Apply before the visa expires and before the current two-year admission ends; the consular interview should be booked with the post’s wait time in mind. Travel abroad after the visa has expired requires the new visa before re-entry.
Renew the visa before it lapses, or stop travelling until it is renewed
The two clocks run separately. The admission period, two years from each entry, governs how long the couple may remain inside the United States; the visa’s validity governs whether they can re-enter after a trip. A couple who leave for La Pêche each summer refresh their admission with every return, so the practical deadline is the visa expiry.
They should consult the consular post’s current published appointment information and schedule the renewal with enough time to gather the business records, rather than assume a fixed lead time. If the visa expires while they are in the United States, they may remain until the admission period ends but cannot leave and re-enter without a new visa, so travel should be planned around the interview. Extending status on Form I-129 without leaving does not renew the visa, so the next trip abroad still requires a consular application.
If the couple want permanent residence, they need a separate immigrant route because E-2 provides no direct path.