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Meta-analysis of safety for DTG versus other ARVs in randomized trials: Analysis of cardiovascular, CNS and IRIS endpoints
 
 
  Reported by Jules Levin
EACS 2017 Oct 25-27 Milan Italy
 
Andrew Hill1, Nikkita Mitchell2
1Liverpool University, Translational Medicine, Liverpool, United Kingdom; 2Imperial College London, Faculty of Medicine, London, United Kingdom
 
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EASC POSTER BELOW
 
This study was published in March 2018 Current Opinion on HIV & AIDS.
 
Risks of cardiovascular or central nervous system adverse events and immune reconstitution inflammatory syndrome, for dolutegravir versus other antiretrovirals: meta-analysis of randomized trials
 
Current Opinion in HIV and AIDS March 2018 - Hill, Andrew, M.a; Mitchell, Nikkitab; Hughes, Sophieb; Pozniak, Anton, L.c
 
Purpose of review Results from nonrandomized cohort studies suggest higher risks of CNS adverse events for dolutegravir, versus other ARVs. There have been two case reports of myocarditis on dolutegravir. Integrase inhibitors have been associated with IRIS in two cohort studies. Meta-analysis of randomized trials can be used to cross-check potential safety signals. This systematic review of drug safety used an EMBASE and MEDLINE search combined with serious adverse event (SAE) reports on the website www.clinicaltrials.gov. Cardiovascular, CNS or IRIS-associated adverse events were analysed for dolutegravir versus other ARVs. Relative risks for the comparison between dolutegravir and other antiretrovirals were calculated for each adverse event. Meta-analyses applied Mantel-Haenszel random-effects models.
 
Recent findings There was a higher risk of Grade 1-4 insomnia adverse events for DTG (6.1%) versus other ARVs (4.5%; P = 0.02). There was no significant difference between DTG and other ARVs in the risk of cardiovascular serious adverse events. In the SINGLE and SPRING-1 trials comparing DTG with efavirenz, there were 5/465 patients with reported suicidality SAEs on DTG (1.1%) versus 6/469 (1.3%) on EFV. In other studies, serious adverse events of suicidality were reported for 15/2250 patients on DTG (0.7%) versus 9/2257 patients on other ARVs (0.4%). Risks of IRIS were low, but event rates were low and the main trials excluded CDC stage C disease.
 
Summary In this meta-analysis, there was no significant effect of dolutegravir on the risk of cardiac, IRIS or suicide-related serious adverse events. There was a higher risk of insomnia for DTG. Other completed randomized trials should be included in new evaluations of DTG safety. Continued pharmacovigilance, with regular meta-analyses, should be used to monitor safety.
 
INTRODUCTION
 
World Health Organization (WHO) guidelines currently recommend first-line treatment for HIV with tenofovir disoproxil fumarate (TDF) and lamivudine (3TC) or emtricitabine (FTC) and either the nonnucleoside efavirenz (EFV) or the integrase inhibitor dolutegravir (DTG) [1]. Treatment guidelines in high-income settings have recently been revised to recommend first-line use of integrase inhibitors in preference to EFV [2-4].
 
A single generic tablet containing tenofovir, 3TC and DTG is becoming available in low-income and middle-income countries for US $75 per year [5,6], which is cheaper than efavirenz-based first-line treatment. The transition to TDF/3TC/DTG has the potential to be a significant step forward in simplifying HIV treatment with improved tolerability and adherence at a cheaper cost [7,8]. Its high genetic barrier to resistance may also make DTG an important option for countries such as Uganda and Namibia, with increased prevalence of pretreatment drug resistance to nonnucleoside reverse transcriptase inhibitors [8]. DTG is being provided on a national scale in Brazil and Botswana, and its use is likely to expand across sub-Saharan Africa in 2018 [8].
 
In randomized clinical trials, DTG has shown lower overall risks of adverse events than the nonnucleoside efavirenz (in the SINGLE trial [9]), and the protease inhibitors darunavir/ritonavir (in the FLAMINGO study [10]), atazanavir/ritonavir (in the ARIA trial [11]) and lopinavir/ritonavir (in the DAWNING trial [12]). Dolutegravir has shown similar rates of adverse events to the integrase inhibitors raltegravir (in the SPRING-2 trial [13]) and bictegravir (in the Gilead 1489 and 1490 trials [14,15]).
 
There are three key limitations, however, in the interpretation of safety data from these randomized trials.
 
Firstly, the inclusion/exclusion criteria for the studies mean that key populations to be treated in low-income and middle-income countries can be either under-represented or excluded. These include pregnant women, people co-infected with tuberculosis (TB), people with CDC stage C disease and/or low CD4 counts. Additional efficacy and safety data may be needed for these key populations, particularly as some countries are already introducing treatment with DTG for pregnant women (in Botswana) and patients with TB (in Botswana and Uganda) [8].
 
Secondly, safety results presented in publications of clinical trials typically only report adverse events occurring above a certain frequency threshold (for example, those recorded in at least 5% of randomized patients), events leading to discontinuation, events of a certain severity grade (for example, Grades 2-4 only), or only those deemed to be drug-related. There may be other important adverse events outside of these restrictions, which are not presented.
 
For some published clinical trials, the journals provide a supplement containing more detailed safety data. These supplements are not standardized and are rarely available. For trials which have already been published, the website www.clinicaltrials.gov lists a summary of all serious adverse events and adverse events of all grades (typically those recorded in at least 5% of patients in either treatment arm). However, this supplementary information may not be available until at least 1 year after the publication of the clinical trial.
 
Thirdly, the originator companies will have access to all the safety data for their clinical trial programme of new antiretroviral (ARV) treatments. However, most companies do not publish meta-analyses of key safety endpoints for their treatments in a standardized format. There are summaries of safety sent from originator companies to regulatory authorities, but these results are not generally published.
 
It is important for academic research groups to conduct regular, independent analyses of available safety data for ARV drugs in widespread use. Detecting safety issues as early as possible will minimize the risks to patients.
 
DOLUTEGRAVIR: SAFETY ANALYSES IN NONRANDOMIZED COHORT STUDIES
 
There was a report of two cases of myocarditis on dolutegravir [16], with one additional case of myocarditis in the FLAMINGO trial, part of the Phase 3 development programme [10]. Data from two recent studies from nonrandomized cohort studies in France and the Netherlands reported an association between the use of integrase inhibitors and a higher risk of Immune Reconstitution Inflammatory Syndrome (IRIS) [17,18]. Results from nonrandomized cohort studies suggest a higher risk of CNS adverse events for dolutegravir compared with other integrase inhibitors [19-22]; insomnia was a particular issue in these studies. Cohort studies are not randomized trials, so there is the potential for bias and confounding in the reported association with these adverse events. There was evidence for 'channeling bias' in the OPERA cohort: patients with preexisting CNS conditions were more likely to be treated with dolutegravir, which could contribute to the higher risks of CNS adverse events seen [23]. It is possible that these reports of adverse events in the observational studies were unusual findings, not seen consistently in other studies. The European Summary of Product Characteristics (SPC) for dolutegravir lists IRIS as an uncommon adverse event, which could occur in 0.1-1% of treated patients [24]. Insomnia, abnormal dreams and depression may occur in 1-10% of treated patients, according to the SPC; suicidal ideation, or suicide attempt (particularly in patients with a preexisting history of depression or psychiatric illness) may occur in 0.1-1% of treated patients. However, it is not clear from the SMPC whether these risks are higher than would be expected when using other, alternative ARVs.
 
Randomized clinical trials of ARVs normally include 200-400 patients per treatment arm. These sample sizes can be too small to detect treatment-related effects on rare adverse events. The increased risk of suicide-related adverse events for efavirenz was only seen when a meta-analysis of clinical trials was conducted, including over 6000 patients [25]. Given the need for independent evaluation of safety, a systematic review and meta-analysis was conducted to evaluate whether dolutegravir is associated with increased risks of cardiovascular, CNS or IRIS-related adverse events, which have been identified as potential issues from observational studies.
 
METHODS
 
Embase and Medline databases were searched in line with PRISMA guidelines from the earliest available date until 20th April 2017. This was supplemented by a search of clinical trials presented at the International AIDS Society Conference in Paris in July 2017.
 
Trials with a randomized controlled design were included, if they had an intervention arm containing dolutegravir at the standard dose of 50 mg once daily versus a control arm with another ARV. Nonstandard doses of dolutegravir were not included. Criteria for exclusion of trials were populations with HIV-2 infection, single-arm or cross-over designs, no active control arms and under 24 weeks of randomized treatment. Trials with dolutegravir in all treatment arms were also excluded.
 
For each clinical trial, data on the number of patients with key adverse events were recorded wherever available. Serious adverse events (SAEs) were collected from the database www.clinicaltrials.gov wherever available, or from the supplementary appendices of trial publications. For cardiac disorders, all SAEs listed under the system organ class 'cardiac disorders' were recorded. For suicide-related disorders, three SAEs were recorded: suicidal ideation, attempted suicide and completed suicide. For insomnia, Grade 1-4 adverse event information from clinical trial publications were recorded. For IRIS, all adverse event information available was recorded.
 
Relative risks for the comparison between dolutegravir and other ARVs were calculated for each adverse event. Meta-analyses applied Mantel-Haenszel random-effects models. The meta-analyses of suicide-related SAEs was stratified by the use of efavirenz, which has been associated with a higher risk in another meta-analysis [25]. The meta-analysis of insomnia was also stratified according to the design of the studies (switch versus nonswitch design). This was because patients already stable on a current treatment might be more likely to show new adverse events whenever switched to a new treatment, versus remaining on their current treatment.
 
To minimize the risk of publication bias, all completed trials of dolutegravir, which had been registered on www.clinicaltrials.gov were checked for availability of results from at least one source. The results were collected independently by two authors (A.H. and N.M.) and cross-checked.
 
RESULTS
 
The PUBMED /EMBASE search identified a total of 496 reports. There were 150 studies identified on www.clinicaltrials.gov, of which 8 trials were eligible for analysis. There was one additional study presented at IAS 2017 which was included in the analysis (NEAT 022). Table 1shows a summary of the nine randomized trials included in this meta-analysis. There was a total of 6647 patient-years of follow-up in these nine randomized studies. Two studies, SPRING-2 and SAILING, compared dolutegravir with another member of the integrase inhibitor class (raltegravir). There were five studies in treatment-nave patients (SINGLE [9], SPRING 1 [26], SPRING 2 [13], FLAMINGO [10] and ARIA [11]), one in treatment experienced patients (SAILING [27]) and three switch studies for patients with HIV RNA suppression at baseline (STRIIVING [28], NEAT 022 [29] and SWORD 1/2 [30]). For the SWORD 1 and 2 studies, there was no serious adverse event data available; only adverse events leading to discontinuation and those recorded for at least 5% of patients in one treatment arm were reported. Therefore, the SWORD studies were not included in the analysis of cardiac SAEs, and only partial information about suicide-related SAEs could be included (only those leading to discontinuation). In the STRIIVING study [28], randomized treatment was for 24 weeks, after which time all patients received dolutegravir: only the initial 24-week randomized phase was included in the meta-analysis. Full safety data were available for only two of the nine studies - SINGLE and NEAT 022. For the other studies, the results included serious adverse events, adverse events leading to discontinuation, and all Grade 1-4 adverse events recorded in at least 5% of patients in one treatment arm. (SPRING-1 was the exception, with data available at a threshold of at least 3% of patients.) Therefore, other adverse events, which were not reported as SAEs or occurring in fewer than 5% of patients, cannot be assessed in this meta-analysis. In addition, all nine studies excluded patients with CDC stage C disease at baseline. CDC stage C disease is associated with a higher risk of IRIS.
 
Table 2 shows the three completed studies and five ongoing studies of dolutegravir, which could not be included in this analysis. The three completed studies - DAWNING [12], Gilead 1489 [14] and Gilead 1490 [15] - have been presented publicly. However, the detailed safety data is not available on the website www.clinicaltrials.gov or as a supplement to the main publication of the trial (for the two Gilead studies). The approximate dates of completion of the ongoing studies - INSPIRING [31], ADVANZ-4 dolutegravir versus efavirenz in HIV/TB coinfection.32. Spanish Immune Recovery study: dolutegravir versus darunavir/ritonavir in patients with CD4 counts < 100/ul. Available at: https://clinicaltrials.gov/ct2/show/NCT02337322?term=dolutegravir&rank=56. [Accessed 26 October 2017]','400')" onMouseOut="javascript:ImageWrapperControl_ImageMouseOut()">[32], NAMSAL [33], ADVANCE [34], D2EFT [35] and VESTED [36] - are listed in Table 2.
 
CARDIAC SERIOUS ADVERSE EVENTS
 
The SINGLE, SAILING, FLAMINGO, SPRING-1, SPRING-2, ARIA, STRIIVING and NEAT 022 trials were included for analysis (Table 3 ). There was a wide range of cardiac SAEs reported, with no clear trend for a particular type of cardiac SAE on dolutegravir. There was one case of myocarditis recorded, in the FLAMINGO trial.
 
Overall, there were 15/2202 (0.7%) patients with cardiovascular SAEs on DTG versus 8/2215 (0.4%) on other ARVs [relative risk (RR) = 1.69, NS, Fig. 1]. There were 25 cardiac SAEs recorded in 23 patients: of these, 1 was considered drug-related (DTG arm of SPRING-2); 1 other cardiac SAE was considered unlikely-drug related (DTG arm of SPRING-1).
 
Additional case information was available for 19 of the 23 patients with cardiac SAEs. Seventeen of 19 patients had underlying cardiac risk factors (89%).
 
SUICIDE-RELATED ADVERSE EVENTS
 
In the SINGLE and SPRING-1 trials, there were 5/465 patients with reported suicidality SAEs on DTG (1.1%) versus 6/469 (1.3%) on EFV (RR = 0.87, NS; Table 4). In the SAILING, FLAMINGO, SPRING-2, ARIA, STRIIVING, SWORD and NEAT 022 trials, SAEs of suicidality were reported for 15/2250 patients on DTG (0.7%) versus 9/2257 patients on other ARVs (0.4%; RR = 1.58, NS, Fig. 2 and Table 5).
 
INSOMNIA
 
The risk of Grade 1-4 insomnia was higher for DTG (Table 6 and Fig. 3): There were 165/2716 patients with Grade 1-4 insomnia on dolutegravir (6.1%) versus 124/2727 on other ARVs (4.5%; RR = 1.30 P = 0.02, Fig. 3). There was no significant difference in risk of insomnia between the studies with a continue versus switching design, and head-to-head studies in nave or experienced patients (Fig. 3).
 
IMMUNE RECONSTITUTION INFLAMMATORY SYNDROME
 
IRIS was reported in 1/414 participants on DTG versus 2/419 participants on EFV in SINGLE, 6/354 (DTG) versus 3/361 (RAL) in SAILING, and 1/411 (DTG) versus 0/411 (RAL) in SPRING-2. There were no reported cases of IRIS in SPRING-1, FLAMINGO, STRIIVING or NEAT 022. There was no significant difference in the risk of IRIS between DTG and other ARVs. However, all the randomized trials excluded patients with CDC grade C disease at baseline.
 
CONCLUSION
 
In this meta-analysis of randomized trials in 6647 patient-years of follow-up, there was a higher risk of Grade 1-4 insomnia adverse events for DTG (6.1%) versus other ARVs (4.5%; P = 0.02).
 
There was no significant difference in the risk of cardiac SAEs between DTG and other ARVs. All cardiac SAEs except two were considered to be unrelated to study medications by the trial investigators, one was possibly drug-related and one was unlikely to be drug-related; 89% of total participants had underlying cardiac risk factors.
 
The analyses of suicidality are currently inconclusive. Risks of IRIS were low, but event rates were low and the main trials excluded CDC stage C disease.
 
There are several limitations to this meta-analysis. Of the nine studies included, only two (SINGLE and NEAT 022) had detailed data on all adverse events by treatment arm available for analysis. For the other studies, the only results available were for serious adverse events, common Grade 1-4 adverse events (>5% in any treatment arm) and those leading to discontinuation. However, a more detailed analysis of less common adverse events, not categorized as SAEs or leading to discontinuation, could lead to other conclusions.
 
Many of the adverse events will not be directly drug-related. Cardiac events may be attributable to other medications taken by participants, HIV-associated chronic inflammation that remains even in treated individuals [37], as well as lifestyle factors such as recreational drug use, alcohol and smoking [38]. HIV is a risk factor for suicide among other psychiatric disorders, which may be a result of social stigma, as well as lifestyle factors [39]. Case narratives for SAEs are not in the public domain, therefore, their nature and cause cannot be determined.
 
Information regarding drug-relatedness of adverse events was not consistently available. For those adverse events that were deemed unrelated, additional data from multiple trials would help to provide confirmation. Medical journals should request that more detailed study reports be made available, in the format of the publication of the SINGLE trial in the New England Journal of Medicine.
 
Three completed clinical trials had no results available on the website www.clinicaltrials.gov. Whenever a clinical trial is published in a medical journal, the more detailed safety data should be posted on this website at the same time. This would allow for independent analysis of the safety results in a standardized format. Finally, there are ongoing randomized trials, conducted by independent research groups and with less restrictive inclusion and exclusion criteria. These clinical trials could improve our knowledge of the safety of dolutegravir in patients with CDC C disease, HIV-TB co-infection and pregnancy.
 
There are plans to switch millions of patients onto dolutegravir-based treatment in sub-Saharan Africa within the next 18 months. This transition needs to be supported by careful analysis of drug safety. Other completed randomized trials should be included in new evaluations of DTG safety: DAWNING (n = 627), SWORD 1 and 2 (n = 1024), Gilead trial 1489 (n = 629) and Gilead trial 1490 (n = 645). Continued pharmacovigilance, with regular meta-analyses, should be used to monitor safety. A recent analysis of the psychiatric disorders reported to the World Health Organization pharmacovigilance database suggests a higher risk of depression, suicide and self-injury for dolutegravir and raltegravir, compared with elvitegravir [40]. Analyses of this type need to be repeated regularly and checked for potential confounding factors.
 
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EACS POSTER
Reported by Jules Levin
EACS 2017 Oct 25-27 Milan Italy
 
Andrew Hill1, Nikkita Mitchell2
1Liverpool University, Translational Medicine, Liverpool, United Kingdom; 2Imperial College London, Faculty of Medicine, London, United Kingdom

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