The effect of PrEP uptake and adherence on the spread of HIV in the presence of casual and long-term partnerships.

A model with both casual and long-term partnerships is considered with respect to the impact of a pre-exposure prophylaxis (PrEP) on the spread of HIV. We consider the effect of the effectiveness of PrEP, the rate that susceptible individuals choose to take PrEP, and compliance with the daily dose of the pre-exposure prophylaxis. The rate of infection in long-term partnerships is computed using a linearized expected value as a means for including the nonlocal effects of long-term partnerships while maintaining computational feasibility. The reproduction numbers for models with casual partnerships, long-term partnerships, and a combination of both are analytically computed and global stability of both disease-free and endemic equilibria is shown. Sensitivity and PRCC analysis results suggest that increasing the compliance among the current PrEP users is a more effective strategy in the fight against the HIV epidemic than increased coverage with poor compliance. Furthermore, an analysis of the reproduction number shows that models with either casual or monogamous long-term partnerships can reach the desired $ R_0 < 1 $ threshold for high enough levels of compliance and uptake, however, a model with both casual and monogamous long-term partnerships will require additional interventions. Methods highlighted in this manuscript are applicable to other incurable diseases or diseases with imperfect vaccines effected by long-term partnerships.

A sexually transmitted infection model with long-term partnerships in homogeneous and heterogenous populations.

Population models for sexually transmitted infections frequently use a transmission model that assumes an inherent partnership length of zero. However, in a population with long-term partnerships, the infection status of the partners, the length of the partnership, and the exclusivity of the partnership significantly affect the rate of infection. We develop an autonomous population model that can account for the possibilities of an infection from either a casual sexual partner or a longtime partner who was either infected at the start of the partnership or was newly infected. The impact of the long-term partnerships on the rate of infection is captured by calculating the expected values of the rate of infection from these extended contacts. We present a new method to evaluate partner acquisition rates for casual or long-term partnerships which produces in a more realistic number of lifetime sexual partners. Results include a SI model with different infectiousness levels for the transmission of HIV and HSV-2 with acute and chronic/latent infection stages for homogeneous (MSM) and heterogeneous (WSM-MSW) groups. The accompanying reproduction number and sensitivity studies highlight the impact of both casual and long-term partnerships on infection spread. We construct an autonomous set of equations that handle issues usually ignored by autonomous equations and handled only through simulations or in a non-autonomous form. The autonomous formulation of the model allows for simple numerical computations while incorporating a combination of random instantaneous contacts between individuals and prolonged contacts between specific individuals.

Influence of concurrency, partner choice, and viral suppression on racial disparity in the prevalence of HIV infected women.

In 1992, Watts and May introduced a simple dynamical systems model of the spread of HIV based on disease transmission per partnership including the length of partnership duration. This model allowed for the treatment of concurrent partnerships, although it was hampered by the assumption of an important latent phase which generated a non-autonomous system. Subsequent models including concurrency have been based on networks, Monte Carlo, and stochastic simulations which lose a qualitative understanding of the effects of concurrency. We present a new autonomous deterministic model of the effect of concurrent sexual partnerships that allows for an analytical study of disease transmission. We incorporate the effect of concurrency through the newly derived force of infection term in a mathematical model of the transmission of HIV through sexual contact in a population stratified by sexual behavior and race/ethnicity. The model also includes variations in population mixing (partner choice) and non-uniform Highly Active Anti-Retroviral Treatment (HAART) leading to viral suppression. We use this mathematical model to understand the non-uniform spread of HIV in women who were infected through heterosexual contact. In addition, an analytical study shows the importance of continued condom use in virally suppressed MSM. Numerical simulations of the reproduction number as a function of concurrency, viral suppression level, and mixing show a reservoir of disease present in both heterosexual and MSM populations. Statistical analysis of parameter values show that viral suppression level, mixing and progression to AIDS without viral suppression have a strong correlation (either positive or negative) with the number of HIV positive women. Concurrency and assortative mixing are shown to be essential to reproduce infection levels in women, as reported by 2010 data from the Center for Disease Control (CDC).

Convective Instabilities in Two Liquid Layers.

We perform linear stability calculations for horizontal fluid bilayers, taking into account both buoyancy effects and thermocapillary effects in the presence of a vertical temperature gradient. To help understand the mechanisms driving the instability, we have performed both long-wavelength and short-wavelength analyses. The mechanism for the large wavelength instability is complicated, and the detailed form of the expansion is found to depend on the Crispation and Bond numbers. The system also allows a conventional Rayleigh-Taylor instability if heavier fluid overlies lighter fluid, and the long-wavelength analysis describes this case as well. In addition to the asymptotic analyses for large and small wavelengths, we have performed numerical calculations using materials parameters for a benzene-water system.

Human papillomavirus vaccines for cervical cancer.

Cervical cancer is one of the most common causes of cancer-related death in women. As a result of several recent advances in molecular biology, the association between human papillomavirus (HPV) infection and cervical cancer has been firmly established, and the oncogenic potential of certain HPV types has been clearly demonstrated. Several lines of evidence suggest the importance of the host's immune response, especially cellular immune response, in the pathogenesis of HPV-associated cervical lesions. These observations form a compelling rationale for the development of vaccine therapy to combat HPV infection. Both prophylactic and therapeutic HPV vaccine strategies are being developed. Prophylactic strategies currently under investigation focus on the induction of effective humoral immune responses against subsequent HPV infection. In this respect, impressive immunoprophylactic effects have been demonstrated in animals using papillomavirus-like particles (VLPs). VLPs are antigenic and protective, but are devoid of any viral DNA that may be carcinogenic to the host. For treatment of existing HPV infection, techniques to improve cellular immunity by enhancing viral antigen recognition are being studied. For this purpose, the oncogenic proteins E6 and E7 of HPV-16 and -18 are the focus of current clinical trials for cervical cancer patients. The development of successful HPV-specific vaccines may offer an attractive alternative to existing screening and treatment programs for cervical cancer.

Induction of specific CD8+ T-lymphocyte responses using a human papillomavirus-16 E6/E7 fusion protein and autologous dendritic cells.

When intracellular viral proteins are degraded, only a limited number of peptide epitopes are capable of eliciting specific CD8+ cellular immune responses for a given human leukocyte antigen (HLA) haplotype. We sought to induce CD8+ T-lymphocyte (CTL) responses to human papillomavirus-16 (HPV-16) E6 and E7 proteins using a recombinant E6/E7 fusion protein and autologous human dendritic cells (DCs). CTLs were generated by in vitro stimulation using a recombinant HPV-16 E6/E7 fusion protein and autologous DCs from a healthy HLA-A*0201 donor. CTL specificity was assessed by cytokine release assays when the cells were reacted with autologous DC targets coincubated with the E6/E7 fusion protein. These CTLs were also reacted with the immunodominant E7 peptides (E711-20 and E7(86-93)) and DCs as a target. As a negative control, DCs were incubated with or without an irrelevant control protein (Helicobacter pylori) as target for the E6/E7-induced CTLs. The E6/E7-induced CTLs were capable of specific recognition of target DCs coincubated with E6/E7 but not the control protein. When E6/E7-specific CTLs were reacted with DCs and either E7(11-20) or E7(86-93), specific peptide recognition was also detected. These data demonstrate that specific CTLs can be elicited using autologous human DCs and a HPV-16 E6/E7 fusion protein. Therefore, extracellular viral proteins seem to be engulfed and processed by DCs; then the immunodominant HLA-A2-restricted peptides become available for CD8+ T-lymphocyte recognition. These data suggest that vaccine strategies using recombinant viral proteins may overcome the limitation of peptide epitopes for specific HLA haplotypes and may, therefore, permit more generalized clinical application.

Cell-mediated immunological responses in cervical and vaginal cancer patients immunized with a lipidated epitope of human papillomavirus type 16 E7.

Human papillomavirus (HPV) infection has been causally associated with cervical cancer. We tested the effectiveness of an HLA-A*0201-restricted, HPV-16 E7 lipopeptide vaccine in eliciting cellular immune responses in vivo in women with refractory cervical cancer. In a nonrandomized Phase I clinical trial, 12 women expressing the HLA-A2 allele with refractory cervical or vaginal cancer were vaccinated with four E786-93 lipopeptide inoculations at 3-week intervals. HLA-A2 subtyping was also performed, and HPV typing was assessed on tumor specimens. Induction of epitope-specific CD8+ T-lymphocyte (CTL) responses was analyzed using peripheral blood leukapheresis specimens obtained before and after vaccination. CTL specificity was measured by IFN-gamma release assay using HLA-A*0201 matched target cells. Clinical responses were assessed by physical examination and radiographic images. All HLA-A*0201 patients were able to mount a cellular immune response to a control peptide. E786-93-specific CTLs were elicited in 4 of 10 evaluable HLA-A*0201 subjects before vaccination, 5 of 7 evaluable HLA-A*0201 patients after two vaccinations, and 2 of 3 evaluable HLA-A*0201 cultures after all four inoculations. Two of three evaluable patients' CTLs converted from unreactive to reactive after administration of all four inoculations. There were no clinical responses or treatment toxicities. The ability to generate specific cellular immune responses is retained in patients with advanced cervical cancer. Vaccination with a lipidated HPV peptide epitope appears capable of safely augmenting CTL reactivity. Although enhancements of cellular immune responses are needed to achieve therapeutic utility in advanced cervical cancer, this approach might prove useful in treating preinvasive disease.

Progress and prospects in vaccine therapy for gynecologic cancers.

Therapeutic and prophylactic vaccines that harness the potential of the immune system against a number of gynecologic cancers are now being developed. The therapeutic vaccines coerce the cellular components of the immune system to attack malignant tissue. The prophylactic vaccines induce the production of antibodies capable of neutralizing viral antigens before they infect host cells. However, malignant tumors are usually a heterogeneous mixture of different malignant cells, and it is likely that variant tumor clones within a tumor may not express the target antigen or may possess defects in their antigen-presenting mechanism. Ultimately, therapeutic vaccines may be better suited for the treatment of preinvasive disease or for use as an adjuvant following primary therapy. The prospects for developing efficacious vaccines to treat or prevent cervical, ovarian, uterine, and other gynecologic cancers are promising, however. This article describes the methodology of and rationale for these vaccines.

Adrenal function following high-dose steroids in ovarian cancer patients.

PURPOSE: Steroid doses similar to those used to prevent paclitaxel-associated hypersensitivity reactions and cisplatin-induced nausea have been associated with hypothalamic-pituitary-adrenal (HPA) axis suppression. We assessed HPA function in patients receiving high-dose steroids as part of their chemotherapy regimen for epithelial ovarian cancer. PATIENTS AND METHODS: From January to July 1994, a cross-sectional study of HPA function was performed on patients receiving dexamethasone (DEX) as part of their paclitaxel and cisplatin chemotherapy regimen (n = 9). Patients received 20 mg of DEX orally, 6 and 12 hr prior to paclitaxel (135 mg/m2) and 10-20 mg intravenously before cisplatin (50-100 mg/m2). In addition, patients received approximately 12 mg/day of DEX orally for 4 days after their chemotherapy as an antiemetic. HPA integrity was evaluated by the administration of synthetic adrenocorticotropic hormone (ACTH). The ACTH stimulation test was performed 11-19 days after the completion of the course of DEX. Patients had fasting baseline cortisol levels drawn at approximately 0800 followed by a 25-unit intravenous injection of ACTH. Post-ACTH cortisol levels were repeated at 30 and 60 min. RESULTS: The mean (+/- SEM) fasting baseline level of cortisol was 12.4 +/- 2.3 micrograms/dl (normal, 7-23 micrograms/dl). At 30 min following ACTH administration, the mean cortisol level rose 17.1 micrograms to 29.5 +/- 1.8 micrograms/dl; at 60 min it rose 21.4 micrograms to 33.8 +/- 2.5 micrograms/dl [P < 0.001] (normal increase 9-39 micrograms). All patients demonstrated a sufficient increase in their plasma cortisol after ACTH stimulation, indicating normal HPA function on the days tested. However, there was a significant trend toward lower increases in plasma cortisol at 30 and 60 min as the interval from ACTH stimulation testing to the DEX regimen decreased (r = 0.986; P < 0.0001). The chemotherapy cycle number had no impact on cortisol response in the multivariate analysis. Based on multiple linear regression, HPA function may be suppressed for approximately 8 days, but up to 14 days from the start of this DEX regimen. CONCLUSION: Current steroid regimens prescribed with chemotherapy transiently decrease HPA function, but do not appear to inhibit the HPA axis long term. HPA function may be suppressed for approximately 8 days from the commencement of chemotherapy cycles involving DEX. Patients presenting within the first 8 days of a chemotherapy cycle using steroids with symptoms attributable to HPA suppression may benefit from HPA axis testing.

Detection and patterns of treatment failure in 300 consecutive cases of "early" endometrial cancer after primary surgery.

From November 1977 to July 1987, 300 consecutive patients with endometrial carcinoma clinically confined to the uterine corpus underwent primary surgery consisting of at least abdominal hysterectomy and adnexectomy. Patients with aggressive disease characteristics received postoperative radiotherapy. Forty-seven patients (16%) demonstrated recurrent disease from 2 to 125 (median of 12.8) months after surgery. Forty-seven percent of the recurrences were detected within the first year following surgery and 70% by 2 years after hysterectomy. Of the 47 recurrences, 29 were at distant sites, 16 were within the pelvis, and 2 consisted of both local and distant recurrences. Patients treated with pelvic radiotherapy after hysterectomy were more likely to experience distant, rather than local recurrences. Only 7 of the 148 patients (5%) treated with postoperative radiotherapy recurred in the pelvis. Approximately half of the recurrences were detected in asymptomatic individuals; physical examination and chest X-ray were the most useful means to detect disease in patients without symptoms. The combination of history, physical examination, pap smear, and chest X ray detected all of the recurrences. Actuarial survivals at 12, 24, and 36 months after recurrence were 42, 24, and 17%, respectively. The site of recurrence, time interval of surgery to recurrence, and use of postoperative pelvic radiotherapy were statistically related to patient prognosis. The identification of patients at risk of recurrence and more effective adjuvant therapy need to be developed in order to decrease the frequency of recurrence. In order to substantially improve the survival of patients with recurrent disease, more sensitive methods of detection, as well as more effective salvage therapy, will be required.