72 weeks post-partum follow-up of dolutegravir versus efavirenz initiated in late pregnancy (DolPHIN-2): an open-label, randomised controlled study.

BACKGROUND: Late initiation of antiretrovirals in pregnancy is associated with increased risk of perinatal transmission and higher infant mortality. We report the final 72-week postpartum results for efficacy and safety of dolutegravir-based compared with efavirenz-based regimens in mothers and infants. METHODS: DolPHIN-2 was a randomised, open-label trial. Pregnant women in South Africa and Uganda aged at least 18 years, with untreated but confirmed HIV infection and an estimated gestation of at least 28 weeks, initiating antiretroviral therapy in third trimester were eligible for inclusion. Eligible women were randomly assigned (1:1) to receive either dolutegravir-based (50 mg dolutegravir, 300 mg tenofovir disoproxil fumarate, and either 200 mg emtricitabine in South Africa or 300 mg lamivudine in Uganda) or efavirenz-based (fixed dose combination 600 mg tenofovir disoproxil fumarate plus either emtricitabine in South Africa or lamivudine in Uganda) therapy. The primary efficacy outcome was the time to a viral load of less than 50 copies per mL measured at 6, 12, 24, 48, and 72 weeks postpartum with a Cox model adjusting for viral load and CD4 cell count. Safety endpoints were summarised by the number of women and infants with events. This trial is registered with ClinicalTrials.gov, NCT03249181. FINDINGS: Between Jan 23 and Aug 15, 2018, 280 women were screened for inclusion, of whom 268 (96%) women were randomly assigned: 133 (50%) to the efavirenz group and 135 (50%) to the dolutegravir group. 250 (93%; 125 [50%] in the efavirenz group and 125 [50%] in the dolutegravir group) women were included in the intention-to-treat analysis of efficacy. Median time to viral load of less than 50 copies per mL was 4·1 weeks (IQR 4·0-5·1) in the dolutegravir group compared with 12·1 weeks (10·7-13·3) in the efavirenz group (adjusted hazard ratio [HR] 1·93 [95% CI 1·5-2·5]). At 72 weeks postpartum, 116 (93%) mothers in the dolutegravir group and 114 (91%) in the efavirenz group had a viral load of less than 50 copies per mL. Of 57 (21%) mothers with a severe adverse event, three (2%) in the dolutegravir group and five (4%) in the efavirenz group were related to the drug (dolutegravir drug-related events were one woman each with suicidal ideation, suicide attempt, herpes zoster meningitis; efavirenz drug-related events were one woman each with suicide attempt and liver cirrhosis, and three people with drug-induced liver injury). Of 136 (56%) infants in whom severe adverse events were recorded, none were related to the study drugs. In addition to the three infant HIV infections detected at birth in the dolutegravir group that have been previously reported, an additional transmission in the efavirenz group occurred during breastfeeding despite optimal maternal viral suppression and serial negative infant tests in the first year of life. INTERPRETATION: Dolutegravir was safe and well tolerated, supporting updated WHO treatment recommendations in pregnant and breastfeeding women. Infant HIV transmissions can occur during breastfeeding despite persistently undetectable maternal viral load highlighting the need for continued infant testing. FUNDING: Unitaid.

Patient experiences of switching from Efavirenz- to Dolutegravir-based antiretroviral therapy: a qualitative study in Uganda.

BACKGROUND: In 2019, the World Health Organisation (WHO) recommended Dolutegravir (DTG) as the preferred first-line antiretroviral treatment (ART) for all persons with HIV. ART regimen switches may affect HIV treatment adherence. We sought to describe patient experiences switching from EFV to DTG-based ART in Kampala, Uganda. METHODS: Between July and September 2019, we purposively sampled adults living with HIV who had switched to DTG at the Infectious Diseases Institute HIV clinic. We conducted in-depth interviews with adults who switched to DTG, to explore their preparation to switch and experiences on DTG. Interviews were audio-recorded, transcribed and analysed thematically using Atlas ti version 8 software. RESULTS: We interviewed 25 adults: 18 (72%) were women, and the median age was 35 years (interquartile range [IQR] 30-40). Median length on ART before switching to DTG was 67 months (IQR 51-125). Duration on DTG after switching was 16 months (IQR 10-18). Participants reported accepting provider recommendations to switch to DTG mainly because they anticipated that swallowing a smaller pill once a day would be more convenient. While most participants initially felt uncertain about drug switching, their providers offer of frequent appointments and a toll-free number to call in the event of side effects allayed their anxiety. At the same time, participants said they felt rushed to switch to the new ART regimen considering that they had been on their previous regimen(s) for several years and the switch to DTG happened during a routine visit when they had expected their regular prescription. Some participants felt unprepared for new adverse events associated with DTG and for the abrupt change in treatment schedule. Most participants said they needed additional support from their health providers before and after switching to DTG. CONCLUSION AND RECOMMENDATIONS: Adults living with HIV stable on an EFV-based regimen but were switched to DTG in a program-wide policy change found the duration between counselling and drug switching inadequate. DTG was nonetheless largely preferred because of the small pill size, once daily dosing, and absence of EFV-like side effects. Community-engaged research is needed to devise acceptable ways to prepare participants for switching ART at scale.

The Potential Teratogenicity Alert for Women Conceiving on Dolutegravir-Based Regimens: An Assessment of Risk Communication by an Urban HIV Clinic in Uganda and Choices made by Women.

INTRODUCTION AND OBJECTIVE: In May 2018, the World Health Organization and other regulatory authorities released a safety alert for dolutegravir related to a risk of neural tube defects among women exposed to dolutegravir at the time of conception. Models of how drug safety information can be shared effectively in the shortest time are necessary to prevent interruptions of public health programs. We sought to describe an implementation process to inform and support women already on dolutegravir-based regimens at the time of conception to make informed choices following the safety alert of a potential teratogenicity risk. We describe the choices made by women, as well as determine the factors associated with women's choices to switch off dolutegravir. METHODS: A clinic response plan was developed in the first week following the alert and clinic staff were trained on safety guidance. All women aged < 55 years taking dolutegravir were identified from the clinic database and contacted by phone for earlier appointments. Non-menopausal and non-surgically sterilized women were referred for urine pregnancy testing and evaluation of pregnancy intentions in the following 12 months and effective family planning was offered. We describe the coverage of women who received the communication as well as the fidelity to the outlined plan from 21 May to 12 September, 2018. We used modified a Poisson regression analysis to determine factors associated with switching off dolutegravir. RESULTS: Of all active patients in the clinic, 9% (690/7963) were identified as female aged < 55 years taking dolutegravir. Ninety-five percent (656/690) were reviewed by September 2018 and informed of the safety alert, implying a high level of uptake. Fidelity to standard operating procedures was also high at 72%. Twenty-two percent (146/656) of patients were menopausal or surgically sterilized. Five hundred and ten women were of reproductive potential with a median age (interquartile range) of 37 years (30-42 years). Five percent (23/510) were human chorionic gonadotrophin positive and all initial ultrasound reports revealed no deformities. Twenty-one percent (108/510) had intentions to conceive and opted to stop taking dolutegravir with 90% (97/108) switching to efavirenz. Seventy-nine percent (402/510) opted to remain taking dolutegravir. However, only 40% (160/402) chose effective contraceptive methods and 60% (242/402) opted for condoms only/no contraceptive method. CONCLUSIONS: A rapid well-coordinated response ensured prompt communication of the dolutegravir safety warning. The process developed by the clinic can act as a model for response during drug safety alerts. Women made informed decisions with most opting to remain taking dolutegravir; however, effective contraception uptake was low.

Dolutegravir versus efavirenz in women starting HIV therapy in late pregnancy (DolPHIN-2): an open-label, randomised controlled trial.

BACKGROUND: Late initiation of HIV antiretroviral therapy (ART) in pregnancy is associated with not achieving viral suppression before giving birth and increased mother-to-child transmission of HIV. We aimed to investigate virological suppression before giving birth with dolutegravir compared with efavirenz, when initiated during the third trimester. METHODS: In this randomised, open-label trial, DolPHIN-2, we recruited pregnant women in South Africa and Uganda aged at least 18 years, with untreated but confirmed HIV infection and an estimated gestation of at least 28 weeks, initiating ART in third trimester. Participants were randomly assigned (1:1) to dolutegravir-based or efavirenz-based therapy. HIV viral load was measured 7 days and 28 days after antiretroviral initiation, at 36 weeks' gestation, and at the post-partum visit (0-14 days post partum). The primary efficacy outcome was a viral load of less than 50 copies per mL at the first post-partum visit, and the primary safety outcome was the occurrence of drug-related adverse events in mothers and infants until the post-partum visit. Longer-term follow-up of mothers and infants continues. This study is registered with ClinicalTrials.gov, NCT03249181. FINDINGS: Between Jan 23, and Aug 15, 2018, we randomly assigned 268 mothers to dolutegravir (135) or efavirenz (133). All mothers and their infants were included in the safety analysis, and 250 mothers (125 in the dolutegravir group, 125 in the efavirenz group) and their infants in efficacy analyses, by intention-to-treat analyses. The median duration of maternal therapy at birth was 55 days (IQR 33-77). 89 (74%) of 120 in the dolutegravir group had viral loads less than 50 copies per mL, compared with 50 (43%) of 117 in the efavirenz group (risk ratio 1·64, 95% CI 1·31-2·06). 30 (22%) of 137 mothers in the dolutegravir group reported serious adverse events compared with 14 (11%) of 131 in the efavirenz group (p=0·013), particularly surrounding pregnancy and puerperium. We found no differences in births less than 37 weeks and less than 34 weeks gestation (16·4% vs 3·3%, across both groups). Three stillbirths in the dolutegravir group and one in the efavirenz group were considered unrelated to treatment. Three infant HIV infections were detected, all in the dolutegravir group, and were considered likely to be in-utero transmissions. INTERPRETATION: Our data support the revision to WHO guidelines recommending the transition to dolutegravir in first-line ART for all adults, regardless of pregnancy or child-bearing potential. FUNDING: Unitaid.

High prevalence and long duration of nervous system and psychiatric adverse drug reactions in Ugandan patients taking efavirenz 600 mg daily.

Background: Efavirenz-related nervous system or psychiatric adverse drug reactions (ADRs) are conventionally reported to resolve soon after initiation, with incidence of dizziness at 8.5% in large clinical trials. Patients of black ethnicity are genetically at greater risk of elevated efavirenz exposure, which has been linked to nervous system toxicity. Patients and methods: The current data derive from a prospective longitudinal observational study of adult HIV-positive outpatients taking current antiretrovirals, at three diverse clinics in central Uganda. As part of an interview about medicine use, patients were asked by trained pharmacy technicians to detail current side effects and to rate their severity on a simple visual analogue scale (1-10). Details of the reported ADRs were verified by case note review. Severity and causality of ADRs were rated by the study team using validated tools. Results: A total of 300 patients taking efavirenz were analysed. Of these, 108 (36%, 95% CI 30.6%-41.7%) were affected by persisting nervous system/psychiatric ADRs (median duration 22 months). Dizziness affected 27.3% (95% CI 22.4%-32.8%) of patients taking efavirenz. Severity of the ADRs was rated by patients at ≥5/10 in 76 (58.5%) cases. In 95 (86%) cases, there was no record of the ADRs in the clinical notes. Conclusions: Strategies are needed to identify and prioritize patients urgently with persisting efavirenz neurotoxicity for a switch to newer regimens as they become available.

Drug interactions and the role of pharmacokinetic trials in guiding choices in first-line HIV therapy in low-income and middle-income countries.

PURPOSE OF REVIEW: Low- and middle-income countries (LMICs) face specific challenges in the treatment of people living with HIV. Drug-drug interactions (DDIs) involving antiretrovirals (ARVs) are prevalent in all settings and have considerable potential to cause clinical harm to patients via toxicity or reduced efficacy of treatment. Differing comorbidities, endemic infections and traditional medicines may complicate ARV therapy (ART) in LMICs, which usually takes a public health approach in these settings, with fewer alternative regimens available. This review discusses the issues surrounding pharmacokinetic DDI studies and their application to ART in LMICs, with particular reference to first-line ART regimens. RECENT FINDINGS: Pharmacokinetic studies with clinical endpoints are the gold standard for informing management of DDIs; however, data relevant to LMICs are sparse and of low quality. There is significant potential for clinically relevant DDIs between ARVs and antimalarials, antimycobacterials and drugs used in the treatment of neglected tropical diseases. SUMMARY: Many pharmacokinetic studies are difficult to interpret in LMICs due to differences in patient factors including weight, disease state and genetic polymorphisms. DDI studies relevant to LMICs may also be lacking due to the neglected nature of relevant comorbidities. The ARVs currently available as first-line ART in LMICs are among those with highest propensity for DDIs.

Development of an evidence evaluation and synthesis system for drug-drug interactions, and its application to a systematic review of HIV and malaria co-infection.

BACKGROUND: In all settings, there are challenges associated with safely treating patients with multimorbidity and polypharmacy. The need to characterise, understand and limit harms resulting from medication use is therefore increasingly important. Drug-drug interactions (DDIs) are prevalent in patients taking antiretrovirals (ARVs) and if unmanaged, may pose considerable risk to treatment outcome. One of the biggest challenges in preventing DDIs is the substantial gap between theory and clinical practice. There are no robust methods published for formally assessing quality of evidence relating to DDIs, despite the diverse sources of information. We defined a transparent, structured process for developing evidence quality summaries in order to guide therapeutic decision making. This was applied to a systematic review of DDI data with considerable public health significance: HIV and malaria. METHODS AND FINDINGS: This was a systematic review of DDI data between antiretrovirals and drugs used in prophylaxis and treatment of malaria. The data comprised all original research in humans that evaluated pharmacokinetic data and/or related adverse events when antiretroviral agents were combined with antimalarial agents, including healthy volunteers, patients with HIV and/or malaria, observational studies, and case reports. The data synthesis included 36 articles and conference presentations published via PubMed and conference websites/abstract books between 1987-August 2016. There is significant risk of DDIs between HIV protease inhibitors, or NNRTIs and artemesinin-containing antimalarial regimens. For many antiretrovirals, DDI studies with antimalarials were lacking, and the majority were of moderate to very low quality. Quality of evidence and strength of recommendation categories were defined and developed specifically for recommendations concerning DDIs. CONCLUSIONS: There is significant potential for DDIs between antiretrovirals and antimalarials. The application of quality of evidence and strength of recommendation criteria to DDI data is feasible, and allows the assessment of DDIs to be robust, consistent, transparent and evidence-based.

Drug-drug interactions between antiretrovirals and drugs used in the management of neglected tropical diseases: important considerations in the WHO 2020 Roadmap and London Declaration on Neglected Tropical Diseases.

The group of infections known as the neglected tropical diseases (NTDs) collectively affect one billion people worldwide, equivalent to one-sixth of the world's population. The NTDs cause severe physical and emotional morbidity, and have a profound effect on cycles of poverty; it is estimated that NTDs account for 534 000 deaths per year. NTDs such as soil-transmitted helminth infections and the vector-borne protozoal infections leishmaniasis and trypanosomiasis occur predominantly in the most economically disadvantaged and marginalized communities. It is estimated that all low-income countries harbour at least five of the NTDs simultaneously. NTDs are neglected because they do not individually rank highly in terms of mortality data, and because they affect populations with little political voice. There is considerable geographic overlap between areas with high prevalence of NTDs and HIV, raising the possibility of complex polypharmacy and drug-drug interactions. Antiretrovirals pose a particularly high risk for potential drug-drug interactions, which may be pharmacokinetic or pharmacodynamic in nature and can result in raising or lowering plasma or tissue concentrations of co-prescribed drugs. Elevated drug concentrations may be associated with drug toxicity and lower drug concentrations may be associated with therapeutic failure. The aim of this paper is to review the currently available data on interactions between antiretrovirals and drugs used in the management of NTDs. It is intended to serve as a resource for policy makers and clinicians caring for these patients, and to support the recent WHO 2020 Roadmap and the 2012 London Declaration on NTDs.

Prediction of drug-drug interactions between various antidepressants and efavirenz or boosted protease inhibitors using a physiologically based pharmacokinetic modelling approach.

BACKGROUND AND OBJECTIVE: The rate of depression in patients with HIV is higher than in the general population. The use of antidepressants can have a beneficial effect, improving antiretroviral therapy adherence and consequently their efficacy and safety. Efavirenz and protease inhibitor boosted with ritonavir are major components of the antiretroviral therapy and are inducers and/or inhibitors of several cytochrome P450 (CYP) isoforms. Although antidepressants are prescribed to a significant proportion of patients treated with antiretrovirals, there are limited clinical data on drug-drug interactions. The aim of this study was to predict the magnitude of drug-drug interactions among efavirenz, boosted protease inhibitors and the most commonly prescribed antidepressants using an in vitro-in vivo extrapolation (IVIVE) model simulating virtual clinical trials. METHODS: In vitro data describing the chemical characteristics, and absorption, distribution, metabolism and elimination (ADME) properties of efavirenz, boosted protease inhibitors and the most commonly prescribed antidepressants were obtained from published literature or generated by standard methods. Pharmacokinetics and drug-drug interaction were simulated using the full physiologically based pharmacokinetic model implemented in the Simcyp™ ADME simulator. The robustness of our modeling approach was assessed by comparing the magnitude of simulated drug-drug interactions using probe drugs to that observed in clinical studies. RESULTS: Simulated pharmacokinetics and drug-drug interactions were in concordance with available clinical data. Although the simulated drug-drug interactions with antidepressants were overall weak to moderate according to the classification of the US FDA, fluoxetine and venlafaxine represent better candidates from a pharmacokinetic standpoint for patients on efavirenz and venlafaxine or citalopram for patients on boosted protease inhibitors. CONCLUSION: The modest magnitude of interaction could be explained by the fact that antidepressants are substrates of multiple isoforms and thus metabolism can still occur through CYPs that are weakly impacted by efavirenz or boosted protease inhibitors. These findings indicate that IVIVE is a useful tool for predicting drug-drug interactions and designing prospective clinical trials, giving insight into the variability of exposure, sample size and time-dependent induction or inhibition.

Cross-sectional study of prescribing errors in patients admitted to nine hospitals across North West England.

OBJECTIVE: To evaluate the prevalence, type and severity of prescribing errors observed between grades of prescriber, ward area, admission or discharge and type of medication prescribed. DESIGN: Ward-based clinical pharmacists prospectively documented prescribing errors at the point of clinically checking admission or discharge prescriptions. Error categories and severities were assigned at the point of data collection, and verified independently by the study team. SETTING: Prospective study of nine diverse National Health Service hospitals in North West England, including teaching hospitals, district hospitals and specialist services for paediatrics, women and mental health. RESULTS: Of 4238 prescriptions evaluated, one or more error was observed in 1857 (43.8%) prescriptions, with a total of 3011 errors observed. Of these, 1264 (41.9%) were minor, 1629 (54.1%) were significant, 109 (3.6%) were serious and 9 (0.30%) were potentially life threatening. The majority of errors considered to be potentially lethal (n=9) were dosing errors (n=8), mostly relating to overdose (n=7). The rate of error was not significantly different between newly qualified doctors compared with junior, middle grade or senior doctors. Multivariable analyses revealed the strongest predictor of error was the number of items on a prescription (risk of error increased 14% for each additional item). We observed a high rate of error from medication omission, particularly among patients admitted acutely into hospital. Electronic prescribing systems could potentially have prevented up to a quarter of (but not all) errors. CONCLUSIONS: In contrast to other studies, prescriber experience did not impact on overall error rate (although there were qualitative differences in error category). Given that multiple drug therapies are now the norm for many medical conditions, health systems should introduce and retain safeguards which detect and prevent error, in addition to continuing training and education, and migration to electronic prescribing systems.

Use of a physiologically-based pharmacokinetic model to simulate artemether dose adjustment for overcoming the drug-drug interaction with efavirenz.

PURPOSE: To treat malaria, HIV-infected patients normally receive artemether (80 mg twice daily) concurrently with antiretroviral therapy and drug-drug interactions can potentially occur. Artemether is a substrate of CYP3A4 and CYP2B6, antiretrovirals such as efavirenz induce these enzymes and have the potential to reduce artemether pharmacokinetic exposure. The aim of this study was to develop an in vitro in vivo extrapolation (IVIVE) approach to model the interaction between efavirenz and artemether. Artemether dose adjustments were then simulated in order to predict optimal dosing in co-infected patients and inform future interaction study design. METHODS: In vitro data describing the chemical properties, absorption, distribution, metabolism and elimination of efavirenz and artemether were obtained from published literature and included in a physiologically based pharmacokinetic model (PBPK) to predict drug disposition simulating virtual clinical trials. Administration of efavirenz and artemether, alone or in combination, were simulated to mirror previous clinical studies and facilitate validation of the model and realistic interpretation of the simulation. Efavirenz (600 mg once daily) was administered to 50 virtual subjects for 14 days. This was followed by concomitant administration of artemether (80 mg eight hourly) for the first two doses and 80 mg (twice daily) for another two days. RESULTS: Simulated pharmacokinetics and the drug-drug interaction were in concordance with available clinical data. Efavirenz induced first pass metabolism and hepatic clearance, reducing artemether Cmax by 60% and AUC by 80%. Dose increases of artemether, to correct for the interaction, were simulated and a dose of 240 mg was predicted to be sufficient to overcome the interaction and allow therapeutic plasma concentrations of artemether. CONCLUSIONS: The model presented here provides a rational platform to inform the design for a clinical drug interaction study that may save time and resource while the optimal dose is determined empirically. Wider application of IVIVE could help researchers gain a better understanding of the molecular mechanisms underpinning variability in drug disposition.

Global patient safety and antiretroviral drug-drug interactions in the resource-limited setting.

Scale-up of HIV treatment services may have contributed to an increase in functional health facilities available in resource-limited settings and an increase in patient use of facilities and retention in care. As more patients are reached with medicines, monitoring patient safety is increasingly important. Limited data from resource-limited settings suggest that medication error and antiretroviral drug-drug interactions may pose a significant risk to patient safety. Commonly cited causes of medication error in the developed world include the speed and complexity of the medication use cycle combined with inadequate systems and processes. In resource-limited settings, specific factors may contribute, such as inadequate human resources and high disease burden. Management of drug-drug interactions may be complicated by limited access to alternative medicines or laboratory monitoring. Improving patient safety by addressing the issue of antiretroviral drug-drug interactions has the potential not just to improve healthcare for individuals, but also to strengthen health systems and improve vital communication among healthcare providers and with regulatory agencies.

Directly acting antivirals for hepatitis C and antiretrovirals: potential for drug-drug interactions.

PURPOSE OF REVIEW: Boceprevir and telaprevir are directly acting antivirals (DAAs) that have recently been licensed for treatment of hepatitis C virus (HCV) infection. Data in both untreated and previously treated patients indicate a significantly increased sustained virological response (SVR) compared with that observed with conventional therapy. However, the advent of DAA therapy poses specific challenges for HCV treatment in terms of managing drug-drug interactions (DDIs). This review aims to provide a comprehensive summary of DDI with the recently licensed DAAs, including pharmacokinetic data and current recommendations made by the manufacturers and with particular reference to antiretrovirals. Potential for DDIs with the DAAs in clinical development and the mechanisms of interaction are also discussed. RECENT FINDINGS: Targeted pharmacokinetic drug interaction studies have demonstrated that both boceprevir and telaprevir are potent inhibitors of the metabolic enzyme cytochrome P4503A4, making them perpetrators of interactions with co-administered medications which are metabolized by this enzyme. In addition, co-administered medications may affect plasma levels of boceprevir and telaprevir via various mechanisms, some of which remain to be fully elucidated. SUMMARY: As a result of DDIs, the concomitant use of some medicines with DAA will be contraindicated, whereas other combinations may require caution, monitoring, or dose modification of the co-administered drug. Management of DDIs with these novel agents will pose a new challenge, and prescriber awareness of the potential for DDIs is fundamental for safe prescribing. Online resources are likely to play a key role in prescriber education and clinical decision-making.

Prevalence of potential drug-drug interactions involving antiretroviral drugs in a large Kenyan cohort.

BACKGROUND: Clinically significant drug-drug interactions (CSDIs) involving antiretrovirals are frequent and under-recognized in developed countries, but data are lacking for developing countries. METHODOLOGY AND PRINCIPAL FINDINGS: To investigate the prevalence of CSDIs between antiretrovirals and coadministered drugs, we surveyed prescriptions dispensed in a large HIV clinic in Kenya. Of 1040 consecutive patients screened, 996 were eligible for inclusion. CSDIs were defined as 'major' (capable of causing severe or permanent damage, contraindicated, avoid or not recommended by the manufacturer, or requiring dose modification) or 'moderate' (manufacturers advise caution, or close monitoring, or capable of causing clinical deterioration). A total of 334 patients (33.5%) were at risk for a CSDI, potentially lowering antiretroviral drug concentrations in 120 (12%) patients. Major interactions most frequently involved rifampicin (12.4%, mostly with efavirenz) and azoles (2.7%) whereas moderate interactions were frequently azoles (13%), steroids (11%), and antimalarials (3%). Multivariable analyses suggested that patients at risk for CSDIs had lower CD4 counts (P = 0.006) and baseline weight (P = 0.023) and WHO Stage 3 or 4 disease (P≤0.007). Risk for CSDIs was not associated with particular regimens, although only 116 (11.6%) patients were receiving WHO second line regimens. CONCLUSIONS: One in three patients receiving antiretrovirals in our programme were at risk of CSDIs. Strategies need to be urgently developed to avoid important drug interactions, to identify early markers of toxicity and to manage unavoidable interactions safely in order to reduce risk of harm, and to maximize the effectiveness of mass antiretroviral deployment in Africa.

Grapefruit-drug interactions.

Grapefruit juice and grapefruit product consumption have potential health benefits; however, their intake is also associated with interactions with certain drugs, including calcium channel blockers, immunosuppressants and antihistamines. The primary mechanism through which interactions are mediated is mechanism-based intestinal cytochrome P450 3A4 inhibition by furanocoumarins resulting in increased bioavailability of administered medications that are substrates. Grapefruit products have also been associated with interactions with P-glycoprotein (P-gp) and uptake transporters (e.g. organic anion-transporting polypeptides [OATPs]). Polyphenolic compounds such as flavonoids have been proposed as the causative agents of the P-gp and OATP interactions. The mechanisms and magnitudes of the interactions can be influenced by the concentrations of furanocoumarins and flavonoids in the grapefruit product, the volume of juice consumed, and the inherent variability of specific enzymes and transporter components in humans. It is therefore challenging to predict the extent of grapefruit product-drug interactions and to compare available in vitro and in vivo data. The clinical significance of such interactions also depends on the disposition and toxicity profile of the drug being administered. The aim of this review is to outline the mechanisms of grapefruit-drug interactions and present a comprehensive summary of those agents affected and whether they are likely to be of clinical relevance.

New directly acting antivirals for hepatitis C: potential for interaction with antiretrovirals.

Recent advances in the development of agents that act specifically to inhibit hepatitis C virus (HCV) are set to fundamentally change the way that patients will be treated. New directly acting anti-HCV agents such as protease and polymerase inhibitors will initially be added to standard of care with pegylated interferon-alpha and ribavirin. However, future therapy is likely to constitute combinations of agents which act at distinct stages of viral replication and have differing resistance profiles. While directly acting anti-HCV agents will undoubtedly improve treatment outcomes, the introduction of combination therapy may not be without complications in some patient groups. HIV-positive patients who are receiving antiretrovirals (ARVs) are relatively highly represented among those with HCV infection, and are at high risk of drug-drug interactions (DDIs). As combination anti-HCV treatment gradually evolves to resemble anti-HIV therapy, it is essential to consider the increased potential for DDIs in patients receiving combination anti-HCV therapy, and particularly in HCV/HIV-co-infected individuals. Therapeutic drug monitoring is likely to play a role in the clinical management of such interactions.

Antiretroviral drug interactions: often unrecognized, frequently unavoidable, sometimes unmanageable.

Patients with HIV who are receiving antiretroviral (ARV) therapy are at high risk for drug-drug interactions (DDIs), which can significantly impact patient care and represent a substantial opportunity cost for healthcare systems. DDIs are prevalent in the developed world and in resource-poor settings, with the cost being potentially greater in the latter. Although practically unavoidable in HIV care, many DDIs can be better managed, reducing the risks to patients and the burden on resources. The scope for DDI management is likely to be greater in the developed world, due to the availability of new agents and second-line drugs, which allow greater flexibility of ARV regimens and co-administered drug choice. The advent of electronic prescribing and patient medication records represents an opportunity to aid the identification and management of DDIs. Searchable electronic databases of HIV drug interactions are available, which are a useful tool for HIV healthcare professionals and non-specialists for managing DDIs involving ARVs. Although general active systems that alert prescribers to DDIs currently exist, there is an indication for the development of specialist active databases to be incorporated into electronic prescribing or dispensing systems, with the aim of improving the quality of prescribing and the safe dispensing of the therapeutically risky drugs and complicated regimens used in HIV management.