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SummaryCirculating CD8+ T lymphocyte numbers rise substantially following infection with HIV-1. This expanded CD8+ T cell population includes HIV-specific CTL and CTL that kill activated uninfected CD4+ lymphocytes. Experimental, epidemiological and clinical evidence supports the possibility that expansion of CD8+ CTL contributes to CD4+ T cell depletion and disease progression in human HIV infection. Therefore, modulation of CD8+ T cell numbers or of certain CD8+ CTL activated in HIV-infected individuals may be beneficial. It was found that 1F7, a mAb against an idiotype common to anti-HIV and anti-simian immunodeficiency virus (SIV) antibodies, selectively inhibited both anti-HIV CTL and CTL against uninfected CD4+ T cells. Alloantigen-specific CTL and NK cells from either HIV-infected individuals or controls were unaffected by 1F7. Prolonged incubation of CD8+ T cells from HIV-infected individuals with 1F7 induces apoptosis, which was shown to be reflected functionally in reduced total CTL activity and in especially reduced CTL activity against uninfected CD4+ lymphocytes. The selective reactivity of 1F7 with certain CD8+ CTL could be applied towards the modulation of CD8+ T cell responses involved in AIDS pathogenesis. [ABSTRACT FROM AUTHOR]

The article discusses reduction in serious AIDS-related or non-AIDS-related illnesses in early HIV infection by immediate antiretroviral therapy (ART) as compared to deferred ART. Topics discussed include establishing criteria for treatment based delivering HIV care, endorsing treatment regardless of CD4+ count by HIV guidelines and prevention of tuberculosis (TB) by Early Antiretroviral Treatment and/or Early Isoniazid Prophylaxis against Tuberculosis in HIV-infected Adults (TEMPRANO) trials.

Background It is unclear whether the reporting quality of antiretroviral (ARV) noninferiority (NI) randomized controlled trials (RCTs) has improved since the CONSORT guideline release in 2006. The primary objective of this systematic review was assessing the methodological and reporting quality of ARV NI-RCTs. We also assessed reporting quality by funding source and publication year. Methods We searched Medline, Embase, and Cochrane Central from inception to 14 November 2022. We included NI-RCTs comparing ≥2 ARV regimens used for human immunodeficiency virus treatment or prophylaxis. We used the Cochrane Risk of Bias 2.0 tool to assess risk of bias. Screening and data extraction were performed blinded and in duplicate. Descriptive statistics were used to summarize data; statistical tests were 2 sided, with significance defined as P <.05. The systematic review was prospectively registered (PROSPERO CRD42022328586), and not funded. Results We included 160 articles reporting 171 trials. Of these articles, 101 (63.1%) did not justify the NI margin used, and 28 (17.5%) did not provide sufficient information for sample size calculation. Eighty-nine of 160 (55.6%) reported both intention-to-treat and per-protocol analyses, while 118 (73.8%) described missing data handling. Ten of 171 trials (5.9%) reported potentially misleading results. Pharmaceutical industry–funded trials were more likely to be double-blinded (28.1% vs 10.3%; P =.03) and to describe missing data handling (78.5% vs 59.0%; P =.02). The overall risk of bias was low in 96 of 160 studies (60.0%). Conclusions ARV NI-RCTs should improve NI margin justification, reporting of intention-to-treat and per-protocol analyses, and missing data handling to increase CONSORT adherence. [ABSTRACT FROM AUTHOR]

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]

Evaluates couples discordant in their HIV-1 infection status for the presence of protective factors. Infectivity of phytohemagglutinin-stimulated CD4 blasts; Risk factors for HIV infection in seronegative subjects; Lysis of infected CD4 cells and B cell lines by autologous cytotoxic T lymphocytes.

Objective: To describe prevalent and persistent oncogenic human papillomavirus (HPV) types detected in women living with HIV (WLWH) in Canada, including women with cervical dyskaryosis, and to determine predictors of type-specific HPV persistence.Methods: Women and girls living with HIV, recruited from 14 sites of HIV care across Canada, were included in a sub-analysis of a prospective vaccine immunogenicity cohort study (two HPV DNA results, at least one cervical cytology result pre-vaccination). Demographic and clinical data were collected alongside cervical samples for cytology and HPV DNA typing between November 25, 2008, and May 19, 2015.Results: Pre-vaccination, HPV16 and HPV52 were the most prevalent oncogenic HPV types. Of the 252 women and girls who met the eligibility criteria, 45% were infected with at least one oncogenic HPV type and one-third of participants had a persistent oncogenic infection. HPV16, 45, and 52 were the most frequently persistent types. Seventeen percent of women had persistent infections with oncogenic HPV types not within currently available vaccines (HPV35/39/51/56/59/68/82). Lower CD4 count significantly predicted HPV persistence (P=0.024). Cervical cytology results were normal for 82.9% of participants, atypical squamous cells of undetermined significance for 2.4%, low-grade squamous intraepithelial lesions for 11.5%, and high-grade squamous intraepithelial lesions for 2.8%.Conclusion: Unvaccinated WLWH were infected with a wide range of oncogenic HPV types. The findings highlighted the importance of optimal treatment of HIV and continued cervical cancer screening as key steps toward the global elimination of cervical cancer. [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]

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]

The article discusses research comparing the rates of decline of CD4 white blood cells (WBCs) counts in HIV-infected adults with prior antiretroviral therapy (ART)–untreated follow-up according to their Herpes simplex virus type 2 (HSV-2) status. Topics include the prevalence of HSV-2 in HIV-infected adults, the research methodology used to determine the research subjects' HSV serostatus, and a discussion of the results.

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]

Describes several scenarios for the implementation of the Canadian consensus guidelines for the care of HIV-positive pregnant women. Introduction to the guidelines; Case of an HIV-infected pregnant woman who is not receiving antiretroviral therapy when pregnancy is confirmed; HIV-infected pregnant woman receiving combination antiretroviral therapy when pregnancy is confirmed; Treatment of a woman diagnosed with HIV infection, who presents or is referred for care within 1 month of term.

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.