L31V) in the replicon had less than a 100 fold increase in resistance to the ledipasvir in Harvoni, while a two amino acid substitution had over a 1000 fold increase in resistance. Genotype 1a had a similar but more substantial increase in resistance with each respective increase in amino acid substitution with resistance associated substitutions at K24R, M28T/V, Q30R/H/K/L, L31M, and or Y93H/N.NS5A polymorphisms also have an effect on viral resistance with the most common resistance-associated amino acid substitutions detected at Q30R, Y93H or N, and L31M in patients with a rapid virological response (RVR). The specific baseline NS5A resistance-associated polymorphisms observed in clinical trials were M28T/V, Q30H, Q30R, L31M, H58P, Y93H, and Y93N in genotype 1a and L28M, A92T, and Y93H in genotype 1b. Patients with multiple baseline NS5A polymorphisms tend to have higher relapse rates when using ledipasvir/sofosbuvir. The difference in relapse rates between treatment naive and treatment experience groups with baseline NS5A polymorphisms ranges from 1% after a 12-week regimen and 0% after a 24-week regimen respectively. NS5B mutations
A single amino acid substitution S282T contributes to viral resistance and decreases the activity of sofosbuvir in ledipasvir/sofosbuvir by approximately 2 to 18 fold. Cross resistance
No cross resistance was seen in the combination of ledipasvir and sofosbuvir in ION phase 1,2 and, 3 clinical trials as ledipasvir was fully active against sofosbuvir-resistance-associated substitutions and vice versa.
In general the surgical treatment is done for improvement of the thumb function. However, an extra advantage of the surgery is the improvement in appearance of the thumb. In the past, surgical treatment of the triphalangeal thumb was not indicated, but now it is generally agreed that operative treatment improves function and appearance. Because an operation was not indicated in the past, there’s still a population with an untreated triphalangeal thumb. The majority of this population doesn’t want surgery, because the daily functioning of the hand is good. The main obstacle for the untreated patients might not be the diminished function, but the appearance of the triphalangeal thumb. The timing of surgery differs between Wood and Buck-Gramcko. Wood advises operation between the age of six months and two years, while Buck-Gramcko advises to operate for all indications before the age of six years. For TPT types I and II of the Buck-Gramcko classification, the surgical treatment typically consists of removing the extra phalanx and reconstructing the ulnar collateral ligament and the radial collateral ligament if necessary. For type III of Buck-Gramcko classification proposable surgical treatments:- smaller trapezoidal phalanx and under six years: removal of the extra phalanx and reconstruction of the ulnar collateral ligament. Lengthening of the radial collateral ligament is only indicated when the clinodactyly is still present after reconstruction of the ulnar collateral ligament. - trapezoidal phalanx and older than six years: partial removal of the extra phalanx with correction of the angle.