Nonnucleoside reverse transcriptase inhibitors (NNRTIs) are a class of antiretroviral compounds that bind in an allosteric binding pocket in HIV-1 RT. 

There are two primary factors that contribute to the emergence of resistance to NNRTIs

Rilpivirine (RPV) IS a human immunodeficiency virus type 1 (HIV-1)-specific nonnucleoside reverse transcriptase inhibitor (NNRTI) indicated for use in combination with other antiretroviral agents in adult patients not previously treated with antiretroviral therapy. RPV is primarily metabolised by the cytochrome P-450 (CYP)3A isoenzyme system. Therefore, providers should be cautious when administering drugs that are inhibitors or inducers of this pathway. Coadministration with CYP 3A inhibitors may lead to increased concentrations of RPV, thereby increasing the risk of adverse effects. Coadministration with inducers of CYP3A isoenzymes or drugs that increase gastric pH may lead to decreased concentrations of RPV, thus promoting virological failure or resistance to RPV. 

There are two primary factors that contribute to the emergence of resistance to NNRTIs: (1) HIV-1 RT can tolerate a wide range of sequences in and around the NNRTI binding pocket and (2) there is extensive HIV-1 genetic variation. Although most HIV-infected individuals are initially infected with a single virion, HIV-1 variants arise rapidly due to high viral loads in HIV-1 infected patients, which leads to the infection of large numbers of cells, the rapid turnover of these infected cells, and to errors made during HIV-1 replication. Ultimately, error-prone replication creates the mutations that enable HIV-1 to develop resistance against antiretroviral drugs. Several drug-resistant mutants were selected in HIV-infected individuals by the first generation NNRTIs (NVP, EFV, and DLV).  

The second-generation NNRTIs, ETR and RPV, were designed to be less bulky and more flexible, and are better able to adapt to the changes in the NNRTI binding pocket caused by resistance mutations. This allows these newer NNRTIs to effectively inhibit both WT HIV-1 and several drug resistant variants. Using a single-round infection assay, Smith et al (2016) identified several RPV analogues that potently inhibited a broad panel of NNRTI-resistant mutants. Additionally, they determined that several resistant mutants selected by either RPV or doravirine (DOR) caused only a small increase in susceptibility to the most promising RPV analogues. 

CONCLUSIONS 

The antiviral data suggested that there are RPV analogues that could be candidates for further development as NNRTIs, and one of the most promising compounds was modelled in the NNRTI binding pocket. This model can be used to explain why this compound is broadly effective against the panel of NNRTI resistance mutants. 

RPV’S PLACE IN THERAPY 

James et al (2012) reviewed the pharmacology, pharmacokinetics, drug interactions, clinical efficacy, adverse effects, dosage and administration, and place in therapy of RPV. 

Two phase III, randomised, double-blind, double-dummy, active-controlled trials compared RPV with EFV in HIV-infected adults not previously treated with an antiretroviral. The investigators concluded that RPV, when combined with two nucleoside or nucleotide reverse transcriptase inhibitors, was noninferior to EFV for reaching the endpoint of confirmed virological response (HIV-1 RNA level of <50 copies/mL) in adults with HIV infection not previously treated with antiretroviral therapy. The most commonly reported adverse effects included depression, insomnia, headache, and rash. RPV is administered as a single 25mg tablet given once daily in combination with other ARV drugs in order to optimise efficacy and reduce resistance. 

Conclusion: RPV is a viable NNRTI for HIV-infected patients who have not previously received antiretroviral therapy.  

The 2022 African Cardio Oncology Conference hosted by the Cardio Oncology Society of Southern Africa (COSOSA) recently emphasised early identification of cardiotoxicity risk and multidisciplinary collaboration at its recent meeting, attended by leading local and international experts.

International knowledge was shared at the COSOSA conference

“It is no use successfully treating cancer, only to allow the cancer patient to succumb to a cardiac event,” says convenor of the meeting, cardiologist and cardio-oncologist Dr YT (Trishun) Singh of the cardio oncology centre at Netcare uMhlanga Hospital, the first such unit to be established in Southern Africa. International attendees included the president of the British Cardio Oncology Society, Professor Alexander Lyon of the Royal Brompton Hospital in London, United Kingdom; Dr Susannah Stanway of the Royal Marsden Hospital in London; and Professor Sebastian Szmit, president of Cardio Oncology, Poland. 

“The inaugural COSOSA meeting was held just before South Africa entered the first Covid-19 hard lockdown on 7 March 2020. We are very pleased that this second meeting could be hosted in a hybrid format, allowing our colleagues from beyond our borders and around the world to participate through in-person or virtual attendance,” says Dr Singh. “Internationally, cardio oncology is well established as a field of medicine with specialised units in North America, Europe, Asia and Australia,” points out Dr Singh, who is the only International Cardio Oncology Society (ICOS) certified cardio oncologist in Southern Africa.   

“In Southern Africa we have a great need to develop more capacity by establishing more cardio oncology centres and developing local expertise. Oncologists, haematologists and cardiologists would benefit from skills that would enable them to implement cardio oncology principles in the daily practices of cancer care.” 

Topics covered during the 2022 conference, held at the Premier Hotel uMhlanga in Durban, included:  

• Cardiotoxicity of cancer therapy and early recognition 
• Baseline cardio oncology assessment of the patient before commencing chemotherapy or radiation
• Thromboembolism and anticoagulation in cancer patients 
• The need for a multidisciplinary approach in cancer treatment with particularly close cooperation between the cardio oncologist and oncologist
• How to establish a cardio oncology centre in South Africa or elsewhere on the African continent 
• Imaging tools in cardio oncology.

“With earlier detection and more advanced treatments, oncology medicine is increasingly successful in treating paediatric and adult cancer patients with modern chemotherapy, radiotherapy or in combination,” Dr Singh says. 

“Nearly all classes of chemotherapy and radiation to the chest may have side effects that put patients at greater risk of heart problems, known as cardiotoxicity. Cardiotoxicity does not just involve the heart muscle, but may also include heart rhythm disturbances, the vasculature (arteries and veins), heart valves, pericardium and conduction system. “Cardiotoxicity in people being treated for cancer is aggravated if underlying cardiac disease already exists, or if the patient has comorbidities such as diabetes, hypertension or dyslipidaemia,” he explains. The COSOSA meeting emphasised that all patients due to have potentially cardiotoxic cancer therapy must have a baseline cardio oncology assessment by an appropriately skilled cardiologist. “Following the guidelines and protocols by recognised cardio oncology societies such as ICOS, ongoing cardio oncology assessment during cancer therapy and post therapy surveillance is considered mandatory,” Dr Singh says. 

“The damage to the heart muscle, heart valves, coronary arteries and pericardium due to radiation to the chest, can manifest a few years after completion of chest radiation and these patients need careful surveillance as guided by the protocols. 

“We also observed that childhood cancer survivors need very careful post therapy surveillance, as they may present many years later with premature heart failure and ischaemic heart disease,” Dr Singh says.  

COSOSA also resolved that a basic foundation in cardio oncology should be introduced in cardiology, oncology and haematology fellowship training programmes, and cardiologists must have at least a level two cardio oncology training and certification to provide cardio oncology opinions for cancer patients. 

“It is imperative that cardio oncologists, oncologists and haematologists work together for better outcomes for people being treated for cancer. The earlier high risk cancer patients are identified for cardiotoxicity, the sooner therapy to mitigate against cardiotoxicity can be started.  

“Now that Covid-19 is settling, COSOSA can pursue our teaching programme, sharing awareness and upskilling all those who are involved in cancer care about cardio oncology for better long-term outcomes for cancer patients,” Dr Singh concluded. 

Formal health facilities are often inaccessible. For some people, the closest health centre is 30 kilometres away and entirely unreachable in the rainy season. For others, the costs of healthcare are too high. For the women that do manage to get to a healthcare centre, they often find it to be dysfunctional, with some facilities having no skilled staff. In Chad, the odds are against you. Some pregnant women do not have access to a delivery kit they wash with after the birth.

According to Souat Ahmat Ramadan, a Chadian midwife: “A traditional birth attendant usually doesn’t have the training or the tools. She delivers the baby on the ground in the woman’s house. With a razor blade, she cuts the umbilical cord without disinfectant. She closes the cord with woollen strings or anything she can find.” [Image: Noor Cornelissen].

Introducing Traditional Birth Attendants

After listening to the struggles women in the communities of Sila face, our Doctors Without Borders (MSF) teams collaborated with them to pilot a traditional birth attendants (TBAs) project to try address some of the most urgent needs. TBAs are women, usually between the ages of 25 and 60, who provide help with childbirth, breastfeeding and other related matters.

The World Health Organization (WHO) estimates that community health workers in maternal health roles fulfil 17 trillion dollars’ worth of healthcare services a year. They are mostly women, almost always unpaid.

According to UNICEF, in Chad, only two out of five births take place in the presence of a skilled birth attendant such as a midwife or doctor. In the Koukou district in Sila province, only three out of 11 health centres have a skilled birth attendant. And as health centres are inaccessible to many, it is clear that TBAs have an invaluable role to play.

Each village elected a TBA to participate in our project. Most TBAs have had no formal education in midwifery; they are simply courageous women who have delivered children themselves after their mothers or grandmothers showed them how.

Souat Ahmat Ramadan, a Chadian midwife, explains, “A traditional birth attendant usually doesn’t have the training or the tools. She delivers the baby on the ground in the woman’s house. With a razor blade, she cuts the umbilical cord without disinfectant. She closes the cord with woollen strings or anything she can find.”

For the 31 elected TBAs, MSF designed a training programme to sharpen their skills in areas like recognising the signs of danger before, during and after a delivery.

Results from the project

After a few months, the first signs of impact are clear. Antenatal care consultations have increased substantially along with referrals to health centres for complicated deliveries. TBAs also report that their skills and confidence are growing.

“This is a worthwhile project. After decades of working in this field, I have not yet worked with such an approach,” says Augustine Nsiloulou, an MSF midwife activity manager in Chad. “We face big challenges. None of the TBAs can read or write. We are limited in what they and we can do. But this approach is sustainable.”

“We listened to the communities, and it led us to a new path,” says Noor Cornelissen, MSF project coordinator. “We are aware that our approach requires careful evaluation and needs to be accompanied by an advocacy strategy targeting structural public health deficits. In the future, MSF would like to train the TBAs on community pre-natal care, sexual violence, family planning and other topics.”

According to a 2017 study by Latif et al, a decline in sperm count might be considered as a ‘canary in the coal mine’ for male health and have much wider implications beyond fertility and reproduction.¹

Endocrine disruption from chemical exposures to for example phthalates have been postulated as possible reasons for the increase in declining sperm counts and quality.

Recent studies have shown that poor sperm count is associated with overall morbidity and mortality. A Danish study report that with men with sperm concentration below 15 million/mL have a higher risk of diabetes and cardiovascular (CV) disease.²

An American study showed that diabetes is associated with a 16% increase in all‐cause and an 18% increase in CV mortality.³  According to the WHO, CVDs are the leading cause of death globally, responsible for an estimated 17.9 million deaths annually.⁴

What causes low sperm count?

Numerous environmental and lifestyle factors affect sperm count – both prenatally and in adult life. Endocrine disruption from chemical exposures or maternal smoking during critical windows of male reproductive development and lifestyle exposure to for example pesticides and other environmental toxins such as phthalates have been postulated as possible reasons for the increase in declining sperm counts and quality.^1,3

Phthalate exposure linked to development abnormalities in male genitals

Phthalates such as Di(2-ethylhexyl)phthalate (DEHP) is widely used to make polyvinyl chloride soft and malleable, increase durability, transparency, and longevity to a variety of consumer, industrial, and medical products, including electronics, medical devices, children’s toys, detergents, pharmaceuticals, paints, waxes, personal care products, cosmetics, and food packaging, among others.^5,6

Because phthalates are not covalently bound in these products, they can leach with product age, use, and ultraviolet light exposure, making them available for biological exposure.⁵ DEHP has come under increased scrutiny as its breakdown products are believed to be endocrine disruptors and more toxic than DEHP itself.⁶

The two most common endocrine developmental abnormalities of male genitals in infants, cryptorchidism, and hypospadias, have also shown increases – again particularly in Western, industrialised countries – over the past few decades.⁵

Shorter anogenital distance (AGD) are increasingly seen in boys with hypospadias and cryptorchidism. In men, shorter AGD has been linked to lower total sperm count and poor semen quality.⁵

In 2005, Swan et al published the first study the first study on AGD and other genital measurements in relation to prenatal phthalate exposure in 134 boys aged two- to 36-months. They found that phthalate metabolites are associated with short anogenital index and incomplete testicular descent. These data support the hypothesis that prenatal phthalate exposure at environmental levels can adversely affect male reproductive development in humans, conclude the team.⁷

Radke et al conducted a systematic review to identify male reproductive effects associated with phthalate exposure. According to the team, there is ‘robust evidence’ of an association between DEHP and dibutyl phthalate exposure (DBP) and male reproductive outcomes. The team showed links between AGD, semen parameters, and testosterone for DEHP exposure and semen parameters and time to pregnancy for DBP exposure.⁸

The future of the human race in peril?

In her book Count Down: How Our Modern World Is Threatening Sperm Counts, Altering Male and Female Reproductive Development, and Imperilling the Future of the Human Race, Dr Shanna Swan, an award-winning scientist based at Mount Sinai (United States) and one of the leading environmental and reproductive epidemiologists in the world, writes that changes in both male and female reproduction over the past few decades signal that ‘it’s no longer business as usual when it comes to human reproduction’. Reproductive changes have been noted in animals as well – signalling that something ‘very wrong is happening in our midst’.⁹

“This much is clear: The problem isn’t that something is inherently wrong with the human body as it had evolved over time, it’s that chemicals in our environment and unhealthy lifestyle practices in our modern world are disrupting our hormonal balance, causing various degrees of reproductive havoc that can foil fertility and lead to long-term health problems…”.⁹

She warns that we are living in an age of reproductive reckoning that has reverberating effects across the planet, and the longer it is allowed to  continue, may threaten human survival.⁹

According to Dr Swan, reversing the various ‘reproduction-sabotaging effects’ will require fundamental change, including changing the kinds and volumes of chemicals we use in manufacturing.⁹

She also provides examples of practical, everyday solutions such as purging harmful chemicals from our homes by reading the ingredients on bathroom and kitchen cleaners. Choosing personal care products that are phthalate-free and paraben-free. Ditching air freshener and scented products. Not microwaving food in plastic, making sure to filter drinking water and toss out plastic food storage containers and non-stick cookware.⁹

Dr Swan concludes her book with a plea for swift national and global actions that ban the use of chemicals to mitigate the effects of those that are impacting health and even life itself.⁹

REFERENCES:

1. Levine H, Jorgensen N, Swan SH, et al. Temporal trends in sperm count: a systematic review and meta-regression analysis. Human Reproduction Update, 2017.
2. Latif T, Jensen K, Mehlsen J, et al.  Semen quality is a predictor of subsequent morbidity. A Danish cohort study of 4,712 men with long-term follow-up. Am J Epidemiol, 2017.
3. Raghavan S, Vassy JL, Ho Y-L, et al. Diabetes Mellitus–Related All‐Cause and Cardiovascular Mortality in a National Cohort of Adults. Journal of the American Heart Association, 2019.
4. Cardiovascular disease. https://www.who.int/health-topics/cardiovascular-diseases#tab=tab_1
5. Johnson KJ, Heger NE, Boekelheide K. Of mice and men (and rats): phthalate-induced fetal testis endocrine disruption is species-dependent. Toxicol Sci, 2012.
6. Erythropel HC, Maric M, Nicell JA, Leask RL, Yargeau V. Leaching of the plasticizer di(2-ethylhexyl)phthalate (DEHP) from plastic containers and the question of human exposure. Appl Microbiol Biotechnol, 2014.
7. Swan SH, Main KM, Liu F, et al. Study for Future Families Research Team. Decrease in anogenital distance among male infants with prenatal phthalate exposure. Environ Health Perspect, 2005.
8. Radke EG, Braun JM, Meeker JD, Cooper GS.Phthalate exposure and male reproductive outcomes: A systematic review of the human epidemiological evidence. Environ Int. 2018.
9. Swan SH and Colino S. Count Down: How Our Modern World Is Threatening Sperm Counts, Altering Male and Female Reproductive Development, and Imperilling the Future of the Human Race. Simon and Schuster, 2020.

Advertorial: The OLFA CTR SK-12 all stainless-steel construction cutter and OLFA SK-15 Disposable Concealed Blade Safety Knife exclusively designed for the food and medical industry.

It is designed and tested for the food and medical industry for cutting light- to heavy-duty materials

With its unique features, Olfa’s cutter range is exclusive to the food and medical industries. However, it can still be used by other industries.

They are made of 100% stainless steel, and the open blade channel design and special metal detectable handle are ideal for food production environments and medical applications, allowing for regular cleaning without rusting or being damaged.

The OLFA CTR SK-12 is the first stainless steel unit with a preloaded safety blade and a slip–resistant handle with convenient notches which help to improve control when cutting. It also has a handy lanyard hole. In addition to its NSF certification, self-retracting design, and fast and easy sanitisation, it has many other features.

Designed and tested for the food and medical industry for cutting light– to heavy–duty materials such as plastic strapping, cardboard, plastic bags, pouches, stretch wrap, film, foil and all medical materials, it is perfect for both industries with its all-stainless-steel construction, self-retracting blade to optimise worker safety and open channel design for enhanced hygiene.

The OLFA SK-15 Disposable Concealed Blade Safety Knife helps reduce the chance of injuries on the job.

This new time–saving cutter is designed for both industries and they are supplied with 10 individually packed blades’.The new unit includes a Tape Slitter, consisting of twin ultra-hard stainless-steel blades with hooks. Its holder is made from a chemical resistant resin material with a unique large lanyard hole. it is Olfa’s latest disposable multi cutter manufactured to make it impossible to cut oneself. It is also NSF approved. To view the full range, go to www.vermontsales.co.za and click on Olfa.

OLFA is a leading brand in the Vermont Sales operation and is available at all leading specialist stores countrywide for more on your nearest retail outlet contact, Vermont Sales on 011 314 7711 or their web site www.vermontsales.co.za

“When a randomised controlled trial has relevant clinical and public health implications and is going to change WHO’s guidelines on second-line antiretroviral therapy (ART) in Africa and other resource-limited settings, it deserves to be called game-changing. It is the dream of every researcher,” Josep M Llibre, Lancet HIV 2022.

Dolutegravir-based and darunavir-based regimens maintain good viral suppression during 96 weeks

World Health Organization (WHO) guidelines recommend dolutegravir plus two nucleoside reverse transcriptase inhibitors (NRTIs) for second-line HIV therapy, with NRTI switching from first-line tenofovir to zidovudine. In The Lancet HIV, Paton et al (2022) report the 96-week data of the randomised, noninferiority NADIA trial comparing dolutegravir vs ritonavir-boosted darunavir (800mg of darunavir plus 100mg of ritonavir) and zidovudine vs tenofovir in second-line ART.

The study was designed to be relevant to the settings in which treatment is delivered and was done at seven sites in Kenya, Uganda, and Zimbabwe. The researchers randomly assigned patients where first-line therapy was failing (HIV-1 viral load, ≥1000 copies per millilitre) to receive dolutegravir or ritonavir-boosted darunavir and to receive tenofovir or zidovudine. All patients received lamivudine.

The researchers enrolled 464 patients at seven sub-Saharan African sites. A week 48 viral load of less than 400 copies per millilitre was observed in 90.2% of the patients in the dolutegravir group and in 91.7% of those in the darunavir group and in 89.6% of those in the zidovudine group. In the subgroup of patients with no NRTIs that were predicted to have activity, a viral load of less than 400 copies per millilitre was observed in more than 90% of the patients in the dolutegravir group and the darunavir group. The incidence of adverse events did not differ substantially between the groups in either factorial comparison.

FINDINGS

Dolutegravir-based and darunavir-based regimens maintain good viral suppression during 96 weeks. Dolutegravir is non-inferior to darunavir but is at greater risk of resistance in second-line therapy.

Tenofovir should be continued in second-line therapy, rather than being switched to zidovudine. The 96-week results of theNADIA trial, taken together with results of two other trials, now provide sufficient evidence to support WHO’s existing recommendation to use dolutegravir with two NRTIs in second-line therapy in the public health approach, and show that this combination will produce durable viral suppression, even when substantial NRTI resistance is present and when delivered with sparse viral load monitoring.

“Darunavir therefore merits an expanded role in the public health approach as a preferred protease inhibitor; its high genetic barrier to resistance also confers a possible advantage over dolutegravir. WHO’s longstanding recommendation to switch from tenofovir to zidovudine for second-line therapy in the public health approach should be revised to recommend maintaining tenofovir (and lamivudine) when introducing a new third drug (either dolutegravir or darunavir),” the researches commented.

REFERENCES:

Llibre J. Game-changing study of second-line HIV treatment. Lancet HIV 2022. Published Online April 20, 2022. https://doi.org/10.1016/S2352-3018(22)00096-0.

Paton N et al. Efficacy and safety of dolutegravir or darunavir in combination with lamivudine plus either zidovudine or tenofovir for second-line treatment of HIV infection (NADIA): week 96 results from a prospective, multicentre, open-label, factorial, randomised, non-inferiority trial. 2022 Lancet HIV. DOI:https://doi.org/10.1016/S2352-3018(22)00092-3.

Paton N et al. Dolutegravir or Darunavir in Combination with Zidovudine or Tenofovir to Treat HIV. N Engl J Med 2021; 385:330-341. DOI: 10.1056/NEJMoa2101609.

It is vital for the financial survival of the business to prevent bad debt and promote a healthy cash flow by collecting outstanding accounts from medical aids and private patients.

The longer accounts are left outstanding, the less likely it is that outstanding fees and expenses can be collected.

The longer accounts are left outstanding, the less likely it is that outstanding fees and expenses can be collected. Debt management involves different phases to minimise patient accounts that are unpaid.

DEBT MANAGEMENT PROCESSES

The Debt Management Business Process diagram is divided into four phases, and each phase is divided into processes that need to be followed. The diagram illustrates the following phases:

1. Business process design

2. Process audit

3. Account clean-up

4. Collection process.

PHASE 1: BUSINESS PROCESS DESIGN

During the Business Process Design phase the practice must decide how the collection process will work. The following must be considered:

1. Journal design – decide who will have access to create journal entries and which journals are going to be used, for example, writing off small balances or bad debts and giving discounts to pensioners. These journals can be pre-configured to post to their respective ledger accounts in the software to minimise user mistakes.

2. The collection cycles must be designed so that the necessary actions will be taken at different dates, for example, sending notifications on days 30 and 60.

3. The configuration of the practice’s management software needs to be planned and configured to guide the collection process.

PHASE 2: PROCESS AUDIT

Users process transactions during the following critical business processes:

• Billing and billing corrections

• Claim administration

• Receipting and receipt corrections.

The Process Audit phase is where the credit controller checks that all transactions have been correctly captured during these critical business processes. This step is vital to ensure that no paid accounts are collected in error and no unpaid accounts are missed. If all transactions were correctly captured, the outstanding amounts on the debtors account will be correct and can be used to start with the debt collecting process.

PHASE 3: ACCOUNT CLEAN-UP

The Account Clean-up phase aims to clear all the clutter and ensure that no unnecessary communication is sent to medical debtors. The following processes are used to pave the way for an optimal debt collection process:

1. Processing journals – get rid of small amounts or amounts that cannot be collected or are not worth collecting so that there can be a singular focus on collecting those worth the effort.

2. Archiving settled accounts – archive dormant accounts so that they don’t clutter the collection process.

3. Hiding zero balances on accounts – When zero accounts are hidden/filtered out the user will only see and focus on outstanding amounts.

PHASE 4: COLLECTION PROCESS

The Collection Process phase can start as soon as the Process Audit phase and the Account Clean-Up phase is completed. Only outstanding debtor accounts are part of the process, and the collection cycles will guide the process. The collection process can be done in two ways:

1. Manually by the Credit Controller

2. Automatically with an automated process in the software.

Even though the collection process can be automated, it is advisable that users understand how the manual collection process works to know how to configure the software for automated processes.

The manual collection process will be guided by the following processes:

• Drawing reports – An age analysis report will guide the credit controller to action only those accounts that are outstanding and, depending on the days outstanding, prescribe the type of action necessary.

• Sending communication is the most important part of debt management. Without communication debt collection cannot be done. Communication consists of sending SMSs, emails or making phone calls. Statements can be added to emails sent to patients.

• Bad debt administration – As soon as it has been decided which accounts are going to be sent for external debt collection, the practice needs to gather the necessary information to be handed over for legal action.

CONCLUSION

Thinking about debt management is never a feel-good experience. However, debt management could be quite a clean process and getting it done properly by competent personnel will take the pain out of this important part of a practice’s business management.

For more information, please click here to read our medical practice management book on our Learning Centre:

Medical Chronicle recently hosted a CPD-accredited, one-hour webinar on An approach to HIV treatment failure. The webinar is sponsored by Johnson & Johnson and was presented by Dr Leon Levin. Dr Leon Levin is a paediatrician who has been treating HIV infected infants, children and adolescents for the past 26 years and is currently Senior Technical Advisor in Paediatrics at Right to Care NGO.

Dr Levin delivered a lively and informative presentation

To watch the replay of this webinar and still earn a CPD point, go to: https://event.webinarjam.com/go/replay/441/n62z6um2tllt2rh1

Email john.woodford@newmedia.co.za to let him know that you have watched the replay.

As always, Dr Levin delivered a lively and informative presentation. He addressed:

• New Research- Earnest, Nadia, Visend ARTIST​
• Failing 1st line NNRTI regimen ​

The finding may explain why similar NSAIDs produce a range of clinical outcomes and could inform how the drugs are used in the future. The study was published in the journal Immunity. 

Yale researchers have uncovered a distinct mechanism by which a subset of NSAIDs reduce inflammation.

Until now, the anti-inflammatory effects of NSAIDs were believed to arise solely through the inhibition of certain enzymes. But this mechanism does not account for many clinical outcomes that vary across the family of drugs. For example, some NSAIDs prevent heart disease while others cause it, some NSAIDs have been linked to decreased incidence of colorectal cancer, and various NSAIDs can have a wide range of effects on asthma. 

Now, using cell cultures and mice, Yale researchers have uncovered a distinct mechanism by which a subset of NSAIDs reduce inflammation. And that mechanism may help explain some of these curious effects. 

The research showed that only some NSAIDs – including indomethacin, which is used to treat arthritis and gout, and ibuprofen – also activate a protein called nuclear factor erythroid 2-related factor 2, or NRF2, which, among its many actions, triggers anti-inflammatory processes in the body. 

“It’s interesting and exciting that NSAIDs have a different mode of action than what was known previously,” said Dr Anna Eisenstein, an instructor at the Yale School of Medicine and lead author of the study. “And because people use NSAIDs so frequently, it’s important we know what they’re doing in the body.” 

The research team can’t say for sure that NSAIDs’ unexpected effects are due to NRF2 – that will require more research. “But I think these findings are suggestive of that,” Dr Eisenstein said. 

Eisenstein is now looking into some of the drugs’ dermatological effects – causing rashes, exacerbating hives, and worsening allergies – and whether they are mediated by NRF2. 

This discovery still needs to be confirmed in humans, the researchers note. But if it is, the findings could have impacts on how inflammation is treated and how NSAIDs are used. 

For instance, several clinical trials are evaluating whether NRF2-activating drugs are effective in treating inflammatory diseases like Alzheimer’s disease, asthma, and various cancers; this research could inform the potential and limitations of those drugs. Additionally, NSAIDs might be more effectively prescribed going forward, with NRF2-activating NSAIDs and non-NRF2-activating NSAIDs applied to the diseases they’re most likely to treat. 

The findings may also point to entirely new applications for NSAIDs, said Dr Eisenstein. 

NRF2 controls a large number of genes involved in a wide range of processes, including metabolism, immune response, and inflammation. And the protein has been implicated in aging, longevity, and cellular stress reduction. 

Dr Eisenstein said, “That NRF2 does so much suggests that NSAIDs might have other effects, whether beneficial or adverse, that we