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Questions: In adults with HIV-1 infection, does immediate antiretroviral therapy (ART) reduce severe illness compared with deferred ART? Does isoniazid preventive therapy (IPT) reduce severe illness compared with no IPT? Methods Design: Randomized, controlled, 2 x 2 factorial trial (TEMPRANO ANRS 12136 trial). ClinicalTrials.gov NCT00495651. Allocation: Concealed.* Blinding: Unblinded.* Follow-up period: 30 months. Setting: 9 centers in Abidjan, Ivory Coast. Patients: 2076 patients ≥ 18 years of age (median age 35 y, 79% women, median CD4+ count 459 to 467 cells/mm[sup 3]) who had HIV-1 infection or dual HIV-1 and HIV-2 infection, CD4+ count < 800 cells/mm[sup 3], and did not meet World Health Organization (WHO) criteria for starting ART. Intervention: ART started immediately (n = 1041) or deferred until WHO criteria for starting ART were reached (n = 1035). Patients were also randomized to IPT, 300 mg/d starting 1 month after randomization and continuing for 6 months (n = 1038), or no IPT (n = 1038). Outcomes: Primary outcome was a composite of all-cause mortality or severe HIV-related illness (AIDS-defining disease, non–AIDS-defining cancer, or non–AIDS-defining invasive bacterial disease). Other outcomes included grade 3 or 4 adverse events (severe or life-threatening events including gastrointestinal, respiratory, cardiovascular, cutaneous, neurologic, or other adverse events, or hematologic or biochemical test abnormalities). Patient follow-up: 85% completed the 30-month visit or died (intention-to-treat analysis). Main results: Immediate ART, with or without IPT, reduced the primary outcome compared with deferred ART, with or without IPT (Table). IPT, with early or deferred ART, reduced the primary outcome compared with no IPT, with early or deferred ART (Table). No interaction was found between treatments and the primary outcome. Immediate ART did not differ from deferred ART and IPT did not differ from no IPT for all-cause mortality (Table). Immediate ART increased grade 3 or 4 adverse events at < 6 months (4.2% vs 1.7%, relative risk increase 154%, 95% CI 46 to 338) and reduced events at 6 to 30 months (2.6% vs 5.6%, relative risk reduction 52%, CI 23 to 69) compared with deferred ART; IPT did not differ from no IPT for grade 3 or 4 adverse events at < 6 months or 6 to 30 months. Conclusion: In adults with HIV-1 infection, immediate vs deferred antiretroviral therapy and isoniazid preventive therapy vs no isoniazid reduced severe illness at 30 months. [ABSTRACT FROM AUTHOR]

Background Human papillomavirus (HPV) vaccination is safe and efficacious in women without human immunodeficiency virus (HIV). Although good immunogenicity has been observed in women living with HIV (WLWH), efficacy data in this population are needed. Methods We enrolled 420 females aged ≥9 years (range, 9–65) living with HIV. Participants were to receive 3 doses of qHPV vaccine (0/2/6 months). The main endpoint was vaccine failure (ie, incident persistent qHPV infection, cervical intraepithelial neoplasia of grade 2 or higher [CIN2+], or genital warts). We compared these rates to published rates in vaccinated and unvaccinated women without HIV as well as unvaccinated WLWH. Results Among 279 eligible women, median follow-up was 2 years. In the intention-to-treat population, the incidence rate (IR) of persistent qHPV (HPV6/11/16/18) was 2.3 per 100 person-years (/100PY) (95% confidence interval [CI], 1.1–4.1), and IR of genital warts was 2.3/100PY (95% CI, 1.2–4.1). In the per-protocol efficacy population, IR of persistent qHPV was 1.0/100PY (95% CI, 0.3–2.6) and of genital warts was 1.0/100PY (95% CI, 0.3–2.5). No cases of CIN2+ occurred. Reported rates of qHPV-related infection and disease within vaccinated women without HIV, unvaccinated women without HIV, and vaccinated WLWH: 0.1 (95% CI, 0.02–0.03), 1.5 (95% CI, 1.1–2.0), and 1.2 (95% CI, 0.2–3.4) /100PY, respectively. The rate of persistent qHPV among vaccinated WLWH was lower than among unvaccinated WLWH (2.3 vs 6.0/100PY). Conclusions Vaccinated WLWH may be at higher risk for vaccine failure than vaccinated women without HIV. However, overall rates of vaccine failure were low, and rates of persistent qHPV were lower than in unvaccinated WLWH. [ABSTRACT FROM AUTHOR]

Background:  Whether a candidate tuberculosis vaccine induces clinically relevant protective T-cell repertoires in humans will not be known until the completion of costly efficacy clinical trials.Methods:  We have developed an integrated immunologic approach to investigate the clinical relevance of T cells induced by a novel tuberculosis vaccine in a phase 1 trial. This approach consists of screening for likely dominant T-cell epitopes, establishing antigen-specific memory T-cell lines for identifying CD8+ and CD4+ T-cell epitopes, determining the ability of vaccine-induced T cells to inhibit mycobacterial growth in infected cells, and examining the genetic diversity of HLA recognition and the clinical relevance of identified T-cell epitopes.Results:  A single-dose immunization in BCG-primed adults with an adenovirus-based tuberculosis vaccine elicits a repertoire of memory T cells capable of recognizing multiple Ag85A epitopes. These T cells are polyfunctional and cytotoxic and can inhibit mycobacterial growth in infected target cells. Some identified T-cell epitopes are promiscuous and recognizable by the common HLA alleles. These epitopes are clinically relevant to the epitopes identified in people with latent Mycobacterium tuberculosis infection and treated patients with tuberculosis.Conclusions:  These data support further clinical development of this candidate vaccine. Our approach helps fill the gap in clinical tuberculosis vaccine development. [ABSTRACT FROM AUTHOR]

Objective To evaluate the immunogenicity and safety of the quadrivalent HPV (qHPV) vaccine in HIV-positive women over 24 months. Design Between November 2008 and December 2012, 372 women aged 15 and older were enrolled from 14 Canadian HIV outpatient clinics in an open label cohort study. The qHPV vaccine (0.5 mL) was administered intramuscularly at months 0, 2 and 6. The primary study endpoint was seroconversion to any of the HPV types targeted by the qHPV vaccine. Antibody levels were measured at 0, 2, 7, 12, 18, and 24 months. Adverse events were recorded throughout. Results Of 372 participants enrolled, 310 (83%) received at least one dose of the qHPV vaccine and 277 (74%) received all three doses. Ninety-five percent (293/308) were seronegative for at least one vaccine type at baseline. The median age was 38 years (IQR 32–45, range 15–66), 36% were white, 44% black and 13% were of Indigenous origin. Seventy-two percent of participants had a suppressed HIV viral load (VL < 40 c/ml) at baseline, with a median CD4 count of 510 cells/mm 3 (376–695). Month 7 HPV type-specific seroconversion rates were 99.0%, 98.7%, 98.1% and 93.6% for HPV types 6, 11, 16 and 18 respectively in the per-protocol population. Participants with suppressed HIV VL at first vaccine had a 1.74–3.05 fold higher peak antibody response compared to those without ( p from 0.006 to <0.0001). Conclusions This study is the first to examine the qHPV vaccine in HIV-positive women out to 24 months and the first to include HIV-positive women through to age 66. The qHPV vaccine was well tolerated, and highly immunogenic. As women with suppressed viral load had higher antibody responses, planning HPV vaccination to occur when persons are virologically suppressed would be optimal for maximizing immune response. Findings provide strong evidence that older HIV-positive women can still benefit from HPV vaccination. Clinical trial registration: http://www.isrctn.com/ISRCTN33674451 [ABSTRACT FROM AUTHOR]

Background. The Canadian Women's HIV Study (CWHS) enrolled human immunodeficiency virus (HIV)–positive and high-risk HIV-negative women in a longitudinal cohort. This analysis considered the effects of HIV and highly active antiretroviral therapy (HAART) on HPV persistence and cervical squamous intraepithelial lesions (SILs).Methods. Longitudinal cytopathologic and HPV DNA results were analyzed using multistate models. States of cervical SIL were defined as absent, present, and treatment; HPV states were defined as negative or positive. Demographic variables and markers of sexual activity were considered predictors. Results were calculated on the basis of transition probabilities and reported as hazard ratios (HRs).Results. The CWHS followed 750 HIV-positive and 323 HIV-negative women during 1993–2002. A total of 467 and 456 women were included in the longitudinal cervical cytopathologic and HPV DNA analyses, respectively. HIV-positive women had increased prevalence (46.6% vs 28.7%; P < .0001), increased acquisition (HR, 2.3; P = .03), and decreased clearance (HR, 0.4; P < .001) of oncogenic HPV as compared to HIV-negative women. Oncogenic HPV infection predicted progression of cervical dysplasia from normal to abnormal SIL (HR, 2.8; P = .002). Among HIV-positive participants, HAART increased the likelihood of regression (from present to absent) of cervical SIL (HR, 3.3; P = .02) and increased the clearance of oncogenic HPV types other than HPV-16 or HPV-18 (HR, 2.2; P = .01).Conclusions. This analysis demonstrated beneficial effects of HAART on cervical SIL in HIV-positive women. [ABSTRACT FROM AUTHOR]

Background: Although some studies show higher antiretroviral concentrations in women compared to men, data are limited. We conducted a cross-sectional study of HIV-positive women to determine if protease inhibitor (PI) and non-nucleoside reverse transcriptase inhibitor (NNRTI) Cmin and Cmax values were significantly different than historical general population (predominantly male) averages and to evaluate correlates of higher concentrations. Methods: HIV-positive women with virologic suppression (viral load < 50copies/mL) on their first antiretroviral regimen were enrolled. Timed blood samples for Cmin and Cmax were drawn weekly for 3 weeks. The ratio of each individual's median Cmin and Cmax to the published population mean values for their PI or NNRTI was calculated and assessed using Wilcoxon sign-rank. Intra- and inter-patient variability of antiretroviral drug levels was assessed using coefficient of variation and intra-class correlation. Linear regression was used to identify correlates of the square root-transformed Cmin and Cmax ratios. Results: Data from 82 women were analyzed. Their median age was 41 years (IQR=36-48) and duration of antiretrovirals was 20 months (IQR=9-45). Median antiretroviral Cmin and Cmax ratios were 1.21 (IQR=0.72-1.89, p=0.003) (highest ratios for nevirapine and lopinavir) and 0.82 (IQR=0.59-1.14, p=0.004), respectively. Nevirapine and efavirenz showed the least and unboosted atazanavir showed the most intra- and inter-patient variability. Higher CD4+ count correlated with higher Cmin. No significant correlates for Cmax were found. Conclusions: Compared to historical control data, Cmin in the women enrolled was significantly higher whereas Cmax was significantly lower. Antiretroviral Cmin ratios were highly variable within and between participants. There were no clinically relevant correlates of drug concentrations. [ABSTRACT FROM AUTHOR]

The prevalence of smoking in HIV-infected subjects is high. As a smoking cessation aid, varenicline (Champix®, Pfizer, Saint-Laurent, QC, Canada or Chantix®, Pfizer, Mission, KS) has not been previously evaluated in HIV-infected smokers. In this multicenter pilot open label study, varenicline 1.0 mg was used twice daily for 12 weeks with dose titration in the first week. Adverse events (AEs) during the treatment period were recorded. Changes from baseline in laboratory tests, vital signs, daily cigarette consumption, nicotine dependence, and withdrawal were measured through week 24. Self-reported abstinence was validated by serum cotinine at week 12. We enrolled 36 subjects with a mean of 29 pack-years of smoking and a minimum of 4 cigarettes per day. All but 1 were male, 33 (92%) were white. The most frequently reported AEs were nausea (33%), abnormal dreams (31%), affect lability (19%), and insomnia (19%). Six (17%) subjects discontinued varenicline due to AEs. No grade 3/4 laboratory abnormalities or serious AEs occurred during the study. There was no significant change in HIV viral load. CD4 counts increased by 69 cells/mm3 ( p=0.001) at week 24. Serum cotinine-verified 4-week continuous abstinence rate through weeks 9-12 was 42% (95% confidence interval [CI]: 26-58%). AEs and abstinence rates were comparable to those in published randomized controlled trials conducted in generally healthy HIV-negative smokers. Varenicline was safe and appears effective among HIV-infected smokers in this exploratory study, although AEs were common. The most common AE was nausea, with no adverse effect on HIV treatment outcome. Close monitoring of liver enzymes and blood pressure is recommended for HIV-positive smokers taking varenicline. [ABSTRACT FROM AUTHOR]

Reports that beta-chemokine RANTES production by T cells and CD8-mediated inhibition of human immunodeficiency virus gene expression before initiation of potent antiretroviral therapy predict sustained suppression of viral replication. Effect of the introduction of potent combinations of antiretroviral drugs or highly active antiretroviral therapy in the treatment of human immunodeficiency virus infection.