Efficacy, safety, and tolerability of dolutegravir-based ART regimen in Durban, South Africa: a cohort study.

BACKGROUND: Dolutegravir is an integrase strand transfer inhibitor that has been recommended for use in first-line antiretroviral regimens by the World Health Organisation and is currently being rolled out globally. There has been safety concerns with dolutegravir which has caused concern about its use in the general population. Dolutegravir first-line regimens have been used in South Africa since early 2020. Therefore, the aim of the present study was to assess the efficacy, safety, and tolerability of first-line dolutegravir-based antiretrovirals amongst adults living with HIV in Durban, South Africa. METHODS: This was a mixed-methods study, which comprised a cross-sectional survey and longitudinal retrospective follow-up of medical records. The study was conducted between October 2020 and January 2022. Data were described using descriptive and summary statistics. Bivariate logistic regression was applied to socio-demographic and clinical variables and crude odds ratios with a 95% confidence interval was calculated. Pearson chi-square tests, paired sample T-tests, and cross-tabulations were performed on selected variables. RESULTS: A total of 461 participants were enrolled in the study. There was a significant change in immunological outcomes (p < 0.001) after dolutegravir initiation. Furthermore, an assessment of laboratory parameters showed that there was a significant decrease in cholesterol (p < 0.001) and increase in creatinine (p < 0.001) levels. Increased weight was shown by 60.7% of the participants but was not associated with age, gender, CD4 counts, and previous antiretroviral usage. The study found that 43.6% of the participants experienced at least one side-effect. A total of 21.6% and 23.2% of the participants experienced neuropsychiatric and central nervous system side-effects, respectively. In the bivariate analyses, only gender was shown to be associated with side-effects, and only 1.7% of the participants discontinued the study due to side-effects. CONCLUSION: Our results suggest that dolutegravir is effective, safe, and well tolerated in the study population.

Perceptions, practices and barriers to reporting of adverse drug reactions among HIV infected patients and their doctors in 3 public sector hospitals of the Ethekwini Metropolitan, Kwa-Zulu Natal: a cross sectional and retrospective analysis.

BACKGROUND: Adverse drug reactions (ADRs) remain a global public health concern. Pharmacovigilance practises are essential in ensuring patients safety and post drug marketing surveillance. This study aimed to describe practices, perceptions and barriers towards ADR reporting practices amongst People Living with HIV/AIDS (PLWHA), who are on Highly Active Anti-Retroviral Therapy (HAART) and their doctors. METHODS: The study took place at 3 public sector hospitals. The first phase of the study was a quantitative cross-sectional study using a closed ended questionnaire that was given to PLWHA. Phase two was a retrospective analysis of these patients' medical files, whilst phase 3 included a descriptive statistics to determine the frequencies and percentages for variables such as ADR reporting practices by doctors. RESULTS: Spontaneous reporting, was evident with 202 patients (48%) indicating that they reported experiencing ADRs to their doctors. Ten doctors (77%) indicated that they received PV training. Eight (62%) doctors indicated that the completed ADR reporting forms were submitted to the pharmacy manager in the hospital for forwarding to the regulatory authority, with 2 (15%) indicating that they submitted directly to the South African Health Products Regulatory Authority. Four (31%) doctors stated that the system of reporting ADRs is ineffective with the majority of the doctors 12 (92%) responding that the reporting of ADRs is very important/critical. A barrier cited by 4 patients (0.9%) for non-reporting of their ADRs was transport cost. Whilst doctors' barriers included reporting being time consuming (31%), and a lack of availability of reporting forms (31%). CONCLUSION: Patients and doctors are reporting ADRs but more education and easier reporting process should be available to strengthen the knowledge and reporting of ADRs. Doctors agree that it is critical to report ADRs. Electronic reporting should be encouraged to lessen the time it takes to report ADRs.

Prevalence and predictors of diabetes mellitus among persons living with HIV: a retrospective cohort study conducted in 4 public healthcare facilities in KwaZulu-Natal.

BACKGROUND: Diabetes mellitus is a chronic non-infectious medical condition which is evident by raised levels of glucose in the blood, because the body cannot produce any or enough of the hormone insulin or use insulin effectively. Diabetes, if not well managed leads to complications such as neuropathy, retinopathy, nephropathy which can be fatal. Some of the factors that predisposes to diabetes include older age, higher body mass index, heredity and hypertension. With the availability of HAART for managing HIV/AIDS infection, life span of persons living with HIV (PLWHIV) has increased significantly. With increased longevity, the aging population of PLWHIV also face chronic diseases such as diabetes in addition to HIV. The burden of both HIV and diabetes is high in South Africa, particularly in KwaZulu-Natal. Nevertheless, the prevalence of diabetes among PLWHIV in KwaZulu-Natal and its predictors is not well understood. Therefore, this study was conducted to determine the prevalence, predictors of diabetes and the outcome of managing diabetes among PLWHIV. METHODS: This retrospective cohort study was conducted in four public health care facilities in KwaZulu-Natal with a total sample size of 1203 after ethical approval and informed consent were obtained. A pretested questionnaire and hospital patient charts were used to collect data. SPSS version 26 was used to analyze the data using descriptive statistics and logistic regression. RESULTS: The prevalence of diabetes among PLWHIV was 9%. Just over 47% of those who had diabetes, had uncontrolled blood sugar, with a mean fasting blood sugar (FBS) of 11.7 mmol/L. The predictors of diabetes among PLWHIV were male gender and older age. Male PLWHIV had 65% less chances of having diabetes and those who were between the ages of 18 and 48 years were 88% less probable to have diabetes compared to those who were older than 48 years. CONCLUSION: Public sector health care facilities in KwaZulu-Natal need to do much more to manage diabetes in PLWHIV in order to prevent diabetic complications and possible negative impact on the outcome of HIV management.

"Knowledge and practices of HIV infected patients regarding medicine disposal among patients attending public ARV clinics in KwaZulu Natal, South Africa".

BACKGROUND: Recent analysis of drinking water in South Africa found the presence of ARVs, other pharmaceutical and personal care products. The environmental and human health risk that this presents is daunting. The increased use of ARVs with poor disposal practices could be the reason for these substances being present in drinking water. Therefore, this study aimed to determine the knowledge and practices of HIV infected patients, regarding medicine disposal. METHOD: A descriptive, cross sectional, quantitative study that utilised a structured, self-administered, questionnaire was undertaken at 3 different public ARV clinics in the eThekwini Metro of KwaZulu Natal, SA. The variables included questions on demographics, knowledge and practices of medicine disposal of ARV and other medications. Data was captured using excel spreadsheets and analysed using SPSS version 25. Chi square tests were used to compare factors between correct and incorrect knowledge and practice groups. RESULTS: Four hundred and eighty four participants agreed to participate in this study, of which the majority (71.1%) were females. Over 87% of the participants knew that improper disposal of medicines were harmful to the environment with only 28.3% knowing that there were laws governing the way medicines should be disposed. Majority of participants that had unused and expired ARVs at home disposed of these medicines. The most common route of medicine disposal for ARVs was by throwing these medicines into the bin (56.4%). Only 24.2% of participants were informed by healthcare professionals about the proper method of medicine disposal. Participants who had secondary and tertiary level of education (p = 0.043) and the ability to speak English (p = 0.001) had appropriate knowledge on medicine disposal. CONCLUSION: This study identified that poor medicine disposal practices and lack of adequate information about the proper methods of medicine disposal were evident among the participant population. There is a need for patient education and healthcare professional intervention to ensure patients are aware of standard proper medicine disposal practices.

Do challenges still exist amongst HIV/AIDS patients in managing their condition? A cross-sectional study of 297 participants in the Ethekwini Metro of KwaZulu-Natal, South Africa.

Background: South Africa has the largest HIV/AIDS epidemic globally and the largest anti-retroviral treatment (ART) programme in the world, yet HIV incidence is still chronically high in South Africa, especially in KwaZulu-Natal province (KZN). In light of this, a study was conducted to investigate the extent of challenges making the management of HIV/AIDS difficult in people living with HIV (PLWH) in KZN, South Africa. Methods: A cross-sectional study was carried out with 297 study participants living with HIV and receiving ART from three selected clinics in the Ethekwini Metro of KZN. A self-administered questionnaire assessed the challenges experienced by PLWH, their knowledge of their condition and their management thereof. One-way frequency tables were used to descriptively assess participant responses. Associations between certain demographic characteristics and responses to HIV treatment management challenges were assessed using chi-square tests, with statistical significance set at p < 0.05. Results: One-fifth of the participants (n = 60; 20.1%) were within the 18-23 age group, with over 53% (n = 158) having secondary level education. Some of the challenges cited included: difficulty in obtaining medication, mainly due to cost; side effects resulting in non-adherence; shame for taking medication in public (younger patients were more likely to feel ashamed for taking their medication in public [χ2 = 20.3, p = 0.009]); and non-disclosure of HIV-positive status to partners. We found a significant association between education and financial status and management of their condition [χ2 = 11.2, p = 0.011]. Conclusion: These findings that challenges still exist have implications for more robust programmes on education and counselling to address such challenges.

Traditional, complementary and alternative medicine use by HIV patients a decade after public sector antiretroviral therapy roll out in South Africa: a cross sectional study.

BACKGROUND: The roll out of antiretroviral therapy in the South African public health sector in 2004 was preceded by the politicisation of HIV-infection which was used to promote traditional medicine for the management of HIV/AIDS. One decade has passed since; however, questions remain on the extent of the use of traditional, complementary and alternative medicine (TCAM) by HIV-infected patients. This study therefore aimed at investigating the prevalence of the use of African traditional medicine (ATM), complementary and alternative medicines (CAM) by adult patients in the eThekwini and UThukela Health Districts, South Africa. METHODS: A cross- sectional study was carried out at 8 public health sector antiretroviral clinics using interviewer-administered semi-structured questionnaires. These were completed from April to October 2014 by adult patients who had been on antiretroviral therapy (ART) for at least three months. Use of TCAM by patients was analysed by descriptive statistics using frequency and percentages with standard error. Where the associated relative error was equal or greater to 0.50, the percentage was rejected as unstable. A p-value <0.05 was estimated as statistically significant. RESULTS: The majority of the 1748 participants were Black Africans (1685/1748, 96.40 %, SE: 0.00045), followed by Coloured (39/1748, 2.23 %, SE: 0.02364), Indian (17/1748, 0.97 %, SE: 0.02377), and Whites (4/1748, 0.23 %, SE: 0.02324), p < 0.05. The prevalence of ATM use varied prior to (382/1748, 21.85 %) and after ART initiation (142/1748, 8.12 %), p <0.05, specifically by Black African females both before (14.41 %) and after uptake (5.49 %), p < 0.05. Overall, 35 Black Africans, one Coloured and one Indian (37/1748, 2.12 %) reported visiting CAM practitioners for their HIV condition and related symptoms post ART. CONCLUSION: Despite a progressive implementation of a successful antiretroviral programme over the first decade of free antiretroviral therapy in the South African public health sector, the use of TCAM is still prevalent amongst a small percentage of HIV infected patients attending public healthcare sector antiretroviral clinics. Further research is needed to explore reasons for use and health benefits or risks experienced by the minority that uses both conventional antiretroviral therapy with TCAM.

Impact of CYP polymorphisms, ethnicity and sex differences in metabolism on dosing strategies: the case of efavirenz.

PURPOSE: Differences in drug metabolism due to cytochrome P450 (CYP) polymorphisms may be significant enough to warrant different dosing strategies in carriers of specific cytochrome P450 (CYP) polymorphisms, especially for drugs with a narrow therapeutic index. The impact of such polymorphisms on drug plasma concentrations and the resulting dosing strategies are presented in this review, using the example of efavirenz (EFV). METHODS: A structured literature search was performed to extract information pertaining to EFV metabolism and the influence of polymorphisms of CYP2B6, ethnicity, sex and drug interactions on plasma concentrations of EFV. The corresponding dosing strategies developed for carriers of specific CYP2B6 genotypes were also reviewed. RESULTS: The polymorphic CYP2B6 enzyme, which is the major enzyme in the EFV metabolic pathway, is a key determinant for the significant inter-individual differences seen in EFV pharmacokinetics and pharmacodynamics (PKPD). Ethnic differences and the associated prevalence of CYP2B6 polymorphisms result in significant differences in the PKPD associated with a standard 600 mg per day dose of EFV, warranting dosage reduction in carriers of specific CYP2B6 polymorphisms. Drug interactions and auto-induction also influence EFV PKPD significantly. CONCLUSION: Using EFV as an example of a drug with a narrow therapeutic index and a high inter-patient variability in plasma concentrations corresponding to a standard dose of the drug, this review demonstrates how genotyping of the primary metabolising enzyme can be useful for appropriate dosage adjustments in individuals. However, other variables such as drug interactions and auto-induction may necessitate plasma concentration measurements as well, prior to personalising the dose.

Comorbidity and concomitant medication use in an integrase strand transfer inhibitor naïve cohort on first-line dolutegravir-based antiretroviral therapy.

Introduction: people living with HIV/AIDS using antiretroviral therapy sometimes present with comorbid conditions or co-infections. This could lead to an increased risk of drug interactions due to the concomitant use of drugs. The aim of the study was to explore the overall impact of dolutegravir on such comorbidities and the effect of concomitant medication on the safety and efficacy of dolutegravir. Methods: data was collected using a survey questionnaire and a retrospective review of medical records of a prospective study sample. Medical records were retrospectively reviewed for up to 12 months after dolutegravir initiation. Concomitantly used drugs and supplements that were identified to have a potential interaction with dolutegravir were further characterized. Descriptive and summary statistics were used to describe the data, t-tests were performed on blood glucose levels and cross-tabulations were done on some variables. Results: of the 461 participants enrolled into the study, 172 (37.3%) and 54 (11.7%) experienced comorbidity and coinfection respectively. More than 50% of the participants used concomitant medicines. Metformin use led to increased blood glucose levels (p=0.009); participants on rifampicin (n=8) received an additional daily dose of dolutegravir. Virological outcomes in participants on sodium valproate (n=2) and St John´s wort (n=1) did not show safety concerns, whilst 3 dolutegravir discontinuations were observed in participants using supplements and antacids containing divalent cations. Conclusion: even though dolutegravir was safe and effective in the study population, with possible drug interactions leading to treatment discontinuations in only 3(0.7%) participants, further investigation into dolutegravir-induced hyperglycemia needs investigation.

Reporting and recording of adverse drug reactions of highly active antiretroviral therapy by HIV infected patients and healthcare professionals respectively in the Ethekwini Metropolitan of Kwa-Zulu Natal, South Africa: a cross-sectional and retrospective comparative study.

Introduction: even though Highly Active Antiretroviral Therapy (HAART) is effective in managing Human Immuno-deficiency Virus (HIV) infection, it is not without its adverse drug effects (ADE) and or adverse drug reactions (ADRs). The study of ADRs associated with HAART in hospitals and clinics is crucial in gauging the burden of the severity of morbidity and mortality in such facilities, hence the reporting of such ADRs is important. Methods: the study was divided into 2 phases: the 1st phase entailed collecting data from HIV infected patients using a questionnaire on ADR experienced, whilst the 2nd phase was a retrospective analysis of respective patients´ medical files to record if an ADR was experienced. Three antiretroviral clinics linked to public sector facilities in EThekwini Metro, Kwa-Zulu Natal were the study sites. Results: seventy-two percent of patients reported at least one ADR after HAART initiation. Skin rash (11%) was the most commonly stated ADR by patients, whilst anemia (29%) and cardiovascular disease (23%) were the most commonly recorded ADRs on the patients´ medical files. Of those patients who reported ADRs, 57% were on the first line regimen consisting of Tenofovir, Emtricitabine and Efavirenz. Thirty-six patients reported that they were admitted to hospitals due to ADRs, however none resulted in death. These ADRs were experienced by patients on different regimens, with 10 admissions from the same regimen. Conclusion: adverse drug reactions were experienced by South African patients, however the reporting of ADRs by patients were inconsistent with what was recorded on their medical files.

Progress in the Consideration of Possible Sex Differences in Drug Interaction Studies.

BACKGROUND: Anecdotal evidence suggests that there may be sex differences in Drug-drug Interactions (DDI) involving specific drugs. Regulators have provided general guidance for the inclusion of females in clinical studies. Some clinical studies have reported sex differences in the Pharmacokinetics (PK) of CYP3A4 substrates, suggesting that DDI involving CYP3A4 substrates could potentially show sex differences. OBJECTIVE: The aim of this review was to investigate whether recent prospective DDI studies have included both sexes and whether there was evidence for the presence or absence of sex differences with the DDIs. METHODS: The relevant details from 156 drug interaction studies within 124 papers were extracted and evaluated. RESULTS: Only eight studies (five papers) compared the outcome of the DDI between males and females. The majority of the studies had only male volunteers. Five studies had females only while 60 had males only, with 7.7% of the studies having an equal proportion of both sexes. Surprisingly, four studies did not specify the sex of the subjects. Based on the limited number of studies comparing males and females, no specific trends or conclusions were evident. Sex differences in the interaction were reported between ketoconazole and midazolam as well as clarithromycin and midazolam. However, no sex difference was observed with the interaction between clarithromycin and triazolam or erythromycin and triazolam. No sex-related PK differences were observed with the interaction between ketoconazole and domperidone, although sex-related differences in QT prolongation were observed. CONCLUSION: This review has shown that only limited progress had been made with the inclusion of both sexes in DDI studies.

Pharmacy students' opinions and experiences working on board the Transnet-Phelophepa Health Care Trains.

OBJECTIVES: The Transnet-Phelophepa Health Care Trains provide primary healthcare services to patients in under-resourced rural communities across South Africa. Selected final-year pharmacy students work on the trains for 1 week. The aim of the study was to determine the experiences and document the work-based activities of pharmacy students engaged in. METHODS: A hyperlink to an online questionnaire was sent to 106 pharmacy students from five Pharmacy Schools (70.75% response rate). Both closed- and open-ended questions were included. Data were captured in Excel. KEY FINDINGS: Respondents expressed that their motivation to volunteer to work on the train was threefold: they wanted to help the community, experience this unparalleled work environment, as well as having heard positive responses from previous volunteers. Students were exposed to a variety of pharmacy-related activities; however, the majority of their time was spent dispensing. Although less than half (n = 33) found it difficult to communicate with patients, almost all responded that the translator helped them communicate with patients. A few saw this as an opportunity to learn a new language. The pharmacy staff was described as approachable, knowledgeable and willing to teach. Most respondents agreed that they were able to apply their knowledge and skills whilst working on the train (mean 4.52 ± 0.93; n = 75). CONCLUSIONS: Pharmacy students felt valued by the community and found it to be a rewarding experience while reporting to apply knowledge and information, improve their communication skills and work as part of a team.

Brain penetration of ketamine: Intranasal delivery VS parenteral routes of administraion.

Ketamine is approved by the FDA to be used as an anesthetic however, recent reports have exhibited its success in the treatment of major depressive disorder (MDD). Studies have suggested that a sub-anesthetic dose produces rapid antidepressant activity providing significant symptomatic relief particularly in patients with a history of treatment resistant depression (TRD). Many reports have been published on the intranasal (IN) efficacy of ketamine in the treatment of depression, however studies that have investigated the effects of the route of administration on drug delivery to the brain appear to be absent in literature. Therefore, in this study, a single dose (15 mg/kg body weight) was administered via different routes of administration [oral (PO), intranasal (IN) and intraperitoneal (IP)] to healthy male Sprague-Dawley rats in order to determine the brain tissue pharmacokinetics of ketamine. A novel validated liquid chromatography-mass spectrometry (LC-MS) method was developed using a fused core column for the determination of ketamine in plasma and brain homogenates. While IP administration resulted in favorable concentrations in the brain and plasma; IN administration, which is supposed to favour drug delivery to the brain, exhibited moderately low drug levels post administration. PO administration produced significantly lower levels due to extensive first-pass metabolism in the liver and intestines. These results have implications for future studies exploring the use of ketamine for the treatment of MDD in order to optimize treatment regimens and suggest that parenteral administration of ketamine should be used in the treatment of depression.

Exploring the use of novel drug delivery systems for antiretroviral drugs.

Novel drug delivery systems present an opportunity for formulation scientists to overcome the many challenges associated with antiretroviral (ARV) drug therapy, thereby improving the management of patients with HIV/AIDS. This paper provides a comprehensive review of the various ARV delivery systems that have been developed for achieving sustained drug release kinetics, specifically targeting drugs to the macrophages, brain and gastric mucosa, and for addressing formulation difficulties such as poor solubility, stability and drug entrapment. Studies on the potential of systems for alternative routes of ARV drug administration, i.e., transdermal, buccal and rectal, are also highlighted. The physico-chemical properties and the in vitro/in vivo performances of various systems such as sustained release tablets, ceramic implants, nanoparticles, nanocontainers, liposomes, emulsomes, aspasomes, microemulsions, nanopowders and Pheroid(TM) are summarised. Further studies that remain to be undertaken for formulation optimisation are also identified. This review highlights the significant potential that novel drug delivery systems have for the future effective treatment of HIV/AIDS patients on ARV drug therapy.

Confirmation of factors that influence antiretroviral regimen change and the subsequent patient outcomes at a Regional Hospital in rural KwaZulu-Natal.

BACKGROUND: Treatment failure (TF) and adverse drug reactions (ADRs) are the main indications for antiretroviral therapy (ART) regimen change. Identification of factors influencing regimen change and subsequent health outcomes of patients after regimen change is essential in providing a sustainable and effective antiretroviral roll-out campaign. AIM: To confirm the factors that influence antiretroviral regimen change and to evaluate patient outcomes post regimen change. METHODS: A retrospective chart analysis of 269 HIV-infected non-pregnant patients (age >18 years), who underwent an antiretroviral (ARV) regimen change and were followed up for approximately one year since initiation, was undertaken at a Provincial Hospital ARV Clinic in KwaZulu-Natal, from January 2008 to December 2012. RESULTS: Of the 269 patients, there were 200 females (75%). Most patients were between the ages 30 and 44 (57.6%). Only five patients had coexisting tuberculosis (TB) infection (2%). The most common first-line ART regimen to be changed was stavudine (D4T)/lamivudine(3TC)/ efavirenz(EFV) n = 111(41%). The most common regimen patients were changed to was tenofovir (TDF)/3TC/EFV n = 89(33%). Stavudine was the most commonly substituted drug (35.5%). Lipodystrophy was the most common ADR (56.8%). ADR was the indication for ART regimen change in 175 patients (65%), whilst TF accounted for ART regimen change in 94 patients (35%). Immunological success (CD4 counts) was shown after regimen change (374.21 ± 243.16 vs. 456.09 ± 250.07, CI: 0.95, p < 0.001). Undetectable viral loads were measured in 172/205 (83.9%) patients post regimen change. CONCLUSION: ADRs were the main cause for antiretroviral regimen change. Stavudine was the most substituted drug with lipodystrophy being the most common side effect. Coexisting TB infection did not influence regimen change. Immunological and virological success was shown after regimen modification.