There are several reasons behind the loss of Italy after its conquest by the Eastern Roman Empire.

• While the East had always been the richest part of the old Roman Empire, Justinian's impressive reconquest of many old Roman provinces had run down the treasury, considering the depopulation and destruction of them since the fall of the West (especially in Italy itself where the war with the Ostrogoths was brutal and protracted).
• The Sassanids had a resurgence right in the middle of the Italian War. The threat from the only superpower to rival Rome, and later Constantinople, meant diverting some of the military capabilities towards the East.
• The outbreak of the Plague of Justinian (up to 25m deaths) further reduced the tax-base at home for generations
• The ERE's most capable general Belisarius fell victim to court intrigue shortly before Justinian died himself.
• The entry of the Lombards combined with the relatively indefensible nature of the Italian geopgraphy (see: Hannibal's campaign) meant that an invading army faced no major obstacles in the country once they confronted the small Roman contingent occupying Italy (with the exception of fortified areas like Ravenna)