Projecting the Potential Clinical and Economic Impact of Human Immunodeficiency Virus Prevention Resource Reallocation in Tennessee.

BACKGROUND: In 2023, Tennessee replaced $6.2 M in US Centers for Disease Control and Prevention (CDC) human immunodeficiency virus (HIV) prevention funding with state funds to redirect support away from men who have sex with men (MSM), transgender women (TGW), and heterosexual Black women (HSBW) and to prioritize instead first responders (FR), pregnant people (PP), and survivors of sex trafficking (SST). METHODS: We used a simulation model of HIV disease to compare the clinical impact of Current, the present allocation of condoms, preexposure prophylaxis (PrEP), and HIV testing to CDC priority risk groups (MSM/TGW/HSBW); with Reallocation, funding instead increased HIV testing and linkage of Tennessee-determined priority populations (FR/PP/SST). Key model inputs included baseline condom use (45%-49%), PrEP provision (0.1%-8%), HIV testing frequency (every 2.5-4.8 years), and 30-day HIV care linkage (57%-65%). We assumed Reallocation would reduce condom use (-4%), PrEP provision (-26%), and HIV testing (-47%) in MSM/TGW/HSBW, whereas it would increase HIV testing among FR (+47%) and HIV care linkage (to 100%/90%) among PP/SST. RESULTS: Reallocation would lead to 166 additional HIV transmissions, 190 additional deaths, and 843 life-years lost over 10 years. HIV testing reductions were most influential in sensitivity analysis; even a 24% reduction would result in 287 more deaths compared to Current. With pessimistic assumptions, we projected 1359 additional HIV transmissions, 712 additional deaths, and 2778 life-years lost over 10 years. CONCLUSIONS: Redirecting HIV prevention funding in Tennessee would greatly harm CDC priority populations while conferring minimal benefits to new priority populations.

Gender Affirming Hormones Do Not Affect the Exposure and Efficacy of F/TDF or F/TAF for HIV Preexposure Prophylaxis: A Subgroup Analysis from the DISCOVER Trial.

Purpose: Transgender women are disproportionately affected by HIV and are underutilizing preexposure prophylaxis (PrEP). The lower uptake of PrEP by transgender women may be, in part, owing to the perception that taking PrEP may lower the efficacy of gender-affirming hormone therapy (GAHT) or to provider concerns that GAHT may lower the efficacy of PrEP. Methods: DISCOVER was a randomized, double-blind, noninferiority trial comparing emtricitabine (FTC, F) and tenofovir alafenamide (F/TAF) versus emtricitabine and tenofovir disoproxil fumarate (F/TDF) as PrEP among transgender women and cisgender men who have sex with men (MSM). This nested substudy of the DISCOVER trial compared the exposure of the active intracellular metabolites of FTC and tenofovir (TFV), FTC triphosphate (FTC-TP) and TFV diphosphate (TFV-DP), in peripheral blood mononuclear cells (PBMC) among transgender women receiving GAHT versus MSM within the F/TAF and F/TDF groups. Results: Our results demonstrate that TFV-DP and FTC-TP levels in PBMC were comparable between transgender women on GAHT and MSM receiving F/TAF, and between transgender women on GAHT and MSM receiving F/TDF. TFV-DP concentrations remained above the EC90 of 40 fmol/106 cells across all groups. No clinically significant drug-drug interactions of GAHT were observed with either F/TAF or F/TDF in this subanalysis. Conclusions: These findings are consistent with the clinical pharmacology of GAHT, FTC, TDF, and TAF reported in previous studies, and support the continued use of F/TAF and F/TDF for PrEP in transgender women.Clinicaltrials.gov registration number: NCT02842086.

Anogenital human papillomavirus virus DNA and sustained response to the quadrivalent HPV vaccine in women living with HIV-1.

OBJECTIVES: People living with HIV have increased Human Papillomavirus (HPV) related lesions and malignancies. We describe HPV DNA recovered from the cervix and anal canal, explore the effect of vaccination on HPV detection, and examine the durability of vaccine titers in women living with HIV-1 who were vaccinated with the quadrivalent HPV vaccine. METHODS: AIDS Clinical Trials Group A5240 was a prospective study of the quadrivalent HPV (qHPV) vaccine in 315 HIV-1 infected women in three CD4 strata (A: >350, B; 201-350, C: ≤200 cells/mm3). Vaccine was administered at entry, week 8 and week 24. Cervical and anal HPV DNA specimens were collected at baseline, weeks 28 and 52; serum for antibody testing was obtained at baseline, weeks 28 and 72. RESULTS: Vaccine antibody titers decreased across all four HPV types at week 72 compared to week 28. Lower proportions of sustained seropositivity were observed in women with lower CD4 counts for all four vaccine types, with the lowest titers for HPV 18. Despite the decrease, the geometric mean titer levels were above the seroconversion cut-off levels for all types except HPV 18 in the lowest CD4 stratum. Of the 174 participants who had a negative baseline HPV 16 antibody and developed antibody response at week 28, 95%, 88%, and 86% retained seropositivity at week 72 in strata A, B, and C respectively. Lower antibody retention was observed in women with CD4 < 200 compared to CD4 > 350 (p = 0.016). Anal HPV detection was more prevalent compared to cervical detection at all visits. Among high risk types, type 52, 31, 16, 18 and 51 were the most common in the cervical compartment, while types 16, 35, 18, and 51 were the most prevalent in the anal canal at baseline (listed in the order of prevalence). Later detection of HPV not present at baseline was uncommon in either compartment. Serial recovery of HPV over time was more commonly observed in the anal canal. CONCLUSION: The qHPV vaccine elicits durable titer response above the seroconversion cut-off levels in HIV-infected women. However, the titer levels were substantially lower by Week 72, most noticeably in type 18. HPV DNA was detected more frequently in the anal canal. Detection of non-vaccine high risk HPV suggests a role for the nonavalent vaccine.

A Randomized, Placebo-Controlled Trial of the Quadrivalent Human Papillomavirus Vaccine in Human Immunodeficiency Virus-Infected Adults Aged 27 Years or Older: AIDS Clinical Trials Group Protocol A5298.

Background: Adults living with human immunodeficiency virus (HIV) are at increased risk for anal and oropharyngeal cancer caused by human papillomavirus (HPV). The efficacy of HPV vaccines in this population is unknown. Methods: In this phase 3, double-blind, randomized, controlled trial, we assigned HIV-infected adults aged ≥27 years to the quadrivalent HPV (types 6, 11, 16, 18) vaccine or placebo (1:1) stratified by sex and presence of anal high-grade squamous intraepithelial lesions on biopsy (bHSIL). The primary endpoint was vaccine efficacy against incident persistent anal infection with quadrivalent vaccine types or single detection at the final visit that were not present at baseline. Secondary endpoints included vaccine efficacy for anal bHSIL after week 52, persistent oral HPV infection. Results: A total of 575 participants were randomized. The Data and Safety Monitoring Board stopped the study early due to futility. Vaccine efficacy was 22% (95.1% confidence interval [CI], -31%, 53%) for prevention of persistent anal infection or single detection at the final visit, 0% (95% CI -44%, 31%) for improving bHSIL outcomes and 88% (95.1% CI 2%, 98%) for preventing persistent oral HPV infection, but was 32% (95.1% CI -80%, 74%) for 6-month persistent oral HPV infection or single detection at the final visit. Conclusions: These results do not support HPV vaccination of HIV-infected adults aged ≥27 years to prevent new anal HPV infections or to improve anal HSIL outcomes. However, our data suggest a role for prevention of oral HPV infections, but this finding should be confirmed in future studies. Clinical Trials Registration: NCT01461096.

High Baseline Anal Human Papillomavirus and Abnormal Anal Cytology in a Phase 3 Trial of the Quadrivalent Human Papillomavirus Vaccine in Human Immunodeficiency Virus-Infected Individuals Older Than 26 Years: ACTG 5298.

BACKGROUND: The quadrivalent human papillomavirus (HPV) vaccine (qHPV; types 6, 11, 16, 18) is indicated for men and women aged 9 to 26 years to prevent HPV associated anogenital high-grade squamous intraepithelial lesions (HSIL) and cancer. ACTG 5298 was a randomized placebo controlled Phase 3 study in human immunodeficiency virus (HIV)-infected men who have sex with men, and women of qHPV to prevent persistent anal HPV infection. Baseline data are presented here. METHODS: Human immunodeficiency virus-infected men who have sex with men, and women 27 years or older without previous anogenital or oral cancer were enrolled. Baseline anal cytology, high-resolution anoscopy and collection of anal, oral, and vaginal specimens for HPV genotyping were performed and acceptability assessed. RESULTS: Five hundred seventy-five (575) participants were enrolled (82% men and 18% women). Median age was 47 years. Race/ethnicity was 46% white, 31% black, and 20% Hispanic. Plasma HIV-1 RNA was less than 50 copies/mL in 83% and median CD4 T count was 602 cells/µL. Abnormal anal cytology was detected in 62%, with corresponding HSIL on biopsy (bHSIL) in 33%. Anal HPV 6, 11, 16, and 18 were detected in 25%, 13%, 32%, and 18% of the participants, respectively. Prevalence of 0, 1, 2, 3, and 4 qHPV types was 40%, 38%, 17%, 4%, and 1%, respectively. Oral infection with 1 or more qHPV type was detected in 10% of the participants. Study procedures were generally acceptable. CONCLUSIONS: At study baseline, there was a high prevalence of abnormal anal cytology, bHSIL, and HPV infection. Sixty percent of the participants had anal infection with preventable qHPV types.

An Insight Into Cervical Cancer Screening and Treatment Capacity in Sub Saharan Africa.

OBJECTIVE: Approximately 85% of cervical cancer cases and deaths occur in resource-constrained countries where best practices for prevention, particularly for women with HIV infection, still need to be developed. The aim of this study was to assess cervical cancer prevention capacity in select HIV clinics located in resource-constrained countries. MATERIALS AND METHODS: A cross-sectional survey of sub-Saharan African sites of 4 National Institutes of Health-funded HIV/AIDS networks was conducted. Sites were surveyed on the availability of cervical cancer screening and treatment among women with HIV infection and without HIV infection. Descriptive statistics and χ or Fisher exact test were used as appropriate. RESULTS: Fifty-one (65%) of 78 sites responded. Access to cervical cancer screening was reported by 49 sites (96%). Of these sites, 39 (80%) performed screening on-site. Central African sites were less likely to have screening on-site (p = .02) versus other areas. Visual inspection with acetic acid and Pap testing were the most commonly available on-site screening methods at 31 (79%) and 26 (67%) sites, respectively. High-risk HPV testing was available at 29% of sites with visual inspection with acetic acid and 50% of sites with Pap testing. Cryotherapy and radical hysterectomy were the most commonly available on-site treatment methods for premalignant and malignant lesions at 29 (74%) and 18 (46%) sites, respectively. CONCLUSIONS: Despite limited resources, most sites surveyed had the capacity to perform cervical cancer screening and treatment. The existing infrastructure of HIV clinical and research sites may provide the ideal framework for scale-up of cervical cancer prevention in resource-constrained countries with a high burden of cervical dysplasia.

Immunogenicity and safety of the quadrivalent human papillomavirus vaccine in HIV-1-infected women.

BACKGROUND: Women infected with human immunodeficiency virus (HIV) are disproportionately affected by human papillomavirus (HPV)-related anogenital disease, particularly with increased immunosuppression. AIDS Clinical Trials Group protocol A5240 was a trial of 319 HIV-infected women in the United States, Brazil, and South Africa to determine immunogenicity and safety of the quadrivalent HPV vaccine in 3 strata based on screening CD4 count: >350 (stratum A), 201-350 (stratum B), and ≤200 cells/µL (stratum C). METHODS: Safety and serostatus of HPV types 6, 11, 16, and 18 were examined. HPV serological testing was performed using competitive Luminex immunoassay (HPV-4 cLIA). HPV type-specific seroconversion analysis was done for participants who were seronegative for the given type at baseline. RESULTS: Median age of patients was 36 years; 11% were white, 56% black, and 31% Hispanic. Median CD4 count was 310 cells/µL, and 40% had undetectable HIV-1 load. No safety issues were identified. Seroconversion proportions among women at week 28 for HPV types 6, 11,16, and 18 were 96%, 98%, 99%, and 91%, respectively, for stratum A; 100%, 98%, 98%, and 85%, respectively, for stratum B, and 84%, 92%, 93%, and 75%, respectively, for stratum C. CONCLUSIONS: The quadrivalent HPV vaccine targeted at types 6, 11, 16, and 18 was safe and immunogenic in HIV-infected women aged 13-45 years. Women with HIV RNA load >10 000 copies/mL and/or CD4 count <200 cells/µL had lower rates of seroconversion rates. Clinical Trials Registration. NCT00604175.

Genetic predictors of cervical dysplasia in African American HIV-infected women: ACTG DACS 268.

OBJECTIVE: To examine genome-wide associations in HIV-infected women with a history of cervical dysplasia compared with HIV-infected women with no history of abnormal Papanicolaou (Pap) tests. DESIGN: Case-control study using data from women analyzed for the HIV Controllers Study and enrolled in HIV treatment-naïve studies in the AIDS Clinical Trials Group (ACTG). METHODS: Genotyping utilized Illumina HumanHap 650 Y or 1MDuo platforms. After quality control and principal component analysis, ~610,000 significant single nucleotide polymorphisms (SNPs) were tested for association. Threshold for significance was P < 5 × 10(-8) for genome-wide associations. RESULTS: No significant genomic association was observed between women with low-grade dysplasia and controls. The genome-wide association study (GWAS) analysis between women with high-grade dysplasia or invasive cervical cancer and normal controls identified significant SNPs. In the analyses limited to African American women, 11 SNPs were significantly associated with the development of high-grade dysplasia or cancer after correcting for multiple comparisons. The model using significant SNPs alone had improved accuracy in predicting high-grade dysplasia in African American women compared to the use of clinical data (area under the receiver operating characteristic curve for genetic and clinical model = 0.9 and 0.747, respectively). CONCLUSIONS: These preliminary data serve as proof of concept that there may be a genetic predisposition to developing high-grade cervical dysplasia in African American HIV-infected women. Given the small sample size, the results need to be validated in a separate cohort.

Immune Activation While on Potent Antiretroviral Therapy Can Predict Subsequent CD4+ T-Cell Increases Through 15 Years of Treatment.

BACKGROUND: While persistent T-cell activation has been cross-sectionally associated with poor CD4+ T-cell restoration in HIV-infected individuals maintaining antiretroviral treatment (ART)-mediated viral suppression, it remains unclear whether CD8+ T-cell activation is of predictive effect on CD4+ T-cell recovery. OBJECTIVE: We assessed whether the extent of persistent CD8+ T-cell activation (% CD38+/HLA-DR+) in the first few years of ART-mediated viral suppression predicted subsequent CD4+ T-cell recovery in 95 subjects with up to 15 years of observation on suppressive ART. RESULTS: Lower CD8+ T-cell activation and higher naïve CD4+ T-cell frequencies (CD45RA+/CD62L+) measured at year 3 to 5 after starting ART independently predicted greater subsequent CD4+ T-cell increases. The mean CD4 count increase from year 0 to year 5 and the increase to the average of year 10 to 15 in the low CD8 activation group (≤18.5%; mean = 13%) were 342 and 458 cells/mm,3 and the increases were 248 and 349 cells/mm3 for the high CD8 activation group (≯18.5%; mean = 29%) (P = .002 and P = .016, respectively, comparing groups). At years 10 to 15, the mean CD4 counts in the groups were 579 and 484 cells/mm3, respectively (P = .026). CONCLUSION: These findings support the need to identify approaches to reduce immune activation in treated HIV disease.

Steady-state pharmacokinetics, cord blood concentrations, and safety of ritonavir-boosted fosamprenavir in pregnancy.

Steady-state pharmacokinetics in pregnant women prescribed ritonavir-boosted fosamprenavir (FPV) to prevent HIV transmission were assessed in the second trimester, third trimester, and postpartum. Compared with postpartum, geometric mean amprenavir (APV, FPVs active metabolite) area under the plasma concentration-time curves were 35% lower in the second trimester and 25% lower in the third trimester. Maternal APV concentrations were 9- to 15-fold above the mean APV protein-adjusted 50% inhibitory concentration for wild-type HIV. Median ratio of cord blood/maternal APV levels was 0.27, and all infants were HIV negative. FPV/ritonavir during pregnancy was well tolerated and led to virologic suppression.

Neuropsychiatric complications of antiretroviral therapy.

Neuropsychiatric adverse effects related to potent antiretroviral therapy are among the complications that can lead to poor adherence, treatment interruptions, or change of antiretroviral therapy regimens. For a historical perspective, we review early literature and case reports with CNS adverse effects attributed to antiretrovirals. The variability of the cerebrospinal fluid penetration of individual antiretrovirals may contribute to their potential for behavioural and psychiatric manifestations. The majority of neuropsychiatric complications related to potent antiretroviral therapy have been associated with the use of the efavirenz. Updates on the risk of neuropsychiatric manifestations with efavirenz use in patients with a history of psychiatric disorders or substance abuse are reviewed. We include a critical review of recently published data on the long-term CNS adverse effects with efavirenz. Special attention is given to the results of recent investigations on the relationship between the pharmacogenomics of genes responsible for efavirenz metabolism and the plasma concentration of efavirenz. It is important to note that there is no established direct correlation of efavirenz concentrations and symptoms. It is not recommended for practitioners to adjust efavirenz doses in order to prevent or alleviate CNS adverse effects. Patients may be placed at risk for virological failure and resistance if they receive suboptimal doses of efavirenz. The aim of this article is to give a concise review and an update on recent literature concerning neuropsychiatric effects of antiretroviral use in HIV-infected patients. Our intent is to present practitioners with data that can be used in a practical way to both educate and improve outcomes in the HIV-infected patient population.

Cardiovascular and Endothelial Disease in HIV Infection.

As combination antiretroviral therapy improves outcome for HIV-infected patients, more focus is directed on the durability of these regimens and the prevention of long-term adverse events. Given the prevalence of metabolic complications associated with combination therapy, namely insulin resistance, dyslipidemia, and truncal adiposity, interest in whether these complications predispose patients to cardiovascular disease prematurely is appropriate. This paper reviews the most recent data regarding the effects of HIV and its treatment on endothelial dysfunction, serum biomarkers, and vascular indices, and provides an update on the risk for cardiovascular events in the HIV-infected patient population.