Main Study Findings and Author’s Conclusions

Nazila Assasi; Aleksandra Grobelna

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Assasi N, Grobelna A. Posaconazole for the Prophylaxis and Treatment of Invasive Aspergillosis: A Review of Clinical Effectiveness and Guidelines [Internet]. Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2017 Jul 13.

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Posaconazole for the Prophylaxis and Treatment of Invasive Aspergillosis: A Review of Clinical Effectiveness and Guidelines [Internet].

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Appendix 4Main Study Findings and Author’s Conclusions

Table 10Summary of Findings of Included Systematic reviews and Meta-analyses

Main Study Findings			Author’s Conclusion
Zhao, 2015¹⁶
Overall incidence of IFIs		reported in 20 / 21 included RCTs	The authors concluded that primary antifungal prophylaxis with POS had a greater effect in preventing IFIs and reducing all-cause mortality, when compared with FLU and ITR.
POS was statistically superior to:	FLU	OR 0.35 (95%CI 0.16, 0.73)
and	ITR (cap)	OR 0.25 (95%CI 0.06, 0.97)
but not	VOR	OR 1.31 (95%CI 0.43, 4.01)
Incidence of IA		reported in 16 / 21 included RCTs
POS was statistically superior to:	PLC	OR 0.12 (95%CI 0.02, 0.61)
and	FLU	OR 0.07 (95%CI 0.01, 0.29)
and	ITR	OR 0.10 (95%CI 0.02, 0.47)
and	VOR	OR 6.46 (95%CI 1.22, 34.04) indirect evidence
All-Cause mortality (at 100 days)		reported in 19 / 21 included RCTs
POS was statistically superior to:	PLC	OR 0.49 (95%CI 0.28, 0.85)
and	FLU	OR 0.54 [95%CI 0.33, 0.88)
and	ITR [sol]	OR 0.49 (95%CI 0.28 to 0.83)
IFI-related mortality		reported in 14 / 21 included RCTs
POS was statistically superior to:	PLC	OR 0.14 (95% CI, 0.04, 0.43)
and	FLU	OR 0.27 (95% CI, 0.10, 0.76)
Need for empirical therapy		reported in 15 / 21 included RCTs
POS was statistically superior to:	FLU	OR 0.35 (95% CI, 0.15 to 0.80)
and	ITR [cap]	OR 0.33 (95% CI, 0.12 to 0.95)
and	ITR [sol]	OR 0.37 (95% CI, 0.15 to 0.91)
Ranking of of treatment effects, based on SUCRA values (1 indicates that the treatment always ranks first, and of 0 indicates that the treatment always ranks last) POS (0.92) > VOR (0.80) > ITR [sol] (0.63) > FLU (0.36) > ITR [cap] (0.27)
Bow, 2015¹⁷
Overall incidence of proven/probable IFIs			The author did not make a firm conclusion due to the paucity of relevant data and wide credible intervals in their mixed treatment analyses. However, based on the limited data, they indicated that the study results supported the selection of mould-active azoles (including POS and VOR) over FLU for antifungal prophylaxis in HSCT recipients. The study results also showed that POS and VOR may be more effective than FLU in protecting IA. The authors suggested that other factors such as long-term tolerability, availability of intravenous formulations, epidemiology of IFIs, and drug costs should also be taken into account, when selecting among mould-active azoles.
Direct (head-to-head) comparison Ullmann et al²²:		reported by 1 / 5 included RCTs
POS		incidence rate = 5% (16/301 pts)
FLU		incidence rate = 9% (27/299 pts)
Mixed treatment comparisons		data from 5 RCTs
POS vs FLU		Med OR 0.56 (IQR 0.32, 0.99)
Incidence of IA
Direct (head-to-head) comparison Ullmann et al²²:		reported by 1 / 5 included RCTs
POS		incidence rate = 2% (7/301 pts)
FLU		incidence rate = 7% (21/299 pts)
Mixed treatment comparisons		data from 5 RCTs
POS vs FLU		Med OR 0. 31 (IQR 0.15, 0.63)
All-Cause mortality
Direct (head-to-head) comparison Ullmann et al²²:		reported by 1 / 5 included RCTs
POS		mortality rate = 19% (58/301 pts)
FLU		mortality rate = 20% (59/299 pts)
Mixed treatment comparisons		data from 5 RCTs
POS vs FLU		Med OR 0.98 (IQR 0.74, 1.27)
Incidence of other licensed antifungal therapy
Direct (head-to-head) comparison Ullmann et al²²:		reported by 1 / 5 included RCTs
POS		incidence rate = 11% (31/291 pts)
FLU		incidence rate = 10% (29/288 pts)
Mixed treatment comparisons		data from 5 RCTs
POS vas FLU		Med OR 1.08 (IQR 0.53, 2.21)
Ziakas, 2014¹⁸
The review identified 20 studies. However, there was a lack of comparisons between POS and other azole agents when used as prophylactic strategies. A single study compared POS with lipid complex amphotericin B in HSCT recipients (n = 40). In this RCT, no proven IFIs reported in either arm. Two 2 probable cases of IFI were detected in the lipid complex amphotericin B arm. Withdrawal rate was reported to be marginally lower in the POS arm than in the amphotericin B arm (OR 0.28; 95% CI, 0.06, 1.24; P = 0.06).			The authors did not make conclusion due to insufficient conclusive evidence on the relative effectiveness of azole agents (including POS) used as IFI prophylaxis for patients undergoing HSCT.
Pechlivanoghlou, 2014¹⁹
Overall incidence of IFIs			The authors concluded that POS can be considered as the most effective antifungal drug for antifungal prophylaxis in patients with neutropenia, particularly those undergoing chemotherapy.
Meta-analysis(direct comparison)		data from study by Cornely et al²¹
POS was statistically superior to:	FLU	RR 0.31 (95%CrI 0.14, 0.67)
Mixed treatment comparisons		data from 25 studies
No statistical differences were found between POS and other antifungal prophylaxis agents
Incidence of IA
Mixed treatment comparisons		data from 25 studies
POS was statistically superior to:	PLC	RR 0.06 (95%CrI 0.01, 0.34)
and	FLU	RR 0.05 (95%CrI 0.01, 0.25)
and	ITR [sol]	RR 0.09 (95%CrI 0.01, 0.51)
All-Cause mortality
Mixed treatment comparisons		data from 23 studies
POS was statistically superior to:	PLC	RR 0.56 (95%CrI 0.30, 0.98)
IFI-related mortality
Mixed treatment comparisons		data from 21 studies
POS was statistically superior to:	PLC	RR 0.09 (95% CrI 0.01, 0.34)
and	FLU	RR 0.22 (95% CrI 0.05, 0.74)
	ITR [tab]	RR 0.08 (95% CrI 0.01, 0.47)
Ping,2013⁵
Incidence of proven/probable IFIs		reported by 2 / 4 included RCTs	The authors concluded that second generation azoles (POS and VOR) can provide a significantly better prophylaxis against IFIs and IA, when compared with first generation azoles (FLU and ITR), with no increased risk of adverse events.
POS was statistically superior to:	FLU/ITR	OR 0.40 (95%CI 0.19, 0.87; P = 0.02)
Incidence of IA		reported by 2 / 4 included RCTs
POS was statistically superior to:	FLU/ITR	OR 0.20 (95%CI 0.06, 0.65; P = 0.008)
All-Cause mortality		reported by 3 / 4 included RCTs
POS was statistically different from:	FLU/ITR	OR 0.77 (95%CI 0.59, 1.01; P = 0.06)
Need for empirical antifungal therapy		reported by 1 / 4 included RCTs
POS was statistically superior to:	FLU/ITR	OR 0.56 (95% CI 0.39, 0.81)

: CI = confidence interval; CrI = credible interval; FLU = fluconazole; IA = invasive aspergillosis; IFI = invasive fungal infection; IQR = inter-quartile range; ITR [cap] = itraconazole capsule; ITR [sol] = itraconazole solution; Med = median; OR = odds ratio; PLC = placebo; POS = posaconazole; pts = patients; RCT = randomized controlled trial; RR = relative risk; SUCRA = Surface Under the Cumulative Ranking; VOR = voriconazole; vs = versus.

Table 11Summary of Findings of Included Randomized Controlled Trials

Main Study Findings					Author’s Conclusion
Shen, 2013²⁰
Study arms:			POS	FLU	The authors concluded that antifungal prophylaxis with POS in patients with AML and myelodysplastic syndrome who receive chemotherapy can be more effective than prophylaxis with FLU in preventing IFIs and reducing the need for other systemic antifungal treatments.
# randomized			129	123
# included in the analyses			117	117
Incidence of proven, probable or possible IFIs
▪ During the treatment phase		POS resulted in a statistically greater absolute risk reduction
POS	11/117	9.4% (95% CI 4.8, 16.2)		ARR –12.8% (95% CI: –22, – 3.6)
FLU	26/117	22.2% (95% CI: 15.1, 30.8)		P = 0.011
▪ Over 100 days observation		POS was statistically superior to FLU
POS	14/117	12.0% (95% CI 6.7, 19.3)		RD –13.7% (95% CI: –23.5, – 3.8)
FLU	30/117	25.6% (95% CI: 18.0, 34.5)		P = 0.006
Incidence of proven and probable IFIs
▪ POS was non-inferior to FLU in preventing IFIs
POS	4/117	3.4% (95% CI 0.9, 8.5)		RD –5.9% (95% CI: NR)
FLU	11/117	9.4% (95% CI: 4.8, 16.2)		P = NS
100 days time to first onset of proven, probable or possible IFIs
▪ Onset rate of IFIs in 100 days was statistically lower in the POS arm (better IFI-free survival)
POS		13.8 ± 3.5%	P = 0.0063
FLU		29.2 ± 4.6%	(log-rank test)
All-cause mortality
▪ POS and FLU were not statistically different in terms of all-cause mortality
POS	3/117	2.5% (95% CI 0.5, 7.3)
FLU	7/117	5.9 (95% CI: 2.4 – 11.9)		P = 0.216
Cornely, 2007²¹
Study arms:	POS	FLU	or	ITR	The authors concluded POS can provide a better prevention of proven or probable IFIs than either FLU or ITR. The study also demonstrated a lower all-cause mortality rate and a longer IFI-free survival rate in POS-users, as compared with patients who received prophylaxis with FUL or ITR. Based on the study results, the authors suggested that adding POS prophylaxis to the standard of care may be a beneficial inpatients with AML or myelodysplastic syndromes who are undergoing remissioninduction chemotherapy.
# randomized	298	240		58
Incidence of proven/ probable IFIs
▪ During the treatment phase		POS resulted in a statistically lower rate of IFIs
POS		7/304	(2%)	ARR –6.0% (95% CI: –9.7, –2.5)
FLU or ITR		25/298	(8%)	P < 0.001
▪ Over 100 days after randomization
POS		15/304	(5%)
FLU or ITR		33/298	(11%)	P = 0.003
Incidence of IA
▪ POS resulted in statistically fewer cases of IA
POS		2/304	(1%)
FLU or ITR		20/298	(7%)	P <0.001
Need for empirical antifungal therapy at 100 days
▪ Statistically fewer patients in the POS group needed empirical antifungal treatments.
POS		81/304	(27%)
FLU or ITR		112/298	(38%)	P = 0.004
All-cause mortality
– Incidence of death		▪ POS resulted in a statistically lower death rate
POS		49/304	(16%)
FLU or ITR		67/298	(22%)	P = 0.048
100 day survival benefit		▪ POS resulted in a statistically significant survival benefit in 100 days (relative reduction in mortality = 33%)
POS		44/304	(14%)	P = 0.04
FLU or ITR		64/298	(21%)	(log-rank test)
IFI-related mortality
Of the 116 deaths that occurred during the study, 21 were considered to be related to fungal infections
▪ POS resulted in a statistically lower IFI-related mortality rate
POS		5/116	(2%)
FLU or ITR		16/116	(5%)	P = 0.01
Ullmann, 2007²²
Study arms:		POS		FLU	The authors concluded that POS and FLU had similar prophylactic effects and all-cause mortality rates among patients with graftversus-host disease after allogeneic HSCT. However, POS was superior to FUL in terms of preventing IA, and IF-related mortality.
# randomized		301		299
Incidence of proven/ probable IFIs ▪ During the treatment phase: POS was non-inferior to FLU in preventing IFIs ▪ During the exposure period^a: POS was statistically superior to FLU in preventing breakthrough IFIs.
Treatment phase
POS		16/301	(5.3%)	OR 0.56 (95% CI 0.30, 1.07)
FLU		27/299	(9%)	P < 0.07
Exposure period^a
POS		7/291	(2.4%)	OR 0.30 (95% CI 0.12, 0.71)
FLU		22/288	(7.6%)	P = 0.004
Incidence of IA
▪ During the treatment phase			POS resulted in statistically fewer cases of IA
POS		7/301	(2.3%)	OR 0.31 (95% 0.13, 0.75)
FLU or ITR		21/299	(7%)	P = 0.006
Breakthrough IA during exposure period^a
POS		3/291	(1%)	OR 0.17 (95% CI 0.05, 0.57)
FLU		17/288	(5.9%)	P = 0.001
112 days to first onset of proven, probable or possible IFIs ▪ POS was statistically superior to FLU in delaying the onset of IFIs during the fixed treatment period The mean day of the onset of IFI was day 102 in the POS group and day 88 in the FLU group. (P = 0.048).
All-cause mortality
▪ POS and FLU groups had similar all-cause mortality rates.
POS		76/291	(25%)
FLU		84/288	(28%)	P = NS
IFI-related mortality
▪ POS resulted in a statistically lower IFI-related mortality rate.
POS		2/291	(1%)
FLU		11/288	(4%)	P = 0.046

: ARR = absolute risk reduction; AML = acute myeloid leukemia; CI = confidence interval; FLU = fluconazole; HSCT = hematopoietic stem-cell transplantation; IA = invasive aspergillosis; IFI = invasive fungal infection; ITR = itraconazole; NR = not reported; NS = not significant; OR = odds ratio; POS = posaconazole; RD = risk difference.
a: Exposure period = The period from the first dose of the study drug to 7 days after receipt of the last dose.

Table 12Summary of Findings of Included Non-randomized Studies

Main Study Findings				Author’s Conclusion
Raad, 2008²³
Comparison Groups	POS	HD-LPD/AMB	Combination therapy HD-LPD/AMB + caspofungin	The authors concluded that salvage therapy of IA with POS, in patients with hematologic malignancies, was more effective than salvage therapy with HD-LPD/ AMB alone or in combination with caspofungin.
# enrolled	53	52	38
Overall response rate to salvage therapy
▪ POS resulted in a statistically better response rate to salvage therapy.
POS	21/53	(40%)
HD-LPD/AMB	4/52	(8%)	P < 0.01
Combination	4/38	(11%)	P = 0.002
▪ In non-critically ill patients who received >7 days of salvage therapy, POS resulted in a statistically higher response rate than the other two treatment options (P<0.03). ▪ In critically ill (ICU) patients who received >7days of salvage therapy, the overall response rates were not statistically different between POS and the other two treatment options (P = 0.14). ▪ When adjusted for confounders in a multivariable analysis, POS independently improved response to treatment (OR 9.5; 95% CI, 2.8, 32.5; P < 0.001).
Aspergillus-related mortality
▪ POS resulted in statistically lower Aspergillus-related mortality rate.
POS	21/53	(40%)
HD-LPD/AMB	36/52	(69%)	P = 0.008
Combination	26/38	(68%)	P = 0.007
Overall survival rate
▪ During the 12 weeks of follow-up, POS-user had a statistically higher overall survival rate, when compared with HD-LPD/AMB and combination therapy arms (P < 0.04).
Walsh, 2007²⁴
Comparison Groups		POS	Standard Care^a (historical controls)	The study showed that salvage therapy with POS was effective in patients with IA who were refractory to or intolerant of conventional antifungal therapy. Based on the study results, the authors concluded that POS can be used as an alternative salvage therapy option in these patients.
# enrolled		107	86
Overall response rate to salvage therapy
▪ POS resulted in a statistically better response rate to salvage therapy.
POS	45/107	(42%)	adj OR 4.06 (95% CI 1.50, 11.04)
Standard Care	22/86	(26%)	P =0.006
▪ Response to POS remained greater than the response in to other standard treatments, when analyzed on the basis of different Aspergillus species or neutropenia status.
Cumulative survival rates
▪ POS was associated with a greater survival benefit, which appeared as early as 30 days after salvage therapy and continued until the end of the study.
▪ At 30 days		▪ POS resulted in statistically fewer cases of IA
POS		(74%)	P = 0.0003
Standard Care		(49%)	(log-rank test)
▪ At the end of treatment
POS		(38%)	P = 0.0003
Standard Care		(22%)	(log-rank test)
Cho, 2015²⁵
Comparison Groups		POS	FLU	The authors concluded that POS was more effective than FLU in preventing of breakthrough IFI and reducing the need for empirical antifungal treatment in patients with AML or myelodysplastic syndrome patients. The study also showed a longer fungus-free survival in POS-users, when compared with those who received FLU.
# enrolled		140	284
Incidence of breakthrough proven/probable IFIs
▪ POS resulted in a statistically fewer breakthrough IFIs.
POS	4/140	(2.9%)	OR 0.077 (95% CI 0.010, 0.600) P = 0.014
FLU	44/284	(15.5%)	adj OR 0.159 (95% CI 0.056, 0.453) P < 0.001
Need for empirical antifungal treatment
▪ Need for empirical antifungal therapy was statistically decreased in the POS group.
POS	18/140	(12.9%,)
FLU	130/284	(45.8%)	P < 0.0001
There was no difference in the duration of empirical antifungal therapy between POS and FLU groups. (10.8 ± 6.0 vs. 11.3 ± 6.8; P = 0.534)
Overall mortality There was no difference in terms of 100-day overall mortality (10.7% vs. 12.8%; P = 0.717) and IFI-related mortality (1.4% vs. 2.1%; P = 0.626) between POS and FLU groups
Fungus-free survival
▪ POS resulted in a statistically longer fungus-free survival.
POS	112/140	(80.1%)	P = 0.003
FLU	213/284	(74.7%)	(log-rank test)
Doring, 2015²⁶
Comparison Groups	POS	FLU	ITR	The authors concluded that POS, FLU, and ITR were comparably effective in preventing IFIs in pediatric patients. The authors also hypothesized that the prophylactic effects of widespectrum azoles might be affected by inadequate dosing or malabsorption. Therefore, they suggested further lager studies were needed in order to make dose recommendations for these drugs in pediatric populations.
# enrolled	30	31	32
Incidence of breakthrough proven, probable or possible IFIs
▪ Incidence of IFIs was similar in all three study groups.
POS	1/30	(1 proven)
FLU	2/31	(1 proven and 1 possible)	P = 0.626
ITR	3/32	(1 proven and 2 possible)
Mortality Seven of the 93 study participants (7.5%) died during the observation period [mortality reasons: relapse of the primary diagnosis (n = 4), multiple organ failure due to sepsis (n = 2), cardiac failure after chemotherapy (n = 1)]. The proportions of patients who died in each study group were not reported. No IFI-related deaths were reported.
Girmenia, 2012²⁷
Comparison Groups		POS	AMB	The authors concluded that primary antifungal prophylaxis with POS was effective in preventing IFIs in AML patients during front-line chemotherapy. The study results showed that POS could result in an early but transitory survival benefit in younger patients.
# enrolled		99	58
Incidence of proven and probable IFIs
▪ POS resulted in a statistically greater absolute risk reduction.
POS	23/99	(23.2%)	ARR -28.5% (95% CI, -12.9, -42.8)
AMB	30/58	(51.7%)	P = 0.0002
▪ IA was documented in 15% in the posaconazole group and 43% of patients in the AMB group (ARR -27.9% (95% CI, -13.4, -42.0); P = 0.0002)
Incidence of proven, probable or possible IFIs
▪ POS was on-inferior to FLU in preventing IFIs.
POS	30/99	(30.3%)	ARR -31.7% (95% CI, -15.7 to -45.8)
AMB	36/58	(62.1%)	P < 0.0001
All-cause mortality ▪ There were no statistically significant survival differences between the two groups at 4 and 12 months after the diagnosis of AML. ▪ In patients aged>60: no survival difference was observed between the two groups. ▪ In patients aged <60: there was a significant survival benefit in the POS group (88.1% versus 71.8%; P = 0.03) at 4 months after AML diagnosis, but the survival rates were no longer statistically different at 12 months (54.2% versus 59.0%; P = 0.9).
Need for Pre-emptive or empirical antifungal therapy
▪ POS resulted in a statistically lower rate of empirical antifungal therapy.
POS	2/99	(2%)	ARR -10.5% (95% CI, -10.1, -22.2)
AMB	9/58	(15.5%)	P = 0.04
Auberger, 2012²⁸
Comparison Groups		POS	No POS Prophylaxis (historical controls)	The study showed no difference between the POS group and the historical control group in terms of the incidence of IFIs. Based on the microbiological diagnosis results, the authors concluded that there was a significant shift in the proportion of breakthrough IFIs to non-Aspergillus spp. (especially to mucormycetes), with the use of POS prophylaxis.
# enrolled		27	62
# treatment courses		202	520
Incidence of breakthrough proven/probable IFIs
▪ Although no statistical test results have been reported to compare the study groups, the incidence of IFIs seems to be comparable between POS-user and the historical controls.
POS	27/202 courses (41% proven and 59% probable IFIs)	(13%)
Controls	62/520 (39% proven and 61% probable IFIs)	(12%)	P = NR
Colonization of fungal pathogens (proven IFIs)
▪ Species diagnosis showed exclusively non-Aspergillus species in the POS group.
POS		55% mucormycetes and 45% Candida spp.
Controls		63% Aspergillus spp., 13% mucormycetes, and 25% Candidaspp.
Mortality
▪ Comparison between the two study groups was not possible due to the lack of mortality data for the control group.
POS		Overall mortality: 16/27 (proven/probable IFIs); 8/11 (proven IFIs) IFI-related mortality: 1/16 deaths
Controls		NR
Michallet, 2011²⁹
Comparison Groups		POS	No Prophylaxis (matched controls)	The authors concluded that prophylaxis with POS during induction chemotherapy can decrease the incidence of IA and significantly improve survival rate at day 100, in AML patients. Based on the study results, they recommended POS prophylaxis in all AML patients during induction chemotherapy.
# enrolled		55	66
Incidence of IA
▪ No proven cases of IA were reported in both groups. When compared with the matched controls, fewer cases of probable IA were reported in the POS group. However, the difference was not statistically significant.
Between days 15 and 32 during the induction period
POS		(4.13%)
Controls		(8.2%)	P = NR
At day 32 during the induction period
POS	2/55	(3.6%)	OR 0.30 (95% CI, 0.00, 1.20)
Controls	8/66	(12.1%)	P = 0.085
At day 100 post-induction period
POS		(7.3%)	OR 0.40 (95% CI, 0.18, 2.00) P = 0.085
Controls		(12.1%)	adj OR 0.28 (95% CI, 0.00, 1.20) P = 0.085
Mortality
All-cause mortality at day 100		▪ Mortality was statistically lower in the POS group.
POS	2/55	(3.64%).	HR 0.103 (95% CI: 0.0238, 0.445)
Controls	7/66	(10.61%)	P = 0.0023
No IFI-related deaths (including deaths due to IA) were reported in the POS group. In the control group, 4/7 patients who died were diagnosed with IA.
Overall survival Median overall survival (at the end of 24-month follow up): POS prophylaxis had no impact on overall survival in the long term
POS		13.3 months	P = 1.0
Controls		23.6 months	(log-rank test of overall survival curves)
The analysis of overall survival based on the presence and absence of IA revealed a statistically lower survival rate in patients with IA (median survival of 7.5 months; P = 0.002).
Vehreschild, 2010³⁰
Comparison Groups		POS	Topical Polyenes	The authors concluded that POS prophylaxis can significantly reduce the risk of IFDs and aspergillosis, and decrease the length of hospitalization in patients with AML.
# enrolled		77	82
Incidence of breakthrough proven and probable IFIs
▪ POS resulted in a statistically lower the risk of developing IFIs
POS	3/77	(3.9%)
Topical Polyenes	16/82	(19.5%)	P = 0.003
The number to treat to prevent one IFI using POS prophylaxis was 7 (95% 4.0, 16.6)
Incidence of breakthrough IA
▪ POS resulted in a statistically lower risk of developing IA
POS	2/77	(2.6%)
Topical Polyenes	11/82	(13.4%)	P = 0.018
All-cause mortality
▪ At 100 days		▪ No statistical differences were reported in terms of overall mortality between the two study groups
POS		(86.6%)	P = NS
Topical Polyenes		(93.5%)	(log-rank test)
IFI-related mortality was also not statistically different between the POS and Polyenes groups (3.7% and 1.3%, respectively)
Fungal-free survival time
▪ Patients in the POS group had a statistically longer fungal-free survival time.
POS		90.4 days	P = 0.024
Topical Polyenes		78.7 days	(log-rank test)
Need for inpatient treatment
Patients in the POS group had a statistically longer fungal-free survival time.
POS		46.0±14.39 days
Topical Polyenes		53.0±24.16 days	P = 0.026

: adj OR = adjusted odds ratio; AMB = amphotericin B; AML = acute myeloid leukemia; ARR = absolute risk reduction; FLU = fluconazole; HD-LPD/AMB = high-dose lipid formulation of amphotericin B; HR = hazard ratio; IA = invasive aspergillosis; ICU = intensive care unit; IFI = invasive fungal infection; ITR= itraconazole; NR = not reported; NS = not significant; POS = posaconazole; spp.= species; vs = versus.
a: Best available standard of care for salvage therapy in accordance with the clinical practice at each centre.

Table 13Summary of Recommendations from the Included Evidence-based Clinical Guidelines

Main Study Findings	Author's Conclusion
IDSA guideline; Patterson, 2016⁶
– Triazoles are suggested as preferred agents for treatment and prevention of IA in most patients (strong recommendation; high-quality evidence). For salvage therapy: – Posaconazole, itraconazole, lipid formulations of AmphotericinB, micafungin, and caspofungin are recommended for salvage therapy of invasive aspergillosis. However, it has been stressed that factors such as prior antifungal therapy, host factors, pharmacokinetics of drugs, and possible antifungal resistance should be taken into account in the the use a triazole as salvage therapy (strong recommendation; moderate-quality evidence). Primary antifungal prophylaxis: – Prophylaxis with posaconazole is recommended during prolonged neutropenia in patients who are at high risk for IA (strong recommendation; high-quality evidence). – Prophylaxis with posaconazole is recommended for allogeneic HSCT recipients with GVHD who are at high risk for IA (strong recommendation; high-quality evidence). Treatment of aspergillosis in pediatrics: – The same recommended therapies in adult patients are suggested to be used for the treatment of aspergillosis in children after appropriate dose adjustments (strong recommendation; high-quality evidence). However, because pediatric dosing has not yet been fully defined for posaconazole, no recommendations are made regarding its use use in pediatric populations. No recommendations were found regarding the use of posaconazole as a first-line treatment of invasive aspergillosis.	The IDSA guideline recommend Posaconazole for the following indications: 1) Salvage therapy of invasive aspergillosis, as an alternative to voriconazole Recommended dose: oral suspension: 200 mg TID; tablet: 300 mg BID on day 1, then 300 mg daily; IV: 300 mg BID on day 1, then 300 mg daily 2) Primary antifungal prophylaxis against invasive aspergillosis in high risk patients (neutropenic patients with AML or myelodysplastic syndrome, and HSCT recipients with GVHD). Recommended dose: Oral suspension: 200 mg TID Tablet: 300 mg BID on day 1, then 300 mg daily IV: 300 mg BID on day 1, then 300 mg daily
NCCN guideline; Baden, 2016³¹
Primary antifungal prophylaxis: – Posaconazole is recommended for antifungal prophylaxis in neutropenic patients with AML and myelodysplastic syndrome receiving induction or re-induction chemotherapy (NCCN category 1 recommendation). – Posaconazole is recommended as prophylaxis in patients who have undergone allogeneic HSCT and require intensive immunosuppressive therapy for GVHD (NCCN category 1 recommendation). No recommendations were found regarding the use of posaconazole as a first-line therapy or salvage therapy for invasive aspergillosis.	The NCCN guideline recommends posaconazole for antifungal prophylaxis in: 1) Neutropenic patients with AML and myelodysplastic syndrome receiving induction or re-induction chemotherapy, until resolution of neutropenia 2) HSCT recipients requiring intensive immunosuppressive therapy for GVHD, until resolution of significant GVHD
ECIL-6 guideline; Tissot, 2016³²
Salvage therapy: – Posaconazole is recommended for salvage therapy of invasive aspergillosis. However, there is no data to support its use in voriconazole failure (Grade BII recommendation). No recommendations were found regarding the use of posaconazole as a first-line treatment of invasive aspergillosis, or as a primary antifungal prophylaxis.	ECIL-6 guideline recommends posaconazole for salvage therapy in patients with invasive aspergillosis.
AGIHO/DGHO guideline; Tacke, 2014³³
Primary antifungal prophylaxis – Posaconazole is recommended as prophylaxis drug of choice in patients with AML and myelodysplastic syndrome who have chemotherapy induced neutropenia, and allogeneic HSCT recipients with GVHS (Grade AI recommendation). – In the pre-engraftment period of HSCT, the following antifungal agents are recommended with equal: voriconazole (Grade BI recommendation), micafungin (Grade BI recommendation), fluconazole (Grade BI recommendation) and posaconazole (Grade BII recommendation). – Insufficient data exist to support the use of posaconazole in the post-engraftment period of HSCT, in patients who do not require steroids for treatment of GVHD. No recommendations were found regarding the use of posaconazole as a first-line therapy or salvage therapy for invasive aspergillosis.	AGIHO/DGHO guideline strongly recommends posaconazole oral suspension as standard of for antifungal prophylaxis in patients with chemotherapy-induced neutropenia with AML or myelodysplastic syndrome, and allogeneic HSCT recipients with GVHD. Recommended dose: oral suspension, 200 mg TID; oral tablet: 300 mg daily
C¹⁷ guideline; Science, 2014⁸
Primary antifungal prophylaxis in children – For children ≥ 13 years of age with AML or myelodysplastic syndrome, posaconazole 200 mg PO TID is suggested as an alternative to fluconazole in centers where there is a high local incidence of mold infections or if fluconazole is not available (weak recommendation, moderate quality evidence). – For children ≥ 13 years of age undergoing allogeneic HSCT with acute Grade II – IV or chronic extensive GVHD, prophylaxis with posaconazole 200 mg PO TID from GVHD diagnosis until resolution of acute grade II-IV GVHD or chronic extensive GVHD is suggested (weak recommendation, moderate quality evidence). No recommendations were found regarding the use of posaconazole as a first-line therapy or salvage therapy in children with invasive aspergillosis.	Given the fact that the evidence on the use of posaconazole in children is scarce and mainly limited to children between the ages of 13 and 18 years, and the lack of defined dose recommendations for children less than 13 years of age, the C¹⁷ guideline do not routinely recommend posaconazole in pediatric patients. However, the guidelines panel suggests posaconazole prophylaxis: 1) As an alternative to fluconazole in patients aged ≥ 13 years with AML or myelodysplastic syndrome during chemotherapy, especially for those considered at higher risk for invasive aspergillosis. 2) As a consideration in children ≥ 13 years of age with GVHD after allogeneic HSCT Recommended dose for both indications: 200 mg PO TID

: AGIHO/DGHO = Infectious Disease Working Party of the German Society of Hematology and Medical Oncology Association; AML = acute myeloid leukemia; BID = 2 times a day; C¹⁷ = a council of pediatric hematology / oncology centres across Canada; ECIL = the European Conference on Infections in Leukemia; GVHD = graft-versus-host disease; HSCT = hematopoietic stem cell transplant; IDSA = Infectious Diseases Society of America; IV = intravenous; NCCN = National Comprehensive Cancer Network; PO= orally; TID= 3 times a day.

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Assasi N, Grobelna A. Posaconazole for the Prophylaxis and Treatment of Invasive Aspergillosis: A Review of Clinical Effectiveness and Guidelines [Internet]. Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2017 Jul 13. Appendix 4, Main Study Findings and Author’s Conclusions.
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Main Study Findings and Author’s Conclusions - Posaconazole for the Prophylaxis ...
Main Study Findings and Author’s Conclusions - Posaconazole for the Prophylaxis and Treatment of Invasive Aspergillosis: A Review of Clinical Effectiveness and Guidelines
Caenorhabditis elegans Onchocerca Related Antigen family (ora-1), mRNA
Caenorhabditis elegans Onchocerca Related Antigen family (ora-1), mRNA
gi|1972266863|ref|NM_068933.8|
Nucleotide
Caenorhabditis elegans Zf-C4pol domain-containing protein (F48F7.6), mRNA
Caenorhabditis elegans Zf-C4pol domain-containing protein (F48F7.6), mRNA
gi|1845980658|ref|NM_077926.7|
Nucleotide

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