Distal Sensory Peripheral Neuropathy in Human Immunodeficiency Virus Type 1-Positive Individuals Before and After Antiretroviral Therapy Initiation in Diverse Resource-Limited Settings.

BACKGROUND: Distal sensory peripheral neuropathy (DSPN) is a complication of human immunodeficiency virus (HIV). We estimate DSPN prevalence in 7 resource-limited settings (RLSs) for combination antiretroviral therapy (cART)-naive people living with HIV (PLWH) compared with matched participants not living with HIV and in PLWH virally suppressed on 1 of 3 cART regimens. METHODS: PLWH with a CD4+ count <300 cells/mm3 underwent standardized neurological examination and functional status assessments before and every 24 weeks after starting cART. Matched individuals not living with HIV underwent the same examinations once.Associations between covariates with DSPN at entry were assessed using the χ2 test, and virally suppressed PLWH were assessed using generalized estimating equations. RESULTS: Before initiating cART, 21.3% of PLWH had DSPN compared with 8.5% of people not living with HIV (n = 2400; χ2(df = 1) = 96.5; P < .00001). PLWH with DSPN were more likely to report inability to work [χ2(df = 1) = 10.6; P = .001] and depression [χ2(df = 1) = 8.9; P = .003] than PLWH without DSPN. Overall prevalence of DSPN among those virally suppressed on cART decreased: 20.3%, week 48; 15.3%, week 144; and 10.3%, week 192. Incident DSPN was seen in 127 PLWH. Longitudinally, DSPN was more likely in older individuals (P < .001) and PLWH with less education (P = .03). There was no significant association between cART regimen and DSPN. CONCLUSIONS: Although the prevalence of DSPN decreased following cART initiation in PLWH, further research could identify strategies to prevent or ameliorate residual DSPN after initiating cART in RLSs.

Correction: Costs and cost-effectiveness of LEEP versus cryotherapy for treating cervical dysplasia among HIV-positive women in Johannesburg, South Africa.

[This corrects the article DOI: 10.1371/journal.pone.0203921.].

Human Immunodeficiency Virus Type 1 and Tuberculosis Coinfection in Multinational, Resource-limited Settings: Increased Neurological Dysfunction.

BACKGROUND: AIDS Clinical Trial Group 5199 compared neurological and neuropsychological test performance of human immunodeficiency virus type 1 (HIV-1)-infected participants in resource-limited settings treated with 3 World Health Organization-recommended antiretroviral (ART) regimens. We investigated the impact of tuberculosis (TB) on neurological and neuropsychological outcomes. METHODS: Standardized neurological and neuropsychological examinations were administered every 24 weeks. Generalized estimating equation models assessed the association between TB and neurological/neuropsychological performance. RESULTS: Characteristics of the 860 participants at baseline were as follows: 53% female, 49% African; median age, 34 years; CD4 count, 173 cells/µL; and plasma HIV-1 RNA, 5.0 log copies/mL. At baseline, there were 36 cases of pulmonary, 9 cases of extrapulmonary, and 1 case of central nervous system (CNS) TB. Over the 192 weeks of follow-up, there were 55 observations of pulmonary TB in 52 persons, 26 observations of extrapulmonary TB in 25 persons, and 3 observations of CNS TB in 2 persons. Prevalence of TB decreased with ART initiation and follow-up. Those with TB coinfection had significantly poorer performance on grooved pegboard (P < .001) and fingertapping nondominant hand (P < .01). TB was associated with diffuse CNS disease (P < .05). Furthermore, those with TB had 9.27 times (P < .001) higher odds of reporting decreased quality of life, and had 8.02 times (P = .0005) higher odds of loss of productivity. CONCLUSIONS: TB coinfection was associated with poorer neuropsychological functioning, particularly the fine motor skills, and had a substantial impact on functional ability and quality of life. CLINICAL TRIALS REGISTRATION: NCT00096824.

Costs and cost-effectiveness of LEEP versus cryotherapy for treating cervical dysplasia among HIV-positive women in Johannesburg, South Africa.

BACKGROUND: Cervical cancer incidence is significant in countries, such as South Africa, with high burdens of both HIV and human papillomavirus (HPV). Cervical cancer is largely preventable if dysplasia is diagnosed and treated early, but there is debate regarding the best approaches for screening and treatment, especially for low-resource settings. Currently South Africa provides Pap smears followed by colposcopic biopsy and LEEP if needed in its public health facilities. We estimated the costs and cost-effectiveness of two approaches for treating cervical intraepithelial neoplasia grade 2 or higher (CIN2+) among HIV-infected women, most of whom were taking antiretroviral treatment, at a public HIV treatment facility in Johannesburg, South Africa. METHODS: Method effectiveness was derived from an intention-to-treat analysis of data gathered in a clinical trial completed previously at the study facility. In the trial, women who were diagnosed with CIN2+ and eligible for cryotherapy were randomized to cryotherapy or LEEP. If women were CIN2+ at six months as determined via Pap smear and colposcopic biopsy, all women-regardless of their original treatment assignment-received LEEP. "Cure" was then defined as the absence of disease at 12 months based on Pap smear and colposcopic biopsy. Health service costs were estimated using micro-costing between June 2013 and April 2014. Capital costs were annualized using a discount rate of 3%. Two different service volume scenarios were considered, and results from an as-treated analysis were considered in sensitivity analysis. RESULTS: In total, 166 women with CIN2+ were enrolled (86 had LEEP; 80 had cryotherapy). At 12 months, cumulative loss to follow-up was 12.8% (11/86) for the LEEP group and 13.8% (11/80) for cryotherapy. Based on the unadjusted intention-to-treat analysis conducted for this economic evaluation, there was no significant difference in efficacy. At 12 months, 83.8% (95% CI 73.8-91.1) of women with CIN2+ at baseline and randomized to cryotherapy were free of CIN2+ disease. In contrast, 76.7% (95% CI 66.4-85.2) of women assigned to LEEP were free from disease. On average, women initially treated with cryotherapy were less costly per patient randomized at US$ 118.00 (113.91-122.10), and per case "cured" at US$ 140.90 (136.01-145.79). Women in the LEEP group cost US$ 162.56 (157.90-167.22) per patient randomized and US$ 205.59 (199.70-211.49) per case cured. In the as-treated analysis, which was based on trial data, LEEP was more efficacious than cryotherapy; however, the difference was not significant. Cryotherapy remained more cost-effective than LEEP in all sensitivity and scenario analyses. CONCLUSIONS: For this cost-effectiveness analysis, using an intention-to-treat approach and taking into consideration uncertainty in the clinical and cost outcomes, a strategy involving cryotherapy plus LEEP if needed at six months was dominant to LEEP plus LEEP again at six months if needed for retreatment. However, compared to other studies comparing LEEP and cryotherapy, the efficacy results were low in both treatment groups-possibly due to the HIV-positivity of the participants. Further research is needed, but at present choosing the "right" treatment option may be less important than ensuring access to treatment and providing careful monitoring of treatment outcomes.

Congenital genital abnormalities detected during routine circumcision at a South African institution: a retrospective record review.

BACKGROUND: Due to the reduction in HIV transmission through male medical circumcisions (MMC), numerous clinics throughout South Africa offer a voluntary free service to boys from the age of ten years and above. An examination prior to the procedure may detect congenital abnormalities missed after birth. OBJECTIVES: The aim of this study was to measure the incidence of these abnormalities, determine the demographic and clinical characteristics of this group and determine what referral systems, interventions, and follow-up is available to them. METHODS: The study was a descriptive, observational, retrospective analysis of de-identified medical records at a routine MMC service at a Johannesburg clinic in 2015. The participants were male patients between the ages of 10 - 49. RESULTS: Out of 1548 participants, 91.0% (n=1409) had a normal genital examination while 3.7% (n=57) had an abnormal examination and 5.1% (n=79) had no examination recorded. Thirty five congenital anomalies were detected and only 2 patients (diagnosed with hypospadias) were seen at the urology out-patient's department. CONCLUSION: The incidence of congenital genital abnormalities of males presenting for routine circumcision is low. Despite the low incidence the effect on fertility, sexuality, ability to urinate and on psychological wellbeing is significant. Referral services to the urology department should be restructured to improve all outcomes.

Intensive adherence counselling for HIV-infected individuals failing second-line antiretroviral therapy in Johannesburg, South Africa.

OBJECTIVE: In resource-limited settings, where genotypic drug resistance testing is rarely performed and poor adherence is the most common reason for treatment failure, programmatic approaches to handling treatment failure are essential. This study was performed to describe one such approach to adherence optimisation. METHODS: This was a single-arm study of patients on second-line protease inhibitor (PI)-based antiretroviral therapy (ART) with a HIV-1 RNA ≥400 copies/ml in Johannesburg, South Africa, between 1 March 2012 and 1 December 2013. Patients underwent enhanced adherence counselling. Those with improved adherence and a repeat viral load of >1000 copies/ml underwent HIV-1 drug resistance testing. We describe results using simple proportions and 95% confidence intervals. RESULTS: Of the 400 patients who underwent targeted adherence counselling after an elevated viral load on second-line ART, 388 (97%) underwent repeat viral load testing. Most of these (n = 249; 64%, 95% CI 59-69) resuppressed (<400 copies/ml) on second line. By the end of follow-up (1 March 2014), among the 139 (36%, 95% CI: 31-41%), who did not initially resuppress after being targeted, 106 had a viral load >400 copies/ml, 11 switched to third line, 5 were awaiting third line, 4 had died and 13 were lost to follow-up. Among the unsuppressed, 48 successfully underwent resistance testing with some resistance detected in most (41/48). CONCLUSIONS: Most (64%) second-line treatment failure in this clinic is related to adherence and can be overcome with careful adherence support. Controlled interventions are needed to determine what the optimal approach is to improving second-line outcomes and reducing the need for third-line ART.

Costs and Cost Effectiveness of Three Approaches for Cervical Cancer Screening among HIV-Positive Women in Johannesburg, South Africa.

BACKGROUND: South Africa has high rates of HIV and HPV and high incidence and mortality from cervical cancer. However, cervical cancer is largely preventable when early screening and treatment are available. We estimate the costs and cost-effectiveness of conventional cytology (Pap), visual inspection with acetic acid (VIA) and HPV DNA testing for detecting cases of CIN2+ among HIV-infected women currently taking antiretroviral treatment at a public HIV clinic in Johannesburg, South Africa. METHODS: Method effectiveness was derived from a validation study completed at the clinic. Costs were estimated from the provider perspective using micro-costing between June 2013-April 2014. Capital costs were annualized using a discount rate of 3%. Two different service volume scenarios were considered. Threshold analysis was used to explore the potential for reducing the cost of HPV DNA testing. RESULTS: VIA was least costly in both scenarios. In the higher volume scenario, the average cost per procedure was US$ 3.67 for VIA, US$ 8.17 for Pap and US$ 54.34 for HPV DNA. Colposcopic biopsies cost on average US$ 67.71 per procedure. VIA was least sensitive but most cost-effective at US$ 17.05 per true CIN2+ case detected. The cost per case detected for Pap testing was US$ 130.63 using a conventional definition for positive results and US$ 187.52 using a more conservative definition. HPV DNA testing was US$ 320.09 per case detected. Colposcopic biopsy costs largely drove the total and per case costs. A 71% reduction in HPV DNA screening costs would make it competitive with the conservative Pap definition. CONCLUSIONS: Women need access to services which meet their needs and address the burden of cervical dysplasia and cancer in this region. Although most cost-effective, VIA may require more frequent screening due to low sensitivity, an important consideration for an HIV-positive population with increased risk for disease progression.

Human papillomavirus (HPV) testing on self-collected specimens: perceptions among HIV positive women attending rural and urban clinics in South Africa.

INTRODUCTION: Cervical cancer is the most common cancer among women in Sub-Saharan Africa. Cervical cancer is treatable if detected timeously, yet only 20% of South African women have ever been for a Pap smear in their lifetime due to limited access to screening, transport or child care responsibilities. OBJECTIVE: To evaluate the acceptability of self-collection for cervical cancer screening. We aimed to identify which self-collection device women prefer and if they would consider using them for routine cervical cancer screening. METHODS: HIV-positive women (>18 years) from urban and rural HIV clinics were interviewed following an education session on HIV, human papillomavirus (HPV) and cervical cancer. Participants were shown three self-collection devices; (i) an Evalyn cervical brush, (ii) a Delphilavager and (iii) a tampon-like plastic wand before completing a short questionnaire. RESULTS: A total of 106 women from the urban (n = 52) and rural (n = 54) clinic were interviewed. Overall 51% of women preferred the cervical brush, while fewer women preferred the tampon-like plastic wand (31%) or lavage sampler (18%). More than 75% of women from the rural site preferred the cervical brush, compared to 22% from the urban site (p < 0.001). Women from the urban clinic preferred the tampon-like plastic wand (45%) and then the lavage sampler (33%), as compared to women from the rural clinic (19% and 4%, respectively). CONCLUSION: Women from urban or rural settings had different preferences for the various self-collection devices. Patient self-collection with HPV testing may be an acceptable way to improve coverage to cervical cancer screening in high risk HIV-seropositive women.

Incident pregnancy and time to death or AIDS among HIV-positive women receiving antiretroviral therapy.

BACKGROUND: Little is known about the impact of pregnancy on response to highly active antiretroviral therapy (HAART) in sub-Saharan Africa. We examined the effect of incident pregnancy after HAART initiation on clinical response to HAART. METHODS: We evaluated a prospective clinical cohort of adult women initiating HAART in Johannesburg, South Africa between 1 April 2004 and 31 March 2011, and followed up until an event, transfer, drop-out, or administrative end of follow-up on 30 September 2011. Women over age 45 and women who were pregnant at HAART initiation were excluded from the study. Main exposure was having experienced pregnancy after HAART initiation; main outcome was death and (separately) death or new AIDS event. We calculated adjusted hazard ratios (HRs) and 95% confidence limits (CL) using marginal structural Cox proportional hazards models. RESULTS: The study included 7,534 women, and 20,813 person-years of follow-up; 918 women had at least one recognized pregnancy during follow-up. For death alone, the weighted (adjusted) HR was 0.84 (95% CL 0.44, 1.60). Sensitivity analyses confirmed main results, and results were similar for analysis of death or new AIDS event. Incident pregnancy was associated with a substantially reduced hazard of drop-out (HR = 0.62, 95% CL 0.51, 0.75). CONCLUSIONS: Recognized incident pregnancy after HAART initiation was not associated with increases in hazard of clinical events, but was associated with a decreased hazard of drop-out. High rates of pregnancy after initiation of HAART may point to a need to better integrate family planning services into clinical care for HIV-infected women.

Treatment outcomes of HIV-infected adolescents attending public-sector HIV clinics across Gauteng and Mpumalanga, South Africa.

There is little evidence comparing treatment outcomes between adolescents and other age groups, particularly in resource-limited settings. A retrospective analysis of data from seven HIV clinics across urban Gauteng (n=5) and rural Mpumalanga (n=2), South Africa was conducted. The analysis compared HIV-positive antiretroviral treatment (ART)-naive young adolescents (10-14 years), older adolescents (15-19), and young adults (20-24 years) to adults (≥25 years) initiated onto standard first-line ART between April 2004 and August 2010. Log-binomial regression was used to estimate relative risk (RR) of failure to suppress viral load (≥400 copies/ml) or failure to achieve an adequate CD4 response at 6 or 12 months. The effect of age group on virological failure, mortality, and loss to follow-up (LTFU; ≥90 days since scheduled visit date) was estimated using Cox proportional hazards models. Of 42,427 patients initiating ART, 310 (0.7%) were young adolescents, 342 (0.8%) were older adolescents, and 1599 (3.8%) were young adults. Adolescents were similar to adults in terms of proportion male, baseline CD4 count, hemoglobin, and TB. Compared to adults, both older adolescents (6 months RR 1.75 95% CI 1.25-2.47) and young adults (6 months RR 1.33 95% CI 1.10-1.60 and 12 months RR 1.64 95% CI 1.23-2.19) were more likely to have an unsuppressed viral load and were more likely to fail virologically (HR 2.90 95% CI 1.74-4.86; HR 2.94 95% CI 1.63-5.31). Among those that died or were LTFU, the median time from ART initiation until death or LTFU was 4.7 months (IQR 1.5-13.2) and 10.9 months (IQR 5.0-22.7), respectively. There was no difference in risk of mortality by age category, compared to adults. Young adolescents were less likely to be LTFU at any time period after ART initiation (HR 0.43 95% CI 0.26-0.69) whereas older adolescents and young adults were more likely to be LTFU after ART initiation (HR 1.78 95% CI 1.34-2.36; HR 1.63 95% CI 1.41-1.89) compared to adults. HIV-infected adolescents and young adults between 15 and 24 years have poorer ART treatment outcomes in terms of virological response, LTFU, and virological failure than adults receiving ART. Interventions are needed to help improve outcomes and retention in care in this unique population.

Tenofovir use and pregnancy among women initiating HAART.

OBJECTIVE: Recent studies have raised concerns about a change in rates of pregnancy among HIV-negative women exposed to tenofovir. Here, our objective was to determine among HIV-positive women whether use of tenofovir at HAART initiation or thereafter is associated with subsequent changes in incidence of pregnancy. DESIGN: Analysis of prospectively collected clinical data. METHODS: We used Cox proportional hazards models and logistic regression to estimate hazard ratios and odds ratios for the association of baseline tenofovir use and first incident pregnancy. We used marginal structural Cox models to estimate hazard ratios for the association of current tenofovir use and time to first incident pregnancy. RESULTS: We studied 7275 women, of whom 1199 were initiated on tenofovir-based HAART regimens, and who experienced a total of 894 pregnancies in 17,200 person-years of follow-up. Analyses showed slight reductions in hazards of pregnancy among women who used tenofovir but without sufficient precision to draw strong conclusions. Sensitivity analyses confirmed main results. CONCLUSIONS: Tenofovir may be associated with a lower hazard or rate of pregnancy in women receiving HAART. However, conclusions are limited by low precision, the observational nature of the data, and possible uncontrolled confounding by temporal trends in contraception use and other factors.

Prevalent pregnancy, biological sex, and virologic response to antiretroviral therapy.

OBJECTIVE: Pregnancy is a common indication for initiation of highly active antiretroviral therapy (HAART) in sub-Saharan Africa. Our objective was to evaluate how pregnancy at treatment initiation predicts virologic response to HAART. METHODS: We evaluated an open cohort of 9173 patients who initiated HAART between April 2004 and September 2009 in the Themba Lethu Clinic in Johannesburg, South Africa. Risk ratios were estimated using log-binomial regression; hazard ratios were estimated using Cox proportional hazards models; time ratios were estimated using accelerated failure time models. We controlled for calendar date, age, ethnicity, employment status, history of smoking, tuberculosis, WHO stage, weight, body mass index, hemoglobin, CD4 count and CD4 percent, and whether clinical care was free. Extensive sensitivity and secondary analyses were performed. RESULTS: During follow-up, 822 nonpregnant women and 70 pregnant women experienced virologic failure. In adjusted analyses, pregnancy at baseline was associated with reduced risk of virologic failure by 6 months [risk ratio 0.66, 95% confidence limits (CL): 0.35 to 1.22] and with reduced hazard of virologic failure over follow-up (hazard ratio: 0.69, 95% CL: 0.50 to 0.95). The adjusted time ratio for failure was 1.44 (95% CL: 1.13 to 1.84), indicating 44% longer time to event among women pregnant at baseline. Sensitivity analyses generally confirmed main findings. CONCLUSIONS: Pregnancy at HAART initiation is not associated with increased risk of virologic failure at 6 months or during longer follow-up.

Prevalence of peripheral neuropathy in antiretroviral therapy naïve HIV-positive patients and the impact on treatment outcomes--a retrospective study from a large urban cohort in Johannesburg, South Africa.

Peripheral neuropathy (PN) is associated with advanced HIV disease and may be a complication of antiretroviral therapy (ART) or anti-tuberculosis (TB) drugs, specifically isoniazid (INH). The effect of non-ART-drug-related PN on treatment outcomes is yet to be determined. We analysed prospectively collected cohort data for HIV-infected ART-naive adults initiating ART at the Themba Lethu Clinic, Johannesburg, South Africa from June 2004 to June 2009. Patients who presented with signs and symptoms of numbness or dysesthesia prior to initiation of ART were defined as having PN. Cox proportional hazard models were used to estimate the effect of PN alone (HIV-related PN) or PN with a history of INH use (TB-related PN) on mortality, lost to follow-up (LTFU), persistent and recurrent PN by 12 months of follow-up. Of the 9,399 patients initiating ART, 3.9 % had HIV-related PN while a further 1.8 % had TB-related PN. Patients with PN did not have a significantly higher risk of mortality compared to those without PN (hazard ratio (HR) 1.17 95 % CI 0.92-1.49). Patients with TB-related PN were less likely to be LTFU by 12 months (HR 0.65 95 % CI 0.44-0.97) compared to those without PN. Patients with HIV-related PN were at increased risk of persistent PN at 3 months post-ART initiation. Patients with HIV-related PN had a similar risk of recurrent PN compared to those with TB-related PN (HR 1.28 95 % CI 0.72-2.27). We demonstrate that patients with PN at initiation of ART present with advanced HIV disease. Completion of TB treatment may reduce the risk of persistent PN in patients with TB-related PN. Use of HIV drugs, even neurotoxic ones, may overall limit neuropathy.

Prevalence of hepatitis B virus (HBV) co-infection in HBV serologically-negative South African HIV patients and retrospective evaluation of the clinical course of mono- and co-infection.

OBJECTIVES: Hepatitis B virus (HBV) infection with undetectable hepatitis B surface antigen (HBsAg) has been reported in HIV patients, but the clinical significance is unknown. This study presents the prevalence of HBV DNA in HIV-positive patients negative for all HBV serological markers and a retrospective evaluation of the clinical course of mono- and co-infection. METHODS: Of 502 HIV-positive patients, 222 tested negative for HBsAg, antibody to hepatitis B surface antigen (anti-HBs), and antibody to hepatitis B core antigen (anti-HBc). An in-house real-time PCR targeting the HBV S-region was used to quantify HBV DNA. HBV isolates were genotyped. Baseline demographic and clinical characteristics of HBV DNA-positive and HBV DNA-negative patients were described. Treatment outcomes of patients at 6, 12, and 24 months after initiation of antiretroviral therapy (ART) were summarized. RESULTS: HBV DNA was detected in 5.4% (12/222) of serologically negative patients. Mean HBV viral load was 5359.2 IU/ml (standard deviation (SD) ±12 768.27). Eleven HBV isolates belonged to genotype A and one to genotype C. There were no significant differences in baseline characteristics or clinical course between the HBV DNA-positive and HBV DNA-negative groups. CONCLUSIONS: We found 5.4% of the HBV serologically-negative HIV-positive patients had low levels of HBV DNA. There were no significant differences in clinical outcome between the mono- and co-infected groups.

A multinational study of neurological performance in antiretroviral therapy-naïve HIV-1-infected persons in diverse resource-constrained settings.

Little is known about how the prevalence and incidence of neurological disease in HIV-infected patients in resource-limited settings. We present an analysis of neurological and neurocognitive function in antiretroviral naïve individuals in multinational resource-limited settings. This prospective multinational cohort study, a substudy of a large international randomized antiretroviral treatment trial, was conducted in seven low- and middle-income countries in sub-Saharan Africa, South America, and Asia. Subjects were HIV-infected and met regional criteria to initiate antiretroviral therapy. Standardized neurological examination and a brief motor-based neuropsychological examination were administered. A total of 860 subjects were studied. Overall 249 (29%) had one or more abnormalities on neurological examinations, but there was a low prevalence of HIV-associated dementia (HAD) and minor neurocognitive disorder (MND). Twenty percent of subjects had evidence of peripheral neuropathy. There were significant differences across countries (p < 0.001) in neuropsychological test performance. In this first multinational study of neurological function in antiretroviral naïve individuals in resource-limited settings, there was a substantial prevalence of peripheral neuropathy and low prevalence of dementia and other CNS diseases. There was significant variation in neurocognitive test performance and neurological examination findings across countries. These may reflect cultural differences, differences in HIV-related and unrelated diseases, and variations in test administration across sites. Longitudinal follow-up after antiretroviral treatment initiation may help to define more broadly the role of HIV in these differences as well as the impact of treatment on performance.

HIV-HBV coinfection among South African patients receiving antiretroviral therapy.

There are approximately 33 million individuals with HIV infection worldwide. The majority of infections are in southern Africa where hepatitis B is also known to be endemic. As access to life-saving antiretroviral therapy (ART) increases, the possibility for hepatitis B treatment resistance increases because most ART regimens contain lamivudine. Patients coinfected with HBV are therefore receiving monotherapy for HBV infection, leading to possible HBV-resistant mutants and the concurrent public health effect thereof. Additional information is needed on the prevalence of HIV-HBV coinfection and treatment response to ART. We present a summary of the information available from South Africa to date.