/?L was 24 months (6-48 months). The proportion that achieved undetectable VL at month 6 and 12 post-initiation of ART were comparable across subtypes. At end of 5th year, there was no statistical difference in proportion with virologic failure. CONCLUSION:No association between HIV subtypes and immunologic or virologic response to therapy was observed, suggesting that current first-line ART may have similar efficacy across subtype predominating in South-West Nigeria.
Project description:BACKGROUND: At the end of 2009, a total of 501 AIDS patients were receiving antiretroviral therapy (ART) in Fujian Province in China, yet there were no assessments to determine treatment efficacy and HIV-1 preventive potency under the current health care delivery system. METHODS: During the period of 2005-2009, we assessed the outcomes of initial ART by following up 381 patients for 12 months in Fujian Province. CD4? T-lymphocyte (CD4) count, plasma viral load (VL), and patient characteristics were analysed. The results were compared between 4 groups divided by the baseline CD4 values at the 25, 50 (median), and 75 percentiles. FINDINGS: Over three-quarters of the subjects reported heterosexual contact as the probable route of transmission. After 12 months of ART, CD4 recovery varied between the 4 groups (P < 0.001), but VL sharply declined regardless of the baseline CD4 count (P = 0.136). Although this VL decline indicates the potency of ART as an HIV-1 prevention tool, the time between positive diagnosis and ART initiation suggests serious delay in both diagnosis and treatment; the medians of periods for the lowest and highest baseline CD4 quartiles were 1.2 and 9.6 months, respectively. CONCLUSION: Current limitations in VL determination make it difficult to assess the efficacy of initial ART, and delays in diagnosis and treatment suggest that subjects contributed to HIV-1 transmission while they were not receiving ART. The current National Free ART scheme does not provide free treatment for sexually transmitted infection (STI), and there is no link between ART and the STI care delivery system. This may interfere with the HIV-1 preventive potency of ART. We highly recommend establishing a collaborating mechanism with STI care, strengthening the VL determination system, and promoting HIV tests and early ART initiation.
Project description:<h4>Background</h4>Plasma HIV-1 RNA monitoring is one of the standard tests for the management of HIV-1 infection. While HIV-1 RNA can be quantified using several commercial tests, no test has been commercialized for HIV-2 RNA quantification. We studied the relationship between plasma HIV-2 viral load (VL) and CD4 count in West African patients who were either receiving antiretroviral therapy (ART) or treatment-naïve.<h4>Method</h4>A cross sectional survey was conducted among HIV-2-infected individuals followed in three countries in West Africa from March to December 2012. All HIV-2 infected-patients who attended one of the participating clinics were proposed a plasma HIV-2 viral load measurement. HIV-2 RNA was quantified using the new ultrasensitive in-house real-time PCR assay with a detection threshold of 10 copies/ mL (cps/mL).<h4>Results</h4>A total of 351 HIV-2-infected individuals participated in this study, of whom 131 (37.3%) were treatment naïve and 220 (62.7%) had initiated ART. Among treatment-naïve patients, 60 (46.5%) had undetectable plasma HIV-2 viral load (<10 cps/mL), it was detectable between 10-100 cps/mL in 35.8%, between 100-1000 cps/mL in 11.7% and >1000 cps/mL in 6.0% of the patients. Most of the treatment-naïve patients (70.2%) had CD4-T cell count ?500 cells/mm3 and 43 (46.7%) of these patients had a detectable VL (?10 cps/mL). Among the 220 patients receiving ART, the median CD4-T cell count rose from 231 to 393 cells/mm3 (IQR [259-561]) after a median follow-up duration of 38 months and 145 (66.0%) patients had CD4-T cell count ? 500 cells/mm3 with a median viral load of 10 cps/mL (IQR [10-33]). Seventy five (34.0%) patients had CD4-T cell count ? 500 cells/mm3, among them 14 (18.7%) had a VL between 10-100 cps/mL and 2 (2.6%) had VL >100 cps/mL.<h4>Conclusion</h4>This study suggests that the combination of CD4-T cell count and ultrasensitive HIV-2 viral load quantification with a threshold of 10 cps/mL, could improve ART initiation among treatment naïve HIV-2-infected patients and the monitoring of ART response among patients receiving treatment.