Cost Effectiveness of Cryptococcal Antigen Screening as a Strategy to Prevent HIV-Associated Cryptococcal Meningitis in South Africa

Objectives

Cryptococcal meningitis (CM)-related mortality may be prevented by screening patients for sub-clinical cryptococcal antigenaemia (CRAG) at antiretroviral-therapy (ART) initiation and pre-emptively treating those testing positive. Prior to programmatic implementation in South Africa we performed a cost-effectiveness analysis of alternative preventive strategies for CM.

Design

Cost-effectiveness analysis.

Methods

Using South African data we modelled the cost-effectiveness of four strategies for patients with CD4 cell-counts <100 cells/µl starting ART 1) no screening or prophylaxis (standard of care), 2) universal primary fluconazole prophylaxis, 3) CRAG screening with fluconazole treatment if antigen-positive, 4) CRAG screening with lumbar puncture if antigen-positive and either amphotericin-B for those with CNS disease or fluconazole for those without. Analysis was limited to the first year of ART.

Results

The least costly strategy was CRAG screening followed by high-dose fluconazole treatment of all CRAG-positive individuals. This strategy dominated the standard of care at CRAG prevalence ≥0.6%. Although CRAG screening followed by lumbar puncture in all antigen-positive individuals was the most effective strategy clinically, the incremental benefit of LPs and amphotericin therapy for those with CNS disease was small and additional costs were large (US$158 versus US$51per person year; incremental cost effectiveness ratio(ICER) US$889,267 per life year gained). Both CRAG screening strategies are less costly and more clinically effective than current practice. Primary prophylaxis is more effective than current practice, but relatively cost-ineffective (ICER US$20,495).

Conclusions

CRAG screening would be a cost-effective strategy to prevent CM-related mortality among patients initiating ART in South Africa. These findings provide further justification for programmatic implementation of CRAG screening.     

Gender,Migration and HIV in Rural KwaZulu-Natal,South Africa

Objectives

Research on migration and HIV has largely focused on male migration, often failing to measure HIV risks associated with migration for women. We aimed to establish whether associations between migration and HIV infection differ for women and men, and identify possible mechanisms by which women''s migration contributes to their high infection risk.

Design

Data on socio-demographic characteristics, patterns of migration, sexual behavior and HIV infection status were obtained for a population of 11,677 women aged 15–49 and men aged 15–54, resident members of households within a demographic surveillance area participating in HIV surveillance in 2003–04.

Methods

Logistic regression was conducted to examine whether sex and migration were independently associated with HIV infection in three additive effects models, using measures of recent migration, household presence and migration frequency. Multiplicative effects models were fitted to explore whether the risk of HIV associated with migration differed for males and females. Further modeling and simulations explored whether composition or behavioral differences accounted for observed associations.

Results

Relative to non-migrant males, non-migrant females had higher odds of being HIV-positive (adjusted odds ratio [aOR] = 1.72; 95% confidence interval [1.49–1.99]), but odds were higher for female migrants (aOR = 2.55 [2.07–3.13]). Female migrants also had higher odds of infection relative to female non-migrants (aOR = 1.48 [1.23–1.77]). The association between number of sexual partners over the lifetime and HIV infection was modified by both sex and migrant status: For male non-migrants, each additional partner was associated with 3% higher odds of HIV infection (aOR = 1.03 [1.02–1.05]); for male migrants the association between number of partners and HIV infection was non-significant. Each additional partner increased odds of HIV infection by 22% for female non-migrants (aOR = 1.22 [1.12–1.32]) and 46% for female migrants (aOR = 1.46 [1.25–1.69]).

Conclusions

Higher risk sexual behavior in the context of migration increased women''s likelihood of HIV infection.     

Spread of extensively drug-resistant tuberculosis in KwaZulu-Natal province, South Africa

Background

In 2005 a cluster of 53 HIV-infected patients with extensively drug-resistant tuberculosis (XDR-TB) was detected in the Msinga sub-district, the catchment area for the Church of Scotland Hospital (CoSH) in Tugela Ferry, in KwaZulu-Natal province (KZN), South Africa. KZN is divided into 11 healthcare districts. We sought to determine the distribution of XDR TB cases in the province in relation to population density.

Methods

In this cross-sectional study, the KZN tuberculosis laboratory database was analysed. Results of all patients with a sputum culture positive for Mycobacterium tuberculosis from January 2006 to June 2007 were included. Drug-susceptibility test results for isoniazid, rifampicin, ethambutol, streptomycin, kanamycin and ofloxacin were available for all patients as well as the location of the hospital where their clinical diagnosis was made.

Findings

In total, 20858 patients attending one of 73 hospitals or their adjacent clinics had cultures positive for M. tuberculosis. Of these, 4170 (20%) were MDR-TB cases. Four hundred and forty three (11%) of the MDR tuberculosis cases displayed the XDR tuberculosis susceptibility profile. Only 1429 (34%) of the MDR-TB patients were seen at the provincial referral hospital for treatment. The proportion of XDR-TB amongst culture-confirmed cases was highest in the Msinga sub-district (19.6%), followed by the remaining part of the Umzinyati district (5.9%) and the other 10 districts (1.1%). The number of hospitals with at least one XDR-TB case increased from 18 (25%) to 58 (80%) during the study period.

Interpretation

XDR-TB is present throughout KZN. More than 65% of all diagnosed MDR-TB cases, including XDR-TB patients, were left untreated and likely remained in the community as a source of infection.     

Cryptococcal Meningitis Treatment Strategies in Resource-Limited Settings: A Cost-Effectiveness Analysis

Background

Cryptococcal meningitis (CM) is the most common form of meningitis in Africa. World Health Organization guidelines recommend 14-d amphotericin-based induction therapy; however, this is impractical for many resource-limited settings due to cost and intensive monitoring needs. A cost-effectiveness analysis was performed to guide stakeholders with respect to optimal CM treatment within resource limitations.

Methods and Findings:

We conducted a decision analysis to estimate the incremental cost-effectiveness ratio (ICER) of six CM induction regimens: fluconazole (800–1,200 mg/d) monotherapy, fluconazole + flucytosine (5FC), short-course amphotericin (7-d) + fluconazole, 14-d of amphotericin alone, amphotericin + fluconazole, and amphotericin + 5FC. We computed actual 2012 healthcare costs in Uganda for medications, supplies, and personnel, and average laboratory costs for three African countries. A systematic review of cryptococcal treatment trials in resource-limited areas summarized 10-wk survival outcomes. We modeled one-year survival based on South African, Ugandan, and Thai CM outcome data, and survival beyond one-year on Ugandan and Thai data. Quality-adjusted life years (QALYs) were determined and used to calculate the cost-effectiveness ratio and ICER. The cost of hospital care ranged from $154 for fluconazole monotherapy to $467 for 14 d of amphotericin + 5FC. Based on 18 studies investigating outcomes for HIV-infected individuals with CM in resource-limited settings, the estimated mean one-year survival was lowest for fluconazole monotherapy, at 40%. The cost-effectiveness ratio ranged from $20 to $44 per QALY. Overall, amphotericin-based regimens had higher costs but better survival. Short-course amphotericin (1 mg/kg/d for 7 d) with fluconazole (1,200 mg/d for14 d) had the best one-year survival (66%) and the most favorable cost-effectiveness ratio, at $20.24/QALY, with an ICER of $15.11 per additional QALY over fluconazole monotherapy. The main limitation of this study is the pooled nature of a systematic review, with a paucity of outcome data with direct comparisons between regimens.

Conclusions

Short-course (7-d) amphotericin induction therapy coupled with high-dose (1,200 mg/d) fluconazole is “very cost effective” per World Health Organization criteria and may be a worthy investment for policy-makers seeking cost-effective clinical outcomes. More head-to-head clinical trials are needed on treatments for this neglected tropical disease. Please see later in the article for the Editors'' Summary.     

Characterizing the Late Pleistocene MSA Lithic Technology of Sibudu,KwaZulu-Natal,South Africa

Studies of the African Middle Stone Age (MSA) have become central for defining the cultural adaptations that accompanied the evolution of modern humans. While much of recent research in South Africa has focused on the Still Bay and Howiesons Poort (HP), periods following these technocomplexes were often neglected. Here we examine lithic assemblages from Sibudu that post-date the HP to further the understanding of MSA cultural variability during the Late Pleistocene. Sibudu preserves an exceptionally thick, rich, and high-resolution archaeological sequence that dates to ∼58 ka, which has recently been proposed as type assemblage for the “Sibudan”. This study presents a detailed analysis of the six uppermost lithic assemblages from these deposits (BM-BSP) that we excavated from 2011–2013. We define the key elements of the lithic technology and compare our findings to other assemblages post-dating the HP. The six lithic assemblages provide a distinct and robust cultural signal, closely resembling each other in various technological, techno-functional, techno-economic, and typological characteristics. These results refute assertions that modern humans living after the HP possessed an unstructured and unsophisticated MSA lithic technology. While we observed several parallels with other contemporaneous MSA sites, particularly in the eastern part of southern Africa, the lithic assemblages at Sibudu demonstrate a distinct and so far unique combination of techno-typological traits. Our findings support the use of the Sibudan to help structuring this part of the southern African MSA and emphasize the need for further research to identify the spatial and temporal extent of this proposed cultural unit.     

Release of rehabilitated Chlorocebus aethiops to Isishlengeni Game Farm in KwaZulu-Natal,South Africa

Chlorocebus aethiops are treated as vermin by some in South Africa, and this has resulted in injury, illness and death of hundreds of C. aethiops, with orphans being very common. Rehabilitation centres care for, rehabilitate and aim to return these monkeys to the wild. This study describes the release of 29 C. aethiops to Isishlengeni Game Farm in KwaZulu-Natal, South Africa. The troop was monitored for six months. Confirmed survival of the troop was 62%, with 17% suspected mortality and 21% of the troop unaccounted for. The release site was not ideal due to hunting activities, the proximity of dwellings and roads and the presence of a wild troop. Preparation for release could be improved through the provision of naturally occurring foods and pre-release disease screening. Post-release monitoring would greatly benefit from the use of tracking devices to allow all animals to be followed post-release.     

HIV incidence remains high in KwaZulu-Natal, South Africa: evidence from three districts

Background

HIV prevalence and incidence among sexually active women in peri-urban areas of Ladysmith, Edendale, and Pinetown, KwaZulu-Natal, South Africa, were assessed between October 2007 and February 2010 in preparation for vaginal microbicide trials.

Methodology/Principal Findings

Sexually active women 18–35 years, not known to be HIV-positive or pregnant were tested cross-sectionally to determine HIV and pregnancy prevalence (798 in Ladysmith, 1,084 in Edendale, and 891 in Pinetown). Out of these, approximately 300 confirmed non-pregnant, HIV-negative women were subsequently enrolled at each clinical research center (CRC) in a 12-month cohort study with quarterly study visits. Women in the cohort studies were required to use a condom plus a hormonal contraceptive method. HIV prevalence rates in the baseline cross-sectional surveys were high: 42% in Ladysmith, 46% in Edendale and 41% in Pinetown. Around 90% of study participants at each CRC reported one sex partner in the last 3 months, but only 14–30% stated that they were sure that none of their sex partners were HIV-positive. HIV incidence rates based on seroconversions over 12 months were 14.8/100 person-years (PY) (95% CI 9.7, 19.8) in Ladysmith, 6.3/100 PY (95% CI 3.2, 9.4) in Edendale, and 7.2/100 PY (95% CI 3.7, 10.7) in Pinetown. The 12-month pregnancy incidence rates (in the context of high reported contraceptive use) were: 5.7/100 PY (95% CI 2.6, 8.7) in Ladysmith, 3.1/100 PY (95% CI 0.9, 5.2) in Edendale and 6.3/100 PY (95% CI 3.0, 9.6) in Pinetown.

Conclusions/Significance

HIV prevalence and incidence remain high in peri-urban areas of KwaZulu-Natal.     

Genotypic Diversity Is Associated with Clinical Outcome and Phenotype in Cryptococcal Meningitis across Southern Africa

Cryptococcal meningitis is a major cause of mortality throughout the developing world, yet little is known about the genetic markers underlying Cryptococcal virulence and patient outcome. We studied a cohort of 230 Cryptococcus neoformans (Cn) isolates from HIV-positive South African clinical trial patients with detailed clinical follow-up using multi-locus sequence typing and in vitro phenotypic virulence assays, correlating these data with clinical and fungal markers of disease in the patient. South African Cn displayed high levels of genetic diversity and locus variability compared to globally distributed types, and we identified 50 sequence types grouped within the main molecular types VNI, VNII and VNB, with 72% of isolates typed into one of seven ''high frequency'' sequence types. Spatial analysis of patients’ cryptococcal genotype was not shown to be clustered geographically, which might argue against recent local acquisition and in favour of reactivation of latent infection. Through comparison of MLST genotyping data with clinical parameters, we found a relationship between genetic lineage and clinical outcome, with patients infected with the VNB lineage having significantly worse survival (n=8, HR 3.35, CI 1.51-7.20, p=0.003), and this was maintained even after adjustment for known prognostic indicators and treatment regimen. Comparison of fungal genotype with in vitro phenotype (phagocytosis, laccase activity and CSF survival) performed on a subset of 89 isolates revealed evidence of lineage-associated virulence phenotype, with the VNII lineage displaying increased laccase activity (p=0.001) and ex vivo CSF survival (p=0.0001). These findings show that Cryptococcus neoformans is a phenotypically heterogeneous pathogen, and that lineage plays an important role in cryptococcal virulence during human infection. Furthermore, a detailed understanding of the genetic diversity in Southern Africa will support further investigation into how genetic diversity is structured across African environments, allowing assessment of the risks different ecotypes pose to infection.     

A Holocene sequence of vegetation change at Lake Eteza, coastal KwaZulu-Natal, South Africa

Palynological and sedimentological data from a core extracted from Lake Eteza shed new light on the Holocene vegetation and climate history in KwaZulu-Natal and can be linked to regional and global climate change. A 2072 cm core with nineteen radiocarbon dates and chronological extrapolation to the bottom of the sequence suggests that sedimentation started ca. 10 200 cal yrs BP. Between ca. 10 200 and 6800 cal yrs BP pollen indicators point to a change from intermediately humid conditions to comparatively drier grassy environments. This is in good agreement with Sea Surface Temperature (SST) fluctuations from a core in the Mozambique Channel which influence precipitation in coastal KwaZulu-Natal, and the beginning of the Holocene Thermal Maximum ca. 10 500 cal yrs BP. The lower section of the core corresponds to gradually increasing Holocene sea levels along the coast and development of freshwater or estuarine conditions at Lake Eteza. The middle Holocene (ca. 6800-3600 cal yrs BP), when the sea level reached its highest stand and SST peak, indicate humid climatic conditions that favoured an increase of forest trees, e.g. Podocarpus, and undergrowth plants like Issoglossa. As a consequence of higher precipitation and increase of the water table, conditions were favourable for the spread of mangrove, swamp and possibly riverine forest. During the late Holocene after ca. 3600 cal yrs BP a decrease of Podocarpus and other trees as well as an increase of Chenopodiaceae/Amaranthaceae, grasses and Phoenix coincide with a return to lower sea levels and drier conditions. The decrease of all trees including Phoenix at ca. 700 cal yrs BP, accompanied by rapid sedimentation rates, possibly reflect forest clearing and upland erosion induced by activities of Iron Age settlers. A dry period at the globally recognized onset of the Little Ice Age might have contributed to these changes. Late Iron Age settlers have probably already introduced Zea mays, which was detected in the profile since ca. 210 BP. The appearance of neophytes like Pinus, Casuarina and pollen of Ambrosia-type in the youngest sediments indicates increased disturbance of European settlements and land use since ca. 100 cal yrs BP.     

Commercial herbal preparations in KwaZulu-Natal, South Africa: The urban face of traditional medicine

The modern trend in traditional medicines reflects an increase in the sale of complex herbal mixtures rather than those prepared from single plants. This trend is well documented in Traditional Chinese Medicine (TCM) and can be seen in recent developments in African traditional medicine. An increase in the prevalence of locally produced herbal preparations, especially those containing complex mixtures of several medicinal plants, sold in numerous retail outlets, including supermarkets and pharmacies has been observed. The appearance of these preparations is not surprising in rapidly urbanizing societies where traditional products are still desired but the users have neither the time nor resources to produce them. The production of these herbal mixtures has resulted in a growing herbal industry with about 50 to 100 private entrepreneurs in the informal market and has also contributed to creation of numerous jobs. The products are extensively advertised in newspapers, on the internet, television and radio programmes as well as through pamphlets and posters. This review examines and documents the prevalence of commercial herbal mixtures and preparations common in Pietermaritzburg, KwaZulu-Natal. Different types of herbal mixtures, claims, ethical and legal implications are discussed. Methods of preparation and marketing strategies as well as the way forward in ensuring economic impact, safety and efficacy of this new aspect of South African traditional medicine are also highlighted.     

An Evaluation of Habitat Rehabilitation on Coastal Dune Forests in Northern KwaZulu-Natal, South Africa

The rehabilitation program conducted by Richards Bay Minerals (RBM) of areas exposed to opencast surface mining of sand dunes north of Richards Bay (28°43'S, 32°12'E) on the coast of northern KwaZulu-Natal Province commenced 16 years before this study and has resulted in the development of a series of known-aged stands of vegetation. By assuming that these spatially separated stands develop along a similar pathway over time, instantaneous sampling should reveal successional or other changes usually associated with aging and should provide an opportunity to evaluate the success of rehabilitation. We compare relative densities of pioneer and secondary species, species richness, and a similarity index of the herbaceous layer, tree, beetle, millipede, bird, and small-mammal communities of rehabilitating areas of known age with those of 30-year-old unmined forests and unmined forests of unknown age adjacent to the rehabilitating area. Species richness for all but the mammalian taxa increased with increasing age of rehabilitating stands. For all taxa but the mammals and herbaceous layer, the unmined stands harbored more species than the mined rehabilitating stands. The relative densities of pioneer species of all the taxa decreased with an increase in the age of rehabilitating stands, whereas those of the secondary species increased with an increase in habitat age. Similarity between unmined stands and rehabilitating stands of different ages increased with increasing regeneration age of rehabilitating stands, suggesting that rehabilitating communities, in terms of species composition and relative densities, are developing towards the status of unmined communities. Rehabilitation based on RBM's management program of limited interference is occurring and may result in the reestablishment of a coastal dune forest ecosystem. But rehabilitation resulting from succession depends on the availability of species sources from which colonization can take place. In the Richards Bay mining operation the present mining path is laid out so that such refuges are present.     

Mapping landscape beta diversity of plants across KwaZulu-Natal,South Africa,for aiding conservation planning

Collective properties of biodiversity, such as beta diversity, are suggested as complementary measures of species richness to guide the prioritisation and selection of important biodiversity areas in regional conservation planning. We assessed variation in the rate of plant species turnover along and between environmental gradients in KwaZulu-Natal, South Africa using generalised dissimilarity modelling, in order to map landscape levels of floristic beta diversity. Our dataset consisted of 434 plots (1000 m²) containing 997 grassland and savanna matrix species. Our model explained 79 % of the null deviance observed in floristic dissimilarities. Variable rates of turnover existed along the major environmental gradients of mean annual temperature, median rainfall in February, and soil cation exchange capacity, as well as along gradients of geographical distance. Beta diversity was highest in relatively warm, drier summer regions and on dystrophic soils. Areas of high beta diversity identify areas that should be included in conservation plans to maximise representation of diversity and highlight areas best suited to protected area expansion. Biome transition areas in high beta diversity areas may be susceptible to climate variability. Including beta diversity turnover rates in regional conservation plans will help to preserve evolutionary and ecological processes that create and maintain diversity.     

Knowledge,Practices, and Attitudes of Emergency Contraception among Female University Students in KwaZulu-Natal,South Africa

Objective

The purpose of this study is to investigate the knowledge, practices, and attitudes among female university students in South Africa regarding emergency contraceptives (EC).

Methods

A cross-sectional study was conducted among 582 female university students who were selected using multi-stage sampling techniques. Multivariate logistic regression analysis was used to find significant predictors for EC awareness.

Results

The average age of the female students was 20.9 years (SD = 3.0) and 57.2% were presently sexually active. Overall, 49.8% of the participants reported having heard about EC prior to the study. Regarding sexual activities among the female students, 53.2% reported to have sex, and 21.2% of the sexually experienced students used EC prior to the study. Regarding the effectiveness of EC, 29.5% students said it could be used up to 72 hours after unprotected sexual intercourse, and 8% said it could be used just before sex. About two-thirds (61.8%) would recommend the use of EC and 63.2% would use it if they needed. The multivariate analysis indicated that students who were older (>20 years), presently sexually active, and living with their parents were more likely to be aware of EC (p<0.05).

Conclusion

The students’ knowledge and utilization of EC were low. Health education and promotion should be targeted towards these students, and the EC services should be offered on campus.