Cost-effectiveness analysis of alternative statin prescribing strategies for the secondary prevention of cardiovascular disease at a South African public sector tertiary hospital

Strokes and ischaemic heart disease are among the top ten causes of death in South Africa. Given that burden of disease, it is important to establish whether interventions aimed at preventing cardiovascular disease are not only effective, but cost effective too. Cost-effectiveness analyses compare interventions in terms of both their costs and consequences and are a useful tool for policymakers. Statins reduce the risk of cardiovascular events such as myocardial infarctions and strokes, by lowering low density lipoprotein cholesterol (LDL-C) concentrations. Several studies, mostly conducted in Europe or North America, have demonstrated that statins are cost effective, particularly when used to reduce the risk of further cardiovascular events in patients who already have cardiovascular disease (secondary prevention). Despite their widespread use, there are no published cost-effectiveness analyses of statins for the secondary prevention of cardiovascular disease in South Africa. There are also only limited local efficacy data from clinical trials and no costing data of cardiovascular events from a public healthcare sector perspective. There is some debate regarding the optimal statin dose. Some guidelines recommend increasing statin doses until target LDL-C concentrations are achieved, while others recommend prescribing statins at a fixed high dose without monitoring LDL-C. Monitoring LDL-C is relatively expensive compared to the cost of statins, but there is limited evidence that it might improve adherence. I compared the costs (from a provider perspective) and outcomes (life years), of increasing statin doses based on regular measurement of LDL-C concentrations, to achieve a target LDL-C concentration of 1 year after any cardiovascular event, and dead. I estimated transition probabilities using published literature. I estimated the costs of hospitalisation for myocardial infarctions, strokes, unstable angina pectoris and coronary revascularisation procedures using health services utilisation and expenditure data from a sample of patients at a public sector hospital. I discounted costs and outcomes at 3% per year; and explored alternative scenarios and timelines in sensitivity analyses. Atorvastatin 80 mg without LDL-C monitoring, was both the cheapest and most effective option over a five-year period. It remained the most effective option over a lifetime period, but with an incremental cost-effectiveness ratio (ICER) of $146.94 per life year gained relative to the status quo. Treat to target was as effective as atorvastatin 80 mg if I assumed adherence rates of 80$54 930.96. Treat to target would dominate atorvastin 80 mg only if the frequency of LDL-C monitoring was reduced from 3-monthly to 6-monthly until targets were reached, and the cost of LDL-C monitoring decreased by $9.25 (84%). Fixed-dose statin treatment without cholesterol monitoring is the most cost-effective option for providing statins for the secondary prevention of cardiovascular disease. The costs of regular LDL-C monitoring currently make a treat to target strategy unaffordable in our setting. These results might be used to help guide policy regarding secondary prevention of cardiovascular disease in South Africa

Systematic review of antiretroviral-associated lipodystrophy: lipoatrophy, but not central fat gain, is an antiretroviral adverse drug reaction

BACKGROUND: Lipoatrophy and/or central fat gain are observed frequently in patients on antiretroviral therapy (ART). Both are assumed to be antiretroviral adverse drug reactions. METHODS: We conducted a systematic review to determine whether fat loss or gain was more common in HIV-infected patients on ART than in uninfected controls; was associated with specific antiretrovirals; and would reverse after switching antiretrovirals. RESULTS: Twenty-seven studies met our inclusion criteria. One cohort study reported more lipoatrophy, less subcutaneous fat gain, but no difference in central fat gain in HIV-infected patients on ART than in controls. Randomised controlled trials (RCTs) showed more limb fat loss (or less fat gain) with the following regimens: stavudine (versus other nucleoside reverse transcriptase inhibitors (NRTIs)); efavirenz (versus protease inhibitors (PIs)); and NRTI-containing (versus NRTI-sparing). RCTs showed increased subcutaneous fat after switching to NRTI-sparing regimens or from stavudine/zidovudine to abacavir/tenofovir. There were no significant between-group differences in trunk and/or visceral fat gain in RCTs of various regimens, but results from efavirenz versus PI regimens were inconsistent. There was no significant between-group differences in central fat gain in RCTs switched to NRTI-sparing regimens, or from PI-containing regimens. CONCLUSIONS: There is clear evidence of a causal relationship between NRTIs (especially thymidine analogues) and lipoatrophy, with concomitant PIs possibly having an ameliorating effect or efavirenz causing additive toxicity. By contrast, central fat gain appears to be a consequence of treating HIV infection, because it is not different from controls, is not linked to any antiretroviral class, and doesn't improve on switching

Abacavir safety and effectiveness in young infants with HIV in South African observational cohorts.

BACKGROUND WHO guidelines recommend abacavir in first-line antiretroviral treatment for children and neonates. However, there is no approved dose <3 months of age, and data in neonates are limited. METHODS We included infants who initiated ART aged <3 months, between 2006 and 2019, in nine South African cohorts. In those who received abacavir or zidovudine, we described antiretroviral discontinuation rates; and 6- and 12-month viral suppression (<400 copies/mL). We compared infants aged <28 and ≥28 days, those weighing <3 and ≥3 kg. RESULTS Overall 837/1643 infants (51%) received abacavir and 443 (27%) received zidovudine. Median (interquartile range, IQR) age was 52 days (23-71), CD4 percentage was 27.9 (19.2-38.0), and weight was 4.0 kg (3.0-4.7) at ART initiation. In those with ≥1 month's follow-up, 100/718 (14%) infants discontinued abacavir, at a median of 17.5 months (IQR 6.5-39.5). Abacavir discontinuations did not differ by age or weight category (p = 0.4 and 0.2, respectively); and were less frequent than zidovudine discontinuations (adjusted hazard ratio 0.14, 95% confidence interval 0.10-0.20). Viral suppression at 12 months occurred in 43/79 (54%) and 130/250 (52%) of those who started abacavir aged <28 and ≥28 days, respectively (p = 0.8); 11/19 (58%) and 31/60 (52%) in those who weighed <3 and ≥3 kg, respectively (p = 0.6); and 174/329 (53%) in those on abacavir versus 77/138 (56%) in those on zidovudine (adjusted odds ratio 1.8, 95% confidence interval 1.0-3.2). CONCLUSION Our data suggest that abacavir may be used safely in infants <28 days old or who weigh <3 kg

Serious adverse drug reactions at two children’s hospitals in South Africa

Abstract Background The high HIV prevalence in South Africa may potentially be shaping the local adverse drug reaction (ADR) burden. We aimed to describe the prevalence and characteristics of serious ADRs at admission, and during admission, to two South African children’s hospitals. Methods We reviewed the folders of children admitted over sequential 30-day periods in 2015 to the medical wards and intensive care units of each hospital. We identified potential ADRs using a trigger tool developed for this study. A multidisciplinary team assessed ADR causality, type, seriousness, and preventability through consensus discussion. We used multivariate logistic regression to explore associations with serious ADRs. Results Among 1050 patients (median age 11 months, 56% male, 2.8% HIV-infected) with 1106 admissions we found 40 serious ADRs (3.8 per 100 drug-exposed admissions), including 9/40 (23%) preventable serious ADRs, and 8/40 (20%) fatal or near-fatal serious ADRs. Antibacterials, corticosteroids, psycholeptics, immunosuppressants, and antivirals were the most commonly implicated drug classes. Preterm neonates and children in middle childhood (6 to 11 years) were at increased risk of serious ADRs compared to infants (under 1 year) and term neonates: adjusted odds ratio (aOR) 5.97 (95% confidence interval 1.30 to 27.3) and aOR 3.63 (1.24 to 10.6) respectively. Other risk factors for serious ADRs were HIV infection (aOR 3.87 (1.14 to 13.2) versus HIV-negative) and increasing drug count (aOR 1.08 (1.04 to 1.12) per additional drug). Conclusions Serious ADR prevalence in our survey was similar to the prevalence found elsewhere. In our setting, serious ADRs were associated with HIV-infection and the antiviral drug class was one of the most commonly implicated. Similar to other sub-Saharan African studies, a large proportion of serious ADRs were fatal or near-fatal. Many serious ADRs were preventable

Real-world use and outcomes of dolutegravir-containing antiretroviral therapy in HIV and tuberculosis co-infection: a site survey and cohort study in sub-Saharan Africa.

INTRODUCTION Dolutegravir is being scaled up globally as part of antiretroviral therapy (ART), but for people with HIV and tuberculosis co-infection, its use is complicated by a drug-drug interaction with rifampicin requiring an additional daily dose of dolutegravir. This represents a disadvantage over efavirenz, which does not have a major drug-drug interaction with rifampicin. We sought to describe HIV clinic practices for prescribing concomitant dolutegravir and rifampicin, and characterize virologic outcomes among patients with tuberculosis co-infection receiving dolutegravir or efavirenz. METHODS Within the four sub-Saharan Africa regions of the International epidemiology Databases to Evaluate AIDS consortium, we conducted a site survey (2021) and a cohort study (2015-2021). The cohort study used routine clinical data and included patients newly initiating or already receiving dolutegravir or efavirenz at the time of tuberculosis diagnosis. Patients were followed from tuberculosis diagnosis until viral suppression (<1000 copies/ml), a competing event (switching ART regimen; loss to program/death) or administrative censoring at 12 months. RESULTS In the survey, 86 of 90 (96%) HIV clinics in 18 countries reported prescribing dolutegravir to patients who were receiving rifampicin as part of tuberculosis treatment, with 77 (90%) reporting that they use twice-daily dosing of dolutegravir, of which 74 (96%) reported having 50 mg tablets available to accommodate twice-daily dosing. The cohort study included 3563 patients in 11 countries, with 67% newly or recently initiating ART. Among patients receiving dolutegravir (n = 465), the cumulative incidence of viral suppression was 58.9% (95% confidence interval [CI]: 54.3-63.3%), switching ART regimen was 4.1% (95% CI: 2.6-6.2%) and loss to program/death was 23.4% (95% CI: 19.7-27.4%). Patients receiving dolutegravir had improved viral suppression compared with patients receiving efavirenz who had a tuberculosis diagnosis before site dolutegravir availability (adjusted subdistribution hazard ratio [aSHR]: 1.47, 95% CI: 1.28-1.68) and after site dolutegravir availability (aSHR 1.28, 95% CI: 1.08-1.51). CONCLUSIONS At a programmatic level, dolutegravir was being widely prescribed in sub-Saharan Africa for people with HIV and tuberculosis co-infection with a dose adjustment for the drug-drug interaction with rifampicin. Despite this more complex regimen, our cohort study revealed that dolutegravir did not negatively impact viral suppression

HIV drug resistance in sub-Saharan Africa: public health questions and the potential role of real-world data and mathematical modelling.

The prevalence of pretreatment resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs) is >10% in many low-income countries. As a consequence, several sub-Saharan African countries have implemented, or are considering the introduction of, non-NNRTI-based first-line antiretroviral therapy (ART) for treatment-naïve and treatment-experienced patients. This is occurring at a time when ART programmes are expanding, in response to the World Health Organization guidelines, which recommend ART initiation regardless of CD4 cell count. Both those developments raise important questions regarding their potential impact on HIV drug resistance and the impact of HIV drug resistance on clinical outcomes. Those issues are particularly relevant to sub-Saharan Africa, where standardised ART regimens are used and where viral load monitoring and resistance testing are often not done routinely. It is therefore essential to forecast the impact of the implementation of universal ART, and the introduction of drugs such as dolutegravir to first-line regimens, on HIV drug resistance in order to inform future policies and to help ensure sustainable positive long-term outcomes. We discuss important public health considerations regarding HIV drug resistance, and describe how mathematical modelling, combined with real-world data from the four African Regions of the International epidemiology Databases to Evaluate AIDS consortium, could provide an early warning system for HIV drug resistance in sub-Saharan Africa

Changes in estimated glomerular filtration rate over time in South African HIV-1-infected patients receiving tenofovir: a retrospective cohort study

Introduction: Tenofovir has been associated with decline in kidney function, but in patients with low baseline kidney function, improvements over time have been reported. Additionally, the magnitude and trajectory of estimated glomerular filtration rate (eGFR) changes may differ according to how eGFR is calculated. We described changes in eGFR over time, and the incidence of, and risk factors for, kidney toxicity, in a South African cohort. Methods: We included antiretroviral-naïve patients ≥16 years old who started tenofovir-containing antiretroviral therapy (ART) between 2002 and 2013. We calculated eGFR using the Modification of Diet in Renal Disease (MDRD), Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI), and Cockcroft-Gault equations. We described changes in eGFR from ART initiation using linear mixed effects regression. We described the incidence of eGFR <30 mL/min on treatment, and identified associations with low eGFR using Cox regression. Results: We included 15156 patients with median age of 35.4 years (IQR 29.9–42.0), median CD4 cell count of 168 cells/µL (IQR 83–243), and median eGFR (MDRD) of 98.6 mL/min (IQR 84.4–115.6). Median duration of follow up on tenofovir was 12.9 months (IQR 5.1–23.3). Amongst those with a baseline and subsequent eGFR  available, mean eGFR change from baseline at 12 months was −4.4 mL/min (95% CI −4.9 to −4.0), −2.3 (−2.5 to −2.1), and 0.6 (0.04 to 1.2) in those with baseline eGFR ≥90 mL/min; and 11.9 mL/min (11.0 to 12.7), 14.6 (13.5 to 15.7), and 11.0 (10.3 to 11.7), in those with baseline eGFR <90 mL/min, according to the MDRD, CKD-EPI (n = 11 112), and Cockcroft-Gault (n = 9 283) equations, respectively. Overall, 292 (1.9%) patients developed eGFR <30 mL/min. Significant associations with low eGFR included older age, baseline eGFR <60 mL/min, CD4 count <200 cells/µL, body weight <60 kg, and concomitant protease inhibitor use. Conclusions: Patients on tenofovir with baseline eGFR ≥90 mL/min experienced small but significant declines in eGFR over time when eGFR was estimated using the MDRD or CKD-EPI equations. However, eGFR increased in patients with eGFR <90 mL/min, regardless of which estimating equation was used. Decreases to below 30 mL/min were uncommon. In settings with limited access to laboratory testing, monitoring guidelines should consider focusing on higher risk patients

First-line antiretroviral drug discontinuations in children

<div><p>Introduction</p><p>There are a limited number of paediatric antiretroviral drug options. Characterising the long term safety and durability of different antiretrovirals in children is important to optimise management of HIV infected children and to determine the estimated need for alternative drugs in paediatric regimens. We describe first-line antiretroviral therapy (ART) durability and reasons for discontinuations in children at two South African ART programmes, where lopinavir/ritonavir has been recommended for children <3 years old since 2004, and abacavir replaced stavudine as the preferred nucleoside reverse transcriptase inhibitor in 2010.</p><p>Methods</p><p>We included children (<16 years at ART initiation) who initiated ≥3 antiretrovirals between 2004–2014 with ≥1 follow-up visit on ART. We estimated the incidence of first antiretroviral discontinuation using Kaplan-Meier analysis. We determined the reasons for antiretroviral discontinuations using competing risks analysis. We used Cox regression to identify factors associated with treatment-limiting toxicity.</p><p>Results</p><p>We included 3579 children with median follow-up duration of 41 months (IQR 14–72). At ART initiation, median age was 44 months (IQR 13–89) and median CD4 percent was 15% (IQR 9–21%). At three and five years on ART, 72% and 26% of children respectively remained on their initial regimen. By five years on ART, the most common reasons for discontinuations were toxicity (32%), treatment failure (18%), treatment simplification (5%), drug interactions (3%), and other or unspecified reasons (18%). The incidences of treatment limiting toxicity were 50.6 (95% CI 46.2–55.4), 1.6 (0.5–4.8), 2.0 (1.2–3.3), and 1.3 (0.6–2.8) per 1000 patient years for stavudine, abacavir, efavirenz and lopinavir/ritonavir respectively.</p><p>Conclusions</p><p>While stavudine was associated with a high risk of treatment-limiting toxicity, abacavir, lopinavir/ritonavir and efavirenz were well-tolerated. This supports the World Health Organization recommendation to replace stavudine with abacavir or zidovudine in paediatric first-line ART regimens in order to improve paediatric first-line ART durability.</p></div

Predictors of discontinuations due to toxicity using cox-proportional hazards regression among children followed up until 5 years (n = 3579).

<p>Predictors of discontinuations due to toxicity using cox-proportional hazards regression among children followed up until 5 years (n = 3579).</p

Characteristics of children initiated on antiretroviral treatment (N = 3579).

<p>Characteristics of children initiated on antiretroviral treatment (N = 3579).</p