Supporting the sexual and reproductive rights of HIV-infected individuals

The past 10 years have seen major advances in health care policy and services that support sexual and reproductive rights in South Africa. Significant milestones include the legalisation of termination of pregnancy (TOP) and the provision of free public sector services for maternal and child health (MCH) and contraception.1 At the same time the HIV epidemic has expanded rapidly during the last decade, and today an estimated 29% of women of reproductive age (15 - 49 years) in South Africa are HIV-infected.2 Despite these parallel developments, little attention has been paid to the way in which advances in sexual and reproductive rights in South Africa are extended to HIV-infected individuals

Failed contraception?

The frequency, cost and harms of the procedure must have been weighed up by the British National Health Service (NHS) — usually pretty sensible about their medical recommendations — which proposed 3-yearly screening for women aged between 50 and 64 years. Obviously more cancers would be discovered by 2-yearly rather than 3-yearly screening, and yet more by annual screening. Six-monthly screening, in turn, would clearly yield more cancers than annual screening. This would fit well with Dr Whitehorn’s ‘simple arithmetic’. However a balance has to be found between benefits and harms, and we chose the NHS one. The following organised screening programmes recommend 2- yearly mammography, most of them for women between 50 and 69 years: Australia, Finland, Iceland, Israel, Netherlands, France, Belgium, Canada, Denmark, Ireland, Italy, Norway, Portugal and Greece. Annual mammography, and mammography at an early age are the usual recommendations of interest groups. They are also the recommendation of the correspondence printed above. Like Dr Paul Sneider, we conclude with a quote from Boyle: ‘Every woman has a right to participate in an organised screening program . . .’. This right, alas, does not apply to this country, where other health care priorities make an organised programme an impossibility. However, should a woman have the privilege of medical aid, or be able to afford mammography, it is her choice to undergo it, a choice open to only a minority of South Africans. The majority of South African women would, in our opinion, be well served by an organised programme of ‘breast awareness’, a proposal that Dr Russell Whitehorn finds difficult to fathom

Knowledge of the abortion legislation among South African women: a cross-sectional study

BACKGROUND: In order to ensure that legalized abortion in South Africa improves reproductive health, women must know that abortion is a legal option in the case of unwanted pregnancy. This study investigated knowledge of abortion legislation eight years after the introduction of legal abortion services in one province of South Africa. METHODS: In 2004/2005, we conducted a cross-sectional study among 831 sexually-active women attending 26 public health clinics in one urban and one rural health region of the Western Cape Province. RESULTS: Thirty-two percent of women did not know that abortion is currently legal. Among those who knew of legal abortion, few had knowledge of the time restrictions involved. CONCLUSION: In South Africa there is an unmet need among women for information on abortion. Strategies should be developed to address this gap so that women are fully informed of their rights to a safe and legal termination of pregnancy

Sexual risk behaviours are influenced by knowing someone with HIV/AIDS

Behavioural risk reduction interventions are a central part of continuing efforts to stem the spread of the HIV epidemic. A range of interventions have been developed and tested in different populations within South Africa. These seek to lower individual risk of HIV infection by discouraging sexual relations with multiple partners and increasing levels of condom use. Many interventions to date have met with mixed success, and understanding the determinants of high-risk sexual behaviour remains a major concern in addressing HIV/AIDS.1 Several studies from other parts of sub-Saharan Africa have suggested that knowing someone with HIV/AIDS may be an important predictor of decreased risk behaviour. One pooled analysis2 found that adult men in Kenya, Zambia and Uganda were more likely to reduce their risk behaviours if they knew someone who had HIV/AIDS. Similar results have been reported in a population-based study3 of women in rural Zimbabwe. However, one previous study from South Africa4 using data from the 1998 Demographic and Health Survey (DHS) found that there was no association between knowing someone with HIV and levels of condom use. Given that the links between knowing someone with HIV and risk behaviours have important implications for HIV prevention efforts, we investigated this association in a survey of individuals attending a public sector health facility in Khayelitsha, near Cape Town

Knowledge and use of emergency contraception among women in the Western Cape province of South Africa: a cross-sectional study

Background: Emergency contraception (EC) is widely available free of charge at public sector clinics in South Africa. At the same time, rates of teenage and unintended pregnancy in South Africa remain high, and there are few data on knowledge of EC in the general population in South Africa, as in other resource-limited settings. Methods: We conducted a cross-sectional, interviewer-administered survey among 831 sexually active women at 26 randomly selected public sector clinics in the Western Cape province. Results: Overall, 30% of the women had ever heard of EC when asked directly, after the method was described to them. Only 15% mentioned EC by name or description spontaneously. Knowledge of EC was independently associated with higher education, being married, and living in an urban setting. Four percent of women had ever used EC. Discussion: These data suggest that knowledge of EC in this setting is more common among women of higher socioeconomic status living in urban areas. For EC to play a role in decreasing unintended pregnancy in South Africa, specific interventions are necessary to increase knowledge of the method, where to get it, and the appropriate time interval for its use before the need for EC arises. Future health promotion campaigns should target rural and low socioeconomic status communities

Tumor Cells Upregulate Normoxic HIF-1 in Response to Doxorubicin

Hypoxia-inducible factor 1 (HIF-1) is a master transcription factor that controls cellular homeostasis. While its activation benefits normal tissue, HIF-1 activation in tumors is a major risk factor for angiogenesis, therapeutic resistance and poor prognosis. HIF-1 activity is usually suppressed under normoxic conditions because of rapid oxygen-dependent degradation of HIF-1α. Here we show that under normoxic conditions HIF-1α is upregulated in tumor cells in response to doxorubicin, a chemotherapy used to treat many cancers. Doxorubicin also enhanced VEGF secretion by normoxic tumor cells and stimulated tumor angiogenesis. Doxorubicin-induced accumulation of HIF-1α in normoxic cells was caused by increased expression and activation of STAT1, the activation of which stimulated expression of iNOS and its synthesis of NO in tumor cells. Mechanistic investigations established that blocking NO synthesis or STAT1 activation was sufficient to attenuate the HIF-1α accumulation induced by doxorubicin in normoxic cancer cells. To our knowledge, this is the first report that a chemotherapeutic drug can induce HIF-1α accumulation in normoxic cells, an efficacy-limiting activity. Our results argue that HIF-1α targeting strategies may enhance doxorubicin efficacy. More generally, they suggest a broader perspective on the design of combination chemotherapy approaches with immediate clinical impact

Knowledge and use of emergency contraception among women in the Western Cape province of South Africa: a cross-sectional study

BACKGROUND: Emergency contraception (EC) is widely available free of charge at public sector clinics in South Africa. At the same time, rates of teenage and unintended pregnancy in South Africa remain high, and there are few data on knowledge of EC in the general population in South Africa, as in other resource-limited settings. METHODS: We conducted a cross-sectional, interviewer-administered survey among 831 sexually active women at 26 randomly selected public sector clinics in the Western Cape province. RESULTS: Overall, 30% of the women had ever heard of EC when asked directly, after the method was described to them. Only 15% mentioned EC by name or description spontaneously. Knowledge of EC was independently associated with higher education, being married, and living in an urban setting. Four percent of women had ever used EC. DISCUSSION: These data suggest that knowledge of EC in this setting is more common among women of higher socioeconomic status living in urban areas. For EC to play a role in decreasing unintended pregnancy in South Africa, specific interventions are necessary to increase knowledge of the method, where to get it, and the appropriate time interval for its use before the need for EC arises. Future health promotion campaigns should target rural and low socioeconomic status communities

Enhancing Cisplatin Delivery and Anti-tumor Efficacy Using Hyperthermia

<p>Mild hyperthermia (39°C-43°C) has numerous therapeutic benefits as an adjuvant therapy in the treatment of a variety of tumor types. Hyperthermia increases tumor blood flow and vascular permeability, promoting drug delivery and tumor oxygenation. Hyperthermia enhances the uptake and efficacy of numerous chemotherapeutic agents, including cisplatin, resulting in increased cytotoxicity. In addition to these biological responses, hyperthermia can be used as a drug-release trigger for temperature-sensitive nanoparticles, resulting in an improved and more targeted drug delivery system. Cisplatin was chosen because 1) it shows broad spectrum activity against a wide range of heatable cancers (i.e., those in sites such as the pancreas, colon and rectum, cervix and bladder, and 2) the same hyperthermic temperatures that enable temperature-sensitive lipsome-drug release also enhance cisplatin-induced cytotoxicity.</p><p>The role of hyperthermia in enhancing cisplatin delivery and cytotoxicity was investigated at both the cellular and tissue levels. While hyperthermia treatment is applicable to a variety of tumor types, the focus of this work was on bladder cancer. The synergistic effects of hyperthermia and cisplatin were investigated, along with the role of copper transport protein 1 (Ctr1) in this process. In addition, cisplatin was encapsulated within temperature-sensitive liposomes, which were used in combination with hyperthermia for targeted drug delivery. These studies demonstrated that the combination of cisplatin and hyperthermia improved drug delivery, and potentially anti-tumor efficacy, and that targeted delivery was enhanced through incorporation of temperature-sensitive liposomes. As many current methods for administering bladder hyperthermia have drawbacks, such as invasiveness and regional heating, the final aim of this study was to develop and test a less-invasive and more focused preclinical bladder heating device in a rat model. </p><p>Hyperthermia sensitizes cells to the cytotoxic effects of the commonly used chemotherapeutic agent cisplatin by increasing drug accumulation and subsequent platinum-DNA adduct formation. However, the molecular mechanisms underlying this enhancement remain unclear. Understanding the fundamental mechanisms involved in the synergistic interaction is necessary to increase the therapeutic benefits of this combination in the clinic. The synergism between the anti-cancer benefits of cisplatin and the drug delivery benefits of hyperthermia may offer a novel and more effective treatment for many cancer patients. We hypothesized that hyperthermia increases cisplatin accumulation and efficacy in part by modulating the function of Ctr1, a major regulator of cellular cisplatin uptake. To test this hypothesis, we examined the significance of Ctr1 during combined hyperthermia and cisplatin therapies and assessed the importance of cisplatin- and hyperthermia-induced Ctr1 multimerization in enhancing cisplatin cytotoxicity. We observed increased Ctr1 multimerization following hyperthermia treatment (41°C) in vitro, compared to normothermic controls (37°C), suggesting that this may be a mechanism for increased cisplatin uptake in heat-treated cells. The impact of increased Ctr1 multimerization was evaluated by measuring platinum accumulation in wild-type (WT) and Ctr1-/- cells. WT cells contained greater levels of platinum compared to Ctr1-/- cells. A further increase in platinum was observed following hyperthermia treatment, but only in the WT cells. Hyperthermia enhanced cisplatin-mediated cytotoxicity in WT cells with a dose-modifying factor (DMF) of 1.8 compared to 1.4 in Ctr1-/- cells. Our data suggest that heat increases Ctr1 activity by increasing multimerization, resulting in enhanced drug accumulation. Although we recognize that the effect of heat on cells is multi-factorial, our results support the hypothesis that Ctr1 is, in part, involved in the synergistic interaction observed with cisplatin and hyperthermia treatment. </p><p>In addition to assessing cisplatin delivery at the cellular level, we evaluated cisplatin delivery at the tissue level, using novel cisplatin-loaded temperature-sensitive liposomes. We hypothesized that delivering cisplatin encapsulated in liposomes under hyperthermic conditions would improve the pharmacokinetic profiles of cisplatin, increase drug delivery to the tumor, decrease normal tissue toxicity, and enhance the anti-tumor activity of cisplatin. We successfully prepared temperature-sensitive liposomes loaded with cisplatin and demonstrated that heat (42°C) sensitizes cisplatin-resistant cells to the cytotoxic effects of cisplatin in vitro. </p><p>Decreased toxicity was observed in animals treated with the cisplatin liposome (± heat) compared to the free drug treatments. A pharmacokinetic study of cisplatin-loaded temperature-sensitive liposomes and free drug was performed in tumor-bearing mice under normothermic and hyperthermic conditions. Cisplatin half-life in plasma was increased following liposome treatment compared to free cisplatin, and cisplatin delivery to the tumors was greatest in mice that received liposomal cisplatin under hyperthermia. These initial in vivo data demonstrate the potential effectiveness of this cisplatin-loaded liposome formulation in the treatment of certain types of cancer. To assess the anti-cancer efficacy of the liposome treatment, a tumor growth delay study was conducted and demonstrated equivalent efficacy for the cisplatin-loaded temperature-sensitive liposome compared to free drug. </p><p>In addition to the liposome work, we developed and evaluated a novel heating device for the bladder. Despite the evidence that hyperthermia is an effective adjuvant treatment strategy, current clinical heating devices are inadequate, warranting the development of a new and improved system. We induced hyperthermia using ferromagnetic nanoparticles and an alternating magnetic field device developed by Actium Biosystems. Initial preclinical studies in a rat model demonstrated preferential bladder heating. However, our preliminary studies show severe toxicity with the direct instillation of the nanoparticles in the bladder, and further studies are needed to potentially modify the nanoparticle coating, the catheterization procedure, as well as to develop a different animal model.</p>Dissertatio